Induction methotrexate, cisplatin and 5-fluorouracil (MPF) versus cisplatin and 5-fluorouracil (PF) followed

by radiotherapy in pediatric nasopharyngeal carcinoma: A retrospective analysis in a tertiary cancer

center

Abdelatif Al Mousa MD, PhD1, Ramiz Abu-Hijlih MD1, Ahmed Salem MD2*, Iyad Sultan MD3, Layth Mula-

Hussain MD1, Taleb Ismael MD3, Issa Mohamad MD1

1. Department of Radiation Oncology, King Hussein Cancer Center, King Hussein Cancer Center, PO

Box 1269, Amman 11941, Jordan

2: Division of Molecular and Clinical Cancer Sciences, University of Manchester, 27 Palatine Rd,

Manchester M20 3LJ, UK

3. Department of Pediatric Oncology, King Hussein Cancer Center, King Hussein Cancer Center, PO Box

1269, Amman 11941, Jordan

* The author was affiliated with Department of Radiation Oncology, King Hussein Cancer Center, Jordan

during the time this project was in progress

Corresponding author: Issa Mohamad MD, Tel: +962799825592, Fax: +96265342567

Email: imohamad@khcc.jo

Disclosures: The authors have no conflicts of interest or funding to disclose

This work was presented at the 4th Regional Congress of Cancer and Blood Disorders of Childhood, 2012

(Amman, Jordan) and the 6th International nasopharyngeal carcinoma Symposium, 2013 (Istanbul,

Turkey).

Running title: Induction chemotherapy in pediatric nasopharyngeal carcinoma

Keywords: Nasopharyngeal; carcinoma; childhood; pediatric; chemotherapy; radiotherapy

Acknowledgments: The authors would like to acknowledge Mrs Ayat Taqash for her help with the

statistical analysis of this paper.

Word count for abstract: 200 words

Word count for main text: 2,640 words

Number of tables: 5 tables

Number of figures: 2 (1a, 1b, 2a, and 2b)

Abstract

Purpose: To compare treatment outcomes of methotrexate, cisplatin and 5-fluorouracil (MPF) or cisplatin

and 5-fluorouracil (PF) in pediatric NPC patients treated with sequential chemoradiotherapy.

Patients and methods: 25 patients aged ≤18 years with stage II-IV NPC treated with IC using PF (n=16)

or MPF (n=9) followed by radiotherapy between 2003 and 2009 were retrospectively reviewed.

Radiotherapy dose was 61.2 – 66.6Gy to the gross disease. Age, stage, radiation dose and

chemotherapy regimen were tested as prognostic factors for event-free and overall-survival (EFS and OS,

respectively) on univariate and multivariate analyses.

Results: The median age at diagnosis was 13.3 years. All patients completed planned chemotherapy. All

patients who received MPF achieved PR whereas 15 patients (93.8%) who received PF achieved PR;

p=1. There were no differences in EFS (68.75% v 66.67%; p=0.84) and OS (81.25% v 66.67%; p=0.39) at

5 years between PF and MPF, respectively. On multivariate analysis, only tumor stage (IV versus II-III)

predicted worse OS (hazard ratio (HR) 10.3, 95% confidence interval (CI); 1.197-88.974) but not EFS (HR

4.805, 95% CI; 0.95-24.336). Distant metastases was the predominant site of failure, seen in 5 patients

(20%).

Conclusions: Omission of methotrexate from the induction chemotherapy regimen did not affect

treatment outcome.

Introduction

Nasopharyngeal carcinoma (NPC) is a rare pediatric malignancy contributing less than 1% of all pediatric

tumors (1,2). NPC is endemic in southern China and Asia, but rare in Europe and North America with an

incidence lower than 1 in 100,000 (2–6). The World Health Organization (WHO) classifies NPC into three

types: squamous cell carcinoma (type I), keratinizing undifferentiated carcinoma (type II) and non-

keratinizing undifferentiated carcinoma (type III) (7). WHO type III, which is strongly associated with

Epstein–Barr virus (EBV), is the most common subtype in children.

