Radiotherapy in lung cancer. Dr. V. Kouloulias
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Radiotherapy in Lung Cancer
Dr. Vassilis Kouloulias Assistant Professor of Radiation Oncologist, 2nd Dpt. Radiology, University of Athens, Greece.
Key Words
Small cell lung cancer (SCLC), Non-small cell lung cancer (NSCLC), radical, palliative,
radiotherapy, prophylactic cranial irradiation (PCI), radiation induced pneumonitis, cyttoprotection.
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Section I. Small cell lung Cancer
I.1. Introduction.
Small cell lung cancer (SCLC) accounts for 20% of all primary lung tumors. It has a high growth
fraction and at diagnosis the disease is usually extended. Bronchial obstruction is present in 30%-
40% of patients and in 14% of cases a solitary peripheral mass is found. Multiagent drug
combinations are more effective than single agents, while SCLC tumors are normally sensitive to
many chemotherapeutic drugs. Complete response to chemotherapy appears in 40-68% of patients
with limited stage disease and in 18%-40% in those with extensive disease.
I.2. Limited stage
Thoracic irradiation: doses, fractionation, target volumes, beam arrangements.
Some medical oncologists question the indication of thoracic irradiation due to the high incidence of
distant metastases. However, several trials have already shown the beneficial role of radiotherapy in
terms of tumor control and survival [1-3]. Mira et al. [4] reported 30-60% of locoregional
recurrences of patients receiving thoracic irradiation in contrast with 75-80% in patients treated with
chemotherapy alone. Perez et al. [5] in a randomized study involving 304 patients, reported an
intrathoracic failure rate of 52% in patients receiving chemotherapy alone compared with 36% in
those receiving adjuvant radiotherapy. The 2-year survival was 40% in those receiving thoracic
irradiation compared with 23% in the group receiving chemotherapy alone. Perry et al. [6] in
prospective randomized trial of 399 evaluable patients reported a significant number of complete
response in favor of radiotherapy (P=0.0013). Nevertheless, by reviewing the current literature in
reported series comparing chemotherapy alone versus chemo-radiotherapy, data concerning response
or failure rates are rather controversial [3,7]. The summary of reported series is shown in table 1. As
it is shown, most of the randomized trials are reported a positive impact of thoracic irradiation in
terms of survival and local control.
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The timing of chemotherapy and radiotherapy is also a matter of discussion. A meta-analysis of
randomized trials by Pignon et al. [8] with or withour radiotherapy, did not identify any optimal
timing for thoracic irradiation. However, most trials showing no benefit of radiotherapy administered
after or late in the treatment course, whereas many trials have shown a beneficial effect of concurrent
or early thoracic irradiation, as shown in table 1. Moreover, Takada et al. [ ] in the recently published
9104 JCOG randomized trial, documented the beneficial effect of concurrent chemo-radiotherapy in
limited stage of SCLC: median survival 19.7 months in the sequential arm versus 27.2 months in the
concurrent arm. Beyond this, the superiority of early or concurrent thoracic irradiation over delayed
is probably based on the prevention of distant micro-dissemination from chemotherapy-resistant
tumor cells. Although, concurrent use of chemotherapy and radiotherapy with doxorubicin-based or
cyclophosphamide-based regimens could not be combined with full doses of RT because of
increased pulmonary toxicity, cisplatin plus etoposide was found to be the optimal regimen for
combination with concurrent RT since it hardly accelerates toxicity at all and the is no recall
phenomenon. We strongly propose the concurrent schedule, while the irradiation dose should be
given with attention in levels over 50Gy.
Table 1. Comparisons of chemotherapy (CT) alone versus combined chemotherapy plus chest
irradiation (RT) in patients with SCLC.
Ref Mean survival (wk)
Survival (%) Local relapse (%)
Study Start time (wk)
No. of patients
CT RT P (survival)
CT CT+RT CT CT+RT CT CT+RT
[5] Perez et al. 5-11 291 CAV 40Gy .04 49 60 19 28 52 36 Pos
[6] Perry et al. 1-9 247 CAV/CVPV 50Gy .009 similar similar 11 20 Pos
[9] Fox et al. 73 CAVM 40Gy 62 68 4 25 68 32 Pos
[10] Bunn et al. 1 96 CMC/ProAV 40Gy .035 47 64 12 28 67 29 Pos
[11] Ostelind et al.
6-10 145 CMVL 48 NS 46 42 12 5 Neg
[12] Hansen et al.
134 CMV-CCNU 40Gy 60 48 10 4 - - Neg
Radiotherapy in lung cancer. Dr. V. Kouloulias
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[13] Looper et al.
123 CAV-CM 35Gy 43 60 14 29 69 26 Pos
[14] Carlson et al.
25-40 48 POCC/VAM 55 NS 81 78 40 40 Neg
[15] Souhami et al.
13 129 AV/CM 40Gy NS similar - - 32 28 Neg
[16] Livingston et al.
333 VMVP/CAV-CVP
48Gy 67 97 - - 92 45 Pos
[17] Kies et al. 12-17 473 VVPAMC 48Gy similar similar 72 50 Neg
[18] Choi et al. 148 44-54Gy 11 13 0 21 80 25 Pos
[19] Greco et al.
1-6 369 CAV 45 <.05 42 48 21 29 Pos
[20] Creech et al.
