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Radiation Therapy for Oropharyngeal Squamous Cell Carcinoma: An ASTRO Evidence 1
Based Clinical Practice Guideline 2
3 David J. Sher, MD, MPH1, David J. Adelstein MD, FACP2, Gopal Bajaj, MD3, David M. Brizel, 4
MD4 , Ezra E. Cohen, MD5, Aditya Halthore, MD6, Louis B. Harrison, MD7, Charles Lu, MD8, 5
Benjamin J. Moeller, MD9, Harry Quon, MD, PhD10, James W. Rocco, MD, PhD11, Erich M. 6
Sturgis, MD, MPH12, Roy B. Tishler, MD, PhD13, Andy Trotti, MD14, John Waldron, MD15, 7
Avraham Eisbruch, MD16 8
9
1. Department of Radiation Oncology, UT Southwestern, Dallas , Texas 10
2. Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer 11
Institute, Cleveland, Ohio 12
3. Department of Radiation Oncology, Inova Dwight and Martha Schar Cancer Institute, 13
Falls Church, VA 14
4. Department of Radiation Oncology, Duke University Medical Center, Durham, North 15
Carolina 16
5. Department of Radiation Oncology, University of California, San Diego, California 17
6. Department of Radiation Medicine, Northwell Health, Lake Success, New York. 18
7. Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida 19
8. Department of Radiation Oncology, UT MD Anderson Cancer Center, Houston, 20
Texas 21
9. Department of Radiation Oncology, North Shore-LIJ Health System, Bellerose, New 22
York 23
10. Department of Radiation Oncology, John Hopkins, Baltimore, Maryland 24
11. Department of Otolaryngology-Head and Neck Surgery, The Ohio State University 25
Wexner Medical Center, Columbus, Ohio 26
12. Department of Head and Neck Surgery and Department of Epidemiology, The 27
University of Texas MD Anderson Cancer Center, Houston, Texas 28
13. Department of Radiation Oncology, Brigham and Women's Physician Organization, 29
Boston, Massachusetts 30
14. Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida 31
15. Department of Radiation Oncology, Princess Margaret Cancer Center, Ontario, 32
Canada 33
16. Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 34
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Conflict of Interest Disclosure Statement 40
The guideline panelists were required to complete disclosure statements before initiating 41
work on this project. These statements are maintained at the American Society for Radiation 42
Oncology (ASTRO) Headquarters in Fairfax, VA, and pertinent disclosures are published within 43
this report. The ASTRO Conflict of Interest Disclosure Statement seeks to provide a broad 44
disclosure of outside interests. The guideline panel chairs (AE and DS), in concert with the 45
ASTRO COI review committee, ASTRO legal counsel, and ASTRO guidelines subcommittee 46
chair and vice-chair, reviewed these disclosures and approved the participation of all task force 47
members for all key questions. 48
49
50
Acknowledgements 51
The authors thank the following individuals who served as expert reviewers of the 52
manuscript: Steven Frank, MD, Nancy Lee, MD, and Cristina Rodriguez, MD, none of whom 53
have any relevant conflicts of interest. Gratitude is extended to Warren Caldwell, for serving as a 54
patient advocate for this guideline. The authors also thank ASTRO staff members Margaret 55
Amankwa-Sakyi, Sokny Lim and Caroline Patton for the systematic literature review assistance 56
and administrative support. 57
The Oropharyngeal Squamous Cell Carcinoma Guideline panel, created by the guidelines 58
subcommittee of the Clinical Affairs and Quality Committee of ASTRO, prepared this 59
document. ASTRO guidelines present scientific, health, and safety information and may to some 60
extent reflect scientific or medical opinion. They are made available to ASTRO members and to 61
the public for educational and informational purposes only. Commercial use of any content in 62
this guideline without the prior written consent of ASTRO is strictly prohibited. 63
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Adherence to this guideline will not ensure successful treatment in every situation. 64
Furthermore, this guideline should not be deemed inclusive of all proper methods of care or 65
exclusive of other methods of care reasonably directed to obtaining the same results. The 66
physician must make the ultimate judgment regarding the propriety of any specific therapy in 67
light of all the circumstances presented by the individual patient. ASTRO assumes no liability 68
for the information, conclusions, and findings contained in its guidelines. In addition, this 69
guideline cannot be assumed to apply to the use of these interventions performed in the context 70
of clinical trials, given that clinical studies are designed to evaluate or validate innovative 71
approaches in a disease for which improved treatments are needed or are being explored. 72
The guideline panel recommends that providers discuss with patients’ shortly after 73
diagnosis what to expect regarding symptoms, treatment-related toxicities, outcomes including 74
risk of recurrence, and effects of the disease and the treatments on quality of life. 75
This guideline was prepared on the basis of information available at the time the panel 76
was conducting its research and discussions on this topic. There may be new developments that 77
are not reflected in this guideline and that may, over time, be a basis for ASTRO to consider 78
revisiting and updating the guideline. 79
80
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Abstract 81
Purpose: To present evidence-based guidelines for the treatment of oropharyngeal squamous 82
cell carcinoma (OPSCC) with definitive or adjuvant radiotherapy (RT). 83
Methods and Materials: The American Society for Radiation Oncology (ASTRO) convened 84
the OPSCC Guideline Panel to perform a systematic literature review investigating the following 85
key questions: (1) When is it appropriate to add systemic therapy to definitive RT in the 86
treatment of OPSCC? (2) When is it appropriate to deliver post-operative RT with and without 87
systemic therapy following primary surgery of OPSCC? (3) When is it appropriate to use 88
induction chemotherapy in the treatment of OPSCC? (4) What are the appropriate dose, 89
fractionation, and volume regimens with and without systemic therapy in the treatment of 90
OPSCC? The GRADE methodology was followed in the construction and assessment of the 91
recommendation statements, and a predefined consensus-building process was implemented to 92
arrive at the final statements. 93
Results: Patients with stage IV and stage T3 N0-1 OPSCC treated with definitive radiotherapy 94
should receive concurrent high-dose intermittent cisplatin (HDIC). Patients receiving adjuvant 95
radiotherapy following surgical resection for positive surgical margins or extracapsular extension 96
should be treated with concurrent HDIC, and individuals with these risk factors who are 97
intolerant of cisplatin should not routinely receive adjuvant concurrent systemic therapy. 98
Induction chemotherapy (IC) should not be routinely delivered to patients with OPSCC. For 99
patients with stage IV and stage T3 N0-1 OPSCC ineligible for concurrent chemoradiotherapy, 100
altered fractionation RT should be used. Patients with tonsillar fossa-only, T1-2 N0-1 OPSCC 101
should receive ipsilateral radiotherapy. Recommendation statements do not vary by human 102
papillomavirus (HPV) status. 103
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104
Conclusion: The successful management of OPSCC requires the coordination and collaboration 105
of radiation, medical and surgical oncologists. When high-level data are absent for clinical 106
decision-making, treatment recommendations should incorporate patient values and preferences 107
to arrive at the optimal therapeutic approach. 108
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Introduction 127
The oropharynx is an anatomic site within the head and neck that includes the tonsils, 128
base of tongue, soft palate, and the upper lateral and posterior pharyngeal walls. It is lined by 129
squamous epithelium, and thus squamous cell carcinoma composes the vast majority of 130
malignancies that arise from the oropharynx. The epidemiology and prognosis of oropharyngeal 131
squamous cell carcinoma (OPSCC) has changed dramatically over the past 30 years, such that its 132
treatment and expected outcomes are nearly unrecognizable from a generation ago. 133
Indeed, human papillomavirus (HPV) associated cancers of the oropharynx are now 134
widely recognized as a distinct clinical disease with regard to risk factor profiles, clinical and 135
molecular characteristics, treatment response and prognosis.1 Human papillomavirus HPV-136
associated cancers arise from the lingual and palatine tonsils within the oropharynx, are poorly 137
differentiated and present with early T stage and advanced N stage. When compared to patients 138
with HPV-negative disease, patients with HPV-positive tumors are more frequently male, young, 139
and possess a favorable performance status. 3 The incidence of HPV-positive OPSCC has 140
increased by over 200% between 1988 and 2004, whereas the incidence of HPV-negative 141
OPSCC declined by half over that same era.2 Individuals with HPV-driven oropharynx cancers 142
have an estimated 50% reduction in risk of death when compared to patients with HPV-negative 143
tumors.3 The recognition of this powerful prognostic and predictive influence of HPV has 144
generated a wide array of treatment paradigms for OPSCC, which further highlights the 145
importance of evidence-based medicine to guide clinical practice. 146
The purpose of this clinical practice guideline is to systematically review the evidence for 147
effective treatment of OPSCC with definitive or adjuvant radiotherapy. Recommendation 148
statements are independent of HPV status, given the current absence of high-level, high-quality 149
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data confirming treatment decisions should differ by cancer etiology. The panel used a 150
formalized literature review process, complemented by expert opinion where appropriate, to 151
make recommendations on the use of concurrent systemic therapy in the primary and post-152
operative settings, adjuvant radiotherapy following curative surgery, neoadjuvant chemotherapy 153
prior to radiotherapy, and dose, fractionation and neck volume decisions faced in the 154
management of this disease. 155
156
Methods and Materials 157
Process 158
The Guidelines Subcommittee of the Clinical Affairs and Quality Council identified 159
OPSCC as a disease that provides many challenges to the radiation oncologist, as well as to the 160
medical and surgical oncology multidisciplinary team. Given its rapidly increasing prevalence 161
and the various treatment options with differing short- and long-term toxicity profiles, OPSCC 162
was considered a high-priority topic in need of an evidence-based practice guideline. In 163
accordance with established ASTRO policy, the Guidelines Subcommittee recruited a guideline 164
panel of recognized experts in oropharyngeal cancer, including radiation oncologists, medical 165
oncologists, otolaryngologists, and a patient advocate. Panel members were drawn from 166
academic settings, private practice, and residency. Four specific key questions (KQs) were 167
proposed, which addressed: (KQ1) the addition of concurrent systemic therapy to radiotherapy, 168
(KQ2) the delivery of post-operative radiotherapy with and without systemic therapy following 169
primary surgery, (KQ3) the use of induction chemotherapy, and (KQ4) the optimal dose-170
fractionation regimens with and without systemic therapy, as well as nodal volumes for primary 171
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tonsillar cancer. In September 2014, the ASTRO Board of Directors approved the proposal and 172
panel membership. 173
Through a series of communications by conference calls and emails between December 174
2014 and February 2016, the guideline panel, with ASTRO staff support, completed the 175
systematic review, created literature tables, and formulated the recommendation statements and 176
narratives for the guideline. The members of the task force were divided into four writing groups 177
by KQs, according to their areas of expertise. The initial draft of the manuscript was reviewed by 178
three expert reviewers (see Acknowledgements) and ASTRO legal counsel. A revised draft was 179
placed on the ASTRO Web site in MONTH 2016 for a four/six-week period of public comment. 180
Following integration of the feedback, the document was submitted for approval to the ASTRO 181
Board of Directors in MONTH 2016. The ASTRO Guidelines Subcommittee intends to monitor 182
this guideline and initiate an update when appropriate, according to existing ASTRO policies. 183
184
Literature Review 185
186 A systematic review of the literature was performed in early 2015 to form the basis of the 187
guideline. An analytic framework incorporating the population, interventions, comparators, and 188
outcomes (PICO) was first used to develop and refine search strategies for each KQ. The 189
searches were conducted in MEDLINE PubMed and designed to identify studies published in 190
English between January 1990 and December 2014 that evaluated adults with OPSCC who were 191
treated with primary radiotherapy, adjuvant radiotherapy, or radiotherapy with concurrent 192
systemic therapy. Both MeSH terms and text words were utilized and terms common to all 193
searches included: oropharyngeal neoplasms, carcinoma squamous cell, and radiotherapy. 194
Additional terms specific to each KQ were also incorporated. The outcomes of interest were 195
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overall and progression-free survival, recurrence rates, toxicity, and quality of life. The initial 196
literature review was conducted in December 2014. The electronic searches were supplemented 197
by hand searches. 198
A total of 2615 abstracts were retrieved. The articles were then reviewed by ASTRO 199
staff, the co-chairs of the guideline, and the writing groups for each KQ. During the first round of 200
screening, 2452 articles were eliminated based on the inclusion and exclusion criteria. The 201
inclusion criteria were: patients ≥18 years or older, all stages of oropharyngeal cancer, and 202
publication date 1990 to 2014. Included treatments were: primary radiotherapy, primary 203
chemoradiation, primary surgery with adjuvant radiotherapy with or without systemic therapy, or 204
IC followed by radiation therapy or chemoradiotherapy. The exclusion criteria were: pre-clinical 205
or non-human studies, case reports/series, non-English language, available in abstract only, 206
pediatric patients, distant metastasis, non-squamous cell carcinoma, and otherwise not clinically 207
relevant to the key clinical questions. The panelists on KQ 1, 3 and 4 generally only considered 208
articles in which the percentage of OPSCC patients was greater than 50%; the panelists on KQ 2 209
did not have an absolute threshold because OPSCC patients typically comprise a minority of 210
individuals in post-operative studies. Ultimately, 119 full-text articles were chosen for inclusion 211
and abstracted into detailed literature tables to provide supporting evidence for the clinical 212
guideline recommendations. 213
Because expression of the p16 protein is typically used as a surrogate for HPV infection, 214
4 the two words – p16-positive and HPV-positive – are sometimes used interchangeably (and 215
incorrectly). However, throughout this guideline, the mention of p16 will be reserved for clinical 216
studies in which its status was assessed and reported. 217
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Grading of Evidence, Recommendations, and Consensus Methodology 219
Guideline recommendation statements were generated from this literature review, with 220
high-quality evidence forming the basis of the statements whenever possible, in accordance with 221
Institute of Medicine (IOM) standards; 5 expert opinion supplemented the evidence base if high-222
level data were not available. The GRADE (Grading of Recommendations, Assessment, 223
Development and Evaluations) methodology was followed in the construction and assessment of 224
the recommendation statements. GRADE is an explicit, systematic approach to defining the 225
recommendation strength and quality of evidence.6,7 226
Recommendation strengths were dichotomized as “strong” or “conditional.” 227
Strong recommendations were made when the panel was very confident that the benefits of the 228
intervention clearly outweighed the harms; conditional recommendations were made when the 229
ratio between risks and benefits was more balanced. Per the GRADE formalism, a “strong” 230
recommendation implies that the panelists believe “all or almost all informed people would make 231
the recommended choice for or against an intervention.” 7 A “conditional” recommendation 232
implies that “most informed people would choose the recommended course of action, but a 233
substantial number would not. When a recommendation is weak, clinicians and other health care 234
providers need to devote more time to the process of shared decision making by which they 235
ensure that the informed choice reflects individual values and preferences.”5 The importance of 236
patient preferences and shared decision-making was highlighted in each conditional 237
recommendation statement. 238
The GRADE methodology defines “quality of evidence” as a rating that indicates “the 239
extent of our confidence that the estimates of an effect are adequate to support a particular 240
decision or recommendation.”6 The quality of evidence underlying each recommendation 241
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statement was categorized as either high, moderate, low. 6 Although GRADE does provide for a 242
“very low” quality, the panel did not consider this rating for consistency with prior ASTRO 243
guidelines. Descriptions of each quality level are below: 244
High: We are very confident that the true effect lies close to that of the estimate of 245
the effect. 246
Moderate: We are moderately confident in the effect estimate: The true effect is 247
likely to be close to the estimate of the effect, but there is a possibility that it is 248
substantially different 249
Low: Our confidence in the effect estimate is limited: The true effect may be 250
substantially different from the estimate of the effect 251
The degree of consensus among the panelists on each recommendation statement was 252
evaluated through a modified Delphi approach. A survey was sent by ASTRO staff to the panel 253
members, who rated their agreement with each recommendation on a five-point Likert scale, 254
ranging from strongly disagree to strongly agree (higher score corresponds with stronger 255
agreement). A pre-specified threshold of ≥ 75% of raters was determined to indicate when 256
consensus was achieved.8 If a recommendation statement did not meet this threshold, it was 257
modified and re-surveyed, or excluded from the guideline. The final set of recommendation 258
statements were achieved after 2 surveys. The guideline statements, along with the 259
corresponding ratings of recommendation strength, quality of evidence, and level of consensus, 260
are listed in Table 1. 261
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Results 265
266
Key Question 1. When is it appropriate to add systemic therapy to definitive radiotherapy 267
in the treatment of oropharyngeal squamous cell carcinoma (OPSCC)? 268 269
1. In the scenario of stage IVA-B disease? 270
271
272 Statement 1A. Concurrent high-dose intermittent cisplatin should be delivered to patients with 273
stage IVA-B oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 274
o Recommendation strength: Strong 275
o Quality of evidence: High 276
277 Statement 1B. Concurrent cetuximab or carboplatin-fluorouracil should be delivered to patients 278
with stage IVA-B oropharyngeal squamous cell carcinoma receiving definitive radiotherapy who 279 are not medically fit for high-dose cisplatin. 280
o Recommendation strength: Strong 281
o Quality of evidence: High 282
283 Statement 1C. Concurrent weekly cisplatin may be delivered to patients with stage IVA-B 284
oropharyngeal squamous cell carcinoma receiving definitive radiotherapy who are not medically 285 fit for high-dose cisplatin, after a careful discussion of patient preferences and the limited 286 prospective data supporting this regimen. 287
o Recommendation strength: Conditional 288
o Quality of evidence: Low 289
290
Statement 1D. Concurrent cetuximab should not be delivered in combination with chemotherapy 291 to patients with stage IVA-B oropharyngeal squamous cell carcinoma receiving definitive 292 radiotherapy. 293
o Recommendation strength: Strong 294
o Quality of evidence: High 295
296 Statement 1E. Intra-arterial chemotherapy should not be delivered to patients with stage IVA-B 297
oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 298 o Recommendation strength: Strong 299
o Quality of evidence: High 300
301
302
Narrative 303 304
The role of concurrent cytotoxic chemotherapy combined with radiotherapy 305
Several phase III trials have randomized patients with locally advanced, non-metastatic 306
head and neck squamous cell carcinoma to treatment with conventionally- or altered-fractionated 307
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radiotherapy alone versus treatment with concurrent chemoradiotherapy (Table 2). All of the 308
studies in this systematic review were predominantly composed of patients with oropharynx 309
cancer, and the clear majority of patients presented with stage IV disease. In the six studies that 310
directly compared standard fractionation radiotherapy to combined concurrent 311
chemoradiotherapy, dose and fractionation schemes were relatively uniform, with total delivered 312
doses approaching 66-70.2 Gy in 1.8-2 Gy fractions.9-15 The chemotherapy regimens were 313
variable, including bolus cisplatin9, weekly cisplatin, 25 carboplatin-fluorouracil, 15,16 daily 314
carboplatin,11 and bleomycin-mitomycin. 14 315
The five trials comparing altered fractionation radiotherapy (3 accelerated, 2 316
hyperfractionated) with and without concurrent chemotherapy also employed a variety of 317
systemic therapy regimens, including carboplatin-fluorouracil,17 daily cisplatin,18 cisplatin-318
fluorouracil,19 high-intensity cisplatin-fluorouracil (bolus cisplatin every 2 weeks),20 and 319
fluorouracil-mitomycin.21,22 However, as opposed to the conventionally fractionated trials, in 320
which the radiotherapy was standardized between the two arms, two of these studies20,21 used 321
different radiotherapy schemes for the radiotherapy-alone arm. The ARO 95-06 trial12 treated 322
patients to a total dose of 77.6 Gy without chemotherapy and 70.6 Gy with chemotherapy, and 323
the GORTEC trial23 delivered 64 Gy in 5 weeks with chemotherapy and the same dose in 3 324
weeks without chemotherapy. 325
326
Impact on overall survival 327
In all but two of the 6 studies of conventionally fractionated radiation therapy, 328
chemoradiotherapy significantly improved overall survival.10,11,14,24,25 Most of these studies 329
reported the statistically significant improvement in OS at 3 years, with the absolute benefit of 330
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chemoradiotherapy ranging between 14% and 24%.10,11,24 The few studies with longer follow-up 331
showed a persistent but smaller survival advantage to concurrent chemotherapy. For example, 332
the 5-year OS difference in GORTEC 94-0126 was 6% (22% vs. 16%, p=0.05), whereas in the 333
AIRO study11 using daily carboplatin, the 5-year survival difference was less than 3%. In 334
contrast, neither the Mumbai trial25 (weekly cisplatin) nor the ORO 93-0127 (carboplatin-335
fluorouracil) showed an OS advantage with concurrent chemotherapy, although disease-free 336
survival was significantly improved with chemotherapy in both studies; it is notable that both of 337
these trials included a third arm of altered fractionation alone, and so the total numbers of 338
patients in each arm were less than 70, likely underpowering the studies for an OS endpoint. 339
Among the 5 studies of chemoradiotherapy with altered fractionation, three of them 340
showed an absolute OS advantage with the addition of concurrent chemotherapy, ranging from 341
5%20 (5-year ARO 95-06, fluorouracil and mitomycin) to 9.8%28 (5-year, Semrau et al, 342
carboplatin and fluorouracil) to 24%19 (3-year, Wendt et al, cisplatin and fluorouracil). Among 343
the other two trials, concurrent daily cisplatin improved cancer-specific survival in SAKK 344
10/9418 by an absolute 12% at 10 years, and concurrent carboplatin-fluorouracil with very 345
accelerated radiotherapy in Bourhis et al.23 reduced the risk of any cancer progression by nearly 346
25%, but toxic deaths precluded a survival benefit. 347
The data from the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-348
NC Meta-analysis) 29 corroborated the conclusions drawn from these individual phase III 349
randomized trials. In the most recent update from this group, Blanchard et al.29 analyzed over 350
5800 patients with oropharynx cancer and showed that the concomitant addition of 351
chemotherapy to radiotherapy resulted in an 8.1% absolute benefit in OS at 5 years30, translating 352
into a relative 22% reduction in overall mortality. By contrast, adjuvant or neoadjuvant 353
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chemotherapy administration was not associated with a survival benefit. There was no significant 354
heterogeneity in chemotherapy treatment effect by fractionation regimen, although only the use 355
of platinum-fluorouracil (HR 0.83, 95% CI 0.75-0.91) or platinum monotherapy (HR 0.70, 95% 356
CI 0.59-0.84) was significantly associated with survival. Additional univariable analyses 357
suggested that the survival benefit with concurrent chemotherapy was largely restricted to 358
younger patients (HR for 61 years or older, 0.97, 95% CI 0.87-1.08) and patients with stage IV 359
disease (HR for stage III disease, 1.01, 95% CI 0.88-1.14). However, multivariable analysis 360
showed that only favorable performance status and type of chemotherapy (i.e. platinum-based 361
chemotherapy with or without 5-FU) were significantly associated with overall survival. 362
363
Impact on locoregional control 364
The three trials of conventionally fractionated radiotherapy that reported locoregional 365
control (LRC) outcomes showed a statistically significant improvement in patients receiving 366
concurrent chemotherapy. Denis et al. and Ruo Redda et al.11,16 demonstrated an absolute 3-year 367
LRC benefit with concurrent chemotherapy of 24% and 8.7%, respectively 11,16, although 368
notably, the LRC difference in Ruo Redda et al.11 was only statistically significant among stage 369
IV patients. Ghosh-Laskar25 found that weekly cisplatin improved LRC by an absolute 17% at 5 370
years. The four studies of concurrent chemotherapy with altered fractionation that presented 371
distinct LRC probabilities consistently found that concomitant treatment significantly reduced 372
locoregional failure, with the absolute benefits of 8% (10-year, SAKK 10/94), 18,28 12% (5-year, 373
Semrau et al), 28 19% (3-year, Wendt et al), 19and 13%22 (3-year, 28 Budach et al). 374
In the recent MACH-NC meta-analysis 31 that did not distinguish by tumor site, Pignon 375
and colleagues showed that concurrent chemoradiotherapy significantly improved LRC, with an 376
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absolute improvement of 9.3% and 13.5% among all studies and those with platinum-377
fluorouracil, respectively. These absolute improvements translated into hazard reductions of 0.74 378
and 0.66 for all studies and those with platinum-fluorouracil, respectively (p<0.0001). 379
380
Impact on distant metastases 381
One of the challenges in interpreting the impact of chemotherapy on distant metastasis is 382
the inability of trials to distinguish between metastasis arising from a first locoregional failure 383
versus metastasis as the first site of failure. That said, none of the randomized studies of 384
concurrent chemotherapy in conventionally fractionated radiotherapy found an improvement in 385
distant control with systemic therapy, and of the five trials of altered fractionation, only the 386
Swiss Group for Clinical Cancer Research (SAKK) trial18 of daily cisplatin showed an 387
improvement in distant metastasis-free survival. In this study, concurrent chemotherapy 388
improved 10-year distant metastasis free survival by 15% at 10 years, but only 9 total patients in 389
the entire study developed an isolated metastasis without prior locoregional failure; thus, one 390