Treatment of pediatric NPC patients is not standardized due to limited prospective studies in this disease.

Secondary to molecular and biological characteristics, NPC is relatively sensitive to chemo-radiotherapy

(8), with evidence to support cisplatin-based induction chemotherapy followed by radiotherapy (3).

Induction chemotherapy with methotrexate, cisplatin and 5-fluorouracil (MPF) followed by radiotherapy

was established as an accepted treatment option associated with long-term event-free and overall-

survival (EFS and OS, respectively) in a seminal Pediatric Oncology Group phase II study (9). Further, an

international randomized phase II study failed to detect any added efficacy, when docetaxel was added to

an induction chemotherapy regimen consisting of PF followed by concurrent chemo-radiotherapy (10).

However, in patients treated with sequential chemo-radiotherapy (induction chemotherapy followed by

radiotherapy), according to our knowledge there are no previously-published studies which have

compared induction chemotherapy regimens. Further, very little is known about the natural history,

presentation, treatment and outcome of this disease in the Middle East. The aim of this study is to

compare the therapeutic efficacy of induction chemotherapy regimens (MPV versus PF) and report the

clinical outcomes and prognostic factors of survival for pediatric NPC treated with induction chemotherapy

followed by radiotherapy in a tertiary cancer center in Jordan.

Patients and methods

Between 2003 and 2009, NPC patients aged ≤18 years treated at King Hussein Cancer Center (Amman,

Jordan) were identified via retrospective review of patient records. Patients were eligible if they had

biopsy-proven, previously-untreated stage II-IV (American Joint Committee on Cancer, 6th edition) NPC

and treated with curative intent using induction chemotherapy followed by radiotherapy. This study was

approved by the institutional review board. All patients granted written informed clinical treatment consent

before the start of their treatment.

Typical pretreatment assessments included complete history and physical examination, fiber-optic

nasopharyngoscopy, routine blood tests, magnetic resonance imaging (MRI) of head and neck, computed

tomography (CT) of the chest, abdomen and pelvis and whole-body bone scan. In addition, all patients

underwent pretreatment cardiac assessment, audiogram, dental evaluation and nutritional assessment.

All cases were discussed at a pediatric oncology multi-disciplinary meeting, prior to initiation of therapy.

Therapeutic radiological response, evaluated using RECIST criteria (version 1.1) (11), was documented

following 4 cycles of indication and at 6-8 weeks post-radiotherapy. Patients who achieved less than

complete response (CR) after radiotherapy were subsequently treated with palliative chemotherapy.

Induction chemotherapy: Two induction chemotherapy protocols were used in this study. Between 2003

and 2006, patients (n=9) were treated with methotrexate 120 mg/m2 intravenous (IV) day 1, cisplatin 100

mg/m2 IV day 1 and 5-fluorouracil (5-FU) 1000 mg/m2/day continuous infusion days 1-5. This regimen

(MPF) was repeated every 21 days for a total of 4 cycles. Between 2007 and 2009, patients (n=16) were

treated with cisplatin 100 mg/m2 IV day 1 and 5-FU 1000 mg/m2/day continuous infusion days 1-5. This

regimen (PF) was repeated every 21 days for a total of 4 cycles.

Radiotherapy: Radiotherapy was initiated one month after completion of induction chemotherapy and

delivered via 3-dimensional conformal radiotherapy (3D-CRT) using once-daily fractions, 5 days a week.