8 310 CML 50 .003 56 68 13 19 Pos
fr: fractions; CAV: cytoxan, adriamycin, vincristine; CVPV: cytoxan, vincristine, cisplatin, vinblastine; CAVM: cytoxan, adrimaycin, vincristine, methotrexate; CMC/ProAV: cytoxan, methotrexate, procarbazine, adriamycin, vinblastine; CMV-CCNU: cytoxan, methtrexate, vincristine, lomustine; CM: cytoxan, methotrexate; AV/CM: adrimycin, vincristine, cytoxan, methotrexate; VMVP/CAV: vincristine, methotrexate, vinblastine, cisplatin, cytoxan, adriamycin, vincristine; CVP: cytoxan, vincristine, cisplatin; VVPAMC: vinblastine, vincristine, cisplatin, adriamycin, methotrexate, cytoxan;
Recently for limited stage SCLC, the common element in all positive randomized or simple
prospective trials is the chemotherapy with etoposide+cisplatin combined with radiotherapy [21].
Takada et al. [22] in a randomized trial compared chemotherapy (etoposide+cisplatin) with either
concurrent or sequential radiotherapy and reported beneficial results for the concurrent scheme.
Moreover, Turrisi et al. [23] in another randomized trial compared chemotherapy
(etoposide+cisplatin) with either once daily or hyperfractionated radiotherapy and concluded that the
twice daily scheme is significantly better (26% 5-year survival versus 16%). The definitions for the
target volumes used in radiotherapy according to ICRU 50 guidelines are shown in table 2.
Table 2. ICRU Planning Volume Terminology. ICRU= International Commission on Radiation
Units and Measurements.
Acronym Term Meaning
GTV Gross Tumor Volume Macroscopic tumor volume as
determined by clinical examination,
surgical exploration and imaging
studies.
Radiotherapy in lung cancer. Dr. V. Kouloulias
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CTV Clinical Target Volume GTV plus additional volume to
account for possible microscopic
spread of disease to regional lymph
nodes, adjacent soft tissues, along
fascial planes, etc, according to the
natural history of the particular
neoplasm.
PTV Planning Target Volume CTV plus additional volume to account
for variation in day-to-day setup,
physiologic patient motion of tumor
and other positional uncertainties.
The portal arrangements for SCLC are a subject of controversy. The main stream concerns portals
that encompassing the prechemotherapy primary tumor with a 1-cm margin plus the high risk nodal
bearing areas. Effective chemotherapy normally takes care of subclinical or microscopic disease.
Kies et al. [17] in a randomized SWOG study of patients with limited stage SCLC analyzed patients
treated with either large fields with the prechemotherapy primary tumor or small fields only the
residual disease after two courses of multiagent chemotherapy. Patients treated with large fields had
a slightly better survival and duration of response. Although the clinical target volume (CTV) and the
optimal fractionation schedule have not been definitely established, we may argue that if a 3D-
conformal technique is used, the radiation induced toxicity is minimal and the large fields technique
(prechemotherapy tumor) should be used. The fractionation size should also be 1.8-2Gy 5 days a
week. The total dose should be 50Gy to patients with complete response after chemotherapy and 60-
66Gy to those with partial response. A typical anterior-posterior portal for SCLC based in pre-
chemotherapy CT scans is shown in figure 1.
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Figure 1. 3D conformal radiotherapy with anterior-posterior fields in SCLC (digital reconstructed radiography, DRR). The red lines represent the pre-chemotherapy bulky mass in the mediastinum as was shown in CT slices. The pre-chemotherapy mass is used for the PTV of the thoracic irradiation. The black line stands for the midline, as this line was used for the registration of CT-images and chest-radiography. Conclusions
• Concomitant chemotherapy and 3D-conformal thoracic irradiation should be the treatment of
choice, while the RT should be given with attention in levels over 50Gy.
• Attention with doxorubicin and methotrexate combined with irradiation due to higher toxicity
rates
In terms of sequential chemo-irradiation:
• 54-56Gy of 3D conformal thoracic irradiation after complete response of chemotherapy
• 60-68Gy of 3D conformal thoracic irradiation after partial response of chemotherapy
In terms of consolidation or concomitant chemotherapy:
Individualized block Individualized
block
Pre-chemotherapy
bulky mass and regional nodes. (+1cm safety
margins).
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• 46-50Gy of 3D conformal thoracic irradiation should be given with precautions concerning
radiation induced pneumonitis.
• In case of bulky disease remaining after the 50 Gy, a boost schedule encompassing only the
gross tumor volume might be administered up to 60Gy.
I.3. Prophylactic cranial irradiation (PCI).
In patients with limited small-cell lung cancer, chemotherapy combined with thoracic
radiotherapy yields complete response rates of 50 to 85 percent, a median duration of survival of 12
to 20 months, and 2-year disease-free survival rates of 15 to 40 percent [23,24]. Five-year survival
rates may exceed 20 percent for patients who have complete responses [23]. With the combined
treatment, the risk of a thoracic recurrence decreases, and as a result, brain metastasis becomes one
of the main types of relapse. Although only 10 percent of patients have brain metastasis at the time of
diagnosis, the cumulative incidence at two years is more than 50 percent, [25] which is consistent
with the rate found in autopsy series [26]. Indeed, back to 1970 Mathews et al. [27] observed that
83% of patients with small-cell lung cancer (SCLC) who died one month after curative resection had
residual disease on autopsy and in 50% of them had brain metastasis. Also in the early 70s Hansen
[28] raised the question whether brain irradiation should be in conjunction with systemic
chemotherapy for the treatment of patients with SCLC. From 1977 up to 1997 eleven prospective
randomized clinical trials were published in which SCLC patients with or without limited disease
and complete response were randomized to receive or not prophylactic cranial irradiation (PCI) [29-
39]. These trials showed that PCI significantly decreased the risk of developing CNS metastases.
Most of the trials reported total irradiation dose 30 to 36 Gy [40,41].