may assume that this presumptive improvement in distant control was a function of reduced 391
locoregional recurrence. 392
In contrast, the MACH-NC meta-analysis31, which benefitted from the increased power 393
of thousands of patients, showed a small but statistically significant improvement in distant 394
control with concurrent treatment; the absolute improvement was 2.5% for all patients, with a 395
relative improvement of 0.88 (95% CI 0.77-1.0, p=0.04). As stated above, this reduction in 396
distant metastasis with concurrent systemic treatment may reflect less propagation from fewer 397
locoregional recurrences. 398
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Complications 400
While most of these phase III randomized studies show that adding chemotherapy to 401
radiotherapy improves survival, the combination clearly increased the risk of severe, acute 402
toxicities. For example, Adelstein et al.24 reported that patients receiving standard fractionation 403
RT with or without concurrent cisplatin had an overall grade 3 to 5 incidence of 85% and 51%, 404
respectively, of which leukopenia, anemia, and renal toxicities were the most significant. In this 405
Intergroup trial, 9 approximately 15% of patients treated with bolus cisplatin did not complete 406
treatment, and delivering three cycles of bolus cisplatin has been consistently challenging. For 407
example, in RTOG 0129, 32 which compared accelerated versus conventional radiotherapy with 408
concurrent bolus cisplatin in both arms, only 69% of patients in the conventional fractionation 409
arm received all 3 cycles, and approximately 24% of patients received only two courses of bolus 410
cisplatin. 411
In a review of the original GORTEC studies, Bourhis et al. showed that 71% of patients 412
receiving radiation with carboplatin and 5-FU developed acute grade 3 or 4 mucositis, compared 413
to only 39% of those receiving RT alone.33 Even weekly cisplatin in the Mumbai trial increased 414
the risk of grade 3 or 4 mucositis (35% vs. 21%, p value not reported), and daily carboplatin also 415
increased the risk of grade 2 toxicities (type not recorded). The combination of mitomycin-C and 416
bleomycin increased the risk of grade 3 or 4 mucositis by almost one-third. 417
The studies of concurrent chemotherapy with altered fractionation also found increases in 418
acute toxicity. The Starr et al. study showed statistically significant worse acute toxicities in the 419
arm receiving carboplatin and 5-FU—grade 3 and 4 mucositis was 68% versus 52% and grade 3 420
and 4 vomiting was 8.2% versus 1.6%.17 Similarly, the use of concurrent cisplatin-fluorouracil 421
with split-course hyperfractionation more than doubled the risk of acute grade 3-4 mucositis 422
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(38% vs. 16%). In the GORTEC accelerated radiotherapy trial, 20 the very accelerated RT-alone 423
arm led to more acute mucosal toxicity, but a high early death rate from non-cancer cause 424
(almost 20% at 1 year) revealed the potentially life-threatening complications of intensive 425
chemotherapy with extreme acceleration. On the other hand, the higher radiation dose in ARO 426
95-06 21 actually showed more mucosal and skin toxicity in the radiotherapy alone cohort, and 427
the SAKK study18 using daily cisplatin found fewer than 10% of chemotherapy patients 428
developed a grade 3-4 hematologic toxicity, with no difference in acute radiotherapy effects. 429
Despite these acute toxicities, these trials consistently showed no significant increase in 430
high-grade late morbidity with concurrent therapy. A careful toxicity analysis of patients treated 431
on GORTEC 94-0126 showed that only grade 3-4 dental toxicity was significantly worse with 432
chemotherapy (44% vs. 12%). The ORO 93-0127 study showed numerically more tissue, skin and 433
mucosal side effects with chemotherapy, but these were not statistically tested and reported to be 434
typically transient. Neither daily carboplatin, weekly cisplatin nor mitomycin-bleomycin 435
increased the risk of late toxicity. Moreover, none of the five trials involving altered fractionation 436
with chemotherapy showed a significant increase in serious late toxicities. 437
438
Comparisons between chemotherapy regimens 439
While the studies mentioned above consistently showed LRC and typically OS benefits 440
from concurrent chemotherapy, it is important to note that the choice of systemic agents varied 441
considerably among each trial—bolus cisplatin, carboplatin/5-fluorouracil, cisplatin/5-442
fluorouracil, low-dose carboplatin alone, and bleomycin/mitomycin C, were each selected and 443
administered at varying schedules and frequencies. Unfortunately, there are far fewer studies 444
comparing different chemotherapy regimens and schedules to each other. 445
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RTOG 970334 randomized over 241 patients to conventionally fractionated radiotherapy 446
plus either concurrent cisplatin-fluorouracil in the last 2 weeks of radiation therapy, daily 447
hydroxyurea-fluorouracil, or weekly cisplatin-paclitaxel; patients receiving daily chemotherapy 448
were treated every other week. Interestingly, all of the arms compared favorably to historical 449
controls, although the arms were not directly compared to each other. However, none of these 450
alternative regimens have been prospectively tested against more standard agents such as bolus 451
cisplatin. 452
The RTOG did not publish an additional randomized trial on competing chemotherapy 453
agents in head and neck cancer until RTOG 0522, which compared bolus cisplatin with bolus 454
cisplatin plus cetuximab, concurrent with accelerated radiotherapy.35 Nearly 900 patients were 455
enrolled in this trial, which confirmed that the addition of cetuximab did not improve outcomes. 456
Locoregional control, disease-free survival, and OS were not significantly different between the 457
two arms, and acute grade 3 and 4 toxicities were uniformly higher in the cetuximab arm, with a 458
low but statistically significant increase in toxic death. Thus, cetuximab should not be combined 459
with cytotoxic chemotherapy unless on a clinical trial. 460
Erlotinib is an oral biologic agent that targets EGFR by tyrosine kinase inhibition. It has 461
been used successfully in treating certain types of non-small cell lung cancer and, like 462
cetuximab, has demonstrated synergism when combined with chemotherapy or radiation in the 463
pre-clinical setting. Martins et al.36 performed a phase II randomized trial of cisplatin and 464
radiotherapy with or without concurrent erlotinib for stage III and IV locally advanced head and 465
neck cancers, most of which were oropharynx cancer. In results that echoed RTOG 0522,35 no 466
improvement was seen in complete response rates, LRC, progression-free survival, or OS at a 467
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median follow up of 26 months, showing that an alternative method of EGFR inhibition is also 468
ineffective in combination with concurrent cisplatin. 469
The RTOG also obliquely asked a chemotherapy question in RTOG 01294,37, whose 470
primary hypothesis involved accelerated fractionation. This study randomized 743 patients to 471
either 3 cycles of bolus cisplatin with conventionally fractionated radiation therapy (RT) or 2 472
cycles of bolus cisplatin with accelerated RT.4,37 The trial showed no difference in any endpoint 473
between the arms, including distant metastasis, again confirming that the primary role of 474
chemotherapy is radiosensitization. In a subset analysis, the authors showed that patients 475
receiving only 1 cycle of cisplatin experienced markedly inferior survival. However, among 476
patients treated with conventionally fractionated RT, there was no statistically significant 477
survival decrement among the 24% of individuals who only received 2 cycles (HR 1.15, 95% CI 478
0.81-1.62). Although this finding casts some doubt on the benefit of the third cycle in the context 479
of standard fractionation, it is notable that (a) the upper end of the confidence interval was 1.62, 480
(b) the survival curve for patients receiving 2 cycles appears to separate from the curve for the 481
cohort receiving 3 cycles, and (c) this analysis was only based on 86 patients. 482
Finally, there is only one phase III trial comparing different modes of cisplatin 483
administration. Historically, there has been interest in delivering cisplatin intra-arterially, to 484
maximize the cisplatin dose to the tumor while infusing sodium thiosulphate systemically to 485
minimize cisplatin toxicity.38 The RTOG performed a multi-institutional phase II trial39 based on 486
this approach that produced results sufficiently promising for further study, and in fact, a 487
randomized controlled trial of this technique has been published. In this Dutch study by Rasch et 488
al.,40 239 patients with stage IV head and neck SCC received once-daily radiotherapy to 70 Gy 489
and were randomized to intravenous (three cycles of bolus infusion) versus intra-arterial (4 490
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courses) cisplatin. 40 At 3 years, there was no difference in OS (51% vs. 47%), distant metastasis-491
free survival (69% vs. 66%), and LRC (65% vs 63%). High-grade (i.e. > grade 2) renal toxicity 492
was more common in patients receiving intravenous cisplatin (9% vs. 1%), although only one 493
patient experienced permanent nephrotoxicity, and this patient was not dialysis-dependent. On 494
the other hand, neurological toxicity (> grade 2) was significantly more common in the intra-495
arterial cohort (8 patients vs. 1) Given the technical and logistical challenges of administration 496
and the absence of any oncologic benefit but an increase in neurological toxicity, intra-arterial 497
chemotherapy should not be administered unless on a clinical protocol. 498
499
Summary of cytotoxic chemotherapy 500
The data are consistent that concurrent chemotherapy in combination with radiation 501
therapy improves LRC for patients with locally advanced oropharyngeal squamous cell 502
carcinoma, treated with either conventional or altered fractionation. In most of these studies, the 503
reduction in locoregional progression translated into a significant and meaningful OS benefit. 504
Although chemotherapy significantly increased acute toxicities, late effects were comparable to 505
treatment with radiotherapy alone, such that the survival benefits of concurrent therapy clearly 506
outweigh the non-trivial but short-term risks. Since the vast majority of the patients in these trials 507
presented with stage IV disease, concurrent systemic therapy should be delivered in this 508
population of patients. 509
510
The role of cetuximab combined with radiotherapy 511
Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor 512
(EGFR), which is a growth factor receptor overexpressed in head and neck cancer and associated 513
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with poor prognosis. Pre-clinical data suggested synergy between cetuximab and radiotherapy, 514
and a preliminary phase I trial produced encouraging tolerability and response rates. These 515
promising outcomes generated a phase III randomized trial comparing radiotherapy alone (using 516
standard or altered fractionation) with radiotherapy plus cetuximab. The results of this trial were 517
first published in 2006 with a median follow-up of 54 months, revealing a clinically and 518
statistically significant improvement in OS with the addition of the antibody (hazard ratio 0.74, 519
95% CI 0.57-0.97), with an absolute 3 year survival difference of 10% (p=0.05). Similar to 520
cytotoxic chemotherapy, the benefit from combined modality therapy was in LRC, with a 521
relative 32% reduction in locoregional failure and absolute difference of 13% at 3 years 522
(p=0.01). There was no difference in distant metastases. There was no significant difference in 523
any acute adverse event except acneiform rash and infusion-related events, which were 524
substantially more common with cetuximab (17% vs. 1% for grade 3 or greater rash, p<0.001; 525
3% vs 0% for grade 3 or greater infusion reaction, p=0.01). The risk of mucositis (any grade) 526
was the same between the arms. 527
The results were updated in 2010 with a median follow-up of 60 months and additional 528
survival data on 40% of the surviving patients. The OS advantage was maintained (HR 0.73, 529
95% CI 0.56-0.95) was an absolute 5-year survival difference of 9%. Patterns-of-failure 530
information was not reported. Patients who developed a prominent rash experienced markedly 531
superior survival in comparison to those who did not (HR 0.49, median survivals 68.8 months vs. 532
25.6 months, p=0.002). A series of subset analyses suggested that the following cohorts 533
experienced significant benefit from cetuximab: oropharynx site, American Joint Committee on 534
Cancer (AJCC) T1-3, USA site, altered fractionation treatment, node-positivity, superior 535
performance status, male gender, and younger age (< 65 years). Of the 110 patients 65 years or 536
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older, there was a non-significant trend favoring radiation therapy alone. It is critical to note, 537
though, that even though patients were stratified by Karnofsky Performance Status (KPS) (90-538
100 vs lower), nodal status (N0 versus N+), tumor stage (T1-3 vs. T4), and radiation 539
fractionation regimen, the numbers in the subgroups were quite small, and so these results should 540
be considered hypothesis-generating. 541
A phase II randomized prospective trial sought to improve upon the results of Bonner et 542
al. by comparing concurrent cetuximab-radiotherapy with the same regimen plus 12 weeks of 543
adjuvant cetuximab.41 The authors of this study hypothesized that continued epidermal growth 544
factor receptor (EGFR) blockade by maintenance cetuximab would serve to eradicate any 545
residual disease after concurrent treatment. Although there was a trend for improved response 546
rates at 12 weeks, with adjuvant cetuximab, there was no significant improvement in LRC or OS 547
between the two arms. Therefore cetuximab should be delivered per the Bonner protocol when it 548
is used in combination with radiotherapy. 549
550
Summary of systemic therapy for stage IVA-B disease 551
There are no randomized trials that have defined an optimal chemotherapy regimen, but 552
individual studies have most commonly incorporated cisplatin and/or fluorouracil. Although 553
high-dose intermittent (i.e. bolus) cisplatin can be challenging to deliver, it has the longest track 554
record in large multi-institutional trials in the United States, with a well-known and largely 555
predictable side effect profile. Carboplatin-fluorouracil has also been shown to improve OS in 556
comparison to radiotherapy alone and is thus a viable alternative to bolus cisplatin. However, 557
there is far less practitioner experience with delivering this regimen concurrently with head and 558
neck radiotherapy, which is significantly more resource-intensive than cisplatin monotherapy. In 559
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addition, there are few reported toxicity data on carboplatin-fluorouracil in the intensity – 560
modulated radiation therapy (IMRT) era, and whether the low-dose bath seen with IMRT would 561
be particularly accentuated by a well-known mucositic agent (fluorouracil) is unknown. Thus, for 562
patients expected to tolerate high-dose intermittent cisplatin administration, the panel strongly 563
recommends its use for patients with stage IVA-B OPSCC. 564
A non-trivial percentage of patients with OPSCC may not tolerate bolus cisplatin 565
administration for a variety of reasons, including hearing loss or compromised renal function. In 566
this circumstance, the panel strongly recommends the use of concurrent carboplatin-fluorouracil 567
or cetuximab with definitive radiotherapy. As detailed above, the former regimen has a 568
consistent history of improving OS in combination with radiotherapy, and concurrent cetuximab 569
was shown in a phase III trial to improve OS in comparison to radiotherapy alone.35 There are 570
several retrospective studies comparing outcomes with cetuximab-radiotherapy with 571
chemoradiotherapy, but these publications are conflicting and too laden with confounding and 572
selection bias for consideration in this guideline. Therefore the panel did not prioritize one drug 573
over another for patients who do not receive high-dose cisplatin. The results from RTOG 1016 574
should provide important guidance in selecting the optimal concurrent systemic therapy for 575
patients with p16-positive oropharyngeal cancer. 576
Although weekly cisplatin may be an acceptable alternative to high-dose administration, 577
the evidence suggesting a survival benefit with its use is significantly weaker and based on 578
extrapolation rather than high-level evidence. So while the panel concluded that weekly cisplatin 579
may be given if the patient is not a candidate for bolus delivery, the lack of data guiding its use 580
must be made very clear to the patient, especially in the face of high-level data supporting OS 581
gains with competing regimens. 582
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The panel recognized that there is a population of patients with stage IVA-B (and stage 583
III) OPSCC who will not be candidates for concurrent systemic therapy. KQ4 discusses the 584
benefits and risks of altered fractionation radiotherapy to provide additional recommendations on 585
optimal treatment of this cohort. 586
587
588
2. In the scenario of stage III disease? 589 590
Statement 1F. Concurrent systemic therapy should be delivered to patients with T3 N0-1 591 oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 592
o Recommendation strength: Strong 593
o Quality of evidence: Moderate 594
595 Statement 1G. Concurrent systemic therapy may be delivered to patients with T1-T2 N1 596
oropharyngeal squamous cell carcinoma receiving definitive radiotherapy who are considered at 597 particularly significant risk for locoregional recurrence, after a careful discussion of patient 598 preferences and the limited evidence supporting its use. 599
o Recommendation strength: Conditional 600
o Quality of evidence: Low 601
602 3. In the scenario of stage I-II disease? 603 604
Statement 1H. Concurrent systemic therapy should not be delivered to patients with stage I-II 605 oropharyngeal squamous cell carcinoma receiving definitive radiotherapy. 606
o Recommendation strength: Strong 607
o Quality of evidence: High 608
609
Narrative 610
611 The addition of concurrent systemic therapy to primary radiotherapy for patients with 612
stage III oropharyngeal squamous cell carcinoma may be appropriate in certain patient 613
subgroups. Randomized controlled trials have generally included both stage III and IV patients, 614
with the stage III subgroup representing a minority (4 – 32%) of the total study population in the 615
studies reviewed. These trials are underpowered to address the magnitude of benefit of 616
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concurrent systemic therapy in the stage III subgroup. In addition, stage III patients are 617
heterogeneous, and include those with T3 N0-1 and T1-2 N1 tumors. 618
Since concurrent systemic therapy improves outcomes primarily through 619
radiosensitization, the key issue is the expected LRC probability with radiotherapy alone in this 620
population. Retrospective studies have shown that local tumor control is strongly related to 621
tumor volume and tumor stage. For example, Lok et al.42 reported the effect of tumor volumes on 622
outcomes of 340 OPSCC patients managed with radiation and concurrent chemotherapy at 623
Memorial Sloan Kettering between 1998-2009. Volumes of the primary site gross tumor (GTVp) 624
were calculated from the original IMRT plans. When dichotomized at the median volume (32.79 625
cm3) GTVp was demonstrated to be an independent predictor of 2 year OS on multivariate 626
analysis (94.3% vs 82.7%, p=0.0003). Similarly, two year probabilities of local failure (LF) at 627
the primary site were 1.3 % vs 10.4% (HR=6.01, p=0.004) based on a GTVp cut-off of 32.79 628
cm. 3 The authors observed that GTVp was a more reliable predictor of OS and LF than T 629
category (dichotomized as T1-2 vs T3-4). 630
Garden et al. 43 have reported a retrospective analysis of 1046 OPSCC treated at MD 631
Anderson between 2000 and 2007. Locoregional control at 5 years for 640 patients presenting 632
with T1-2 disease was 91% for those given concurrent chemotherapy and 95% for those treated 633
with radiation alone. In contrast, patients with T3-4 disease treated with concurrent 634
chemoradiotherapy achieved a LRC probability of only 77%, which dropped to 63% with 635
radiotherapy alone. A comparable retrospective analysis from the University of Florida described 636
the LRC outcomes in 130 OPSCC patients treated with definitive radiotherapy, 89% and 61% of 637
whom received AccF and/or concurrent chemotherapy, respectively. When evaluating their local 638
control outcomes, the authors found that T1 and T2 lesions experienced 5-year control 639
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probabilities of 93% and 91%, respectively, whereas T3 and T4 tumors recurred locally 82% and 640
67% of the time, respectively. These data are persuasive that patients with larger volume disease 641
need additional local therapy beyond conventional radiotherapy alone. In fact, the MACH-NC 642
meta-analysis31 showed a significant OS improvement with chemotherapy for patients with stage 643
III head and neck cancer, although the results were not broken down by T stage. Since 644
concurrent chemotherapy is consistently associated with LRC and OS benefits in the 645
aforementioned randomized trials, the panel strongly recommends that patients with T3 N0-1 646
OPSCC receive concurrent systemic therapy with primary radiotherapy. 647
The degree to which low-bulk disease, namely non-T3 stage III (T1-T2, N1) OPSCC, 648
benefit from treatment intensification with concurrent systemic therapy is uncertain, and it 649
remains controversial whether the added toxicity of concurrent systemic therapy is warranted in 650
this population. Consider that the volume of a T2 tumor may range from 8 cm3 to 64 cm3, and 651
thus the baseline risk of local recurrence may vary significantly in this tumor category. Other 652
tumor features may also impact the perceived locoregional failure risk for a patient with T1-2 N1 653
disease, such as its human papillomavirus (HPV) status and the patient’s smoking history. For 654
most patients with the T1-2 N1 OPSCC, the panel believes that radiotherapy alone should be 655
sufficient to obtain LRC. However, certain patients with T1-2 N1 OPSCC who are considered at 656
particularly significant risk for locoregional recurrence may receive concurrent systemic therapy 657
with primary radiotherapy, since the absolute benefit of combined modality therapy may warrant 658
its toxicities in this population. The potential benefit of concurrent systemic therapy is even less 659
compelling in smaller tumors, unless there are other features suggesting radioresistance. Patient 660
preferences must be engaged on the toxicity of concurrent therapy versus modestly improved 661
tumor control, and the limited data guiding this recommendation should be made explicit. 662
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The use of concurrent systemic therapy has not been rigorously examined in patients with 663
stage I and II OPSCC, a population with favorable LRC outcomes with radiotherapy alone. For 664
example, in the MACH-NC meta-analysis, 31 just over 500 patients with stage I-II disease were 665
included in the study (versus over 6,000 for stage IV cancer), and the hazard ratio for 666
chemotherapy was approximately one. Therefore these patients should not be treated with 667
concurrent systemic therapy. 668
669
Key Question 2: When is it appropriate to deliver post-operative radiotherapy with and 670
without systemic therapy following primary surgery of oropharyngeal squamous cell 671
carcinoma (OPSCC)? 672
1. In the scenario of positive margins and/or extracapsular nodal extension (ECE)? 673
674 Statement 2A. Concurrent high-dose intermittent cisplatin should be delivered with post-675
operative radiotherapy to patients with positive surgical margins and/or extracapsular nodal 676
extension; this high-risk population includes patients independent of HPV status or the extent of 677
extranodal tumor. 678
o Recommendation strength: Strong 679
o Quality of evidence: Moderate 680
681
Statement 2B. Concurrent weekly cisplatin may be delivered with post-operative radiotherapy to 682
patients who are considered inappropriate for standard high-dose intermittent cisplatin after a 683
careful discussion of patient preferences and the limited evidence supporting this treatment 684
schedule. 685
o Recommendation strength: Conditional 686
o Quality of evidence: Low 687
688 Statement 2C. For the high-risk post-operative patient unable to receive cisplatin-based 689
concurrent chemoradiotherapy, radiotherapy alone should be routinely delivered without 690
concurrent systemic therapy; given the limited evidence supporting alternative regimens, 691
treatment with non-cisplatin systemic therapy should be accompanied by a careful discussion of 692
the risks and unknown benefits of the combination. 693
o Recommendation strength: Strong 694
o Quality of evidence: Moderate 695
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696 Statement 2D. Patients treated with post-operative radiotherapy should not receive concurrent 697
weekly carboplatin. 698
o Recommendation strength: Strong 699
o Quality of evidence: Moderate 700
701 Statement 2E. Patients treated with post-operative radiotherapy should not receive cetuximab, 702
either alone or in combination with chemotherapy, although such regimens are currently under 703
investigation. 704
o Recommendation strength: Strong 705
o Quality of evidence: Low 706
707 Statement 2F. Patients treated with post-operative radiotherapy should not routinely receive 708
concurrent weekly docetaxel given the limited evidence supporting its use, although such 709
regimens are currently under investigation. 710
o Recommendation strength: Strong 711
o Quality of evidence: Low 712
713 Statement 2G. Patients treated with post-operative radiotherapy should not receive concurrent 714
mitomycin-C, alone or with bleomycin, given the limited evidence and experience supporting 715
its use. 716
o Recommendation strength: Strong 717
o Quality of evidence: Moderate 718
719 Statement 2H. Post-operative chemotherapy should not be delivered alone or sequentially with 720
post-operative radiotherapy. 721
o Recommendation strength: Strong 722
o Quality of evidence: High 723
724
Narrative 725
726 Is there a patient population that will benefit from the addition of chemotherapy to post-727
operative radiotherapy? What drug and treatment schedule should be used? 728
The results of two landmark trials of adjuvant chemoradiotherapy, EORTC 2293144 and 729
RTOG 950145, were published simultaneously in 2004 (Table 3). Both studies compared post-730
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operative radiotherapy (PORT) with post-operative chemoradiotherapy, using concurrent high-731
dose intermittent cisplatin (100 mg/m2 every three weeks for three doses) in patients deemed at 732
high risk for disease recurrence. High-risk disease was defined as positive surgical margins, or 733
extracapsular nodal involvement in both trials, but the RTOG study45 also included involvement 734
of two or more regional nodes, and the EORTC study44 included perineural disease, vascular 735
embolism, or level 4 or 5 nodal involvement in oral cavity or oropharynx primary cancers. It 736
should be noted that in the RTOG trial, a positive surgical margin was defined as microscopic 737
tumor at the tumor specimen edge. In the EORTC trial44 however, tumor within 5 mm of the 738
specimen edge was considered a positive margin. Initial results from both studies demonstrated 739
an improvement in LRC and disease/progression-free survival with chemoradiotherapy. Overall 740
survival was statistically better in the EORTC study44 but only trended towards improvement in 741
the first RTOG report. Long-term follow-up from the RTOG trial has been reported46, however, 742
and it no longer demonstrated any statistical benefit from the chemotherapy in the primary 743
comparisons. 744
It is of note that distant metastases were not reduced by the chemotherapy in either trial, 745
and all three cisplatin doses could be given to only 49% and 61% of the EORTC44 and RTOG45 746