Total radiotherapy dose was determined based on induction chemotherapy response. Patients with

complete or partial response (PR) received 61.2Gy in 34 fractions while patients with stable or

progressive disease (SD and PD, respectively) received 66.6Gy in 37 fractions. An elective radiotherapy

dose of 50Gy in 25 fractions to bilateral neck nodes and areas at risk for local tumor spread was delivered

in all patients. Patients were immobilized in the supine position with a custom aquaplastic head and neck

mask. Target localization was accomplished with computed tomography (CT) simulation using 5 mm thick

slices extending from the vertex to 5 cm inferior to the clavicular heads. Target volume definition was

guided by pre-induction chemotherapy MRI, which was manually registered with planning CT. The gross

tumor volume (GTV), which included primary nasopharyngeal tumor and lymph nodes greater than 1 cm

or any node with necrotic center, was delineated. The clinical target volume (CTV) denoted the subclinical

regions at risk for tumor spread. Different CTVs were defined as follows: CTV61.2 (in patients with CR or

PR)/ 66.6 (in patients with SD or PD)-Primary = GTV + 5 mm isotropic margin around primary tumor,

CTV61.2/66.6-Nodal = GTV + 5 mm isotropic margin around gross nodes, CTV50 = GTV-Primary /Nodal

+ 1 cm margin + areas at risk for microscopic involvement (entire nasopharyngeal mucosa, skull base,

half of clivus in early-stage/ whole clivus in T3-4 disease, pterygoid fossae, bilateral parapharyngeal

spaces, sphenoid sinus, posterior third of the nasal cavity/ maxillary sinuses including the pterygopalatine

fossae, lateral retropharyngeal nodal region and levels Ib-V (node positive) or II-V (node negative)). To

account for uncertainties of daily set-up, a planning target volume (PTV) of 5 mm was added to each of

the above CTVs. Symptomatic supportive therapy was prescribed as required during treatment. Acute

radiotherapy toxicity was not completely reported but late radiotherapy toxicity was retrieved and recorded

as present (if the patient reported any significant symptoms, affection of quality of life or required

treatment) or absent.

Follow-up: Patients were followed up weekly during radiotherapy, 2 weeks pot-radiotherapy, at three

monthly intervals for the first two years and then at four monthly intervals for the third year. Follow-up

consisted of physical examination, endoscopic examination and laboratory tests. Head and neck MRI was

performed every 6 months for 2 years and then annually or as clinically indicated.

Statistical Analysis

Overall survival (OS) was defined as the time from diagnosis to death, from any cause. Patients who

remained alive were censored at the date of their last follow-up. Event-free survival (EFS) was defined as

the time from diagnosis to the first progression or relapse at any site or death from any cause. Patients

who remained alive without disease progression or relapse were censored at the date of their last follow-

up. Survival analyses were estimated using the Kaplan-Meier method. Patient groups were compared in

terms of survival using the log rank test. Cox regression model was used to identify significant prognostic

factors. Age, stage, radiation dose and chemotherapy regimen were tested as prognostic factors for EFS

and OS on univariate and multivariate analyses. Statistical significance was accepted when the p-value

was <0.05. Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

Results

Over the study period, twenty eight eligible patients were identified from the chart review. Three patients

had no follow-up information and were excluded; 25 patients were included in the analysis. All patients

had undifferentiated NPC (WHO type III). EBV testing was not routinely performed during the study

period. The majority were males (n=16). The median age at diagnosis was 13.3 years (range, 7-17.1

years). Two patients harbored stage II (8%), 13 stage III (52%) and 10 stage IV (40%). Bilateral neck

swelling (59%), hearing loss (26%) and epistaxis (19%) were the most common presenting symptoms.

The median time between onset of symptoms and diagnosis was 14 weeks (range, 4-52 weeks). Baseline

patient characteristics are summarized in table 1. As shown, the majority of patients >14 years old were

treated with MPF (88.9%) compared to PF (37.5%) induction chemotherapy; p=0.033. This difference was

also reflected in varying patient height and weight at diagnosis for the 2 chemotherapy cohorts. Follow-up

for patients treated with MPF was significantly longer (median, 86.4 months) compared to patients treated

with PF (median, 48 months) induction chemotherapy; p=0.0435.