A thorough meta-analysis by Auperine et al. [42] published by the Prophylactic Cranial
Irradiation Overview Collaborative Group evaluated prophylactic cranial irradiation in 987 patients
with small-cell lung cancer in complete remission and showed that prophylactic cranial irradiation
Radiotherapy in lung cancer. Dr. V. Kouloulias
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leads to a small but significant absolute reduction in mortality (5.4 percent), even after adjustment for
the extent of initial disease. Additionally, irradiation not only significantly reduced the risk of brain
metastasis, as previously shown in individual trials, but also improved overall and disease-free
survival; these results confirm that prophylactic cranial irradiation prevents and does not simply
delay the emergence of brain metastases. Meert et al. [43] in another meta-analysis of twelve
randomised trials (1547 patients) revealed a decrease of brain metastases incidence (hazard ratio
(HR): 0.48; 95 % confidence interval (CI): 0.39 - 0.60) for all the studies and an improvement of
survival (HR: 0.82; 95 % CI: 0.71 - 0.96) in patients in complete response in favour of the PCI arm.
Auperine et al. also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with
earlier administration of cranial irradiation after the initiation of induction chemotherapy. Summary
data of the survival rate and the relevant hazard ratio are shown in table 3.
Table 3. Results of two meta-analyses of PCI in patients with SCLC in complete remission.
a denotes for Auperine et al. and b denotes for Meert et al. Rate (%) is assessed over a 3-year of
period.
Endpoint Relative risk
(95% confidence
interval)
Rate (%) in the
treated group
Rate (%) in the
control group
Absolute benefit
Overall survival 0.84(0.73-0.97)a
0.82 (0.71-0.96)b
20.7a
-
15.3a
-
5.4a
-
Disease free
survival
0.75(0.65-0.76)a
-
23.3a
-
13.5a
-
8.8a
-
Cumulative
incidence of brain
0.46(0.38-0.57)a
0.49(0.39-0.62)b
33.3a
-
58.6a
-
-25.3a
-
Radiotherapy in lung cancer. Dr. V. Kouloulias
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metastases
Radiation induced neurotoxicity comes as the main argument of the opponents of PCI [44].
From a radiobiological point of view, concerning the early injury of central nervous system, van der
Kogel [45] reported some reactions within the first 6 months after radiation. These radiation injuries
comprise demyelination (somnolence syndrome) or leukoencephalopathy. The pathogenesis is
focused on damages in oligodendrocytes and astrocytes. Some reviews of PCI studies since 1980
investigated neuropsychological effects of brain irradiation and reported cognitive disabilities,
mental abnormalities and neurological disorders [46,47]. Conflicting reports exist regarding the
cognitive effects of prophylactic brain irradiation. Retrospective analyses performed in the 1980s
reported neuropsychological modifications after PCI [48-50]. On the contrary, several randomized
trials [46,51] showed no significant evidence of neurotoxicity. All these years two major questions
are coming trough persistently: is PCI beneficial for SCLC and also is PCI neurotoxic?
Pedersen et al. [52] in a thorough review among 715 patients states that the incidence of
central nervous system relapse in those not receiving PCI was 22% versus 6% in those receiving
irradiation. However the neurological sequelae for a PCI course of 30Gy in ten fractions ranges from
0-12.5%, when chemotherapy is administered concomitant with the PCI. In table 4, the fractionation
and the neurological toxicity of several PCI courses are shown. There are articles emphasizing the
impact of radiotherapy schedule to the incidence of neurotoxicity by means of a critical value of 3
Gy per fraction and up to 30 Gy for total dose [39,41]. Moreover, the toxicity rate after PCI is rather
minimized in the first year of follow-up [41]. Additionally, previous studies suggested that the
concurrent chemotherapy in conjunction with total radiation dose more than 30 Gy in the brain might
affect higher function modifications [47,48,53,54]. Along with this, the younger the patient, the
greater the side effects of the treatment [44,55-59].
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Table 4. Neurological sequelae of PCI in small cell lung cancer patients.
Study No. patients Clinical (%) Radiological Concomittant
CT
Dose/fractions
Lee et al. [60] 24 12.5 yes 30Gy/10
Looper et al. [13] 13 77 yes 30Gy/10
Licciardello et al. [61] 7 42 yes -
Livingston et al. [16] 17 6-12 yes 30Gy/10
Van Oosterhout et al
[62]
32 0 0 No 30Gy/10
Laukkanen et al.[63] 12 50 50 30Gy/10
Twijnsta et al.[64] 14 Yes 30Gy/10
Johnson et al.[65]
Parageorgiou et al.
[66]
11 0 No 30Gy/10
A typical PCI is shown in figure 2.
Reed’s line
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Figure 2. Typical PCI with isodose-lines. The red line stands for the Reed’s line representing the
base of the scalp.
Conclusions
• Concurrent chemotherapy and PCI should be avoided.
• The schedule of 30Gy in 10 fractions seems safe if concurrent chemotherapy is excluded and
performance status is good.
• PCI should be administered in case of complete response of the primary tumor without any
distant metastases. Performance status should not be poor for the administration of PCI.
• PCI should be administered early after the completion of chemotherapy.
• PCI decreases relapses by 23% and prolongs survival by 5%.
• Radiation induced neurotoxicity of PCI seems minimal. Many confounding factors, such as
age, long-term tobacco use, paraneoplastic syndromes, micrometastases, and the
neurotoxicity of anticancer drugs, may have effects erroneously attributed to irradiation
I.4. SCLC: extensive disease
Intensive initial chemotherapy induces a complete response rate of 18% to 40 % in patients with
extensive disease in contrast with 40% to 70% in those with limited disease. The role of radiotherapy
in patients with extensive disease SCLC is not well documented [3]. Delaney et al. [67] in a decision
making model proposed thoracic irradiation only in symptomatic patients with good performance
status. The management of bone or brain metastases definitely includes the administration of
palliative irradiation with conventional or short-term schedules (either 5X400cGy or 10X300cGy). In
general the prognosis is dismal and hardly extends beyond 6 months [3]. Details of the proposed
treatment schedules depending on the stage and performance status are given in figure 3.