patients respectively. Acute toxicity, specifically mucositis, myelosuppression, nausea and 747
vomiting, was increased in the chemoradiotherapy patients. However, no statistically significant 748
increase in total late grade 3-5 toxicity could be identified after chemoradiotherapy in either 749
study. This acute toxicity burden must temper any enthusiasm to use concurrent chemotherapy 750
in an unselected population of patients receiving PORT. 751
The difference in survival outcomes, and the long-term results from the RTOG study 752
merit further discussion. Bernier and colleagues47 performed a pooled analysis of the 750 753
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patients from both trials, and confirmed an improvement in all endpoints, including OS, in the 754
patients treated with chemotherapy. They suggested, however, that not all of the “high-risk” 755
eligibility criteria conferred sufficient risk to merit the addition of concurrent chemotherapy. In 756
their retrospective, unplanned subgroup analysis from these two trials, the addition of concurrent 757
cisplatin proved beneficial only in those high-risk patients with either positive surgical margins 758
or extracapsular nodal involvement. While benefit in patients with the other risk features 759
remained a possibility, it could not be statistically demonstrated. Similar conclusions were drawn 760
from the long-term RTOG 9501 follow-up report.46 Again using retrospective, unplanned 761
subgroup analysis, an improved loco-regional control and disease-free survival (with a strong 762
trend towards an improved OS) was identified in the chemoradiotherapy-treated patients with 763
positive surgical margins or extracapsular nodal extension. These observations have led to the 764
current strong recommendations for the addition of concurrent high-dose intermittent cisplatin to 765
adjuvant radiotherapy in these two high-risk post-operative populations. Patients with other risk 766
features, whose surgical procedure and/or pathologic findings imply a particularly significant 767
risk of locoregional recurrence may still benefit from concurrent cisplatin, although the evidence 768
is limited and inconclusive. 769
The improved prognosis and increasing incidence of HPV-positive oropharynx cancer, 770
however, could not be assessed in these trials and may have impacted the observed results.48 In 771
the EORTC study 30% of the patients had an oropharynx cancer compared to 42% in the RTOG 772
report (48% on the chemoradiotherapy arm and 37% of the radiotherapy alone arm). It is 773
unknown if these good prognosis HPV-positive patients require or benefit from more intensive 774
adjuvant therapy, even in the presence of conventional “high-risk” features. 775
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The implications of extracapsular nodal extension in oropharynx cancer, and in 776
particular, the HPV-positive patient have also been questioned. Retrospective reports from 777
several groups have suggested that extracapsular nodal disease has limited prognostic importance 778
in these patients, especially when it is only microscopically present in an HPV-positive patient.49-779
52 Prospective studies that replicate these provocative retrospective results are needed before 780
PORT alone can be recommended for HPV-positive head and neck cancer with ECE. In addition, 781
to enhance its prognostic power, ECE reporting has recently been refined with the introduction 782
of a five point scale (0-4), and further multi-institutional study is required for this modification to 783
be used in clinical practice.53 784
Reasonable concern clearly exists about the applicability of RTOG 950145 and EORTC44 785
22931 to the growing population of patients with HPV-positive oropharynx cancer48 and the 786
prognostic implications of early extracapsular nodal involvement. To date, however, these two 787
trials provide the best available evidence and continue to drive the current adjuvant 788
recommendations. Well-designed HPV-specific trials are currently underway to better address 789
these many unresolved questions. Similar concerns have also led to greater sophistication and 790
nuance in the studies designed for the definitive management of oropharynx cancer. Such 791
concerns do not render current treatment standards invalid; they only lend urgency to further 792
investigation. 793
794
Can radiotherapy and a weekly concurrent cisplatin administration schedule be used instead of 795
giving 100 mg/m2 given every three weeks? 796
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The high-dose, every three week cisplatin administration schedule (100 mg/m2 q3weeks 797
for 3 doses) has proven difficult to administer. It is associated with gastrointestinal, renal, 798
mucosal and neurologic toxicity, and most large multi-institutional studies (including RTOG 799
9501 and EORTC 22931) have reported that only 50-70% of patients can receive all three drug 800
doses. In recent years there has been considerable interest in the lower dose weekly drug 801
administration schedules (30-40 mg/m2/week) based on the unproven assumption being made 802
that such regimens will produce less toxicity, and, as such will allow equivalent or greater drug 803
administration with equal treatment efficacy. No prospective, randomized comparisons have yet 804
been completed comparing these two drug treatment schedules, however, and their equivalence 805
is unknown. 806
In the post-operative setting Bachaud et al. 54,55 reported the results of a very small phase 807
III trial comparing PORT alone with radiotherapy and weekly cisplatin; 50 mg/week 808
(approximately 25-30 mg/m2) for 7-9 doses in 83 patients (14% oropharynx cancer). Both 809
disease-free and OS, as well as OS without locoregional treatment failure, were significantly 810
improved in the chemotherapy treated patients. Distant metastases were not impacted by the 811
chemotherapy, although toxicity was significantly worse. 812
Geiger et al.56 conducted a retrospective analysis of 104 post-operative patients treated 813
with radiotherapy and either concurrent high-dose intermittent (100 mg/m2 q3weeks for 3 doses), 814
or low dose weekly (25-30 mg/m2/week for 6 doses) cisplatin. Sixty-one percent of the patients 815
had an oropharynx cancer, and 86% of these oropharynx cancers were HPV/p16 positive. Total 816
drug administration was significantly greater in the high-dose intermittent group, but no 817
difference was observed in either relapse-free or OS between patients treated with the two 818
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different cisplatin schedules. There was also no outcome difference identified when the analysis 819
was limited to the HPV-positive oropharynx cancer patients. 820
Because of the increasing community acceptance of weekly cisplatin regimens despite 821
this lack of demonstrated equivalence, the NRG adopted weekly dosing as the control arm in 822
RTOG 1216, its current phase II/III trial exploring the substitution of docetaxel and cetuximab 823
for cisplatin in the postoperative adjuvant treatment of patients with high risk disease. Despite 824
the inclusion of weekly cisplatin as the control arm in this study, the panel does not feel the 825
evidence supporting its use is currently sufficient to strongly recommend its delivery in lieu of 826
high-dose intermittent cisplatin when the latter would be tolerated, as the high-dose regimen was 827
evaluated in two large prospective phase III randomized trials with positive results. 828
829
Are there alternative systemic treatment regimens that can be used concurrently with 830
radiotherapy, particularly in the medically compromised patient? 831
Cisplatin remains the only systemic agent with level 1 evidence supporting its use 832
concurrently with radiotherapy in high-risk post-operative patients. Several other systemic agents 833
have been tested in small phase II and phase III trials with limited success (Table 4). All studies 834
report greater toxicity when chemotherapy is added to radiotherapy without a proven survival 835
benefit. 836
Radiotherapy and concurrent single agent mitomycin C (15 mg/m2 for 1-2 doses) has 837
been compared to a radiation therapy control arm in three separate randomized trials at Yale 838
University.57-61 Pooled results from the 205 post-operatively treated patients (23% oropharynx 839
cancer) have been reported. Conventional high-risk features were not required for entry on these 840
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trials although 27% had positive surgical margins and 34% had more than one positive node. 841
Locoregional control proved statistically superior in those patients treated with mitomycin C; 842
however, no difference was observed in the rate of distant metastases or in overall survival. 843
Post-operative radiotherapy with mitomycin C (15 mg/m2) was also studied by Smid, 844
Zakotnik et al.,62,63 who combined it with bleomycin (5 mg twice weekly) and compared it to 845
radiotherapy alone in 114 patients (30% oropharynx cancer); 59% of whom had either positive 846
surgical margins or extracapsular nodal extension. Both LRC and disease-free survival were 847
significantly improved in the chemotherapy treated patients, although OS only trended better 848
(55% vs. 37%, p=0.09). Distant metastases were not improved by the use of chemotherapy. 849
This work, from both groups, provided modestly encouraging evidence of a potential role 850
for mitomycin C in this setting, although patient sample sizes were small. Mitomycin C has not 851
been further pursued in part due to the stronger data that emerged about concurrent cisplatin, and 852
in part due to general concerns about the toxicity of this agent. Because of both the lack of an OS 853
benefit and absence of modern experience of combining this agent with radiotherapy, the panel 854
strongly recommends not combining mitomycin C with post-operative radiotherapy. 855
Concurrent carboplatin has also been studied. Racadot et al.64 report the results of a 856
randomized comparison between PORT alone, and PORT with concurrent carboplatin (50 mg/m2 857
twice weekly) in 144 patients (49% oropharynx cancer) with node positive disease. No outcome 858
differences were observed. Similarly, Argiris et al.65 studied a post-operative patient population 859
(32% oropharynx cancer) defined by positive margins, multiple node positivity, angiolymphatic 860
or perineural invasion (PNI), or extracapsular nodal involvement, randomizing between 861
radiotherapy and radiotherapy with concomitant carboplatin 100 mg/m2 weekly. Only 72 patients 862
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were evaluated on the trial and no statistically meaningful outcome difference was observed, 863
perhaps reflecting the insufficient sample size. Further studies of post-operative carboplatin and 864
radiotherapy have not been reported, and since both randomized trials were negative, the panel 865
strongly recommends against using concurrent carboplatin in the post-operative setting. 866
A large multi-institutional phase III study from the United Kingdom randomly compared 867
PORT with radiotherapy and chemotherapy (either methotrexate alone, or methotrexate, 868
vincristine, bleomycin and fluorouracil) in 253 post-operative patients (23% oropharynx cancer). 869
Patients were described as “generally at high risk due to margin status or advanced stage of 870
disease.” No outcome benefit was observed in the chemotherapy treated patients using this non-871
platinum containing regimen.66 872
Cetuximab and the other EGFR inhibitors have been considered promising agents in the 873
management of head and neck squamous cell cancer. When combined with radiotherapy in the 874
definitive treatment of locoregionally advanced disease, a survival benefit (but no impact on 875
distant metastases) has been demonstrated in comparison to radiation therapy alone. This result 876
has suggested the possibility that radiotherapy and cetuximab may also be a valuable post-877
operative adjuvant regimen to explore. The NRG is currently comparing this combination to 878
radiation therapy alone in “intermediate risk” patients after surgical resection in RTOG 0920.67 879
However, since there are no prospective or even retrospective studies suggesting efficacy in this 880
scenario, the panel strongly recommends against using cetuximab with PORT if not on clinical 881
trial. 882
The taxanes (paclitaxel and docetaxel) have been investigated by the RTOG in a series of 883
post-operative trials.68 RTOG 0024 explored immediate post-operative paclitaxel followed by 884
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
concurrent chemoradiotherapy with weekly paclitaxel and cisplatin in 70 high-risk post-operative 885
patients (34% oropharynx cancer) in a single arm phase II trial.68 Toxicity appeared acceptable 886
and results comparable to historical controls using high-dose cisplatin. This study was followed 887
by RTOG 0234, a phase II randomized trial comparing post-operative cetuximab and 888
radiotherapy with either concurrent weekly cisplatin or weekly docetaxel, in 203 high risk 889
patients (36% oropharynx cancer).69 The radiotherapy, cetuximab and docetaxel arm appeared 890
more promising and this combination is now being formally tested in a phase II/III trial70 in 891
comparison to radiotherapy and cisplatin. Pending the results of this study, though, the use of 892
docetaxel with PORT – a combination never prospectively evaluated – should not be routinely 893
implemented with post-operative radiotherapy. 894
It should again be noted that the benefit from cisplatin reflects an improvement in loco-895
regional control, not a reduction in distant metastases. There is no phase III evidence 896
demonstrating an improvement in distant metastatic recurrence from any systemic agent in this 897
setting. In patients with a contraindication to cisplatin, radiation therapy alone provides a LRC 898
benefit, and is the recommended treatment choice, even when the risk of disease recurrence is 899
high. 900
901
Is there a role for post-operative adjuvant chemotherapy alone, or for the sequential 902
administration or chemotherapy and radiotherapy, rather than concurrent treatment? 903
The MACH-NC Meta-analysis 31,71 reported on 12 trials of more than 2500 patients, 904
comparing adjuvant chemotherapy after locoregional treatment to locoregional treatment alone. 905
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
No impact could be identified on either disease recurrence or death from the use of the adjuvant 906
chemotherapy. Adjuvant chemotherapy is not considered a standard approach in this disease. 907
Laramore et al.72 reported the results of Intergroup study 0034, a phase III randomized 908
trial conducted in 448 patients (25% oropharynx cancer) comparing PORT alone, with sequential 909
chemotherapy (fluorouracil and cisplatin for 3 cycles) followed by radiotherapy. No difference in 910
LRC, disease-free survival or OS could be identified between the two treatment arms, although a 911
statistically significant increase in distant metastases was seen in the patients not given 912
chemotherapy. Sequential treatment with post-operative chemotherapy and radiotherapy is not 913
recommended in this disease. 914
915
2. In the scenario of intermediate-risk pathologic factors such as lymphovascular invasion 916
(LVI), perineural invasion (PNI), T3-4 disease, or positive lymph nodes? 917
918 Statement 2I. Patients with intermediate-risk factors should not routinely receive concurrent 919
systemic therapy with post-operative radiotherapy. 920
o Recommendation strength: Strong 921
o Quality of evidence: Moderate 922
923 Statement 2J. Patients with intermediate-risk factors whose surgical procedure and/or 924
pathologic findings imply a particularly significant risk of locoregional recurrence may receive 925
concurrent cisplatin-based chemotherapy after a careful discussion of patient preferences and the 926
limited evidence supporting its use in this scenario; alternative systemic treatment regimens 927
should only be used in the context of a clinical trial. 928
o Recommendation strength: Conditional 929
o Quality of evidence: Low 930
931 Statement 2K. Post-operative radiotherapy should be delivered to patients with pathologic T3 or 932
T4 disease. 933
o Recommendation strength: Strong 934
o Quality of evidence: Low 935
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
936 Statement 2L. Post-operative radiotherapy should be delivered to patients with pathologic N2 or 937
N3 disease. 938
o Recommendation strength: Strong 939
o Quality of evidence: Low 940
941 Statement 2M. Post-operative radiotherapy may be delivered to patients with pathologic N1 942
disease after a careful discussion of patient preferences and the limited evidence of outcomes 943
following surgery alone in this scenario. 944
o Recommendation strength: Conditional 945
o Quality of evidence: Low 946
947 Statement 2N. Post-operative radiotherapy may be delivered to patients with LVI and/or PNI as 948
the only risk factor(s) after a careful discussion of patient preferences and the limited evidence of 949
outcomes following surgery alone in this scenario. 950
o Recommendation strength: Conditional 951
o Quality of evidence: Low 952
953
Narrative 954
955 The risk of locoregional recurrence following definitive surgical resection and neck 956
dissection is influenced by several factors. The clinical and pathologic features most clearly 957
associated with subsequent locoregional progression are positive margins and extracapsular 958
nodal extension, the implications of which were discussed above. On the other hand, due to the 959
paucity of prospective randomized trials of adjuvant radiotherapy alone versus observation 960
following surgery, the vast majority of data implicating other risk factors with locoregional 961
recurrence are retrospective. Thus, there is almost no high-level evidence to guide adjuvant 962
treatment recommendations in the negative margin, non-ECE setting, despite several other risk 963
factors serving as eligibility criteria for active prospective randomized trials evaluating the role 964
of adjuvant radiation therapy with or without chemotherapy. Nevertheless, this population 965
comprises a significant percentage of patients for whom PORT must be considered, and so the 966
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panel used higher-quality retrospective data and expert opinion to derive treatment 967
recommendations (Table 5). 968
Pathologic nodal stage is a commonly used pathologic risk factor in the adjuvant 969
decision-making process. Resection of bulkier nodes may leave behind occult microscopic 970
disease, and with more pathologically involved nodes, there is theoretically a higher likelihood 971
of additional microscopic nodal deposits in dissected or undissected tissue. Indeed, the evidence 972
supports a significant risk of regional progression in patients with N2 or N3 disease. In one of the 973
few prospective trials of adjuvant radiotherapy dose escalation, Peters et al. showed that among 974
all patients, those with more than 1 positive node (i.e. N2b) experienced a higher risk of 975
locoregional recurrence (30% vs 16%, p=0.08), despite radiotherapy delivery to all patients. 976
Langendijk et al.73 performed a large retrospective analysis to define subgroups of patients with 977
locally advanced head and neck cancer (20% oropharyngeal cancer) at higher risk for 978
locoregional recurrence following surgery and post-operative radiotherapy. On multivariable 979
analysis, patients with pN2b-N2c and pN3 disease had significantly higher risks of locoregional 980
recurrence in comparison to pN0-N2a status (RR 1.7 and 3.5, respectively), and patients with an 981
N3 neck were placed in the “very high risk” category (5 year LRC of 58%) regardless of ECE or 982
the primary tumor characteristics. Similarly, Ambrosch et al.74 reported a large series of 503 983
patients treated with neck dissection with or without adjuvant radiotherapy. The 48 patients with 984
N2 disease treated without adjuvant radiotherapy experienced a 3-year neck recurrence risk of 985
24%, in comparison to 7% of the 188 N2-positive treated with post-operative radiotherapy. 986
Notably, among all patients with regional recurrence, successful salvage was feasible in only 987
24% of patients, and 67% of patients died specifically from the neck progression. In a smaller 988
surgical series from Mayo Clinic, 2 out of 11 (17%) pathologic N2b oropharynx cancer patients 989
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
observed after neck dissection developed a regional recurrence, as did 1 of 2 pathologic N3 990
patients. 991
The risk of regional recurrence in patients with a pathologically N1 neck is more 992
controversial. In a paper restricted to individuals with pN1 disease without extracapsular 993
extension (29% oropharynx), Jackel et al.75 reported the risks of locoregional recurrence with 994
and without adjuvant radiotherapy. Patients observed after primary surgery (n=72) experienced a 995
crude risk of any regional recurrence of 21%, with 10% of observed patients developing an 996
isolated nodal failure; the estimated 3-year risk of isolated neck recurrence in this population was 997
11.2% (vs. 2.9% in patients who were irradiated, p=0.09); three of the 7 patients with isolated 998
regional recurrence died from cancer. Somewhat conflicting data on the N1 neck were presented 999
in the Ambrosch study,74 in which the 3-year neck recurrence risk for the 48 pN1 patients treated 1000
with surgery alone was 6.3%. This number was only slightly higher than the neck recurrence risk 1001
in pN0 patients observed after surgery (5.5% out of 213 patients). However, only 28% of these 1002
patients had oropharyngeal cancer, and the majority was either oral cavity or larynx, which have 1003
different patterns of nodal spread. In particular, oropharyngeal cancer is significantly more likely 1004
to metastasize to the retropharyngeal nodes, which are treated with radiotherapy but not accessed 1005
with conventional neck dissection; the absolute risk of retropharyngeal lymph node involvement 1006
in OPSCC has been reported between 20-30%.76,77 Smaller, modern series in oropharynx cancer 1007
also suggest high control rates following neck dissection alone for N1 disease. None of the 10 1008
patients observed with pN1 disease in the Mayo clinic series developed a regional recurrence, 1009
and none of the 10 patients with pN1 disease in the Penn prospective study of transoral robotic 1010
surgery (TORS) 78 alone developed a neck progression. One significant consideration in 1011
evaluating all of these data is the reality that the quality of the neck dissections was not formally 1012
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standardized, both in terms of surgical technique (e.g. levels dissected and number of nodes 1013
harvested) and pathologic evaluation processes. Thus one must recognize this limitation in 1014
applying these results to a given neck dissection. 1015
Two related surveillance, Epidemiology, and End Results Program (SEER) studies 1016
investigated the survival benefit of adjuvant RT following surgery for non-nasopharynx head and 1017
neck carcinoma with positive lymph nodes, and both showed a significant OS advantage for all 1018
nodal stages. For instance, Kao et al.79 showed that the absolute survival gains for patients with 1019
N1, N2a, N2b, and N2c-3 were 8.2%, 16.6%, 23.9%, and 12.2%, respectively (all p<0.0001). 1020
Patients with oropharyngeal cancer experienced an absolute survival improvement of 8.2% with 1021
adjuvant radiotherapy (p=0.0003). Although these survival improvements are impressive, any 1022
SEER study is limited by the nature of its retrospective, population-based data collection. For 1023
example, performance status, chemotherapy administration, ECE status, and pre-treatment 1024
imaging were all unknown. Nevertheless, these data do support a benefit of adjuvant 1025
radiotherapy for all node-positive disease. 1026
Taken together, this evidence is persuasive that individuals with pathologic N2 and N3 1027
disease experience an unacceptably high regional recurrence risk without radiotherapy, and 1028
therefore the panel strongly recommends that these patients receive adjuvant RT. Patients with 1029
pathologic N1 oropharynx cancer are clearly at lower risk for nodal progression following neck 1030
dissection, but there is substantial uncertainty on the true probability of regional recurrence in 1031
this population. Moreover, while it is intuitive and accepted that patients not receiving 1032
radiotherapy will have improved quality-of-life in comparison to those who do, the poor salvage 1033
ability (and potential mortality) of a neck recurrence must be considered in this decision. Since 1034
the panel favors a potential progression and/or survival benefit over modest, albeit meaningful, 1035
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
quality-of-life improvements, it conditionally recommends adjuvant radiotherapy in this 1036
population. That said, it is critical to discuss the uncertainty in the recurrence risk with the 1037
patient, and the physician should engage patient preferences and values on the balance between 1038
the risks of radiotherapy versus the potential for unsalvageable regional progression. 1039
Pathologic T stage has also been frequently investigated in retrospective studies as a 1040
predictor of locoregional recurrence. Leemans et al80 reported on 244 head and neck cancer 1041
patients (13% oropharynx) treated with primary surgery with or without adjuvant radiotherapy. 1042
Clinical T stage was the most significant predictor of local recurrence, with a crude recurrence 1043
risk of 5.3% for T1-2 versus 16.2% for T3-4 disease (p=0.015), and the actuarial absolute 1044
difference at 5 years was almost 20%. In a retrospective analysis of 420 oropharyngeal and 1045
hypopharyngeal patients from the Centre Henri Becquerel treated with surgery and PORT 1046
radiotherapy, advancing T stage was strongly associated locoregional relapse (relative risk 1.85, 1047
p<0.0001) on multivariable analysis, with T stage treated as a continuous variable; absolute risks 1048
were not stated. In the Langendijk73 analysis in which all patients received adjuvant 1049
radiotherapy, T stage did not correlate with LRC on univariable analysis. However, after 1050
identifying patients with positive or close margins (5 mm or less, which is typically seen in 1051
larger tumors of the oropharynx), patients with T3-4 disease experienced significantly worse 1052
LRC than those with T1-2 disease (absolute difference 10%). The majority of these failures were 1053
in the T3 population (5-year LRC of 51%). 1054
A retrospective analysis of p16-positive patients by Haughey et al.81 nicely showed a 1055
significant increase in the risk of any recurrence as a function of pathology T stage: 1.5%, 5.5%, 1056
11.5%, and 28.6% for T1, T2, T3 and T4 respectively. Indeed, on multivariable analysis of 1057
disease-free survival, both clinical T stage (T3-4 vs T1-2) and pathologic T stage (T3-4 vs T1-2) 1058
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
increased the hazard by over 3-fold. However, there were only 2 local recurrences in the entire 1059
series (both in T3 patients, 1 of whom did not receive adjuvant radiotherapy), so T stage was not 1060
a predictor of local-only recurrence. In the Ambrosch et al.74 study that primarily focused on 1061
regional recurrences after neck dissection, pT3/pT4 disease was significantly associated with 1062
worsened OS on multivariable analysis (risk ratio 1.6, p=0.0009), but local failure patterns were 1063
not mentioned. 1064
Both of these latter studies highlight a major challenge in analyzing the literature to 1065
derive adjuvant treatment recommendations in patients with T3-4 disease: almost all of these 1066
individuals received post-operative radiotherapy. While the retrospective data are convincing 1067
that these patients have a worse overall prognosis, it is hard to calculate an absolute local 1068
recurrence risk with and without radiotherapy. Nevertheless, the panel concluded that the 1069
existing literature support an increased risk of local recurrence with pathologic T3 or T4 disease 1070
even with radiotherapy, and moreover, there are insufficient LRC data to support the oncologic 1071
safety of observation following resection of T3-4 oropharyngeal cancer. Therefore the panel does 1072
strongly recommend adjuvant RT in this population. 1073
It is particularly difficult to estimate the risk of locoregional recurrence in patients for 1074