All patients completed 4 cycles of chemotherapy, as planned. All patients who received MPF achieved PR

whereas 15 patients (93.8%) achieved PR in the PF group; p=1. One patient had PD following PF and

was switched to gemcitabine and carboplatin with SD thereafter. On follow-up imaging 6-8 weeks after

completion of radiotherapy, CR was documented in 19 patients (76%), PR in 4 patients (16%) while PD

was observed in 2 patients (8%). There was no difference in radiological response post-radiotherapy

between the 2 chemotherapy groups (table 2).

After a median follow-up of 56 months (range, 14-103 months), 19 patients (76%) were alive of whom, 17

(68%) with no evidence of disease. The 5-year EFS was 67.56% (figure 1a) while the 5-year OS was

75.79% (figure1b) for the whole patient population. Patients aged ≤14 years (c.f. >14 years) had better

EFS (90.91% versus 48.98% at 5 years respectively; p=0.02). Superior EFS (86.15% v 40% at 5 years;

p=0.01) and OS (92.86% versus 50% at 5 years; p=0.01) was seen for patients with stage II-III versus IV,

respectively. There were no differences in EFS (68.75% v 66.67% at 5 years; p=0.84) and OS (81.25% v

66.67% at 5 years; p=0.39) between PF versus MPF, respectively (figure 2). Similarly, there were no

differences in EFS (71.43% v 70.59% at 5 years; p=0.97) and OS (71.43% v 82.35% at 5 years; p=0.54)

between 66.2Gy v 61.2Gy, respectively. There was no difference in EFS and OS between male and

female genders. On multivariate analysis, only tumor stage (IV versus II-III) predicted worse OS (hazard

ratio (HR) 10.3, 95% confidence interval (CI); 1.197-88.974) but not EFS (HR 4.805, 95% CI; 0.95-

24.336); table 3. Eight patients (32%) had disease recurrent disease on follow-up (5 (31.3%) in the PF

and 3 (33%) in the MPF group; p=1). The pattern of treatment failure is shown in table 4. Overall, distant

metastases was the predominant site of failure seen in 5 patients (20%).

In the whole study population, the following late radiotherapy-related side-effects were recorded:

hypothyroidism in 10 patients (transient, n=2), xerostomia (n=9), dysphagia (n=8), dental pain (n=8),

hearing loss (n=4), trismus (n=4) and neck fibrosis, hypogonadotropic hypogonadism, short stature,

behavior problems, depression, neck pain, leukodystrophy, malnutrition and nasal speech each seen in 1

patient.

Discussion

The incidence of pediatric NPC varies widely according to racial and geographical factors. We treat

around 4-7 pediatric NPC cases every year. It is noteworthy that in Jordan, the overwhelming majority of

pediatric cancer patients are treated at our tertiary cancer referral center. This study revealed a peak

presentation in late childhood and male predominance, both findings were reported in previous studies

(1,3,5,12,13). Further, all patients were diagnosed with WHO type III tumors, a finding also similar to

previous pediatric NPC studies (14,15). Patients with WHO type III tumors are more likely to present with

advanced stage at presentation (14). In our study, 23 patients (92%) harbored stage III/ IV disease. EBV

is endemic in Jordan, positive staining for EBV by in-situ hybridization was seen in 92.3% of NPC

specimens in Jordan (16). Unfortunately, EBV status was not available in our study. Cervical

lymphadenopathy is the most common presenting symptom of NPC. Other symptoms include nasal

obstruction, epistaxis, headache and auditory dysfunction (6). Bilateral neck swelling (59%), hearing loss

(26%) and epistaxis (19%) were the most common presenting symptoms in our study. Clinical stage and

age >12 years were shown to be associated with improved OS and EFS in a relatively large analysis of

95 patients with NPC <20 years of age (17). In our study, patients aged ≤14 years had significantly better

EFS compared to their older counterparts. It is unclear whether this finding could be explained by varying

molecular tumor characteristics in younger patients.