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Figure 3. Decision tree for radiotherapy in small cell lung cancer.
Section II. Non Small Cell Lung Cancer
II.1. Introduction
Non-Small Cell Lung Cancer (NSCLC) accounts for 70–80% of all lung cancers.
Unfortunately 2/3 of them are diagnosed in advanced stages. Stage III or locally advanced cancer
comprises approximately 40% of all NSCLC and consists a major therapeutic problem in every day
clinical practice for the radiation oncologist. Stage III NSCLC represents a heterogeneous group of
disease with a great variation of the clinical extent. To add to controversy the borders between
resectable and unresectable Stage III tumors have recently become less clear. New techniques (3D
SCLC
Limited stage
Good PS
Poor PS
Extensive disease
Good PS
Poor PS
Symptomatic local disease
Thoracic RT (54-56G y)+ PCI (30Gy/10fractions) Complete response after chemotherapy Partial response after chemotherapy
Thoracic RT (60-68Gy) +
Thoracic RT (50Gy), (PCI questionable) Complete response after chemotherapy Partial response after chemotherapy
Thoracic RT (60Gy), (PCI questionable)
Asymptomatic local disease
Brain metastases Brain RT
No RT
No brain or bone metastases
Bone metastases
No RT
Local RT
Brain metastases
Bone metastases
Brain RT
Local RT
Thoracic RT (50Gy)
No brain or bone metastases
PCI (ONLY after complete response post RT)
Concomitant chemo-radiotherapy Or consolidation chemo-RT
Early thoracic RT (50Gy) +early PCI (ONLY after complete response post RT)
Concomitant scheme (preferable)
Sequential scheme
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conformal), fractionation schedules (hyperfractionation, CHART etc), combined Chemotherapy-
Radiotherapy (CHT-RT) have been tried with encouraging results, although long term results are not
available yet.
II.2. Postoperative adjuvant radiotherapy
Generally, postoperative radiotherapy has been advocated for positive or close surgical margins. The
definitions of positive/close or clear margins are rather arbitrary. If tumor cells are found in the
surgical margins these are called positive. If less than 0.5cm of normal tissue is present adjacent to
the tumor edge, the surgical margin is usually considered close. More than 1cm of normal tissue is
considered a clear margin. In situations of not clear margins a course of 60 to 66 Gy (2Gy/fraction) is
usually recommended. If during thoracotomy, a complete and thorough resection of mediastinal
nodes is performed and all nodes are negative, then the portal of irradiation should encompass only
the tumor bed with 1.5-2cm safety margins due to respiratory movements.
It is generally agreed that in patients after complete resection and with clear margins as well
as without nodal involvement (T1N0, T2N0), no adjuvant postoperative treatment is needed. Van
Houtte et al. [68] in a randomized trial with 222 patients (T1,2N0) with complete resection, no
beneficial effect of postoperative irradiation was noted. However, there are conflicting reports on the
beneficial effect of postoperative irradiation in patients with N1 disease. Ferguson et al. [69] reported
on 34 patients with T1,2N1 with a 10% survival for surgery alone and 40% for postoperative
radiation therapy. On the other hand Martini et al. [70] reported negative results with 45% for
surgery alone and 13% for postoperative radiotherapy. Recommendations for N2 patients are less
controversial. The Lung Cancer Study Group (LCSG) [71] reported in 1986 the results of
randomized trial in patients with stage II to III epidermoid carcinoma of the lung after complete
resection receiving either postoperative radiotherapy or no treatment. The postoperative radiotherapy
significantly reduced the rate of local recurrence but without any benefit to survival. In general the
causes of controversy for postoperative radiotherapy concerning the randomized trials are mainly due
to the following: lack of proper selection of patients, lack of uniformity in anatomic description of
nodal regions or nodal surgical resection, lack of uniformity in radiotherapeutic target volume or
radiation dose. The survival with postoperative irradiation in NSCLC is shown in table 5.
Table 5. Survival with postoperative irradiation in NSCLC.
Survival rate (%) Median dose
Study Years Surgery alone Radiotherapy (Gy)
Radiotherapy in lung cancer. Dr. V. Kouloulias
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Choi et al. [72] 5 (adeno-Ca)
4 (squamous)
8
33
43
42
45
Chung et al. [73] 3 10 40 46
Green et al. [74] 5 3 35 50
Israel et al. [75] 3 50 70 50
Kirsh et al. [76] 5 0 23 50
Paterson et al. [77] 3 36 33 45
Pavlov et al. [78] 5 24 38 45
Van Houte [68] 5 45 20 60
Wesenburger et al.
[71]
5 53 56 50
II.3. Radical Radiotherapy
Definitive radiotherapy is indicated for approximately 40% of patients presenting with newly
diagnosed non-small cell cancer. Two groups deserve comment: medically inoperable patients with
early stage NSCLC and those with local recurrence. Studies with stage I,II NSCLC medically
inoperable report excellent results in patients with tumors smaller than 2-4cm, good performance
status and doses of 60Gy or more [79]. In terms of postoperative thoracic recurrence, patients with
more favorable outcome included these with a recurrence more than 1 year after surgery, a bronchial
rather than a nodal or chest wall recurrence, younger age, female gender, good performance status,
absence of weight loss and squamous histology. The addition of chemotherapy did not improve
survival.