whom PNI or LVI is the only adverse pathologic factor. These characteristics are often found in 1075
patients with other known risk factors for recurrence and this confounding can be difficult to 1076
resolve.81 Secondly, retrospective studies don’t always comment on these factors because they 1077
are not always properly recorded in the pathology report. Finally, historically radiation 1078
oncologists have always treated patients with LVI or PNI, and there is very little information on 1079
outcomes without adjuvant radiotherapy. For example, the large retrospective analysis from 1080
Langendijk et al.73 found that patients with PNI had a significantly higher risk of locoregional 1081
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recurrence (31% vs 22% at 5 years, p<0.026), as did patients with angioinvasive (33% vs 21%, 1082
p=0.011) or lymphangioinvasive growth (38% vs. 23%, p=0.046). However, none of these 1083
factors were significant on multivariable analysis. Haughey et al. found on univariable analysis 1084
that angioinvasion was borderline associated with disease-free survival (p=0.062) and powerfully 1085
associated with disease-specific survival (HR 13.16, p=0.002). These relationships became non-1086
significant on multivariable analysis. Moreover, only 26 patients had this pathologic factor, and 1087
of these 26, five recurred but 4 were distant metastases. There was no association between PNI 1088
and outcome in this large analysis. 1089
There are data supporting these characteristics as independent risk factors for 1090
locoregional recurrence. In a retrospective analysis of 80 consecutive head and neck patients 1091
(28% oropharynx) treated with primary surgery at the University of Utrecht, LVI was 1092
significantly associated with local failure on both univariable analysis (50% failure with vs. 16% 1093
without, p=0.001) and multivariable analysis (p=0.005). Perineural invasion was qualitatively 1094
associated with local failure (27% with and 15% without), but it was non-significant on both 1095
univariable and multivariable analysis.82 In the retrospective study from the Centre Henri 1096
Becquerel,83 individuals with tumor emboli in the vessels or nerves experienced an 1097
approximately 10% increased risk of locoregional recurrence. However, in a multivariable 1098
analysis of local relapse incorporating T and N stage, margin status, age, tumor emboli was 1099
marginally non-significant (relative risk 1.48, p=0.061). In another bi-institutional retrospective 1100
analysis of oral cavity and oropharyngeal cancer (33% oropharynx), McMahon et al.84 showed 1101
that PNI was a significant predictor of local recurrence in both institutions, and vascular and LVI 1102
was a significant predictor of local recurrence in only one of them. However, on multivariable 1103
analysis incorporating all patients, only PNI (over all other variables) was significantly 1104
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associated with local recurrence. Neither PNI nor LVI were independently associated with 1105
disease-specific survival on multivariable analysis. Fagan et al.85 retrospectively evaluated the 1106
prognostic influence of PNI in 142 patients (66 with oral cavity or oropharynx) treated with 1107
primary surgery with or without adjuvant radiotherapy. Over half of the patients had PNI, and it 1108
was significantly associated with local recurrence (23% vs. 9%, p=0.02) and disease-specific 1109
mortality. Finally, Lanzer and colleagues analyzed locoregional and distant recurrence patterns 1110
in 291 head and neck cancer patients, 32% of whom had oropharynx cancer. Among all patients, 1111
the presence of PNI was associated with a higher risk of ipsilateral and contralateral lymph node 1112
recurrence, but there were no independent associations between PNI and disease-free or overall 1113
survival.86 1114
Two retrospective analyses restricted to oral cavity cancer highlight the uncertainty in the 1115
adjuvant management of this population. In a large series of 460 patients with node-negative oral 1116
cavity cancer87, Liao et al. showed that the presence of PNI was not associated with local control 1117
or OS and the addition of radiotherapy to patients with PNI did not improve any outcome; only 1118
44 patients with PNI were observed. On the other hand, Chinn et al.88 reported on a cohort of 88 1119
node-negative oral cavity patients from the University of Michigan, finding that PNI was 1120
associated with worse LRC (35% vs. 12%, p=0.037) and a shorter disease-free interval on 1121
multivariable analysis; in addition, the addition of radiotherapy significantly improved both 1122
endpoints.88 However, only six patients with PNI were observed, limiting the interpretation of 1123
this comparison. 1124
In summary, these entirely retrospective data are mixed on the relationship between 1125
locoregional failure and LVI and PNI, but there is certainly the suggestion that they reflect more 1126
aggressive locoregional disease. Given the morbidity and mortality risk of local recurrence, 1127
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adjuvant radiotherapy may be used for patients with either pathologic factor as the only adverse 1128
characteristic. Both the lack of high-quality evidence and the conflicting retrospective data 1129
guiding this recommendation need to be described to patients, and their preferences and values 1130
on toxicity versus the risk of recurrence need to be explored. 1131
3. In the scenario of no pathologic risk factors? 1132
1133
Statement 2O. Post-operative radiotherapy may be delivered to patients without conventional 1134
adverse pathologic risk factors only if the clinical and surgical findings imply a particularly 1135
significant risk of locoregional recurrence, after a careful discussion of patient preferences and 1136
the potential harms and benefits of radiotherapy. 1137
o Recommendation strength: Conditional 1138
o Quality of evidence: Low 1139
1140
Narrative 1141
1142 There are limited prospective data that report outcomes following primary surgery alone 1143
for oropharyngeal cancer. In a multi-institutional prospective trial evaluating a post-surgical 1144
adjuvant therapy paradigm, Ang et al.89 demonstrated that when the surgical bed was at a low 1145
risk for relapse, defined by the absence of any adverse pathologic features (i.e. T1-2, N0, 1146
negative margin, no PNI, non-oral cavity site), observation was associated with a local-regional 1147
relapse of approximately 10% at 5-years, despite significantly older staging and surgical 1148
techniques. Investigators from University of Pennsylvania characterized the oncologic results of 1149
30 patients treated with TORS alone on a prospective trial.78 Positive margins were defined as 1150
tumor within 2 mm of the margin, and the surgeons paid exquisite detail to the margin 1151
evaluation. All patients in this cohort had final negative margins, although one patient required 1152
an additional resection for carcinoma in situ at the inked margin. Three patients had ECE, and 15 1153
patients were node-positive (10 N1, 5 N2a or N2b). With a minimum follow-up of 18 months, 1154
one patient (3% of total) with initial T2N0 stage developed a local recurrence, successfully 1155
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salvaged with chemoradiotherapy. Three patients (10% of total) experienced a regional 1156
recurrence, two of whom had N2b nodal stage at original presentation and refused the 1157
recommendation to receive adjuvant radiotherapy. One patient with T2N0 cancer recurred in the 1158
ipsilateral high-neck. All patients were alive without evidence of disease at the time of the 1159
publication. 1160
Psychogios et al.90 published a retrospective series of 228 patients with T2 N0-3 1161
oropharyngeal cancer treated with primary surgery with or without adjuvant radiation treatment. 1162
Out of the 69 patients with negative margins and no pathologically involved lymph nodes, there 1163
was no difference in disease-specific survival between the 20 observed patients versus the 49 1164
treated with radiation therapy (81.5% vs. 80.0%, p=0.361). 1165
A joint publication from Mayo-Jacksonville and Mayo-Arizona retrospectively analyzed 1166
outcomes following transoral laser microsurgery alone in 69 patients, all of whom had negative 1167
margins. 91 Twenty-five of these patients had an indication for RT (i.e. ECE, N2 status, LVI) but 1168
declined, and 44 individuals did not have an indication for RT. After a mean follow-up of 44 1169
months, only 3 patients recurred at the primary site (two T1, one T2 cancer, for a 5-year local 1170
control estimate of 95%). Forty-four patients were recommended to undergo observation, and 4 1171
of these patients recurred in the neck, leading to 5-year LRC estimates of only 90%, 73%, and 1172
70% for stage I, II and III, respectively. However, two of those 4 patients did not have a neck 1173
dissection and were observed. The 5-year disease-specific and OS probability for stage I and II 1174
disease was 88% and 79%, respectively. Of the 25 patients with an indication for adjuvant 1175
radiotherapy, 4 developed a regional failure, with a 5-year estimate of LRC of 74%. 1176
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One of the challenges in interpreting pathologic data following transoral excision of 1177
oropharyngeal cancer is the lack of meaningful data on the appropriate surgical margin, which is 1178
not standardized. The most comprehensive study of margin status in head and neck cancer was 1179
based on 827 oral cavity cancer patients (343 stage I-II) and suggested that local control rates 1180
were significantly improved with a margin width of 7 mm or more, although even wider margin 1181
distances also seemed to predict for local failure.87 Of course, none of these patients had 1182
oropharyngeal cancer, and it is unclear whether these results can be translated to a separate 1183
disease site with different anatomy and even biology. For example, Wong and colleagues found 1184
no difference in local recurrence between close (1-5 mm) and negative (> 5 mm) margins treated 1185
with surgery alone, although only 32 of 192 patients had oropharyngeal cancer.92 There is a 1186
general consensus among head and neck surgeons that invasive cancer within 5 mm or less is an 1187
adverse prognostic feature requiring adjuvant therapy, 92 but whether this rule of thumb holds 1188
with modern surgical techniques in the oropharynx is unknown. Thus, while patients with 1189
pathological stage I-II disease with wide margins, a pathologically negative neck and no other 1190
adverse pathologic factors can typically be observed, patients whose surgical procedure or 1191
margin width are more concerning for local recurrence may be considered for adjuvant therapy. 1192
Careful discussion and collaboration between the members of the multidisciplinary team is 1193
necessary to optimize locoregional therapy, and patient preferences on the relative risks and 1194
benefits of radiotherapy versus observation must be understood. 1195
The active phase II study Eastern Cooperative Oncology Group (ECOG) 331193 will 1196
significantly improve our ability to estimate LRC rates following surgery alone for patients with 1197
p16-positive oropharynx cancer. Patients with T1-2, N0-N1 (without extracapsular extension) 1198
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and clear (> 3 mm) margins, will be observed after transoral surgery, and the final results of this 1199
study will further refine these recommendations. 1200
1201
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Key Question 3: When is it appropriate to use induction chemotherapy in the treatment of 1202
oropharyngeal squamous cell carcinoma (OPSCC)? 1203
1204 Statement 3A. Induction chemotherapy should not be routinely delivered to patients with 1205
OPSCC. 1206 o Recommendation strength: Strong 1207 o Quality of evidence: High 1208
1209
Narrative 1210
1211 The curative treatment for the majority of patients with locally advanced OPSCC requires 1212
a multidisciplinary effort, often involving various combinations of radiotherapy, chemotherapy, 1213
and surgery. Despite decades of clinical research (Table 6), however, the optimal integration of 1214
chemotherapy with radiotherapy in this setting has been controversial, and study interpretation 1215
has been complicated by changing local therapy paradigms and epidemiologic shifts. It has been 1216
recognized since the mid-1980s that patients demonstrated high response rates to neoadjuvant or 1217
IC, and the clinical utility of IC was established in landmark trials of advanced larynx (VA 1218
Larynx) and pyriform sinus (EORTC) cancers, which revealed that radical surgery was avoidable 1219
without any decrement in survival. However, whether IC improves outcomes in OPSCC requires 1220
a different calculus, since OSrather than organ preservation is the key issue and outcome of 1221
concern. 1222
One of the earliest studies of IC using modern regimens was an Italian multi-center 1223
randomized trial,94,95 which compared 4 cycles of cisplatin-fluorouracil (PF) followed by 1224
locoregional therapy with locoregional therapy alone. Operable patients were treated with 1225
resection and adjuvant RT, and inoperable patients received definitive RT alone (65-70 Gy). 1226
Slightly over half of all patients on both arms of the study had OPSCC. When the operable and 1227
inoperable patients were pooled, there was essentially no impact of IC on OS, or local control 1228
(LC), but a significant improvement in distant relapse-free survival (DRFS) was seen. A subset 1229
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analysis of the inoperable group demonstrated significantly improved LC, DRFS and OS; in 1230
terms of toxicity, over a third of IC patients had at least one dose reduction, and grade 2 or 1231
greater toxicities were common, including hematologic, stomatitis, vomiting, renal and cardiac 1232
changes. 1233
The French cooperative group GETTEC96 performed the only available randomized 1234
study of IC strictly in patients with OPSCC, demonstrating a significant improvement in OS 1235
(median OS 5.1 vs. 3.3 years) with PF-based IC followed by local therapy (either surgery and 1236
PORT alone or definitive radiotherapy alone to 70 Gy) compared to an identical non-IC arm. 1237
These survival gains were seen despite the trial closing early due to concerns of the 1238
appropriateness of a chemotherapy-alone arm. The toxicity reported here focused exclusively on 1239
the induction component of the treatment and consisted of hematologic (26%), digestive (22%) 1240
and mucosal (13%) side effects. 1241
The updated meta-analysis of chemotherapy in head and neck cancer 31 provided 1242
additional information on the benefits of IC. This study found that in comparison to radiotherapy 1243
alone, concurrent chemoradiotherapy improved LRC (HR 0.74, p<0.0001), distant metastasis 1244
(HR 0.88, p=0.04), and overall survival (HR 0.81, 95% CI 0.78-0.86). In contrast, the analysis of 1245
31 trials that compared IC plus local therapy with local therapy alone found that IC did not 1246
improve overall survival(OS) or LRC, but it did significantly and meaningfully improve the risk 1247
of distant failure (HR 0.73, p=0.0001). However, IC did improve OS in the subset of trials using 1248
PF (HR 0.90, 95% CI 0.82-0.99), supporting the hypothesis that a reduction in distant metastases 1249
with modern chemotherapy regimens may translate into an OS benefit, despite the high 1250
competing risk of locoregional failure in this population. 1251
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It is critical to note that radiotherapy alone – not concurrent chemoradiotherapy – was the 1252
standard non-surgical locoregional therapy in both of these randomized trials, as well as the non-1253
surgical arms included in the meta-analysis. Since concurrent chemoradiotherapy is now 1254
understood to improve LRC and OS, the inadequate local therapy arm in these trials of IC may 1255
entirely explain the survival gain with neoadjuvant chemotherapy. This limitation in trial design 1256
was only recently rectified in published randomized trials, as will be described below. 1257
The insight that PF-based therapies were associated with a survival benefit produced 1258
substantial interest in improving the efficacy of IC, eventually leading to 3-drug regimens, of 1259
which TPF (taxane, cisplatin, and 5-FU) was the most frequently tested. This triplet was 1260
shown to be highly active in early trials and set the stage for two landmark randomized trials 1261
comparing TPF with PF. The TAX 324 study examined what has become the North American 1262
model for IC, termed “sequential therapy,” involving IC followed by concurrent 1263
chemoradiotherapy.97 1264
Patients were eligible if they had squamous cell carcinoma of the oropharynx, oral 1265
cavity, larynx or hypopharynx; slightly more than 50% of the patients in each arm had OPSCC. 1266
Patients received 3 cycles of IC followed by daily radiation therapy (2 Gy per fraction to 70-74 1267
Gy total) with weekly carboplatin. The addition of docetaxel significantly improved OS (3-year 1268
OS 62% vs. 48%), which was apparently mediated through an improvement in locoregional 1269
failure (38% vs. 30%), rather than distant metastasis. Hematologic toxicity was substantial, as 1270
grade 3-4 neutropenia (83% vs. 56%) and grade 3-4 thrombocytopenia (11% vs. 4%) were also 1271
each significantly increased in the docetaxel arm. Importantly, more than 20% of patients in both 1272
arms never completed chemoradiotherapy per protocol. 1273
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The TAX 323 study98 had different entry criteria, only allowing unresectable patients, 1274
and a slightly altered treatment schema consisting of 4 cycles of IC, followed by radiation 1275
therapy alone (standard or accelerated fractionation). Oropharyngeal cancer represented 1276
slightly less than 50% of the total. Similar results were obtained as in TAX 324, 97,99 though 1277
the magnitude of clinical benefit was smaller (median OS 18.8 vs. 14.5 months). 1278
Approximately 10% of patients in the TPF arm did not receive radiotherapy, and an additional 1279
5% did not complete the full course. In a follow up quality of life (QoL) study, van Herpen et 1280
al.100 demonstrated trends for improved QoL with TPF both during treatment and through 6 1281
months of follow-up, although the magnitude of improvement was not deemed “clinically 1282
meaningful.” 1283
After these data established that TPF was superior to the previously accepted standard 1284
regimen, PF, the next logical question was whether IC adds substantially to concurrent 1285
chemoradiotherapy, which had been the established standard-of-care for locally advanced 1286
disease. Two small phase II studies first investigated this hypothesis. Pacagnella and colleagues94 1287
compared TPF IC followed by concurrent chemoradiotherapy (70 Gy with 2 cycles of concurrent 1288
PF) to concurrent chemoradiotherapy alone in 101 patients. Just over 50% of the patients in this 1289
study had OPSCC. The primary endpoint (rate of radiologic complete response at 6-8 weeks 1290
post-radiation) was significantly increased for the IC arm (21% vs. 50%). One limitation of this 1291
study was the non-standard concurrent regimen in this trial, consisting of two cycles of 1292
chemotherapy spaced 5 weeks apart, with conventionally fractionated RT. Another randomized 1293
phase II study, from India,101 assigned 105 eligible oropharyngeal cancer patients to either 1294
concurrent chemoradiotherapy (weekly cisplatin with 66-70 Gy) or 2-3 cycles of TPF IC 1295
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
followed by the same chemoradiotherapy. There were no significant differences in clinical 1296
outcomes or toxicities between the two arms. 1297
Three recent phase III studies directly compared optimal induction and optimal 1298
concurrent treatment. The Dana-Farber Cancer Institute-based multi-institutional group 1299
(PARADIGM)102 looked at a comparison between TPF IC followed by chemoradiotherapy 1300
(weekly carboplatin or docetaxel with 70-72 Gy) versus a concurrent regimen consisting of 1301
concomitant boost radiation therapy and 2 cycles of concurrent bolus cisplatin. The University of 1302
Chicago-based DeCIDE study103 used a slightly different model: the chemoradiotherapy 1303
consisted of Taxotere, 5-FU and hydroxyurea with BID radiotherapy (1.5 Gy per fraction), every 1304
other week, versus two 21-day cycles of IC followed by the same CRT regimen. The primary 1305
end point for both trials was OS. Just over half of patients in these studies had OPSCC. Both 1306
studies closed prematurely without meeting their accrual targets, and both ultimately were 1307
underpowered, due in part to the underestimation of OS in the standard arm. Neither 1308
demonstrated significant improvements in clinical outcomes between the IC and traditional 1309
chemoradiotherapy arms, although patients treated with IC clearly experienced higher toxicity. 1310
In PARADIGM,102 more induction patients developed febrile neutropenia, and there were more 1311
serious adverse events (52 versus 22) with IC. Similarly, there were substantially more serious 1312
adverse events in the induction arm of DeCIDE 103 (47% vs. 28%), and 5 patients died due to 1313
treatment-related toxicity in the induction arm, versus none in the CRT cohort. 1314
The Spanish Head and Neck Cancer Cooperative Group104 performed a 3-armed phase 3 1315
study comparing the two induction combinations (TPF vs. PF) and concurrent 1316
chemoradiotherapy. Patients were treated with either 3 cycles of IC, followed by a concurrent 1317
regimen consisting of 70 Gy with 3 cycles of bolus cisplatin, or the same concurrent regimen 1318
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
alone. Inclusion criteria specified unresectable, locally advanced head and neck cancer, and 55% 1319
of the patients had OPSCC. No significant improvement in any clinical outcome was found 1320
between any of the 3 arms of the study when analyzed on an intention-to-treat basis. However, a 1321
remarkable fraction of patients treated with IC – approximately 30% – never received 1322
radiotherapy, and an additional number could not complete the planned chemoradiotherapy. 1323
Moreover, of those induction patients who proceeded to CRT, there was significantly more grade 1324
3-4 stomatitis and dysphagia in patients previously treated with IC. An unplanned “per protocol” 1325
subset analysis was able to demonstrate improved progression-free survival (HR 0.7) for the 1326
induction arms versus the concurrent arm, without an associated improvement in OS, potentially 1327
reflecting the selection bias for induction patients tolerant of and responsive to chemotherapy. 1328
These three randomized trials found no progression-free or OS benefit with IC, yet all 1329
three studies confirmed higher rates of serious adverse events. Thus, induction chemotherapy 1330
should not be routinely implemented in patients with stage IV OPSCC. 1331
1332
Considerations in the discussion of induction chemotherapy 1333
The panel considered the potential indications for IC at length, and as expected, there was 1334
robust discussion. Several key limitations of the available studies on the question of IC for 1335
OPSCC were noted. First, the vast majority of the referenced studies enrolled locally advanced 1336
head and neck cancer patients with diverse primary subsites, including the oral cavity and 1337
pharyngolaryngeal axis. Oropharyngeal cancer representation on most of these studies ranged 1338
from only 40-60%. Clearly, prognosis varies widely across the diseases encountered in the non-1339
OPSCC subsites, and the resulting mixed outcomes in the pooled analyses may obscure 1340
conclusions that could be drawn specifically from the data on OPSCC patients. 1341
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Second, the epidemiology of OPSCC has shifted during the evolution of the IC literature, 1342
with the emergence of HPV-related disease, and none of the reported IC trials had the 1343
opportunity to factor these shifts into their statistical plans. Recent studies have shown better-1344
than-anticipated disease control rates, likely reflecting the increased predominance of HPV-1345
related OPSCC (representing over 80% of OPSCC patients on the DeCIDE study, for example). 1346
With such sizeable changes in expected-to-observed outcomes, the initial power calculations for 1347
both PARADIGM and DeCIDE 102,103 were incapable of accurately predicting the number of 1348
patients required to address the primary hypothesis, and the resulting statistical power suffered 1349
from the small number of events. 1350
Furthermore, there is significant uncertainty in the optimal patient population that would 1351
potentially benefit from IC. As seen in several individual trials and confirmed in the meta-1352
analysis, IC reduces the risk of distant metastasis. Thus patients with more modest risks of 1353
distant disease are unlikely to see OS gains with systemically-active chemotherapy; the toxicity 1354
of IC and the risk of compromising successful local therapy will outweigh the improved 1355
treatment of micrometastatic disease. Only 10% and 23% of patients in PARADIGM102 1356
presented with N3 or T4 disease, respectively, and thus one could argue that the baseline risk of 1357
metastatic disease was too low to expect to see a survival advantage with IC, irrespective of the 1358
prevalence of HPV-positive disease. 1359
Subset analyses of DeCIDE103 provide some insight into the potential benefit of IC in 1360
these advanced cases. Among the 96 patients with N2c or N3 nodal disease, there was a non-1361
significant trend (p=0.19) for improved survival with IC. Moreover, the cumulative incidence of 1362
distant metastasis in patients with LRC was significantly worse with CRT alone (absolute 1363
difference approximately 10%, p=0.043), supporting the hypothesis that improved systemic 1364
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
control may translate to an OS benefit in patients at sufficiently high risk for distant metastasis, 1365
such as in those with advanced nodal presentations. 1366
Indeed, although historically the risk of locoregional failure has been substantially greater 1367
than that of metastasis, certain populations of patients do appear to be at particularly high risk for 1368
distant spread. For example, in a retrospective analysis of over 300 patients treated at the 1369
University of Chicago105 (slightly under half with OPSCC), patients with N2c or N3 disease 1370
experienced a greater than 2-fold risk of distant failure in comparison to lower volume nodal 1371
stage; nearly 40% of these patients treated with CRT-alone developed distant metastases. More 1372
recent data restricted to oropharyngeal cancer suggest similar patterns of failure. Investigators 1373
from Princess Margaret Cancer Centre performed a retrospective analysis of patients with 1374
oropharyngeal cancer treated with RT alone or CRT and described subgroups of both HPV-1375
negative and HPV-positive disease that were at significantly higher risk for distant spread106. 1376
Individuals with HPV-negative, T3-4 or N3 cancer, experienced a distant metastasis risk of 28%, 1377
and those with HPV-positive, T4 or N3 cancer experienced a metastasis risk of 22%, which may 1378
be sufficiently high to see a survival gain with IC. On the other hand, the locoregional failure 1379
risks in the high-risk HPV-positive and negative cohorts were 18% and 38%, respectively, so 1380
that the competing risks of locoregional failure may mitigate any theoretical survival gain from 1381
micrometastasis eradication. Regardless of the therapeutic paradigm, though, it is important to 1382
recognize that there are sub-populations of even HPV-positive patients whose survival outcome 1383
need significant improvement. In fact, in a separate analysis, these investigators found that 1384
younger HPV-positive patients with T4 or N3 disease achieved a 5-year survival of only 57% 1385
with CRT, implying that substantial improvements in their treatment paradigm are critically 1386
needed.107 1387
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Unfortunately, it is unlikely that the comparative benefit of IC in a higher-risk cohort will 1388
ever be answered or even revisited through future clinical trials. Induction chemotherapy is 1389
currently incorporated into clinical trials in order to select responsive HPV-positive patients for 1390
subsequent de-escalation,108 which is a research question to be answered in the coming years. 1391
One may conclude from the MACH meta-analysis109 that IC using modern agents appears to 1392