A systematic review and meta-analysis revealed that patients treated with combined radiotherapy and

chemotherapy achieved better outcomes compared to those treated with radiotherapy alone (18). This

study showed that the mean disease-free survival rate was 66% (95 % CI, 56-76%) among fifteen studies

which included 865 patients. Induction chemotherapy with MPF followed by radiotherapy was associated

with 4-year EFS and OS rate of 77% and 75%, respectively in a seminal Pediatric Oncology Group phase

II study (9). Further, few studies have shown good outcomes with induction chemotherapy followed by

concurrent chemo-radiotherapy (19,20). A recently reported international randomized phase 2 study failed

to detect any added efficacy, evaluated by achievement of complete response, when docetaxel was

added to an induction chemotherapy regimen consisting on PF followed by concurrent chemo-

radiotherapy (10). Excellent outcomes (OS and EFS rates >90%) are achievable with the use of

chemotherapy, radiotherapy and adjuvant interferon (IFN)-beta (21,22), but this treatment is not widely

adopted in many developing countries or less-advanced cancer centers due to financial considerations or

lack of expertise.

Very few robust evidence exists to guide the choice of induction chemotherapy regimen in pediatric NPC

patients treated with radiotherapy. Younger patients are at higher risk of developing treatment-related

complications (23) particularly related to radiotherapy (14). In 2007, we omitted methotrexate form the

induction chemotherapy regimen for pediatric patients with NPC in an attempt to decrease treatment-

related side-effects. Although the rate of radiological tumor response was non-statistically higher in

patients who received MPF versus PF induction chemotherapy in our study, we failed to detect any

significant survival difference between the two regimens in pediatric NPC patients. Our findings also

demonstrate that acceptable results can be reproduced in developing countries, in lieu of international

randomized trials, with both induction chemotherapy regimens suggesting appropriate omission of

methotrexate in these patients. Distant metastases remains the main failure site in patients treated with

induction chemotherapy followed by radiotherapy/ chemo-radiotherapy (24). This was also confirmed in

our study where 5 patients (20%) developed distant metastases.

A radiation dose higher than 65Gy is associated with improved local tumor control, albeit results are

inconsistent across studies (18). Good response to induction chemotherapy is an important

prognosticator and radiotherapy dose reduction has been proposed for these patients (25). The GPOH-

NPC Study Group now recommends that radiotherapy doses can be safely reduced to 59.4-54.4Gy in

patients who achieve CR on positron emission tomography following induction PF when treated with

concurrent chemo-radiotherapy (26). We have elected not reduce our radiotherapy dose, as following

induction chemotherapy, our patients are treated with radiotherapy alone.

The use of intensity-modulated radiotherapy (IMRT) has been proposed to improve target coverage and

decrease radiotherapy-related side-effects (27–29). This is particularly true in pediatric NPC patients as

most are locally-advanced at diagnosis (30). Although complete information regarding radiotherapy side-

effects were missing from our study (e.g. grading not available), we reported a relatively high rate of late

radiotherapy-related side-effects during the study period. At the time of this study, our pediatric NPC

patients were treated using 3D-CRT technique. Recently, we adopted IMRT as the standard radiotherapy

delivery technique for these patients and anticipate that this will result in lower incidence of late

xerostomia, dysphagia and hearing loss and possibly, improved target volume coverage.

There are a number of limitations of this study. This study included a relatively small number of patients,

treated in a single center over an extended period of time (2003-2009). Chemotherapy-related side-

effects were also not available in this study. As such, we are unable to confirm whether the omission of

methotrexate leads to less treatment-related toxicity. Further, a larger percentage of patients aged >14

years were treated using MPF, while the omission of methotrexate later in the study led to a shorter

follow-up for those treated with PF chemotherapy. To overcome these limitations, there is a strong need

for large, international collaborative studies in this disease (31). In the Middle East and developing

countries with limited resources, induction chemotherapy using PF followed by radiotherapy is a valid

treatment option in pediatric NPC patients. We have shown that the omission of methotrexate from the

induction chemotherapy regimen did not affect treatment outcome. A relatively high rate of distant

metastases was demonstrated in our patients, development of more effective but economical systemic

therapies should become a research priority.