The portals of radiation fields should include the gross tumor volume (GTV) and the
subclinical disease in terms of regional lymphnodes and/or median carcinomatous pneumonitis. The
planning target volume (PTV) should take into account the respiratory movements of the lungs. The
RT schedule should normally be divided into 2 or more phases, with the technique of shrinking
fields. A typical scheme of target volumes for NSCLC is shown in figure 4.
Radiotherapy in lung cancer. Dr. V. Kouloulias
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Figure 4. Theoretical diagram of target delineation; GTV = gross tumor volume; PTV2 =
planning target volume around the GTV; CTV = clinical target volume (elective treated areas
thought to contain micrometastasis); PTV1 = planning target volume around CTV.
It is common practice to design treatment portals with a 2cm margin around any gross tumor
seen on posterior-anterior radiographs and approximately 1cm margin around electively treated
regional lymphnode areas. Multiple beams and oblique portals are required to deliver adequate tumor
dose with sparing the spinal cord in order to keep the dose below 45Gy. When traditional portals are
used to cover potential lymphatic drainage, the following guidelines are suggested:
If the primary tumor is in the upper lobe the ipsilateral supraclavicular region should be
included in the treatment portal. The inferior portal should be 5 to 6 cm below carina. If the primary
tumor is located in a middle or lower lobe and no mediastinal lymphadenepathy is present, there is
no need to treat the supraclavicular areas. Examples of portals used for irradiation of NSCLC
depending on the anatomic location of the primary tumor are showed in figures 5,6,7. The two
phases of treatment (phase I with tumor, microscopic disease and regional lymhnodes; phase II with
gross tumor volume) are also shown.
CTV2
CTV1
CTV2
CTV1
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Figure 5. Portals used for anterior-posterior fields for NSCLC. CTV1 encompasses regional
lymphnodes of the mediastinal area and CTV2 encompasses mainly the primary tumor. CTV3
encompasses the supraclavicular node (boost).
CTV2
CTV1
CTV3
CTV2
CTV1
Individualized block
A
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Figure 6. A: 3D conformal radiotherapy for Non Small Cell Lung Cancer. The red lines are for the
PTV. The brown lines are for the organs at risk: spinal cord and contralateral lung. B: Isodose lines
in a representative CT slice. The spinal cord and the contralateral lung are sparing safely.
Figure 7. A verification portal (anterior-oblique field for sparing the spinal cord) of a residual mass
of NSCLC after chemotherapy. The energy used is 18MV.
B
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In a recent paper Komaki et. al. [80] performed a recursive partitioning analysis (RPA) of
1547 patients with inoperable NSCLC included in 4 RTOG trials and were treated by radical RT.
Patients in class I (Median Survival Time, MST, of 12.6 months) where those with Karnofsky
Performance Status (KPS) 80–100, negative nodes, age younger than 70, weight loss <5% and
radiation dose ≥66 Gy and they had a 2-year survival rate of 25%. In class II (MST 8.3 months)
patients were of KPS 80–100, node positive, age ≤60 years old, WL<5% and radiation dose <66Gy
and they experienced a 2-year survival rate of 13%. Classes III and IV carried the most dismal
prognosis (table 6).
Table 6. The four classes of recursive partitioning analysis (RPA), by Komaki et al. [80] for patients
treated by radiotherapy alone (WL: Weight Loss, KPS: Karnofski Performance Status).
Class I II III IV
KPS:80–100 KPS:80–100 KPS≤70 KPS ≤70
Main characteristics
Node negative
Age <70
WL <5%
RT Dose ≥66Gy
Node positive
Age >60
WL >5%
RT Dose <66Gy
Pleural effusion
(-)
Pleural
effusion (+)
Median Survival Time
(Months)
12.6 8.3 6.2 3.3
2-year survival rate 25% 13% 8% 5%
Most studies agree that PS is a prognostic factor of absolute significance in inoperable
NSCLC are in agreement on the absolute significance of PS on patients’ prognosis. Most trials
include patients with PS of 0 or 1 and WL <5% when treating patients with radical intent. But there
are also some that include patients with Karnofski PS ≥70 or even 60 [81], which corresponds to PS
≤ 2 in ECOG scale. Therefore, it seems logical to start with a careful evaluation of KPS even before
the staging of these patients. Those with high PS are candidates for radical treatment. Elderly patients
–in case of radical treatment-should also be treated by conventional RT schedule. Movsas et. al re-
evaluated six Phase II and III RTOG trials and found that the elderly patients (i.e. those >70 years
old) were better treated by the conventional scheme of 60 Gy [82].
If radical RT is planned, we have to decide upon the optimal RT scheme. In UK it is a rather
common practice to treat radically patients with stages I-IIIa with a hypofractionated RT scheme of
Radiotherapy in lung cancer. Dr. V. Kouloulias
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20 fractions, while patients with ‘bulky’ stage IIIa,b are usually treated with palliative intent [83].
For this group of patients radical RT is not recommended in UK outside randomized clinical trials. In
the USA more radical treatments are usually given even for those with bulky disease. The ‘golden
standard’ of 60 Gy in 30 fractions is useful, however all authors agree that higher doses are needed to
eradicate NSCLC; on the other hand a higher incidence of morbidity is associated with a dose above
60 Gy given by conventional fractionation. In some studies dose escalation has a positive impact on
tumor control; promising results have been reported by Armstrong et al from the 3D conformal RT
for NSCLC (median dose 70.2 Gy); the authors propose that total dose increase, results in a better
outcome (MST 15.7 months and 2-year survival rate 32%) [84]. 3D conformal RT demands for high-
tec equipment, although in some centers, special techniques have been developed; Wurstbauer et al.
[85] described an interesting technique (target splitting by asymmetric collimation) which can be
easily applied by departments without available 3D planning systems.