modestly improve survival over RT alone or surgery through its effect on distant metastasis, 1393
which supplies the proof of principle that treating micrometastatic disease may improve oOS. 1394
Nevertheless, the high-level data do not support this conclusion when the standard comparator is 1395
chemoradiotherapy. Three phase III randomized trials comparing IC and chemoradiation therapy 1396
(CRT) with CRT alone were all clearly negative; IC was associated with more toxicity without a 1397
proven survival benefit. While each study has recognized limitations, in light of this high-level 1398
evidence, the panel chose not to specify a high-risk cohort of patients for whom IC may be 1399
considered. 1400
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Key Question 4: What are the appropriate dose, fractionation, and volume regimens with 1401
and without systemic therapy in the treatment of oropharyngeal squamous cell carcinoma 1402
(OPSCC)? 1403
1404
In the scenario of definitive non-surgical therapy? 1405
1406 Statement 4A. A dose of 70 Gy over 7 weeks should be delivered to gross primary and nodal 1407
disease in patients with stage III-IV oropharyngeal squamous cell carcinoma selected to receive 1408
standard, once-daily definitive radiotherapy. 1409
o Recommendation strength: Strong 1410
o Quality of evidence: Moderate 1411
1412 Statement 4B. The biologically equivalent dose of approximately 50 Gy in 2 Gy fractions or 1413
slightly higher should be delivered electively to clinically- and radiographically-negative regions 1414
at-risk for microscopic spread of tumor. 1415
o Recommendation strength: Strong 1416
o Quality of evidence: Low 1417
1418
Statement 4C. Altered fractionation should be used in patients with stage IVA-B oropharyngeal 1419
squamous cell carcinoma treated with definitive radiotherapy who are not receiving concurrent 1420
systemic therapy. 1421
o Recommendation strength: Strong 1422
o Quality of evidence: High 1423
1424
Statement 4D. Either accelerated radiotherapy or hyperfractionated radiotherapy may be used in 1425
patients with oropharyngeal squamous cell carcinoma treated with altered fractionation definitive 1426
radiotherapy after a careful discussion of patient preferences and the limited evidence supporting 1427
one regimen over the other. 1428
o Recommendation strength: Conditional 1429
o Quality of evidence: High 1430
1431
Statement 4E. Either standard, once-daily radiotherapy or accelerated fractionation may be used 1432
when treating oropharyngeal squamous cell carcinoma with concurrent systemic therapy after a 1433
careful discussion of patient preferences and the risks and benefits of both approaches. 1434
o Recommendation strength: Conditional 1435
o Quality of evidence: High 1436
1437
Statement 4F. Altered fractionation should be used in patients with T3 N0-1 oropharyngeal 1438
squamous cell carcinoma treated with definitive radiotherapy who do not receive concurrent 1439
systemic therapy. 1440
o Recommendation strength: Strong 1441
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
o Quality of evidence: Moderate 1442
1443
Statement 4G: Altered fractionation may be used in patients with T1-2 N1 or T2 N0 1444
oropharyngeal squamous cell carcinoma treated with definitive radiotherapy alone who are 1445
considered at particularly significant risk of locoregional recurrence, after a careful discussion of 1446
patient preferences and the limited evidence supporting its use in this scenario. 1447
o Recommendation strength: Conditional 1448
o Quality of evidence: Low 1449
1450
Narrative 1451
1452 A relatively large body of literature has reported outcomes for OPSCC patients in the 1453
setting of randomized clinical trials. Important caveats in interpreting this literature, much of 1454
which directly tested dose and fractionation, must include the recognition that most of these 1455
studies included patients with advanced squamous carcinomas arising in sites other than the 1456
oropharynx, including oral cavity, larynx and hypopharynx. Although these studies described 1457
the relative proportions of these primary sites, their conclusions were often based on a pooled 1458
analysis. Human papillomavirus-associated OPSCC has been increasing in prevalence and 1459
proven to have a much more favorable prognosis than non-HPV related OPSCC.2 The proportion 1460
of OPSCC patients with HPV-related cancers in most landmark studies of fractionation remains 1461
unknown and is likely to be significantly lower than in contemporary patient populations, raising 1462
the question of the generalizability of older studies to modern cohorts. The panel recognizes 1463
there is important ongoing work examining the different outcomes between and within HPV 1464
positive and negative OPSCC in order to define prognostic subgroups. 89,107,110 This research has 1465
led to the development and implementation of prospective clinical trials examining treatment de-1466
intensification strategies for favorable prognostic subgroups.93 In the future, these studies may 1467
result in significant changes in the recommended radiotherapy doses for the management of 1468
favorable-risk disease. To date, the results of radiotherapy de-intensification approaches are not 1469
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
yet available and there are no prospective randomized data suggesting that HPV-positive patients 1470
gain any less benefit from altered fractionation regimens. Thus any recommendation made for 1471
oropharyngeal cancer patients within these guidelines apply equally to HPV-positive and 1472
negative individuals. 1473
Primary radiation therapy has long been a standard-of-care for the management of 1474
OPSCC, and acceptable doses to gross disease and elective regions is the first consideration in 1475
the discussion of dose and fractionation regimens. There have been no randomized trials 1476
comparing total radiotherapy dose delivered once-daily for OPSCC, and a variety of dose-1477
fractionation regimens have evolved over the years. In the United Kingdom, the treatment 1478
approach classically delivered 50-55 Gy in 15-20 fractions over 3-4 weeks, while in Europe and 1479
most of North America, more extended fractionation schemes were employed, delivering 66-72 1480
Gy in 32-40 fractions over 6.5 to 8 weeks.111 Though retrospective in nature, comparisons 1481
between these regimens suggested that shorter courses delivering less total dose with larger 1482
fraction sizes resulted in lower rates of control for advanced disease with increased late 1483
effects.111 This observation, combined with the enhanced toxicity in combining concurrent 1484
chemotherapy with fraction sizes greater than 2 Gy, resulted in the emergence of a total dose of 1485
68-70 Gy delivered in 33-35 fractions over 6.5 to 7 weeks as the most common once-daily 1486
fractionation regimen. 1487
The delivery of 70 Gy to gross disease has been selected as the standard treatment 1488
approach for many practice-defining randomized trials of both fractionation and concurrent 1489
chemotherapy, including RTOG 9003, 112 EORTC 22851,113 the US Intergroup study,9 and 1490
RTOG 0129.37 Thus, when choosing a conventionally fractionated, once-daily radiotherapy 1491
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
regimen for patients with stage III-IV OPSCC, the panel considers 70 Gy over 7 weeks to be the 1492
reference standard. 1493
1494
Standard Prophylactic Dose to Elective Volumes at Risk of Microscopic Disease 1495
The radiotherapeutic management of all stages of OPSCC requires treatment to be 1496
delivered electively beyond areas of apparent gross disease. Elective volumes include margins 1497
around gross disease as well as nodal levels at risk of harboring microscopic nodal metastasis. 1498
The location and extent of these elective volumes will be dictated by specific characteristics of 1499
the primary tumor (size and anatomic extent) and grossly involved nodes. The anatomic 1500
delineation of node levels at risk should be consistent with published guidelines.114 The dose and 1501
volume of elective irradiation is often the driver of dose to critical organs-at-risk, including 1502
salivary glands and dysphagia-associated structures such as the larynx and pharyngeal 1503
constrictors, emphasizing the importance of considering the dose necessary to sterilize 1504
microscopic disease. 1505
Although the evidence is nearly entirely retrospective, prophylactic radiotherapy at 2 Gy 1506
per day to a total dose of 50 Gy has been widely regarded as the standard dose for the elective 1507
treatment of areas at risk for subclinical or microscopic involvement. This dose was first 1508
suggested by Fletcher based on observations of control rates in head and neck and breast cancer 1509
patients.115 Withers et al.111 expanded these observations to a wider range of patients, concluding 1510
a dose of 50 Gy in 2 Gy fractions was necessary to achieve a 90% reduction in the incidence of 1511
recurrence within the electively irradiated tissues. Although this dose has been utilized in many 1512
clinical trials, many do not specifically report rates of nodal failure, or distinguish between in-1513
field versus elective failure. Nevertheless, some insights may be gleaned from these trials. 1514
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
For example, the DAHANCA 6/7 trials116 limited dose to a maximum 50 Gy in 2 Gy 1515
fractions to elective neck regions and observed isolated neck failure (elective and therapeutic 1516
regions) in only 69/1476 (4.7%) patients. Goshal et al.117 delivered 44-45 Gy to the elective neck 1517
regions and reported isolated regional failures in 37/285 (12.9%) patients. The ARTSCAN 1518
randomized trial7 comparing conventionally-fractionated radiotherapy with treatment over 4.5 1519
weeks118 treated the elective nodal regions to 46 Gy and reported isolated nodal failure in 34/733 1520
(4.6%) patients. These three randomized studies have cumulatively reported isolated nodal 1521
failures in 140/2494 (5.6%) of patients receiving the equivalent of 50 Gy in 2 Gy fractions or less 1522
to elective nodal regions. These recurrences would have included failures occurring in pre-1523
existing nodes, and therefore the failure rates in the elective volumes could be assumed to be less 1524
than this. 1525
Retrospective analyses that have specifically identified electively irradiated neck failures 1526
include Lambrecht et al.119, observing only 2 recurrences out of 368 (<1%) in elective neck 1527
regions receiving 44-50 Gy. More recently, investigators from MD Anderson reported a risk of 1528
elective regional failure with primary control of only 4/776 (< 1%), and many of these controlled 1529
patients were treated with a low anterior neck field to 50 Gy.120 With the emergence of routine 1530
IMRT planning and simultaneous integrated boost/“dose-painting” approaches, radiotherapy 1531
plans are now often delivered in a single phase, rather than the conventional, serial cone-down 1532
approach using 2 Gy per fraction. Thus, a plan delivering 70 Gy in 35 fractions to sites of gross 1533
disease must simultaneously deliver 56 Gy in 35 fractions of 1.6 Gy to areas of subclinical or 1534
microscopic involvement to achieve the radiobiologic equivalent of 50 Gy in 25 fractions. Using 1535
this approach, Duprez et al.121 have a reported regional relapse risk in 3/286 (1%) patients within 1536
the elective neck volumes receiving 56 Gy. 1537
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
The panel therefore believes there is sufficient evidence to strongly recommend the 1538
ongoing use of a radiobiologic equivalent of 50 Gy delivered in 2 Gy fractions to electively treat 1539
areas at risk of subclinical or microscopic involvement. The high rates of neck control observed 1540
with this approach raise the possibility of elective dose reduction, which would be expected to 1541
reduce dose to the salivary tissue and pharyngeal constrictors. In fact, if one considers that 1542
concurrent chemotherapy increases the biologically effective dose of any given dose of 1543
irradiation,122 treatment with concurrent chemoradiotherapy may afford the opportunity for dose 1544
reduction. At this time, however, there is insufficient data to recommend elective doses reduction 1545
below the equivalent of 50 Gy in 2 Gy fractions, although this is an area of active research.123 1546
1547
Altered fractionation radiotherapy without concurrent chemotherapy 1548
Poor historical outcomes for patients with stage III-IV OPSCC treated with 1549
conventionally-fractionated radiotherapy alone10 led to efforts to improve oncologic results by 1550
intensifying treatment. This intensification utilized two distinct approaches. One approach was 1551
the addition of cytotoxic systemic therapy delivered concurrently with radiotherapy, and the 1552
other was to alter the radiotherapy fractionation schemes from standard, once-daily 1553
administration. 1554
The concept of altered fractionation (AF) refers to fractionation regimens that differ from 1555
standard, once-daily treatment. Altered fractionation-regimens are based on radiobiologic 1556
principles that suggest giving a higher total dose and/or giving it over a shorter total treatment 1557
time (to counter tumor repopulation) will result in improved tumor control. Similar principles 1558
suggest delivering this dose with reduced fraction sizes (< 2 Gy) should result in reduced late 1559
tissue effects permitting delivery of a higher total dose. Altered fractionation regimens may be 1560
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
classified as either accelerated, delivering a similar or reduced total dose over a shorter total 1561
time, or hyperfractionated, delivering an increased total dose over a similar time with multiple 1562
small daily fractions. Many AF regimes represent a hybrid of these approaches. 1563
Altered fractionation regimens for the treatment of head and neck squamous carcinomas, 1564
including OPSCC, have been compared to standard radiotherapy in a number of randomized 1565
phase III clinical studies (Table 7). The majority of these studies have demonstrated that AF 1566
regimens improve LRC by 8-20% compared to once-daily radiotherapy alone, but the increased 1567
control in the primary site and neck generally did not translate into an OS advantage. In addition, 1568
this disease control improvement frequently came at the cost of increased but manageable acute 1569
toxicity, with a variable impact on the risk for late toxicities. 1570
Accelerated regimens with or without a total dose reduction have been the AF approach 1571
most often compared with standard radiotherapy. In the landmark RTOG 9003 trial124 reported 1572
results on 1073 patient randomized to one of three AF arms compared to standard radiotherapy 1573
(70 Gy in 2 Gy fractions over 7 weeks). Two of these arms represented accelerated treatment 1574
delivered over 6 weeks. One arm delivered twice-daily (BID) treatment throughout but had a 1575
two-week break, to achieve a total dose of 67.2 Gy, while the other arm employed a scheme 1576
without a break, delivering once daily 1.8 Gy for six weeks with a second 1.5 Gy fraction as a 1577
concomitant boost to the primary on the last 12 treatment days for a total dose of 72 Gy. The 1578
concomitant boost arm demonstrated an absolute improvement of 9.5% and 7.6% in two year 1579
LRC and disease free survival (DFS) (p=0.05 and 0.054 respectively) which came at a cost of an 1580
absolute increase of 24% in grade 3 or higher acute toxicity (multiple endpoints). The split 1581
course arm demonstrated no significant improvement in LRC or DFS and neither arm improved 1582
OS. The recent final analysis of RTOG 9003112 demonstrated that the initially improved LRC 1583
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with accelerated radiotherapy lost its statistical significance with longer follow-up, and overall 1584
survival (OS) was still unaffected by this regimen. Although the continuous acceleration arm did 1585
improve disease-free survival (HR 0.82, p=0.05), there were non-significant trends for worse late 1586
toxicity in this arm. Notably, patients who were disease-free at 1-year were significantly more 1587
likely to be feeding tube dependent with continuous accelerated radiotherapy (1-year probability 1588
13.4% vs. 4.6%, p=0.02). 1589
The DAHANCA group125 randomized 1485 patients with squamous cell carcinoma of the 1590
head and neck (larynx, pharynx and oral cavity) to receive standard radiotherapy (66-68 Gy in 1591
2Gy fractions) delivered 5 days per week versus the same dose delivered in an accelerated 1592
fashion with 6 fractions per week. They observed a statistically significant 10% benefit in 5 year 1593
LRC (70% vs 60%) and a 13% benefit in DFS (73% vs 66%) for the accelerated regimen. No 1594
benefit in OS was observed. Patients treated with the accelerated regimen experienced a 20% 1595
higher risk of acute confluent mucositis, and the duration of this acute mucositis was longer, but 1596
there was no significant difference in longer-term mucosal toxicities. A similar LRC benefit 1597
(absolute 12%) was observed with this regimen when the study was later replicated in 908 1598
patients with more advanced disease, 126 with a parallel increase in acute but not late mucosal 1599
toxicity. In an interesting subgroup analysis of the original DAHANCA study,127 the LRC 1600
benefit of radiotherapy acceleration was maintained in p16 positive (mostly oropharynx) patients 1601
and was perhaps even greater than that observed in p16 negative (mostly non-oropharynx) 1602
patients.127 1603
The EORTC 22851 trial113 randomized 500 patients to receive 72 Gy delivered in twice-1604
daily fractionation over 5 weeks versus standard fractionation (70 Gy in 2 Gy fractions over 7 1605
weeks). Although this study demonstrated a 13% improvement in LRC at 5 years the actuarial 1606
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rates of grade 3-4 late toxicity in the accelerated arm was 37% at 3 years versus 15% for the 1607
control arm. This finding, coupled with increased rates of acute toxicity and the lack of an 1608
overall or cancer-specific survival benefit, led the authors to conclude that a less toxic scheme 1609
should be used and emphasizes that there is a limit to the degree of safe acceleration. 1610
It should be noted not all studies have demonstrated significant benefits to accelerated 1611
radiotherapy. The TROG group128 reported outcomes for 343 patients (67% OPSCC) randomized 1612
to accelerated radiotherapy (59.4 Gy in 1.8 Gy bid over 24 days) versus standard 70 Gy in 2 Gy 1613
fractions over 7 weeks). In this modest sized study they observed a nonsignificant trend towards 1614
improved disease free and disease specific survival at 5 years (41% and 46% vs 35% and 40% 1615
respectively, p=0.323 and 0.398) for the accelerated arm. The multicenter Swedish ARTSCAN 1616
study7 randomized 750 patients (48% OPSCC) to standard radiotherapy (68 Gy in 2 Gy fractions 1617
over 7 weeks) versus accelerated radiotherapy (1.1 Gy + 2 Gy/day over 4.5 weeks to 68 Gy). No 1618
significant difference was observed in OS or loco-regional control between the two arms. 1619
The use of pure hyperfractionation has been demonstrated to improve outcomes. The 1620
EORTC 22791 study 129 reported the results of 325 patients with T2-T3, N0-N1 OPSCC 1621
randomized to receive 70 Gy in 35 daily fractions over 7 weeks or hyperfractionated treatment 1622
delivering 1.15 Gy BID to a total dose of 80.5 Gy over 7 weeks. A significant improvement was 1623
seen in 5 year rates of local control at the primary site (59% vs 40% p=0.02) in the 1624
hyperfractionation arm, although improvement in OS was only borderline significant (p=0.08). 1625
There was a significant increase in acute mucositis with hyperfractionation (18% absolute 1626
increase in grade 3 mucositis), but there was no difference in any late effect between the two 1627
arms. 1628
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
One arm of RTOG 9003112 utilized a hyperfractionated approach, delivering 68 BID 1629
fractions of 1.2 Gy to a total dose of 81.6 Gy. The final analysis observed not only an improved 1630
and sustained rate of LRC (relative reduction in locoregional failure of 21%) but also an OS 1631
advantage when patients were censored at 5 years (HR 0.81, p=0.05). This benefit was lost with 1632
longer follow-up, which may relate to second primary cancers or death from other causes 1633
obscuring a disease control benefit from hyperfractionation. Treatment with hyperfractionation 1634
was associated with significantly more acute toxicity: 54% of patients in this cohort experienced 1635
at least one grade 3 toxicity, versus 35% of patients treated once-daily. However, there was no 1636
significant increase in late toxicities with hyperfractionation, although disease-free patients were 1637
more likely to be gastrostomy-dependent in comparison to disease-free individuals treated with 1638
standard fractionation (17.3% vs. 4.6%, p<0.01). 1639
These results were largely echoed by a large meta-analysis (MARCH) based on 1640
individual patient data, which examined outcomes for 6,515 patients enrolled in 15 randomized 1641
trials comparing standard to AF radiation therapy (accelerated or hyperfractionated) for 1642
advanced head and neck cancers.130,131 Oropharyngeal cancer comprised approximately 44% of 1643
all patients. This meta-analysis reported absolute reductions in the 5-year risk of locoregional 1644
recurrence of 9.4% and 7.3% in patients treated with hyperfractionation or accelerated 1645
fractionation (without dose-reduction) regimens, respectively. Most of this benefit was due to 1646
reduced recurrence at the primary site. The absolute probability of OS at 5 years was 1647
significantly improved by 3.4% with altered fractionation. There was no significant difference in 1648
this benefit for tumors arising in the oropharynx compared to hypopharynx larynx or oral cavity, 1649
but the survival advantage with AF was lost in patients older than 71 years. The survival benefit 1650
was significantly greater with hyperfractionation (8.2% vs. 2% at 5 years for patients receiving 1651
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hyperfractionation and accelerated radiotherapy without a dose-reduction, respectively). 1652
Although one may conclude that hyperfractionation may be the superior approach, the trials of 1653
acceleration and hyperfractionation evaluated fundamentally different patient populations; 1654
accelerated radiotherapy was more often employed in larynx cancer and patients with earlier-1655
stage disease, such that improved LRC was less likely to translate into an OS benefit. 1656
Although individual trials were unable to confirm an OS advantage with altered 1657
fractionation, the majority of studies have demonstrated consistent and meaningful 1658
improvements in LRC and trends towards reductions in overall mortality. The influential 1659
MARCH meta-analysis provided further evidence for the superiority of AF in patients with 1660
locally advanced head and neck cancer. Given the adverse clinical consequences of locoregional 1661
failure and the potential for a survival gain with its use the panel strongly recommends AF 1662
radiation therapy should be used for patients with stage IVA-B OPSCC managed with primary 1663
radiation therapy without concurrent systemic therapy. In comparison to treatment with 1664
concurrent chemotherapy, in which late toxicities were comparable to patients treated with 1665
radiotherapy alone, there were somewhat consistent signals that AF modestly worsened late 1666
toxicities. One particularly important late toxicity is swallowing dysfunction, which in the worst 1667
case can lead to the long-term requirement for enteral feeding. However, modern radiotherapy 1668
techniques may minimize these risks, as a large multi-institution pooled analysis of 2,315 1669
OPSCC patients managed with IMRT concluded that there was no difference in one year rates of 1670
gastrostomy tube dependence between patients managed with standard versus accelerated 1671
radiotherapy.132 Nevertheless, in patients treated with altered fractionation, particular attention 1672
must be paid to the dysphagia organs-at-risk and early and persistent swallowing rehabilitation. 1673
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It is unclear whether hyperfractionation or acceleration is a better treatment paradigm. 1674
The only study comparing the two concepts was RTOG 9003, 112 which slightly favored 1675
hyperfractionation, but this study was not designed to compare the experimental arms; the 1676
MARCH meta-analysis also suggested an improvement with hyperfractionation, but as detailed 1677
above, there are significant flaws with this indirect comparison. Nevertheless, hyperfractionation 1678
regimens delivered without concurrent chemotherapy are not in wide-spread use for the 1679
management of OPSCC. This pattern is in part due to the increased resources required to deliver 1680
these treatments, coupled with the emergence of concurrent chemotherapy approaches that 1681
mitigated the benefit of altered fractionation. Accelerated radiotherapy, particularly using the 1682
DAHANCA approach, 125 is significantly more convenient than BID treatments over 7 weeks, 1683
and provides a more practical platform for both clinical trials and routine practice. That said, at 1684
the present time, the panel concludes the available evidence supports the use of either form of 1685
AF for the management of stage IVA-B OPSCC in patients not receiving systemic therapy, and 1686
the relative strengths and weaknesses of the strategies should be carefully discussed with 1687
patients. 1688
1689
Altered fractionation radiotherapy for patients with stage III oropharyngeal cancer 1690
Deriving recommendations for patients with stage III OPSCC is more challenging; stage 1691
III disease may present with a wide range of primary tumor volumes (T1-T3, N1). The majority 1692
of patients in randomized studies of AF presented with stage IV disease, and thus the advantages 1693
of this approach are less clear with lower-bulk disease. Although most of the studies included 1694
patients with stage III disease, the proportion of patients with this stage was typically less than 1695
30%, and the outcomes were rarely stratified by T and N or AJCC stage. One exception is 1696
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EORTC 22791, 129 which randomized patients with T1-3 N0-1 oropharyngeal cancer to 1697
hyperfractionation or conventional daily radiotherapy. Although the study showed an overall 1698
benefit in LRC, this gain was strictly in patients with T3 tumors. Similarly, in EORTC 22851, 113 1699
which randomized stage III and IV patients (all disease sites) to accelerated or conventional 1700
radiotherapy, the LRC advantage with acceleration was only seen in N2-3 or T4 patients. Both 1701
studies emphasize the concept that relative benefit of AF is greatest with larger volume disease. 1702
As detailed in the narrative of KQ1, single institution retrospective reports have also 1703
described significant differences in local control as a function of T-stage or tumor volume. The 1704
preponderance of data strongly suggest that patients with larger volume disease need additional 1705
local therapy beyond conventional radiotherapy alone. Since concurrent systemic therapy is most 1706
consistently associated with superior LRC and OS, patients with T3 N0-1 disease who are 1707
candidates for concomitant systemic therapy should receive it, as detailed in KQ1. For 1708
individuals who would not tolerate such treatment, the panel strongly recommends AF alone. 1709
The data guiding radiotherapy fractionation recommendations for stage II and III (T1-2 1710
N1) are far less compelling, and there is significant volume heterogeneity even in this cohort. For 1711
individuals with T2 N0 and T1-2 N1 stage III disease considered at particularly significant risk 1712
for primary and/or nodal recurrence, AF may be employed, but the clinician must weigh the 1713
patient’s estimated risk of locoregional failure with conventional treatment against the 1714
recognized toxicities of altered fractionation. The relative lack of data guiding this 1715
recommendation should be carefully discussed with patients. 1716
The use of modestly accelerated radiotherapy alone was shown to result in excellent 1717
outcomes in RTOG 0022, 133 which treated 67 patients with T1-2 N0-1 OPSCC with 66 Gy in 30 1718
fractions. Most (75%) of these patients had T2 disease. There were 7 locoregional failures, all in 1719
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