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Table 1. Baseline patient characteristics. Significant p-values in bold.

Category Value Total number Chemotherapy (%) p-value

MPF PF

Gender Female 9 4 (44.4%) 5 (31.3%) 0.671

Male 16 5 (55.6%) 11 (68.8%)

Age Age ≤14 11 1 (11.1%) 10 (62.5%) 0.033

Age >14 14 8 (88.9%) 6 (37.5%)

TNM stage II

III

IV

2

13

10

1 (11.1%)

4 (44.4%)

4 (44.4%)

1 (6.3%)

9 (56.3%)

6 (37.5%)

0.849

Category CTX group Mean (95% CI) Median (min, max) p-value

Height at

diagnosis

MPF

PF

160 (156, 164)

145 (140, 151)

160 (149, 169)

148 (125, 168)

0.0029

Weight at

diagnosis

MPF

PF

53.6 (43.6,63.5)

39.3 (33.9, 44.8)

50.5 (35.0,83.0)

39.6 (22.4,70.3)

0.0444

follow up MPF

PF

75.8 (48.5, 103)

51.4 (45.4, 57.4)

86.5 (14.0, 102)

48.0 (33.0, 70.0)

0.0435

Table 2. Radiological response post treatment in the 2 chemotherapy groups

Category Value Total number Chemotherapy (%) p-value

MPF PF

Post chemotherapy PR

PD

24

1

9 (100%)

0 (0%)

15 (93.8%)

1 (6.2%)

1.000

Post radiotherapy CR

PR

19

4

6 (66.7%)

2 (22.2%)

13 (81.3%)

2 (12.5%)

0.803

PD 2 1 (11.1%) 1 (6.3%)

Table 3. Univariate and multivariate analysis of prognostic factors for EFS and OS. Significant p-values in

bold.

Univariate analysis

Prognostic factor Category Hazard ratio

95% confidence interval

p-value

Stage

IV versus II/III

OS 10.32 1.19-88.97 0.0337

EFS 5.76 1.15-28.72 0.0339

Radiotherapy dose

66 versus 61.2Gy

OS 1.78 0.27-10.74 0.5278

EFS 1.03 0.20-5.39 0.9711

Age

>14 versus ≤14 years

OS 4.99 0.58-42.92 0.1434

EFS 7.71 0.94-63.05 0.0568

Chemotherapy

PF versus MPF

OS 0.497 0.1-2.47 0.3929

EFS 0.87 0.21-3.66 0.8492

Multivariate analysis

Stage

IV versus II/III

OS 10.32 1.19-88.97 0.0337

EFS 4.805 0.95-24.366 0.0581

Table 4. Pattern of treatment failure in the 2 chemotherapy groups.

Chemotherapy group Site of treatment failure

PF Lung metastases (n=2)

Bone metastases (n=1)

Bone and lung metastases (n=1)

Loco-regional recurrence (n=1)

MPF Loco-regional recurrence (n=2)

Bone metastases (n=1)

Table 5. abbreviations key

MPF methotrexate, cisplatin and 5-fluorouracil

PF cisplatin and 5-fluorouracil

NPC Nasopharyngeal carcinoma

EFS Event free survival

OS Overall survival

WHO World health organization

EBV Epstein bare virus

MRI Magnetic resonance imaging

CT Computed tomography

CR Complete response

PR Partial response

SD Stable disease

PD Progressive disease

3DCRT 3D conformal radiotherapy

GTV Gross tumor volume

CTV Clinical target volume

PTV Planning target volume

HR Hazard ratio

CI Confidence interval

IFN-B Interferon beta

IMRT Intensity modulated radiation therapy

Figure legends

Figure 1: Kaplan-Meier survival curve for OS (1a) and EFS (1b) in the entire study population.

Figure 2: Kaplan-Meier survival curve comparing OS (2a) and EFS (2b) in patients according to induction

chemotherapy regimen.