Indication exists that some subtypes of NSCLC proliferate rapidly with a potential doubling
time of about 5 days. So there is a clear need for these tumors to be treated by a high dose in a
shorter total treatment time. Such RT schemes are termed accelerated fractionation.
RTOG 83 11 was a phase II dose escalation trial in which patients were randomized to
receive total doses of 60, 64.8, 74.4, and 79.2 Gy hyperfractionated. This trial suggested that there
was a favorable subgroup with good PS, WL<5% and received total dose of greater than 69.6 Gy
[86].
The published CHART-lung trial [87] reported 2-year survival rates of 20% for standard RT
of 60 Gy/30 fr., and 29% for the CHART arm. In the subgroup of patients with non-squamous cell
histology, the conventional RT resulted in a better 2-year survival of 27 vs. 21%, but it did not reach
statistical significance. Some authors have criticized the inclusion of stage I and II patients (30 and
7% respectively). These earlier stage patients frequently had unfavorable features such as older age,
coincidental disease, etc; all patients had to be of PS 0.1. A modified CHART scheme, the
CHARTWELL (weekend less) i.e. 60 Gy in 18 days is currently being tested [88]. The option for
CHT given with CHART is also considered [87].
II.4. Chemoirradiation
Combined chemotherapy and radiation is now considered the treatment of choice for locally
advanced inoperable non-small cell lung cancer in patients with good performance status and
absence of weight loss. The results of most randomized trials showed the superiority of sequential
chemo-radiotherapy or combined chemo-radiotherapy versus radiotherapy alone [3]. Trials that
Radiotherapy in lung cancer. Dr. V. Kouloulias
20
failed to show a difference in survival did not use cisplatin-based chemotherapy or gave low doses of
irradiation [89,90].
Despite the promising results of modified fractionation schemes both local control and distant
metastases rate are far from satisfactory. Therefore combined modality treatment is being
investigated. Chemotherapy is administered as inductive, alternating, concurrent or various
combinations with RT. A meta-analysis with updated data on individual patients, involving 52
randomized clinical trials has recently been published. Trials comparing RT with RT plus CHT gave
a 13% reduction in the risk of death (absolute benefit of 4% at 2 years) [91]. Numerous other trials
advocate the combination of RT-CHT reporting acceptable toxicities (table 6) while the few trials
reporting negative results have been criticized [92,93]. The majority of these trials include patients
with KPS of ≥70. Komaki et.al. compared the three arms of trials RTOG 88–08/ECOG 4588 and
they concluded that the addition of chemotherapy decreases the risk of distant metastases and
increases survival for non-squamous NSCLC; survival rates were similar among the treatment arms
for patients with squamous-cell carcinomas [94].
Cox et. al. in a similar study performed an evaluation of the influence of chemotherapy on
therapeutic result of the combined treatments for various histologies of stage III NSCLC [95]. They
analyzed data from 4 RTOG RT-alone studies (1415 patients) and 5 RTOG combined- treatment
studies (350 patients). The main conclusions were very important:
Conclusions
• Patients with low PS should be treated by short-term palliative RT courses
• Chemotherapy reduces distant metastases in all types of NSCLC
• Chemotherapy has different effects on the primary tumor by cell type
• Chemotherapy has no effect on the development of brain metastases
• Squamous cell carcinomas should be approached in a different manner than the other
histological types. Dose escalation studies from the radiotherapeutic point of view might be
the key point
• The high risk of brain metastases in patients with non squamous-cell NSCLC probably
justifies the use of prophylactic cranial irradiation in these patients.
Similar conclusions are drawn by Movsas et al. [83], who have re-evaluated the 979 patients
treated in 6 prospective Phase II and III clinical trials from 1982 to 1995. Treatment regimens ranged
from conventional, to hyperfractionated (69.6 Gy), induction chemotherapy plus conventional RT,
Radiotherapy in lung cancer. Dr. V. Kouloulias
21
induction+concomitant+conventional RT, etc. Patients with low KPS (50–70) had the lowest MST
(7.8 months), patients <70 years of age had improved survival with the use of aggressive therapy,
while those with >70 years of age were better treated by the conventional schedule. A dramatic
improvement was seen in patients with squamous cell histology who received induction+concomitant
chemotherapy plus conventional RT (median survival 25.7 months).
Trials RTOG 88 08 and ECOG 45 88 [96] compared in a three arm study conventional RT,
induction chemotherapy – conventional RT and hyperfractionated. The 2-year survival rates were
20%, 31% and 24% and the MST 11.4, 13.6 and 12.3 months respectively. There was a consistent
difference between radiation alone and chemo-irradiation that was statistically significant (log-rank p
= 0.05), while hyperfractionated RT was better than conventional RT at every time point but
differences were not statistically significant. Primary tumor was equally controlled with the use of
either induction chemotherapy or hyperfractionated RT. Distant metastases were less for chemo-
irradiation compared to RT alone groups. Survival rates were similar among the treatment arms for
patients with squamous cell neoplasms. Among patients with non-squamous histologies, failure
patterns did not differ by treatment group, but survival was significantly better in those treated by
induction chemotherapy (p = 0.04).
Jeremic et. al. [97] have reported a significant improvement in median survival time (MST)
and 2-year survival probability for patients treated with hyperftactionated RT plus weekly concurrent
chemotherapy (VP16, Carboplatin). The arm treated by hyperfractionated RT only gave results
similar to that given by the RTOG 83 11 trial. Toxicity of combined treatment was acceptable. None
patient died of treatment related toxicity. The same authors conducted a second trial with two arms
[98]. Hyperfractionated RT in a dose of 69.6 Gy was given in both, while chemotherapy was given to
the second arm, but it was administered in a more continuous way on each RT day and using a lower
dose per administration. The combined treatment arm experienced a MST of 22 months and a 2-year
survival of 43% vs 14 months and 26% in the RT alone arm. The problem of controlling distant
metastases remains. The additional use of intensive sequential chemotherapy should be considered.