current or former smokers (7/36, accounting for crude 19% risk of failure in this cohort), 1720
although 2 of these recurrences were in patients with major dosimetric violations. Only six 1721
patients had new or continuing grade 3 or 4 toxicity after 15 months. In total, these prospective 1722
data suggest that this accelerated regimen is a reasonable approach for selected patients. 1723
1724
Altered fractionation radiotherapy with concurrent chemotherapy 1725
The therapeutic alternative to AF for locally advanced head and neck cancer is concurrent 1726
chemoradiotherapy, the benefits of which were discussed in a prior narrative (KQ1). A large 1727
meta-analysis has reported improved survival and LRC with the addition of concurrent 1728
chemotherapy to radiotherapy,31 a benefit maintained using either standard or altered 1729
fractionation. The emergence of data demonstrating improved outcomes with either AF approach 1730
or the addition of chemotherapy to standard, once-daily radiotherapy naturally led to studies 1731
examining the addition of chemotherapy to AF radiation therapy. Initially the addition of 1732
chemotherapy to AF radiotherapy was compared to AF radiotherapy alone. Several randomized 1733
studies have demonstrated improved LRC and survival with such a strategy.17,134-136 For 1734
example, Brizel et al.134 achieved this with similar levels of toxicity, but this required a reduced 1735
radiotherapy dose and treatment break. Bensadoun et al. maintained the same dose of 1736
radiotherapy in both arms (75.6-80.4 Gy) while delivering full dose cisplatin (100 mg/m2) and 5-1737
fuorouracil infusion. Although the reported toxicity data was similar between the two arms they 1738
described a 13.6% risk of “early death” in the combined treatment arm, emphasizing the 1739
potential risk in this treatment strategy. 1740
The next logical question was whether accelerated chemoradiotherapy was superior to 1741
conventionally-fractionated chemoradiotherapy, a hypothesis that was examined in two large 1742
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phase III studies. RTOG 012932 randomized 743 patients to standard fractionation (70 Gy in 35 1743
fractions over 7 weeks) delivered with 3 cycles of concurrent cisplatin or accelerated 1744
fractionation (70 Gy in 35 fractions over 6 weeks) delivered with 2 cycles of concurrent 1745
cisplatin.37 The mature results of this study (median follow-up 7.9 years) indicated no difference 1746
in progression free survival or OS with similar acute and late toxicities. Groupe d'Oncologie 1747
Radiothérapie Tête et Cou (GORTEC) 99-0223 was a three arm study randomizing 840 patients 1748
to either standard chemoradiotherapy (70 Gy in 7 weeks plus 3 cycles carboplatin-fluorouracil) 1749
versus accelerated chemoradiotherapy (70 Gy in 6 weeks plus 2 cycles carboplatin-fluorouracil) 1750
versus very accelerated radiotherapy alone (64.8 Gy in 1.8 Gy bid over 3.5 weeks).23 No 1751
difference was observed between the chemoradiotherapy and accelerated chemoradiotherapy 1752
arms in 3 year rates of locoregional failure, distant metastasis, progression-free survival, OS or 1753
acute or late toxicity, with both chemotherapy arms superior to the very accelerated radiotherapy 1754
approach in all aspects. 1755
The addition of chemotherapy to aggressive AF approaches must be considered with 1756
caution given the potential for increased acute and late effects associated with this approach. For 1757
this reason, both RTOG 012932 and GORTEC 99-02137 delivered less chemotherapy in the AF 1758
arm than the standard fractionation arm. This strategy seems to have been successful in 1759
maintaining equivalent toxicities between the arms without compromising tumor control. In 1760
RTOG 0129, there were no statistically significant differences in acute or late toxicities, although 1761
there was a trend for increased long-term gastrostomy dependence in the accelerated arm (13.2% 1762
vs. 5.9% at 5 years, p=0.08). On the other hand, more patients received the correct numbers of 1763
cisplatin cycles in the accelerated arm (88% vs. 69%), owing to the challenge of managing the 1764
toxicities with bolus cisplatin. Similarly, in GORTEC 9902, 137 92% of patients in the 1765
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accelerated chemoradiotherapy arm received the correct number of cycles, in comparison to only 1766
71% of individuals in the conventional arm. 1767
Since two large phase III trials have shown no significant difference in oncologic 1768
outcomes or toxicities between conventional and accelerated fractionation (AccF) with three and 1769
two cycles of bolus cisplatin or carboplatin/fluorouracil, respectively, the panel concludes either 1770
fractionation approach may be considered for patients with stage IVA-B oropharyngeal cancer 1771
treated with these chemotherapy regimens. The relative risks and benefits of more chemotherapy 1772
versus more intensive radiation treatment should be carefully discussed with the patient, and the 1773
decision should be made on a patient-specific basis, in concert with their preferences and values. 1774
1775
In the scenario of adjuvant post-operative radiotherapy? 1776
1777 Statement 4H. Adjuvant post-operative radiotherapy should be delivered to regions of 1778
microscopically-positive primary site surgical margins and extracapsular nodal extension at 2 1779 Gy/fraction once daily to a total dose between 60 and 66 Gy. 1780
o Recommendation strength: Strong 1781 o Quality of evidence: Moderate 1782
1783 Statement 4I. Adjuvant post-operative radiotherapy delivered without concurrent systemic 1784
therapy should treat regions of microscopically-positive primary site surgical margins and 1785 extracapsular nodal extension at 2 Gy/fraction once daily to a total dose of 66 Gy, although there 1786 are limited data guiding this recommendation. 1787
o Recommendation strength: Conditional 1788 o Quality of evidence: Weak 1789
1790 Statement 4J. Adjuvant post-operative radiotherapy should be delivered to the tumor bed and 1791
involved, dissected lymph node regions at 2 Gy/fraction once daily to a total dose of 60 Gy in the 1792 absence of primary site positive margins and extracapsular nodal extension. 1793
o Recommendation strength: Strong 1794 o Quality of evidence: Moderate 1795
1796
1797
Narrative 1798
1799 A dearth of prospective randomized data exist addressing dose-fractionation issues in the 1800
post-operative, high-risk setting. Peters et al.138 randomized patients receiving PORT alone (18% 1801
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oropharynx) to one of four dose levels depending on the type and number of adverse pathologic 1802
risk factors. Patients deemed lower-risk were first randomized to 52.2-54 Gy versus 63 Gy, but 1803
an interim analysis showed this lower dose was inadequate, and the study was completed 1804
comparing 57.6 Gy in 32 fractions with 63 Gy in 35 fractions in this lower-risk population. The 1805
higher-risk patients were randomized to 63 Gy in 35 fractions versus 68.4 Gy in 38 fractions. 1806
Because the risk stratification was a function of both the type and number of adverse 1807
characteristics, patients with ECE and positive margins (less than 5 mm) were included in all 1808
dose levels. The authors found no difference in 2 year recurrence rates for all higher-risk 1809
patients. However, in a post hoc subset analysis, patients with ECE experienced superior 2-year 1810
LRC with 63 Gy and 68.4 Gy versus 57.6 Gy, but no difference between the higher dose levels 1811
(74% and 72% versus 52%, respectively, p=0.03). Consistent with this finding, in a retrospective 1812
analysis of 102 oral cavity/oropharynx patients treated with differing doses of PORT, Zelefsky et 1813
al.139 showed that non-oral tongue patients with positive or close margins receiving a minimum 1814
of 60 Gy had significantly improved LRC versus lower doses (92% vs. 44% at 7 years, 1815
p=0.0007). 1816
Ang et al.4 performed a randomized assessment of AccF vs conventional fractionation 1817
(CF) in high-risk post-operative patients (63 Gy/5 weeks vs 63 Gy/7weeks). There were trends 1818
towards improved LRC (p=0.11) and OS (p=0.08) with acceleration, the latter result partially 1819
owing to a 33 % incidence of distant failure. Accelerated fractionation increased grade 3 mucosal 1820
toxicity (62% vs 36%). Sanguineti et al.140 also compared AccF vs CF (64 Gy/5 weeks vs 60 1821
Gy/6 weeks). There were no differences with respect to local-regional control, distant failure, nor 1822
overall survival. Grade 3 mucosal toxicity was significantly increased, however (53% vs 27%). 1823
Suwinski et al.141 also compared post-operative AccF against CF. Approximately 40% of the 1824
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patients had oral cavity/oropharynx primaries, and AccF resulted in significantly better local-1825
regional control (74% vs 53%) in this subset. There was no difference in OS with accelerated 1826
treatment. Again the cost was a significantly higher incidence of grade 3 mucosal toxicity with 1827
AF (60% vs 33%). 1828
Caution should be exercised in attempting to apply these data to the clinical setting. The 1829
vast majority of patients with high-risk pathologic features now receive concurrent 1830
chemoradiotherapy rather than RT alone. Additionally, a minority of the patients treated on the 1831
aforementioned trials had OPC primary tumors (17-40%). These trials enrolled most of their 1832
subjects during the 1980s and 1990s, and OPC itself has evolved since then from a smoking 1833
related disease to one that is predominantly caused by HPV infection. Most investigational 1834
efforts for the latter are focused on therapeutic de-escalation given its more favorable prognosis. 1835
Changes in RT delivery techniques must also be kept in mind when interpreting these 1836
data. Most of the patients were treated with Co-60 or 4 MV photons using 2-D parallel opposed 1837
fields prescribed at mid-plane. It is likely that the prescribed daily dose of 1.8 Gy was 10-15% 1838
higher (2.0-2.1 Gy) in the neck as a consequence of dose inhomogeneity. In this respect, past is 1839
prologue for patients treated with contemporary IMRT dose painting techniques that commonly 1840
deliver daily doses of 2.2 Gy to high risk regions. Lukens et al. have shown a significantly 1841
increased risk of soft tissue necrosis when daily fractions of this size are used for PORT in 1842
OPSCC.142 1843
In summary, the small volume of randomized data suggests improved LRC with 1844
treatment doses beyond 57.6 Gy for patients with positive margins and/or ECE. The three 1845
randomized trials of accelerated radiotherapy provided mixed results on LRC, but they were 1846
consistent in showing no OS benefit and markedly increased mucosal toxicity with intensified 1847
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treatment. Therefore the panel strongly recommends that patients receiving adjuvant PORT for 1848
positive margins and/or ECE are treated using daily fraction sizes of 2 Gy to a total dose between 1849
60 and 66 Gy. This dose (60 Gy) is comparable to the 63 Gy in 7 weeks from Peters et al. while 1850
reducing the total package time (i.e. time from surgery to the end of radiotherapy). 1851
There are insufficient data to properly answer whether dose-escalation beyond 60 Gy 1852
provides additional clinical benefit in patients with high-risk pathology. As detailed above, the 1853
Peters trial138 showed no further benefit to 68.4 Gy in this population. That said, the landmark 1854
RTOG 950145,46 and EORTC 2293144 trials used post-operative doses of 60-66 Gy (RTOG) and 1855
66 Gy (EORTC) to regions of highest risk. Without concurrent cisplatin, patients in the RTOG 1856
trial with positive margins and/or ECE had a 10-year locoregional recurrence risk of 33%, and 1857
individuals in the EORTC study treated with radiotherapy alone had a 5-year locoregional 1858
recurrence risk of 31%. Given these poor LRC outcomes with radiotherapy alone, the expert 1859
panel is more concerned with the complications of locoregional failure than mucositis. The panel 1860
conditionally recommends that patients with positive margins and/or ECE receiving PORT alone 1861
receive a total dose to these regions of 66 Gy in 2 Gy fractions, although the lack of high-quality 1862
data guiding this statement must be acknowledged. 1863
The evidence guiding dose and fractionation regimens in the setting of negative margins 1864
and no ECE is similarly scant. The Peters study initially randomized low risk patients to 52.2-54 1865
Gy vs 63 Gy at 1.8 Gy per fraction. Because of a higher incidence of local failure in the low dose 1866
cohort (p=0.02), the total dose subsequently was increased to 57.6 Gy. No advantages were 1867
observed with 63 Gy vs 57.6 Gy, but grade 3-4 toxicity was higher (7.7% vs 3.3%) with the 1868
higher dose. Low risk was defined as having not more than one of the following factors: oral 1869
cavity primary, mucosal margins close or positive, nerve invasion, ≥2 positive lymph nodes, 1870
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largest node > 3 cm, treatment delay greater than 6 weeks, and performance status > or = 2. 1871
Ang’s trial4 used the same clinical and pathologic criteria with low risk defined as having none 1872
of them and intermediate risk as having only one exclusive of ECE. Low-risk patients were 1873
observed; all intermediate risk patients (n=31) received 57.6 Gy and had the same local-regional 1874
control as the low risk patients. 1875
The panel considers that the dose of 57.6 Gy in 1.8 Gy fractions is approximately 1876
equivalent to 56 Gy in 2 Gy fractions. The daily dose is higher and total treatment time is shorter 1877
with 2 Gy fractions, arguing in favor of 56 Gy as the reference dose. However, because there are 1878
few data showing successful long-term control outcomes with 56 Gy, and as stated above, the 1879
true dose to involved stations using opposed lateral fields was presumably higher than the 1880
nominal dose, the panel chose a more conservative level and strongly recommends delivering 60 1881
Gy to the tumor bed and involved lymph node stations in the absence of positive surgical margin 1882
(PSM) and ECE. 1883
Currently, the most significant issue concerns the distinction between low risk and high-1884
risk disease. It is important to recognize that most patients with high risk disease now receive 1885
adjuvant chemoradiotherapy (vide supra). Features including perineural invasion (PNI) and 1886
multiple positive lymph nodes in addition to PSM and ECE conferred eligibility into the RTOG 1887
and EORTC trials that developed this standard. The majority of the patients on these trials did 1888
not have oropharyngeal cancer, however, and secondary analyses have shown that chemotherapy 1889
did not clearly augment the effectiveness of RT for lower-risk pathologic features such as PNI 1890
and multiple nodes. Consequently, one could rationally infer in a contemporary setting that there 1891
is no benefit to be gained from dose escalation or acceleration without PSM or ECE. 1892
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Consensus still exists that primary site PSM is a high risk feature. For surgically treated 1893
HPV(+) disease, however, some recent large retrospective studies suggest that minimal nodal 1894
ECE no longer constitutes high risk disease49,50 and that these patients do just as well with 1895
adjuvant RT only (60 Gy) instead of adjuvant chemoradiotherapy. The older studies of post-1896
operative irradiation followed the traditional paradigm of dose intensification to improve 1897
outcome. Since HPV (+) driven disease has a much more favorable prognosis than its HPV(-) 1898
counterpart, current developmental strategies are focused on therapeutic deintensification. ECOG 1899
331193 is a randomized phase 2 study enrolling p16-positive oropharyngeal cancer patients who 1900
have undergone transoral resection. Patients with “intermediate-risk” pathologic factors (defined 1901
as PNI, LVI, 2-4 LN’s, <1 mm ECE, and/or margins <3 mm) will be randomized to receive 2 Gy 1902
daily either on an investigational arm of 50 Gy or a control arm of 60 Gy. The outcomes of this 1903
trial will help to redefine the standard-of-care for patients receiving adjuvant PORT in this 1904
population, but pending the mature results of this study, post-operative treatment dose and 1905
fractionation should not vary by p16 status. 1906
1907
1908
In the scenario of early T-stage tonsillar carcinoma? 1909 1910
Statement 4K. Unilateral radiotherapy should be delivered to patients with well-lateralized 1911 (confined to tonsillar fossa), T1-T2 tonsillar cancer and N0-N1 nodal category. 1912
o Recommendation strength: Strong 1913 o Quality of evidence: Moderate 1914
1915 Statement 4L. Unilateral radiotherapy may be delivered to patients with lateralized (< 1 cm of 1916
soft palate extension but without base of tongue involvement) T1-T2 N0-N2a tonsillar cancer 1917 without clinical or radiographic evidence of extra-capsular extension, after careful discussion of 1918 patient preferences and the relative benefits of unilateral treatment versus the potential for 1919 contralateral nodal recurrence and subsequent salvage treatment. 1920
o Recommendation strength: Conditional 1921 o Quality of evidence: Low 1922
1923
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1924
Narrative 1925
1926 The hypothetical advantages of ipsilateral-only radiotherapy for tonsillar cancer include 1927
improved short- and long-term functional outcomes and quality-of-life. In addition, the smaller 1928
treatment volumes may potentially lower the small but non-zero long-term risk of radiation-1929
associated malignancies, particularly in the younger population of patients with HPV-associated 1930
disease. The key concern of restricting radiotherapy to the ipsilateral side is the risk of 1931
contralateral nodal recurrence. 1932
As suggested from both historical surgical literature on patterns of cervical metastases as 1933
well as more recent surgical series of tonsillar cancer patients undergoing bilateral neck 1934
dissections, contralateral nodal spread typically occurs either directly through soft palate or base 1935
of tongue involvement or via aberrant/retrograde flow from bulky unilateral nodal disease. In a 1936
review of 352 patients with oropharyngeal cancer (197 with tonsillar cancer) treated with 1937
surgical resection including bilateral neck dissection, investigators from Ludwig Maximilians 1938
University in Munich143 demonstrated that contralateral nodal metastasis was dramatically lower 1939
for tonsillar cancers (14.7%) as compared to cancers of the base of tongue, soft palate, or 1940
pharyngeal wall (28.8%, 25.9%, and 50.0%, respectively). Among tonsillar cancers risk for 1941
contralateral metastasis increased with higher T-category (6.3% for T1, 17.5% for T2, and 17.3% 1942
for T3-4), though local extension of tonsillar cancers to involve the base of tongue, soft palate or 1943
pharyngeal wall was not described. Additionally, risk for contralateral nodal metastases among 1944
all patients was strongly associated with N2b ipsilateral nodal category (P < 0.001). Investigators 1945
from Hallym University in Seoul144 have described a series of 76 patients with tonsillar cancer 1946
treated with surgery (including 14 having elective contralateral neck dissection for contralateral 1947
N0 status). Contralateral metastases were significantly associated with T3 category, base of 1948
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tongue involvement, soft palate involvement, and ipsilateral neck multilevel involvement, though 1949
only ipsilateral multilevel involvement was significant after multivariate adjustment. In another 1950
publication from this group on a subset of 53 patients,145 these contralateral nodal metastases 1951
were also associated with posterior pharyngeal wall involvement and extracapsular spread in the 1952
ipsilateral nodal metastases. Investigators from Yonsei University in Seoul146 reported on the 1953
pathologic findings in 43 patients with tonsillar cancer treated with surgery including elective 1954
contralateral neck dissection (contralateral N0 status). The authors did not comment on soft 1955
palate or base of tongue invasion, but there was a correlation of contralateral occult metastatic 1956
rate with T-category (0% for T1, 4.5% for T2, and 33.3% for T3-4) and N-category (0 for N0, 1957
18.2% for N1-2a, and 27.3% for N2b). Consequently, these well-documented patterns of cervical 1958
metastases from tonsillar cancer treated with surgery provide support that the concept of 1959
unilateral radiotherapy for patients with early-stage, lateralized tonsillar cancer. 1960
The evidence in the literature supporting the above consensus statement regarding 1961
ipsilateral-only radiotherapy is chiefly comprised of retrospective data with inherit selection and 1962
publication biases, variable follow-up time, limited evidence using modern radiotherapy 1963
techniques, and a lack of data on whether these findings apply specifically to oropharyngeal 1964
cancer resulting from HPV. In developing these guideline statements, we have identified 10 1965
studies which met our initial criteria for review (Table 8 and 9). 1966
One study was described as an “investigational trial” of ipsilateral-only radiotherapy, 147 1967
and this small study included 22 oropharyngeal cancers (13 of the tonsil) patients of whom only 1968
15 were treated with definitive radiotherapy (7) or chemoradiotherapy (8). Primary endpoints of 1969
this study were prospectively recorded patient recurrence in the contralateral neck and reported 1970
xerostomia score. There were 2 (9%) patients with oropharyngeal cancer (both of the tonsil) who 1971
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recurred in the contralateral neck; both were T3 N2b. No patient developed grade 2-3 1972
xerostomia. The other prospective study of ipsilateral-only radiotherapy148 included only 20 1973
patients with tonsillar cancers (none of which involved the base of tongue or soft palate) of 1974
whom only 6 received definitive chemoradiotherapy (using IMRT approximately half the time). 1975
No patient developed a contralateral nodal recurrence. Only one patient developed a grade 2 1976
xerostomia and there were no grade 3 or late toxicities; however, 11 patients did require a 1977
treatment break. 1978
Of the remaining 8 studies, all were retrospective with 3 being generally small. 149-151 In a 1979
study of 32 patients with oropharyngeal cancer (12 with soft palate primaries and 20 with tonsil 1980
primaries, 7 with soft palate extension and 5 with base of tongue extension) treated with 1981
ipsilateral-only radiotherapy (38% received concurrent carboplatin), Kagei et al.149 found no 1982
patient developing a contralateral nodal recurrence. Only 3 patients developed grade 2 1983
xerostomia, and with exception of one case of grade 3 osteoradionecrosis, there were no grade 3 1984
or late toxicities. In a study of 20 patients with tonsillar cancer, of whom 70% received post-1985
operative ipsilateral-only radiotherapy, Koo et al150 found no patient developed a contralateral 1986
nodal recurrence. Only one patient developed grade 2 xerostomia, and there were no grade 3 or 1987
late toxicities. In a study of 58 patients with tonsillar cancer treated with unilateral radiotherapy, 1988
Liu et al.151found no patient developed a contralateral nodal recurrence. Of note, this is the only 1989
study with p16 data: of 15 patients tested, 60% were p16 positive. Only 4 patients treated 1990
unilaterally developed late toxicities, a significantly smaller percentage than the rate of late 1991
toxicity (22%) of among patients with tonsillar cancer treated with bilateral radiotherapy. 1992
While the remaining 5 studies are also retrospective, each included more than 100 1993
patients with oropharyngeal cancer and all but one with exclusively tonsillar cancer patients as 1994
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well as all but one having the vast majority of patients (>90%) treated with definitive radiation 1995
therapy. Jackson et al.152 reviewed 178 patients with tonsil cancer treated with ipsilateral-only 1996
definitive radiotherapy, although the local extent of disease was not stated beyond T category. 1997
The details of contralateral nodal recurrence were detailed only for the 155 with N0-N1 disease 1998
and among these there were 4 (2.6%) contralateral recurrences (initial stage: one T2N0, one 1999
T3N0, and 2 T1-3N1). Three out of 82 patients (3.6%) of patients with stage III disease 2000
developed a contralateral recurrence, though it is possible that many patients in this older series 2001
(1975-1993) were under staged due to substandard (by today’s standards) imaging. Reported late 2002
toxicities included 2 with grade 2 soft tissue necrosis, 4 with grade 3 osteonecrosis, and 2 with 2003
grade 4 osteonecrosis. 2004
In the largest study to date, O’Sullivan et al.153 reported on 228 patients with tonsillar 2005
cancer treated with definitive ipsilateral-only radiotherapy. Eight patients (3.5%) developed 2006
contralateral nodal recurrence; however, 5 were detected synchronously with a primary site 2007
recurrence and 3 also had ipsilateral nodal recurrence. There were only 3 patients (1.3%) with 2008
exclusive contralateral nodal recurrence, and of these 3, 2 had T3 primaries (all 3 with significant 2009
[>1cm] palate involvement and 2 with significant base of tongue involvement). Of the 30 2010
patients with T3 primaries, 3 developed a contralateral recurrence. Notably, none of the 36 2011
patients with lateral palate involvement (< 1 cm) developed a contralateral recurrence, although 2 2012
out of 39 (5%) patients with lateral base of tongue invasion did, one of which was the only site of 2013
recurrence. While all contralateral nodal recurrences occurred among the 41 N1 patients and 2014
none among the 36 patients with N2 disease (28 N2a, 8 N2b), this is an older series of patients 2015
(1970-1991) in which cross-sectional imaging was “not employed for stage allocation.” 2016
Consequently, it is likely that some proportion of the N1 patients would have been classified as 2017
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N2b had contemporary imaging tools been available. The reported 5-year rate of grade 3-4 2018
toxicity was 3.4% (chiefly osteonecrosis), although the radiotherapy was 2D-based, without CT-2019
planning. 2020
A recent series by Lynch et al.154 reported the outcomes of 136 patients with tonsillar 2021
cancer treated with primary surgical resection and post-operative ipsilateral-only radiotherapy 2022
with or without chemotherapy. None of these patients had base of tongue involvement, and only 2023
7 patients had lateral (< 1cm) soft palate extension. Eight patients (6%) recurred in the 2024
contralateral neck with 6 (4% of total) of those recurrences being the solitary site of progression. 2025
All 6 of these patients presented with the initial nodal category N2b, with 5 having extra-capsular 2026
extension and 5 being current smokers with >10 pack-years smoking history. Two of the 7 2027
patients with lateral soft palate involvement developed a contralateral recurrence. Late toxicity 2028
included grade 3 osteonecrosis in 9 (7%) and grade 3 fibrosis in 3 (2.2%), and only 8 patients 2029
(6%) required a feeding tube. 2030
The final 2 papers were large series with a majority of patients treated with definitive 2031
intensity modulated radiation therapy (IMRT) and very small proportion receiving 2032
chemotherapy. Chronowski et al.155 found a contralateral recurrence rate of 2% in a series of 102 2033
patients with tonsillar cancer treated with ipsilateral-only radiotherapy, though one of these was 2034
likely a second primary of the contralateral base of tongue. Only patients with primaries 2035
confined to the tonsillar fossa or with less than 1 cm of soft palate extension (base of tongue 2036
involvement was an exclusion) were considered for ipsilateral radiotherapy. A total of 43 N2 (21 2037
N2a, 22 N2b) patients were included in this analysis, and none of them developed a contralateral 2038
recurrence. Long term toxicity rates were not reported, though 9% of patients required feeding 2039
tubes during radiotherapy. In the study by Al-Mamgani et al,156 185 patients (47 with soft palate 2040
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
primaries and 32 with N2b nodal metastases) were treated with ipsilateral-only radiotherapy, 2041
there were only 2 contralateral recurrences (1.1% of the entire cohort), and one of these was 2042