Komaki et.al. studied two different combinations of RT and chemotherapy in a randomized trial with
two arms [99]. Patients in the first arm were treated with induction chemotherapy followed by
concurrent chemo-irradiation: Vinblastine was administered weekly and cisplatin on days
1.29.50.71.92; RT started on day 50. 63 Gy were given in 34 fractions/7 weeks. In the second arm,
patients received concurrent chemo-irradiation: RT started on day 1 and a total dose of 69.6 Gy /58
fr. was given. DDP was given in days 1 and 8 and VP16 was given during the first 10 days. Patients
had to be of PS ≥70 and WL<5%.The first arm showed greater haematologic toxicity while the
Radiotherapy in lung cancer. Dr. V. Kouloulias
22
second greater acute and late esophageal toxicity. The MST was 15.5 and 14.4 months respectively;
1-year survival 65% and 58% and 2-year survival were approximately 28% for each arm.
Therapeutic outcome was similar for both groups and similar in absolute numbers to the ‘concurrent’
arms of other trials (table 2) [100–103]. The ‘every-two-weeks’ concurrent chemo-irradiation was
tested in a trial conducted by Blanke et. el. [104]. The MST and 2-year survival rates were similar
between arms of RT, and chemo-RT (table 7). The alternating hyperfractionated RT – chemotherapy
(rather similar to the above-mentioned schedule) was tested in GOTHA I and II trials [105], giving
an MST of 13.6 months and 2-year survival of 27% with acceptable toxicity. The rates were better
than those reported by Blanke et.al., although the study included patients with KPS of 70–100.
The reported results in terms of 2-year survival rates are rather in favor of lower daily doses
of chemotherapeutic agents. In this way chemotherapeutic agents seem to behave like
radiosensitizers. Nevertheless such a regimen failed to control effectively distant metastases. To
improve overall survival further, additional use of CHT should also be considered in future
randomized clinical trials.
Table 7. Trials of combined chemotherapy-radiotherapy (CHT-RT).
CHT: Chemotherapy, CONC: Concurrent, IND: Induction, ALT: Alternating, STD: Standard (30x2Gy),
ACCEL: Accelerated,
AUTHORS ARMS CHT RT SCHEME RT DOSE Nm
Patient
s
1-year
survival
2-year
survival
1 - 50 48 25 Soresi et al. [106]
2 Cisplatin
25X5 50
45 73 40
1 - 55 110 46 13 Schaake-Konig et.
al. [107] 2 Cisplatin
10X3-, 3 week rest-
10x2.5 55 110 54 26
1 - 45 85 Trovo et. al. [92]
2 Cisplatin,
15x3
45 86
1 - 65 177 14 Arriagada et. al.
[100] 2 VCPC
26X2.5
65 176 21
Dillman et. al. [101] 1
Cisplatin
Vinblastine
30X2 60 78 26
Radiotherapy in lung cancer. Dr. V. Kouloulias
23
2
- 60 77 13
1 - 60–65 105 45 13 Blanke et. al [104]
2 Cisplatin
30X2
60–65 110 43 18
1 - 69.6 203 Komaki et. al [86]
2 Cisplat/ VP16
Hyperfractionated
69.6 76 22 35
1 Vinblastine
Cisplatin
35X1.8 63 80 65 Komaki et. al [99]
2 VP16
Cisplatin
Hyperfractionated 69.6 82 58
1 - 60 152 20
2 Cisplatin-
Vinblastine
30X2
60 152 31
Komaki et. al. [94]
3 - Hyperfractionated 69.6 154 24
1 - 69.6 66 68 26 Jeremic et. al [98]
2 Carboplat
VP16,
Concurrent
/daily
Hyperfractionated
69.6 65 74 43
1 - 64.8 61 39 25
2 Carboplat
VP16,
Concurrent
/weekly
64.8 52 73 35
Jeremic et. al [97]
3 Carboplat
VP16,
Concurrent
/1.3.5 weeks
Hyperfractionated
64.8 56 50 27
1 63 65 56 27 Miramanoff et. al.
[105]
2
Hyperfractionated
63 67 56 27
Radiotherapy in lung cancer. Dr. V. Kouloulias
24
1 Vinblast
+Cis-plat
60 120 54 26 Clamon et. al. [102]
2 Vinblast+Cis-
platine +carbo
30X2
60 130 56 29
1 NO 30X2 60 225 21
2 NO CHART 54 338 30
Saunders et. al. [88]
CHART 2
_ Hyperfractionated 63.9 50 60 18
The locoregional or intrathoracic failure rate within the irradiated volume is dose dependent. It is a
common secret that local recurrences especially in the gross tumor volume are the main problem in
NSCLC. In all trials with irradiated dose less than 60 Gy the local recurrence is ranging from 40% to
48% [3,108]. The rates of recurrences after chemoradiotherapy is shown in table 8.
Table 8. Local failure rates. The failure rate is apparently dose dependent.
Irradiated dose Local failure rate
40Gy continuous dose 48%
40Gy split course 38%
50Gy continuous 38%
60Gy 27%
70Gy <20%
As a boost to the primary tumor seated inside the bronchus (endobroncial disease) the
radiation oncologist may also administer intraluminar irradiation as brachytherapy [109].
II5. Stage IIIA-N2. Chemo-irradiation, surgery or combination?
RT or surgery alone have had limited success in treating patients with both occult and marginally
resectable overt N2 disease. Current investigations are exploring various means of integrating
surgery, RT, and chemotherapy. To date, no studies have established the optimal chemotherapy or
chemotherapy/RT regimen for N2 patients, but most induction regimens have used platinum-based
chemotherapy.