initially T1N2b (the other T2N0; both confined to the tonsillar fossa). Late grade 3 toxicity was 2043
only 2.2%, while late grade 2 toxicity was 13%. 2044
The oncologic safety of ipsilateral-only radiation therapy for HPV-associated tonsillar 2045
cancer is suggested by high control rates and low contralateral metastases rates in these relatively 2046
modern series, in which a substantial proportion of patients presumably had disease attributable 2047
to HPV. However, the propensity of small HPV-associated oropharyngeal cancers to metastasize 2048
to lymph nodes raises some concern of whether this population has a higher risk of occult 2049
contralateral lymph nodes and subsequent contralateral nodal recurrence. In a small retrospective 2050
study restricted to T1-T2 tonsillar cancers reported by Shoushtari et al.,157 25% of 28 patients 2051
with p16 positive T1-T2 tonsillar cancer presented with clinically-evident, contralateral nodal 2052
metastases, as compared to none of the 13 patients with p16 negative T1-T2 tonsillar cancer. 2053
The key issue, though, is not the incidence of contralateral clinically-evident lymph node 2054
metastases but rather the baseline risk of occult contralateral lymph node metastases and the risk 2055
of subsequent contralateral recurrence. However, to date there are no data available to inform 2056
whether HPV-associated tonsillar cancers have a higher baseline risk of occult contralateral 2057
lymph node metastases and risk of subsequent contralateral recurrence. Also, whether these risks 2058
are modified by past smoking history is unknown. Consequently, the recommendations regarding 2059
the use of ipsilateral-only radiation therapy are made independent of HPV status and smoking 2060
history. 2061
A substantial experience supports the use of ipsilateral only radiation therapy for tonsillar 2062
cancer confined to the tonsillar fossa with limited nodal metastases as effective therapy with high 2063
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
survival rates, expected in-field control, and very rare contralateral recurrence. In addition, the 2064
majority (9 of 10) of N0-N1 patients with contralateral recurrence were observed in series dating 2065
back to the 1970s, with many such patients likely with under-staged N-category due to lack of 2066
modern cross-sectional imaging. Ipsilateral treatment should also reduce the risk of late 2067
toxicities, including xerostomia, dysphagia, and second primary malignancies. The panel 2068
therefore strongly recommends ipsilateral treatment in this cohort. Care in the use of ipsilateral-2069
only radiation therapy must be taken in cases of T1/T2 category OPSCC with soft palate 2070
involvement and/or N2a categories (Table 10). There is limited clinical experience that can 2071
confirm low contralateral recurrence rates in these scenarios, although the existent data reviewed 2072
above are sufficiently encouraging that ipsilateral radiotherapy may be used in this population, 2073
provided patient preferences are fully engaged on the expected quality-of-life benefits versus the 2074
uncertain risk of contralateral recurrence. 2075
On the other hand, the vast majority of reported contralateral recurrences occurred in 2076
patients with classical contraindications to unilateral treatment (e.g. significant involvement of 2077
soft palate, base of tongue and/or T3 primary size) or tumor characteristics that suggest aberrant 2078
lymphatic flow (i.e. ECE, advanced N2b cases) (Table 9). Thus the panel does not consider 2079
ipsilateral radiotherapy reasonable in the presence of these factors. The panel did discuss whether 2080
patients with small-volume N2b disease or those with minimal base of tongue invasion should be 2081
eligible for ipsilateral radiotherapy. Because of the paucity of data suggesting a low contralateral 2082
recurrence risk in these individuals, they are not included in the conditional recommendation for 2083
the use of ipsilateral radiotherapy. 2084
Future research will hopefully provide additional guidance on this important treatment 2085
planning decision. For example, we eagerly await outcomes and contralateral recurrence risk to 2086
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
be reported on series of HPV-associated T1-T2 tonsillar cancers. At present, neither the more 2087
favorable prognosis not the propensity for lymph node metastases of HPV-associated tonsillar 2088
cancer can inform the decision to spare the contralateral neck from radiation therapy. Similarly, 2089
prospective studies of patients with N2b nodal category are needed to better understand the 2090
contralateral recurrence risk with ipsilateral radiotherapy and further motivate treatment 2091
decisions in this relatively common clinical presentation. 2092
2093
2094
2095
2096
2097
2098
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Epilogue: Reflections from the patient advocate 2099
2100 ASTRO clinical practice guidelines include a patient advocate to ensure the patient 2101
perspective is considered during the guideline process and maximize the patient-centeredness of 2102
the product. We asked the patient advocate (Warren Caldwell) for this guideline to provide his 2103
“recommendations” on how medical professionals can improve the care for individuals 2104
diagnosed with oropharyngeal squamous cell carcinoma. His thoughts are below: 2105
2106
1. The sound of a silent cell phone of one awaiting biopsy results is deafening. It will be a 2107
kindness of unimaginable proportion to inform patients in an expeditious manner of the 2108
results of biopsies and scans. When it is clinically possible, avoid scheduling these tests 2109
when results will be extended over a weekend. 2110
2111
2. There is no bad way to inform a patient of good news and no good way to inform them of 2112
such existentially bad news. Make these calls when you have time to patiently respond to 2113
a hundred questions as this is not one of life’s multi-tasking moments for your patient. 2114
They will be riveted to your every word. 2115
2116
3. When the call has ended, the patient’s brain will race: I am self-employed. Will I be able 2117
to work? Should I sell my nice car and get a clunker? Why didn’t I buy life insurance? 2118
Will I see my son earn his Eagle Scout? Will I be at his wedding? Will I play with 2119
grandkids? 2120
2121
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
4. How much knowledge is too much for a new patient? A new patient may self-triage with 2122
their need to know, but discuss their desire to hear details early in the conversation. 2123
2124
5. An important blade on the Swiss Army Knife of a patient’s resources to fight the fight is 2125
empowerment. The sudden discovery that so many things are out of one’s control places 2126
a premium on the things that are under one’s control. A shift away from the traditional 2127
paternalistic form of physician/patient relationship towards a teammate approach fosters a 2128
sense of self-control in a world that is madly spinning out of control. 2129
2130
6. The emerging science behind treatment options of OPSCC suggest that there are some 2131
gray areas in utilizing the tools of surgery, radiotherapy and systemic treatment. The 2132
engagement of patient preferences in determining treatment options is a preferred means 2133
of practicing medicine. Explain, Engage and Ask. Formulate a plan together. 2134
2135
7. Establish an understanding of a patient’s aversion to risk versus embrace of reward. Do 2136
they have a predisposition to be more aggressive with a possible loss of quality of life or 2137
less aggressive with the cancer more likely to recur? 2138
2139
8. If a patient elects to go less aggressively, this position should be afforded the same 2140
respect as any other. If they choose to reject some aspect of the recommended treatment, 2141
afford them the dignity and feeling of control of self-directed treatment. 2142
2143
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
9. Engage the family during the new patient discussion and enlist them as part of the team. 2144
One could successfully beat it without family but it would be immeasurably more 2145
difficult. 2146
2147
10. Are we getting better and better at fighting the actual disease process but not providing a 2148
great deal of formal attention to the psychosocial aspects of the ordeal? Everyone has 2149
their own unique journey and no amount of counseling or therapy will standardize it (nor 2150
should it) but the lack of the same leaves patients to their own devices and some are 2151
better equipped than others. 2152
2153
11. There will be quite a lot of data management that most will not be used to handling. 2154
Encourage them to buy a Spandex type file in which to keep all appointment calendars, 2155
labs, reports, documents, insurance, and written prescriptions in one place. Use pill 2156
containers to help manage medications. Consider giving them these things as part of a 2157
new patient package. 2158
2159
12. The prospect of the loss of one’s teeth is terrifying to comprehend. Impossibly so. It is 2160
disquieting to be a fortunate ex-patient counseling a less fortunate ex-patient who is sad 2161
that “I used to be attractive, now I look like a different person.” Encourage patients to use 2162
their dental trays in the shower. It gives them a regular routine to use them and they are 2163
able to spit excess fluoride saliva down the drain. 2164
2165
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
13. The radiation mask is a special hurdle. The loss of control by being imprisoned by 2166
something one millionth of an inch from one’s face is near complete. If a patient exhibits 2167
complete anxiety, medicate them. But if a patient must drive themselves to appointments 2168
and cannot be medicated, encourage them to leave home early for the appointment to 2169
avoid traffic stress. Listen to comforting music on the way to the hospital. Breathe slowly 2170
and deeply. Close one’s eyes during treatment. Offer them the opportunity to listen to 2171
music of their choice during the treatment. 2172
2173
14. The loss of taste is much more of a loss than it would seem on the surface. It is shocking 2174
how important the sensation of taste is in driving a person’s appetite. Indeed, when one 2175
cannot taste, the act of eating is actually a tiresome ordeal in itself. 2176
2177
15. Have patients keep Magic Mouthwash (a lidocaine mixture) right next to their chair and 2178
bedside, not in the kitchen. Keep it super-convenient and they will use it more regularly. 2179
Recommend that patients keep moisturizer in their vehicles so that they may slather it on 2180
their necks immediately after the treatment. Make the supportive care as convenient as 2181
possible for themselves. 2182
2183
16. Post-surgical and radiation mucositis can make it very difficult to sleep in a normal 2184
position. Encourage patients to purchase and utilize a reclining chair to sleep in and when 2185
they transition back to a bed, have them elevate with multiple pillows. When awake and 2186
in the chair, set up a TV tray and line up all the accoutrements of healing. Water, spit cup, 2187
prescriptions, books, TV remote. 2188
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
2189
17. Encourage the patient to take mastery over their mind. Have them hang a white dry erase 2190
board or the like at their home or office. Sequentially number the amount of treatments 2191
(30, 29, 28….1, DONE). Make it a ceremony to “X” out each number as it progresses. 2192
Look forward to it. Engage family and allow them to “X” out some of the days. Write 2193
slogans of encouragement on this board. 2194
2195
18. Once the miraculous “tah-dah” moment of finishing treatment is reached, the “New 2196
Normal” begins. As the treatment “gift” keeps on giving in the weeks and months 2197
following radiation, a patient may feel the need for additional sleep. Encourage naps as 2198
necessary. This “lack of productivity” can result in financial strain due to reduced income 2199
but it is a matter of aligning things in their necessary hierarchy of importance. 2200
2201
19. The effect of radiotherapy on the skin can cause the neck to look twenty years older than 2202
the rest of the patient. Don’t discount the importance of trying to reduce the long-term 2203
visible side effects of treatment. 2204
2205
20. The hiring process for staff should place a special premium on the human quality of 2206
kindness. The smallest act of kindness will be something the patient will remember for 2207
life. Begin with the valet in the parking lot. They are the first face a patient will encounter 2208
and the last to see and have an opportunity to place their positive imprint on the entire 2209
visit. The same care should be extended with check-in staff, nurses and of course, 2210
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
physician assistants and physicians. By doing so, you will be treating patients as a human 2211
being instead of a disease, which is crucial to maintain dignity throughout the process. 2212
2213
21. If the patient has children, forcefully encourage (and remind) them to vaccinate their kids 2214
against HPV. Motivate them to be strong advocates for HPV vaccination for their 2215
extended family and friends. 2216
2217
2218
22. If you have read this far, I thank you from the depths of my heart. It is because of 2219
you and people like you that I backpacked 110 miles at Philmont Scout Ranch with 2220
my son last year. Remember why you do what you do! 2221
2222
2223
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
TABLES 2224
2225 Table 1. Recommendation statements, including recommendation strength, quality of evidence, and percent consensus. 2226
2227
Guideline statement Strength of
recommendation
Quality of
evidence
Percent (%) agreement
with guideline
statement
KQ1. When is it appropriate to add systemic therapy to definitive radiotherapy in the treatment of oropharyngeal
squamous cell carcinoma (OPSCC)?
In the scenario of stage IV A-B disease:
A. Concurrent high-dose intermittent cisplatin should be
delivered to patients with stage IVA-B oropharyngeal
squamous cell carcinoma receiving definitive radiotherapy. Strong High 100%
B. Concurrent cetuximab or carboplatin-fluorouracil should
be delivered to patients with stage IVA-B
oropharyngeal squamous cell carcinoma receiving definitive
radiotherapy who are not medically fit for high-dose
cisplatin.
Strong High 88%
C. Concurrent weekly cisplatin may be delivered to patients
with stage IVA-B oropharyngeal squamous cell carcinoma
receiving definitive radiotherapy who are not medically fit
for high-dose cisplatin, after a careful discussion of patient
preferences and the limited prospective data supporting this
regimen.
Conditional Low 94%
D. Concurrent cetuximab should not be delivered in
combination with chemotherapy to patients with stage IVA-
B oropharyngeal squamous cell carcinoma receiving
definitive radiotherapy.
Strong High 100%
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
E. Intra-arterial chemotherapy should not be delivered to
patients with stage IVA-B oropharyngeal squamous cell
carcinoma receiving definitive radiotherapy. Strong High 100%
In the scenario of stage III disease:
F. Concurrent systemic therapy should be delivered to
patients with T3 N0-1 oropharyngeal squamous cell
carcinoma receiving definitive radiotherapy. Strong Moderate 100%
G. Concurrent systemic therapy may be delivered to patients
with T1-T2 N1 oropharyngeal squamous cell carcinoma
receiving definitive radiotherapy who are considered at
particularly significant risk for locoregional recurrence, after
a careful discussion of patient preferences and the limited
evidence supporting its use.
Conditional Low 88%
In the scenario of stage I-II disease:
H. Concurrent systemic therapy should not be delivered to
patients with stage I-II oropharyngeal squamous cell
carcinoma receiving definitive radiotherapy. Strong Low 100%
KQ2. When is it appropriate to deliver post-operative radiotherapy with and without systemic therapy following primary
surgery of oropharyngeal squamous cell carcinoma (OPSCC)?
In the scenario of positive margins and/or extrascapsular nodal extension (ECE)?
A. Concurrent high-dose intermittent cisplatin should be
delivered with post-operative radiotherapy to patients with
positive surgical margins and/or extracapsular nodal
extension; this high-risk population includes patients
independent of HPV status or the extent of extranodal tumor.
Strong Moderate 100%
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
B. Concurrent weekly cisplatin may be delivered with post-
operative radiotherapy to patients who are considered
inappropriate for standard high-dose intermittent cisplatin
after a careful discussion of patient preferences and the
limited evidence supporting this treatment schedule.
Conditional Low 94%
C. For the high-risk post-operative patient unable to receive
cisplatin-based concurrent chemoradiotherapy, radiotherapy
alone should be routinely delivered without concurrent
systemic therapy; given the limited evidence supporting
alternative regimens, treatment with non-cisplatin systemic
therapy should be accompanied by a careful discussion of the
risks and unknown benefits of the combination.
Strong Moderate 94%
D. Patients treated with post-operative radiotherapy should
not receive concurrent weekly carboplatin. Strong Moderate 88%
E. Patients treated with post-operative radiotherapy should
not receive cetuximab, either alone or in combination with
chemotherapy, although such regimens are currently under
investigation.
Strong Low 94%
F. Patients treated with post-operative radiotherapy should
not routinely receive concurrent weekly docetaxel given the
limited evidence supporting its use, although such regimens
are currently under investigation.
Strong Low 88%
G. Patients treated with post-operative radiotherapy should
not receive concurrent mitomycin-C, alone or with
bleomycin, given the limited evidence and experience
supporting its use.
Strong Moderate 100%
H. Post-operative chemotherapy should not be delivered
alone or sequentially with post-operative radiotherapy. Strong High 94%
In the scenario of intermediate-risk pathologic factors such as lymphovascular invasion (LVI), perineural invasion (PNI), T3-
4 disease, or positive lymph nodes:
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
I. Patients with intermediate-risk factors should not routinely
receive concurrent systemic therapy with post-operative
radiotherapy. Strong Moderate 88%
J. Patients with intermediate-risk factors whose surgical
procedure and/or pathologic findings imply a particularly
significant risk of locoregional recurrence may receive
concurrent cisplatin-based chemotherapy after a careful
discussion of patient preferences and the limited evidence
supporting its use in this scenario; alternative systemic
treatment regimens should only be used in the context of a
clinical trial
Conditional Low 88%
K. Post-operative radiotherapy should be delivered to
patients with pathologic T3 or T4 disease. Strong Low 94%
L. Post-operative radiotherapy should be delivered to patients
with pathologic N2 or N3 disease. Strong Low 100%
M. Post-operative radiotherapy may be delivered to patients
with pathologic N1 disease after a careful discussion of
patient preferences and the limited evidence of outcomes
following surgery alone in this scenario.
Conditional Low 88%
N. Post-operative radiotherapy may be delivered to patients
with LVI and/or PNI as the only risk factor(s), after a careful
discussion of patient preferences and the limited evidence of
outcomes following surgery alone in this scenario.
Conditional Low 100%
In the scenario of no pathologic risk factors:
O. Post-operative radiotherapy may be delivered to patients
without conventional adverse pathologic risk factors only if
the clinical and surgical findings imply a particularly
significant risk of locoregional recurrence, after a careful
discussion of patient preferences and the potential harms and
benefits of radiotherapy.
Conditional Low 88%
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
KQ3. When is it appropriate to use induction chemotherapy in the treatment of oropharyngeal squamous cell carcinoma
(OPSCC)?
A. Induction chemotherapy should not be routinely delivered
to patients with OPSCC. Strong High 100%
KQ4. What are the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the
treatment of oropharyngeal squamous cell carcinoma (OPSCC)?
In the scenario of definitive non-surgical therapy:
A. A dose of 70 Gy over 7 weeks should be delivered to
gross primary and nodal disease in patients with stage III-IV
oropharyngeal squamous cell carcinoma selected to receive
standard, once-daily definitive radiotherapy.
Strong Moderate 100%
B. The biologically equivalent dose of approximately 50 Gy
in 2 Gy fractions or slightly higher should be delivered
electively to clinically- and radiographically-negative regions
at-risk for microscopic spread of tumor.
Strong Low 100%
C. Altered fractionation should be used in patients with stage
IVA-B oropharyngeal squamous cell carcinoma treated with
definitive radiotherapy who are not receiving concurrent
systemic therapy.
Strong High 94%
D. Either accelerated radiotherapy or hyperfractionated
radiotherapy may be used in patients with oropharyngeal
squamous cell carcinoma treated with altered fractionation
definitive radiotherapy after a careful discussion of patient
preferences and the limited evidence supporting one regimen
over the other.
Conditional High 100%
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
E. Either standard, once-daily radiotherapy or accelerated
fractionation may be used when treating oropharyngeal
squamous cell carcinoma with concurrent systemic therapy,
after a careful discussion of patient preferences and the risks
and benefits of both approaches.
Conditional High 88%
F. Altered fractionation should be used in patients with T3
N0-1 oropharyngeal squamous cell carcinoma treated with
definitive radiotherapy who do not receive concurrent
systemic therapy.
Strong Moderate 94%
G. Altered fractionation may be used in patients with T1-2
N1 or T2 N0 oropharyngeal squamous cell carcinoma treated
with definitive radiotherapy alone who are considered at
particularly significant risk of locoregional recurrence, after a
careful discussion of patient preferences and the limited
evidence supporting its use in this scenario.
Conditional Low 100%
In the scenario of adjuvant postoperative radiotherapy:
H. Adjuvant post-operative radiotherapy should be delivered
to regions of microscopically-positive primary site surgical
margins and extracapsular nodal extension at 2 Gy/fraction
once daily to a total dose between 60 and 66 Gy
Strong Moderate 100%
I. Adjuvant post-operative radiotherapy delivered without
concurrent systemic therapy should treat regions of
microscopically-positive primary site surgical margins and
extracapsular nodal extension at 2 Gy/fraction once daily to a
total dose of 66 Gy, although there are limited data guiding
this recommendation.
Conditional Weak 100%
J. Adjuvant post-operative radiotherapy should be delivered
to the tumor bed and involved, dissected lymph node regions
at 2 Gy/fraction once daily to a total dose of 60 Gy in the
absence of primary site positive margins and extracapsular
nodal extension.
Strong Moderate 100%
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
In the scenario of early T-stage tonsillar carcinoma:
K. Unilateral radiotherapy should be delivered to patients
with well-lateralized (confined to tonsillar fossa), T1-T2
tonsillar cancer and N0-N1 nodal category. Strong Moderate 88%
L. Unilateral radiotherapy may be delivered to patients with
lateralized (< 1cm of soft palate extension but without base
of tongue involvement) T1-T2 N0-N2a tonsillar cancer
without clinical or radiographic evidence of extra-capsular
extension, after careful discussion of patient preferences and
the relative benefits of unilateral treatment versus the
potential for contralateral nodal recurrence and subsequent
salvage treatment.
Low Conditional 100%
2228
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 2: Summary of phase III randomized trials comparing definitive radiotherapy with definitive radiotherapy plus 2229
concurrent systemic therapy (Key Question 1) 2230 2231
Author and
year
Number
of
patients
%
oropharynx
% stage
III Radiotherapy regimen
Chemotherapy
regimen/
schedule
LRC benefit OS benefit
Adelstein,
20039
295 total
(271
analyzed)
59% 4% 70 Gy in 35 fx over 7 weeks
Bolus cisplatin q3
weeks vs. cisplatin
+ 5-FU with split-
course
--
YES
3-year: 23% (RT) vs.
37% (RT + bolus) vs.
p=0.014
Ruo Redda,
201011
164 (157
analyzed) 56% 23%
70 Gy in 35 daily fx over 7
weeks
Carboplatin q2
weeks NO
YES
5-year: 6.9% (RT) vs.
9% (CRT), p=0.02
Zakotnik,
199814 64 64% 6%
66-70 Gy in 33 to 35 daily
fx over 7 weeks
Mitomycin C after
10 Gy and on last
day of RT +
bleomycin twice
weekly
--
NO
Except 10% vs. 38%
for oropharyngeal,
p=0.019
Denis,
200416 226 100% 32%
70 Gy in 35 daily fx over 7
weeks
Carboplatin and 5-
FU q3 weeks
YES
5-year: 24.7% (RT)
vs. 47.6% (CRT),
p=0.002
YES
5-year: 15.8% (RT)
vs. 22.4% (CRT),
p=0.05
Semrau,
200617 240 74% 4%
50.4 Gy in 28 daily fx over
38 days + 19.5 Gy boost in
13 daily fx (total 69.9 Gy)
Continuous
infusion 5-FU and
carboplatin for 5d,
weeks 1 and 6
YES
5-year survival with
LRC: 12.6% (RT)
vs. 22.7% (CRT),
p=0.01
YES
5-year: 15.8% (RT)
vs. 25.6% (CRT),
p=0.016
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author and
year
Number
of
patients
%
oropharynx
% stage
III Radiotherapy regimen
Chemotherapy
regimen/
schedule
LRC benefit OS benefit
Ghadjar,
201218
224 100%
29% (plus
5% stage
II)
74.4 Gy in 62 fx BID
Daily cisplatin 20
mg/m2 for 5d,
weeks 1 and 5
YES
10-year: 40% (CRT)
vs. 32% (RT)
p=0.049
NO
Wendt,
199819
298 (270
analyzed) 42%
Not
reported;
5% T1-2,
35% N0-1
70.2 Gy in 39 fx BID over
51 days in 3 cycles of 23.4
Gy with 11 days in between
Cisplatin, 5-FU,
and leucovorin q3
weeks
YES
3-year: 17% (RT)
vs. 36% (CRT),
p<0.004
YES
3-year: 24% (RT) vs.
48% (CRT),
p<0.0003
Bourhis,
201120 109 62% 0%
64 Gy in 32 fx BID (very
accelerated RT alone) vs.
62-64 Gy in 31-32 fx BID
with RT every other wk
(CRT)
Cisplatin and 5-FU
q2 weeks
YES
5-year freedom from
locoregional or
distant failure:
49.1% (CRT) vs.
25% (RT), p=0.005
NO
Budach,
200522
384 60% 6%
16 Gy in 8 daily fx + 61.6
Gy in 44 fx BID (total 77.6
Gy) (RT) vs. 30 Gy in 15
daily fx + 40.6 Gy in 29 fx
BID (total 70.6 Gy)(CRT)
Continuous
infusion
fluorouracil on
days 1-5 + bolus
mitomycin on days
5 and 36
YES
5-year: 37.4% (RT)
vs. 49.9% (CRT),
p=0.001
YES
5-year: 23.7% (RT)
vs. 28.6% (CRT),
p=0.023
Bourhis,
201223 840 66% N/R
70 Gy in 35 daily fx over 7
weeks (CRT) vs. 40 Gy in
20 daily fx over 4 weeks
plus 30 Gy in 20 fx BID
over 2 weeks (AccRT) vs.
64.8 Gy in 36 fx BID over
3.5 weeks (VeryAccRT)
Carboplatin (3
cycles of 4 days
for CRT, 2 cycles
of 5 days for
AccRT) +
YES
3-year: 58.3%
(CRT) vs. 54.6%
(AccRT) vs. 50.1%
(VeryAccRT),
YES
3-year: 42.6% (CRT)
vs. 36.5%
(VeryAccRT),
p=0.040
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author and
year
Number
of
patients
%
oropharynx
% stage
III Radiotherapy regimen
Chemotherapy
regimen/
schedule
LRC benefit OS benefit
fluorouracil (q3
wks for CRT, q4
wks for AccRT)
p=0.033 (AccRT vs.
VeryAccRT),
p=0.045 (CRT vs.
VeryAccRT)
Ghosh-
Laskar,
201425
186 89%
46%
(stage II
and III)
66-70 Gy in 5 fx per week
(CRT) vs. 66-70 Gy in 6 fx
per week (AccRT)
Weekly cisplatin
30 mg/m2
YES
5-year: 32%
(ConvRT) vs. 49%
(CRT) vs. 27%
(AccRT), p=0.049
NO
Fallai, 200627
Olmi,
2003158 192 100% 27% (all
T3 N0-1)
66-70 Gy in 33-35 daily fx
(RT arm 1, CRT) vs. 64-
67.2 Gy in 40-42 fx BID,
with 2 week break (RT arm
2)
Carboplatin and 5-
FU q4 weeks
YES
5-year: 21% (RT 1)
vs. 18% (RT 2) vs.
48% (CRT), p=0.02
NO
Ang, 201435 891 70% 14%
72 Gy in 42 fx (3d-CRT) or
70 Gy in 35 fx (IMRT) over
6 weeks
Bolus cisplatin q3
weeks vs. bolus
cisplatin +
cetuximab
NO NO
Nguyen-Tan,
201437
Ang, 20104
743 (721
analyzed) 60% 22%
70 Gy in 35 fx over 7 weeks
(ConvRT) vs. 72 Gy in 42
fx over 6 weeks (AccRT)
Bolus cisplatin q3
weeks (3 cycles for
ConvRT, 2 cycles
for AccRT)
NO NO
Rasch,
201040 239 63% 5%
46 Gy in 23 daily fx + 24
Gy boost in 12 daily fx
(total 70 Gy)
Weekly intra-
arterial cisplatin
vs. intravenous
cisplatin q3 weeks
NO NO
Bonner,
2006159,160 424 60% 25%
70 Gy in 35 daily fx over 7
weeks or 72-76.8 Gy in 60-
64 fx BID over 10 weeks or
Weekly cetuximab
(+ loading dose YES
YES
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author and
year
Number
of
patients
%
oropharynx
% stage
III Radiotherapy regimen
Chemotherapy
regimen/
schedule
LRC benefit OS benefit
32.4 Gy in 18 daily fx +
39.6 Gy boost in 24 fx BID
one week before
RT)
3-year: 34% (RT)
vs. 47% (CRT),
p<0.01
3-year: 45% (RT) vs.
55% (CRT), p=0.05
5-year: 36.4% (RT)
vs. 45.6% (CRT),
p=0.018
Abbreviations: CRT = Chemoradiotherapy; -- = Not Reported, NS= Not significant; ConvRT: Conventional radiotherapy; AccRT: 2232
Accelerated radiotherapy; Fx: Fractions; BID: Twice daily; LRC = locoregional control; OS = overall survival. 2233
2234
2235
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 3. Summary of phase III randomized trials comparing postoperative radiotherapy with postoperative radiotherapy plus 2236
concurrent high-dose intermittent cisplatin (Key Question 2). 2237
Trial number
Number
of
patients
Median
follow-up
%
oropharynx LRC Benefit DM Benefit DFS/PFS Benefit OS Benefit
Bernier,
200444
(EORTC
22931)
334 5 years 30%
YES
5-year cumulative
incidence of
recurrence: 18%
CRT vs. 31% RT
(p=0.007)
NO
YES
5-year: 47%
(CRT) vs. 36%
(RT) (p=0.04)
YES
5-year: 53%
(CRT) vs. 40%
(RT) (p=0.02)
Cooper, 200445
(NRG 9501) 416 3.8 years 42%
YES
At median follow-
up 45.9 months,
cumulative
incidence of
recurrence: 19%
CRT vs. 30%
CRT (p=0.01)
NO
YES
Hazard ratio 0.78
(p=0.04) favoring
CRT
NO
Cooper, 201246
(NRG 9501) 410 9.4 years 42% NO NO NO NO
Abbreviations: EORTC = European Organisation for Research and Treatment of Cancer; NRG =; LRC = locoregional control; DM = 2238
distant metastasis; DFS = disease-free survival; OS = overall survival; CRT = chemoradiotherapy; RT = radiotherapy 2239
2240
2241
2242
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 4. Summary of phase III randomized trials comparing postoperative radiotherapy with postoperative radiotherapy plus 2243
concurrent systemic therapy not using high-dose intermittent cisplatin (Key Question 2) 2244
Author
and year
Number
of
patients
Patient risk
factors
%
oropharyn
x
Chemotherap
y
schedule
RT dose/
schedule LRC Benefit DM Benefit DFS Benefit OS Benefit
Bachaud,
199654
Bachaud,
199155
83
ECE: 100%
PSM: 35%
≥3 positive
nodes or
bulky mass:
33%
15%
Cisplatin
weekly 50 mg
x 7-9
54 Gy in 32 fx
over 6.5
weeks
Close/positive
margins: boost
to 65-70 Gy in
1.8-2.0 Gy fxs
Metastatic
nodes: boost
to 65-74 Gy in
3 Gy fxs
YES
5-yr survival
without LRR
55% (RT) vs.
70% (CRT),
p=0.05
NO
YES
5-year: 23%
(RT) vs. 45%
(CRT), p<0.02
YES
2-year: 13%
(RT) vs. 36%
(CRT), p<0.01
Rewari,
200657 205
PSM
27%
≥2 positive
nodes: 34%
23%
Mitomycin C
15 mg/m2 x 1-
2
At least 54 Gy
in 27-30 fxs
over 5.5-6
weeks, median
60 Gy
YES
5-year (crude):
69.9% (RT)
vs. 85.3%
(CRT),
p=0.008
NO -- NO
Zakotnik,
200763
Smid,
200362
114
ECE: 53%
PSM: 12%
LVI: 18%
PNI: 4%
30%
Mitomycin C
15 mg/m2
Bleomycin
5 mg twice
weekly
56–70 Gy in
28-35 fxs over
5.5-7 weeks
YES
5-year: 65%
(RT) vs. 88%
(CRT),
p=0.026
NO
YES
5-year: 33%
(RT) vs. 53%
(CRT),
p=0.035
NO
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author
and year
Number
of
patients
Patient risk
factors
%
oropharyn
x
Chemotherap
y
schedule
RT dose/
schedule LRC Benefit DM Benefit DFS Benefit OS Benefit
Racadot,
200864 144
ECE: 31%
PSM:
22%
≥2 positive
nodes: 36%
49%
Carboplatin 50
mg/m2 twice
weekly x 6-8
weeks
54 Gy in 30 fx
over 6 weeks
for negative
margins
72 Gy in 40 fx
over 8 weeks
for positive
margins
NO -- -- NO
Argiris,
200865 72
ECE: 75%
PSM: 29%
PNI: 10%
32%
Carboplatin
100 mg/m2
weekly x 6
weeks
At least 59.4
Gy in 33 fxs
over 6.5 weeks
(boost
allowed)
NO NO NO NO
Tobias,
201066
253
(pts who
received
surgery)
PSM: 53% 23%
Methotrexate
or vincristine,
bleomycin,
fluorouracil +
methotrexate
on days 1 + 14
of RT
Varied by
center -- -- NO NO
Abbreviations: RT: Radiation Therapy; CRT: Chemoradiotherapy; Pts: Patients; Fx: Fractions; Yrs = Years; -- = Not reported; DM = 2245
Distant metastases; OS = overall survival; LRC = locoregional control; LRF = locoregional failure; w/o = Without; NS = Not 2246
significant; Min = Minimum; DFS = disease-free survival; ECE = extracapsular extension; PSM = positive surgical margins; PNI = 2247
perineural invasion; LVI = lymphovascular invasion; 2248
2249
2250
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 5. Summary of key studies investigating intermediate-risk pathologic factors for recurrence following primary surgical 2251
resection with and without adjuvant radiotherapy (Key Question 2) 2252 2253
Author and
year
Number of
patients
%
oropharynx
N stage:
N0/N1/N2/
N3
T stage:
T1/T2/T3/T
4
Prevalence
of LVI
and/or PNI
LRF Impact DFS Impact OS Impact
Langendijk,
200573
801
20%
N0: 29%
N1: 15%
N2a: 3%
N2b: 37%
N2c: 13%
N3: 3%
T1: 12%
T2: 24%
T3: 32%
T4: 32%
LVI: 4%
PNI: 16%
YES (LVI, PNI)
5-year:
33% (LVI present)
vs. 21% (LVI
absent), p=0.011
31% (PNI present)
vs. 22% (PNI
absent), p=0.026
YES
5-year: 65% (class
I) vs. 47% (class
II) vs. 32% (class
III), p<0.0001*
YES
5-year: 67% (class
I) vs. 50% (class II)
vs. 36% (class III),
p<0.0001*
Ambrosch,
200174 503 28%
N0: 50%
N1: 18%
N2a: 2%
N2b: 26%
N2c: 5%
T1: 14%
T2: 38%
T3: 30%
T4: 18%
(oropharynx
only)
--
P values not reported
3-year: 8.5%
(surgery) vs. 4.7%
(surgery + RT)
Failure in neck
without RT:
pN0: 5.5% vs. 0%
pN1: 6.3% vs. 3%
pN2: 24% vs. 7%
--
YES
pT category: risk
ratio 1.6, pT3/4 vs.
pT1/2 (p=0.0009)
pN category: risk
ratio 1.9 and 2.8 for
pN1 and pN2,
respectively vs.
pN0 (p=0.0001)
Jackel,
200875 118 29% N1: 100%
T1: 24%
T2: 38%
T3: 27%
--
NO (+/- RT)
Any regional failure
without RT: 9% vs.
-- NO (+/- RT)
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author and
year
Number of
patients
%
oropharynx
N stage:
N0/N1/N2/
N3
T stage:
T1/T2/T3/T
4
Prevalence
of LVI
and/or PNI
LRF Impact DFS Impact OS Impact
T4: 12%
(oropharynx
only)
21% (10% isolated,
no p value)
3-year risk of
isolated regional
recurrence: 11.2%
(no RT) vs. 2.9% RT
(p=0.09)
Leemans,
199480 244 13% N/R
Tx: 2%
T1: 7%
T2: 27%
T3: 43%
T4: 21%
--
YES (T stage)
94.7% (T1-2) vs.
83.8% (T3-T4),
p=0.015
(primary site failure)
-- --
Haughey,
201281 171 100%
N0: 9%
N1: 14%
N2a: 18%
N2b: 42%
N2c: 10%
N3: 7%
T1: 41%
T2: 34%
T3: 16%
T4: 9%
LVI: 15%
PNI: 12%
--
NO (T-stage) --
Ravasz,
199382 80 28% N/R
T1-T2: 15%
T3-T4: 85%
LVI: 41%
PNI: 13%
YES (LVI)
50% (LVI present)
vs. 16% (LVI
absent), p=0.005
(local only failure))
(PNI not significant)
-- --
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author and
year
Number of
patients
%
oropharynx
N stage:
N0/N1/N2/
N3
T stage:
T1/T2/T3/T
4
Prevalence
of LVI
and/or PNI
LRF Impact DFS Impact OS Impact
Bastit,
200183 420
45%
N0: 32%
N1: 29%
N2: 34%
N3: 5%
T1: 5%
T2: 30%
T3: 55%
T4: 11%
Either LVI or
PNI: 18%
YES (LVI)
Tumor emboli RR
1.48, p=0.061
-- --
McMahon,
200384
237
Sydney, 95
Lanarkshir
e
42%
Sydney,
23%
Lanarkshire
Sydney
N0: 43%
N1: 15%
N2a: 3%
N2b: 29%
N2c: 7%
N3: 3%
Lanarkshire
N0: 69%
N1: 10%
N2a: 2%
N2b: 13%
N2c: 4%
N3: 1%
Sydney
T1: 18%
T2: 41%
T3: 30%
T4: 11%
Lanarkshire
T1: 17%
T2: 63%
T3: 17%
T4: 4%
--
YES (PNI)
(on multivariable
analysis)
--
NO (PNI, LVI)
Fagan,199885 142
47% (oral
cavity and
oropharynx)
N/R
T1: 8%
T2: 42%
T3: 26%
T4: 24%
PNI: 52%
YES (PNI)
23% (PNI present)
vs. 9% (PNI absent),
p=0.02
(local only; oral
cavity + oropharynx)
--
--
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author and
year
Number of
patients
%
oropharynx
N stage:
N0/N1/N2/
N3
T stage:
T1/T2/T3/T
4
Prevalence
of LVI
and/or PNI
LRF Impact DFS Impact OS Impact
Lanzer,
201386 291 32%
N0: 37%
N1: 13%
N2a: 10%
N2b: 31%
N2c: 5%
N3: 4%
T1-2: 52%
T3-4: 30%
Tx: 8%
LVI: 7%
PNI: 8%
YES (PNI)
Ipsilateral regional
recurrence:
26% (PNI present)
vs. 6% (PNI absent),
p=0.001
19% (LVI present)
vs. 7% (LVI absent),
p=0.048
Contralateral
regional recurrence:
9% (PNI present) vs.
1% (PNI absent),
p=0.002
LVI: negative
NO (PNI, LVI)
NO (PNI, LVI)
Peters,
1993138 240 18%
Nx: 8%
N0: 38%
N1: 18%
N2: 22%
N3: 15%
Tx: 11%
T1: 2%
T2: 18%
T3: 50%
T4: 22%
PNI: 24% NO (PNI) -- --
Abbreviations: LVI: Lymphovascular invasion; PNI: Perineural invasion; --: Not reported; LRF = locoregional failure; DFS = 2254
disease-free survival; OS = overall survival 2255
* Class I (intermediate risk): free surgical margins and no extranodal spread; class II (high risk): T1, T2, and T4 tumors with close or 2256
positive surgical margins or one lymph node metastasis with extranodal spread; class III (very high risk):T3 tumors with close or 2257
positive surgical margins or multiple lymph node metastases with extranodal spread or N3 neck. 2258
2259
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 6. Summary of phase III randomized trials comparing radiotherapy (or chemoradiotherapy) with induction 2260
chemotherapy followed by the same (Key Question 3) 2261
Author
and year
Number of
patients
%
oropharynx
Induction
regimen
Concurrent
regimen
Radiotherapy
regimen
LRC
Benefit DM Benefit OS Benefit
Induction chemotherapy followed by local therapy (surgery or radiotherapy alone)
Zorat 2004,
Pacagnella
199494
237
59.3%
(group A),
54.6%
(group B)
Cisplatin-5FU x
4 cycles None
Resection and
adjuvant RT
(45-50 Gy) for
operable pts
and definitive
RT for
inoperable
(65-70 Gy)
(group B)
YES
84% (group
A) vs 72%
(group B),
p=0.05
YES
3 years: 24% DM
(IC) vs. 42% DM
(RT only),
(p=0.04)
YES
5/10 years:
21%/16% vs.
8%/6%, p=0.04 for
inoperable patients
Domenge,
200096
318 (161pts -
no IC grp) 100%
Cisplatin-5FU x
3 cycles None
70 Gy/35 fx
over 7 weeks,
plus 5 Gy
boost to
residual tumor;
or resection
NO NO
YES
Median 5.1 yr in
IC vs. 3.3 yr RT/
surgery alone
(p=0.03)
Lewin,199
7161 461 55%
Cisplatin-5FU x
3 cycles None
64-70 Gy in 2
Gy daily fx -- NO NO
Sequential (Induction chemotherapy followed by chemotherapy)
Hitt,201416
2
439 pts: 155
(TPF-CRT),
156 ( PF-
CRT ) and
128 (CRT
alone)
43%
Cisplatin-5FU
vs. Cisplatin-
5FU-Docetaxel x
3 cycles
Bolus
cisplatin q3
weeks
70 Gy/35 daily
fx NO NO NO
Haddad,
2013102
145 55%
Cisplatin-5FU-
Docetaxel x 3
cycles
Bolus
cisplatin q3
weeks (no
CRT: 72 Gy in
6 weeks NO NO NO
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author
and year
Number of
patients
%
oropharynx
Induction
regimen
Concurrent
regimen
Radiotherapy
regimen
LRC
Benefit DM Benefit OS Benefit
IC); weekly
carboplatin
(AUC 1.5)
after TPF for
good
responders,
weekly
docetaxel (20
mg/m2) for
poor
responders
(accelerate
boost)
Post-IC: 72 Gy
in 6 weeks for
poor
responders; 70
Gy in 7 weeks
for good
responders
Cohen,
2014103 285 58%
Cisplatin-5FU-
Docetaxel x 2
cycles
Docetaxel,
hydroxyurea,
5-FU
74-75 Gy in 4
courses of BID
RT, 1 week
apart
NO
NO
Except
~10% (IC) vs.
20% (CRT) DM
without prior LRR
(p=0.043)
NO
Abbreviations: CRT = Chemoradiotherapy; RT = Radiotherapy; -- = Not Reported; IC = induction chemotherapy; NS= Not 2262
significant; Fx: Fractions; BID: Twice daily; DM = distant metastasis; Gy = Gray; LRR = locoregional recurrence. FU = fluorouracil; 2263
TPF = docetaxel, cisplatin, fluoruracil; AUC = area under curve. 2264
2265
2266
2267
2268
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 7: Summary of phase III randomized trials comparing radiotherapy with altered fractionation radiotherapy. (Key 2269
Question 4) 2270 2271
Author
and year
Number
of
patients
%
oropharynx
% stage
III
Altered
fractionation RT
regimen
Reference
RT regimen
Chemotherapy
regimen/
schedule
LRC Benefit OS Benefit
Bourhis,
201223
840 66% --
40 Gy in 20 daily
fx over 4 weeks
plus 30 Gy in 20
fx BID over 2
weeks (AFX),
64.8 Gy in 36 fx
BID over 3.5
weeks (VeryAFX)
70 Gy 35
fractions over
7 weeks
Carboplatin (3
cycles of 4 days
for CRT, 2
cycles of 5 days
for AFX) +
fluorouracil (q3
wks for CRT,
q4 wks for
AFX)
YES (to CRT)
3-year: 58.3% (CRT)
vs. 54.6% (AFX) vs.
50.1% (VeryAFX),
p=0.033 (AFX vs.
VeryAFX), p=0.045
(CRT vs. VeryAFX)
YES (to CRT)
3-year: 42.6%
(CRT)
vs. 36.5%
(VeryAFX),
p=0.040
Nguyen-
Tan,
201437
743 (721
analyzed)
60% 21%
AFX with boost
plus cisplatin (72
Gy in 42 fxs over
6 weeks)
70 Gy in 35
fractions over
7 weeks plus
cisplatin
Bolus cisplatin
q3 weeks (3
cycles for SFX,
2 cycles for
AFX)
NO NO
Beitler,
2014112 1076 60%
Not
reported
HFX (81.6 Gy
BID);
AFX-continuous
(72 Gy in 6
weeks); AFX-split
(67.2 Gy with 2-
wk rest after 38.4
Gy)
70 Gy/35 fx,
once-daily None
NO
Except HFX vs. SFX
HR 0.79, p=0.05 (if
censoring after 5
years)
NO
Except HFX vs.
SFX HR 0.81,
p=0.05 (if
censoring after 5
years)
Horiot,
1997113 500 100% --
Hyperfractionated
and AFX (72 Gy
in 45 fx over 5
weeks)
70 Gy in 35 fx None
YES
5 years: 46% SFX arm
vs. 59% AFX arm;
p=0.02
NO
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Author
and year
Number
of
patients
%
oropharynx
% stage
III
Altered
fractionation RT
regimen
Reference
RT regimen
Chemotherapy
regimen/
schedule
LRC Benefit OS Benefit
Zackrisson,
2011118 750 49% 28%
AFX (68 Gy in 23
fxs of 2 Gy and 20
daily boost fxs of
1.1 Gy,over 4.5
weeks)
68 Gy/34 fx,
once-daily None NO NO
Overgaard1
25 1476
29%
(pharynx) 21%
AFX, 66-68
Gy/33-34 fx, 6 fx
per week
66-68 Gy in
33-34 fx, 5 fx
per week
None
YES
5-year: 70% (AFX) vs
60% (SFX)
group
p = 0.0005
NO
Overgaard1
26 900
53%
(pharynx) 37%
AFX, 66-70
Gy/33-35 fx, 6 fx
per week
66-68 Gy in
33-34 fx, 5 fx
per week
None
YES
5 years: 42% (AFX)
vs 30% (SFX)
group
p = 0.004
NO
Poulsen,
2001128 343 67%
Favorable-
12 %
Unfavorab
le- 19%
AFX (59.4 Gy in
33 fxs over 24
days)
70 Gy in 35
fxs over 49
days
None NO NO
Horiot,
1992129 325 100% 56%
80.5 Gy in 70 BID
fractions in 7
weeks
70 Gy 35
fractions over
7 weeks
None
YES
5-year: 59% (HFX) vs.
40% (SFX) (p=0.02)
NO
Abbreviations: OS: Overall survival; DFS: Disease free survival; AFX: Accelerated radiotherapy; Not reported; SFX: Standard 2272
fractionation; fx: Fractions; CRT: Conventional chemoradiotherapy; BID = twice per day. 2273
2274
2275
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 8. Studies exploring the role of ipsilateral-only radiation therapy in patients with oropharyngeal cancer squamous cell 2276
carcinoma, including years, primary site distribution, treatment, and TNM staging (Key Question 4) 2277
Author and
year Years of
Treatment
Number of
patients
(#OP)
% OP
Cancers
in the
Tonsil
%
Definitiv
e XRT
% IMRT %
Chemo
% T-
Category
% N-Category
% Stage
O’Sullivan
et al110 1970-1991 228 (228) 100 100 0 0
Tx: 0
T1: 32
T2: 52
T3: 13
T4: 3
Nx: 0
N0:58
N1:25
N2a:12
N2b:4
N3:1
I: 19
II: 33
III: 28
IV: 20
Corvo et al147 2001-2002 30 (22) 59 68 0 53 -- -- --
Rusthoven et
al148 2003-2007 20 (20) 100 30 45 95
Tx: 0
T1: 55
T2: 35
T3: 10
T4: 0
Nx: 0
N0: 0
N1: 20
N2a: 15
N2b: 65
N3: 0
I: 0
II: 0
III: 20
IV: 80
Kagei et al149 1989-1996 32 (32) 63 100 0 0
Tx: 0
T1: 21
T2: 38
T3: 37
T4: 6
Nx: 0
N0:69
N1:16
N2a:13
N2b:13
N3:3
--
Koo et al150 2003-2011 20 (20) 100 30 30 30
Tx: 0
T1: 35
T2: 60
T3: 5
T4: 0
Nx: 0
N0: 10
N1: 40
N2a: 10
N2b: 40
N3: 0
I: 5
II: 45
III: 50
IV: 0
Liu et al*151 1990-2002 58 (58) 100 100 0 -37 Tx: 2 Nx: 0 I: 10
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
T1: 15
T2: 52
T3: 29
T4: 2
N0: 43
N1: 24
N2a: 18
N2b: 7
N3: 9
II: 17
III: 40
IV: 33
Jackson et al152 1975-1993 178 (178) 100 100 0 0
Tx: 0
T1: 21
T2: 45
T3: 29
T4: 5
Nx: 0
N0:57
N1:30
N2a: 4
N2b: 4
N3: 9
I: 13
II: 24
III: 46
IV: 17
Lynch et al**154 1995-2011 136 (136) 100 43 0 -63
Tx: 0
T1: 42
T2: 54
T3: 4
T4: 0
Nx: 0
N0: 20
N1: 15
N2a: 23
N2b: 40
N3: 2
--
Chronowski et
al155 1970-2007 102 (102) 100 92 67 5
Tx: 17
T1: 51
T2: 33
T3: 0
T4: 0
Nx: 2
N0: 32
N1: 22
N2a: 21
N2b: 22
N3: 0
--
Al-Mamgani et
al156 2000-2011 185 (185) 70 100 100 6
Tx: 0
T1: 27
T2: 66
T3: 7
T4: 0
Nx: 0
N0: 50
N1: 23
N2a: 10
N2b: 17
N3: 0
--
*Smoking status available for 53 patients with 38% current smokers and 17% never smokers; P16 available for 15 patients with 60% 2278
P16 positive 2279
**Smoking status available for 113 patients with 54% having >10 pack/years and 37% never smokers 2280
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 9. Studies exploring the role of ipsilateral-only radiation therapy in patients with oropharyngeal cancer with details of 2281
survival and contralateral nodal metastases (Key Question 4) 2282 2283
Author and year % Grade
3+
Late
Toxicity
5yr %
Overall
Survival
5yr %
Disease
Specific
Survival
5yr %
Local
Recurrence
5yr %
Regional
Recurrenc
e
Crude
Contralater
al Nodal
Recurrence
Risk (%)
Isolated
(no other
site of
recurrence)
Contralater
al
Recurrence
Risk (%)
TNM of Those
with Isolated
Contralateral
Recurrence
O’Sullivan et al110 3.4 N/R 76 (3yr) 23 (3yr) 19 (3yr) 3.5 3 T2N1 (SP-BOT
ext.)
Corvo et al147 N/R N/R N/R N/R N/R 6.7 6.7 T3N2b
Rusthoven et al148 0 80 (2yr) 80 (2yr
DFS) 21 (2yr) 0 0 0 N/A
Kagei et al149 3.1 64 (3yr) 79 (3yr) 26 19 0 0 N.A.
Koo et al150 0 95 95 (PFS) 5 0 0 0 N/A
Liu et al*151 7 N/R 83 (crude
DFS) 9 4 0 0 N/A
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Jackson et al152 3.4 56 69 25 14 2.6 N/R
T2N0
T3N0
T1-3N1
T1-3N1
Lynch et al**154 9 89 86 2 (crude) 7 (crude) 5.9 4.4
T2N2b
T2N2b (ECE)
T2N2b (ECE)
T2N2b (ECE)
T2N2b (ECE)
T2N2b (ECE)
Chronowski et al155 N/R 95 96 (DFS) 0 2 2 1 T2N0 (spm)
Al-Mamgani et al156 2.2 70 84 (DFS) 9 4 1.1 1.1 T1N2b
T2N0
Abbreviations: YR: year; N/R: Not Reported; DFS: Disease-free survival; PFS: Progression-free survival; N/A: Not applicable; SP-2284
BOT ext.: Soft palate and/or base of tongue extension; spm: most likely a second primary malignancy of contralateral base of tongue 2285
with nodal metastasis; ECE: Extra-capsular nodal extension 2286
2287
2288
2289
2290
2291
2292
2293
2294
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
Table 10. Consensus statement for use of ipsilateral-only radiation therapy in patients with oropharyngeal squamous cell 2295
carcinoma (Key Question 4). 2296 2297
Strongly
recommended
(if all of the
following)
Conditionally
recommended
(based on extension or N
category)
Primary Site Tonsil Tonsil
Soft Palate involvement None <1cm
T Category T1 or T2 T1 or T2
N Category N0 or N1 N2a
Extra-Capsular Nodal Extension None None
Human Papillomavirus Status Unknown impact Unknown impact
2298
NOT TO BE COPIED, DISSEMINATED OR REFERENCED
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