Radiotherapy in lung cancer. Dr. V. Kouloulias
25
In the only other trial comparing surgical and nonsurgical treatment in this setting, Shepherd
and associates [110] have reported a randomized trial of chemotherapy plus surgery vs. RT alone for
biopsy-proven Stage IIIA NSCLC. Thirty-one patients were randomized. The median survival was
16.2 and 18.7 months for RT alone and chemotherapy plus surgery, respectively, with no
improvement in long-term survival seen with combined-modality surgical treatment.
Do any other data suggest that RT with or without chemotherapy is a reasonable alternative to
surgery with or without chemotherapy? A common conception is that RT alone is significantly
inferior to surgery alone for N2 disease. However, N2 patients referred for RT are not a comparable
group of patients to those who undergo surgery; such patients are usually rejected for surgery
because of disease bulk or medical contraindications. Accordingly, few RT data are available for a
surgically suitable group of N2 patients. The existing evidence suggests that hyperfractionated RT to
69.6 Gy in 6 weeks yields survival results surprisingly close to those for surgery. On analysis of
completed RTOG lung trials using RT alone, a group of patients was identified that had clinical N2
disease, favorable prognostic factors (Karnofsky performance score >70, and <5% weight loss), and
a T-stage distribution similar to surgical series. For standard fractionation RT, the 3-year survival
rate was only 7%, but for hyperfractionated RT it was 20% [111]. This result is similar to that in
several of the surgical series [112-113]. There will not likely ever be a direct comparison of RT and
surgery for N2 disease. [114]. Thus, even with the best locoregional treatment, one could not expect
to control the disease in more than 40% of patients. For patients with overt N2 involvement, even if
nonbulky, the risk of systemic disease is even higher, and locoregional treatment alone would fail in
90% of patients.
Some promising results have come from two small Phase III trials of chemotherapy induction
followed by surgery, with and without RT. The median survival in the first study was 26 months for
induction chemotherapy followed by surgery and RT and was 8 months without induction
chemotherapy [115]. In the second study, the median survival had not yet been reached using
induction chemotherapy followed by surgery compared with 18 months for surgery alone [116].
Moreover, Arriagada et al. [117] in a well documented meta-analysis concluded that there was no
effect of postoperative radiotherapy in patients with N2 disease, while there was no doubt for the
deleterious effect of post-RT in N0,N1 patients. These results sugest that the optimum scheme of
combined treatment for N2 patients is the following: chemo-irradiation (up to 50Gy) and in case or
respectability, then surgery. In case of unresectability, then chemotherapy in consolidation therapy.
Conclusions
Radiotherapy in lung cancer. Dr. V. Kouloulias
26
• Radiotherapy after chemotherapy and surgery for N2 patients is not recommended.
• Concomitant chemo-irradiation ±surgery might be the treatement of choice
• The dose of pre-operative radiotherapy should not exceed 50Gy.
II.6. In the context of chemoradiotherapy: sequential, concomitant, induction or consolidation
chemotherapy?
Cancer and Leukemia Group B (CALGB) study 8433 compared induction chemotherapy consisting
of cisplatin and vinblastine followed by daily radiation to daily radiation alone [101]. The induction
chemotherapy-containing arm showed improvement in median survival from 9.7 to 13.8 months. The
benefit of sequential induction chemotherapy followed by daily radiation was confirmed in an inter-
group trial (RTOG 8808, ECOG 4588, SWOG 8992) [118]. Sequential chemoradiotherapy appears
to improve survival by lowering the rate of systemic relapse and does not appear to improve local
control compared to radiotherapy alone [119]. Concomitant chemoradiotherapy also improves
survival compared to radiation alone and appears to improve survival primarily by improving local
control [120].
Sequential or concurrent chemotherapy added to daily radiation has now been compared in
phase III randomized trials. A trial by the West Japan Group compared sequential full dose
mitomycin, vindesine and cisplatin followed by daily radiation to a dose of 56 Gy to the same
chemotherapy given concurrently with a split course of daily radiation to a dose of 56 Gy [119]. The
concomitant therapy arm had a median survival of 16.5 months compared to 14.2 months in the
sequential treatment arm. Radiation Therapy Oncology Group (RTOG) trial 9410 compared
sequential versus concomitant chemotherapy as used in CALGB 8433 added to daily radiation of 2
Gy to a total dose of 60 Gy [120]. The third arm of RTOG 9410 was concomitant cisplatin and oral
etoposide with twice-daily radiation of 1.2 Gy to a total dose of 69.6 Gy. Median survival was 17
months for concomitant chemotherapy with daily radiation versus 14.6 months for sequential therapy
(P=0.038) and 15.6 months for concomitant chemotherapy and twice daily radiation. A French
randomized phase III trial compared sequential chemoradiotherapy consisting of cisplatin and
vinorelbine followed by radiation to 66 Gy to concurrent chemoradiotherapy with cisplatin and
etoposide followed by cisplatin and vinorelbine and reported a trend toward improved survival for
the concurrent therapy arm [121]. A Czech randomized phase II trial comparing sequential versus
concurrent chemoradiotherapy with cisplatin and vinorelbine showed a median survival of 396 and
619 days, respectively [122]. The results of these studies suggest that the current standard of care
should be concomitant platinum-based chemotherapy and once daily radiation for patients with good
Radiotherapy in lung cancer. Dr. V. Kouloulias
27
performance status. Patients with poor performance status, significant weight loss or pleural effusion
were excluded from RTOG 9410 and there have been no randomized trials comparing sequential to
concurrent chemoradiotherapy in that group of patients. Adding full dose chemotherapy to eradicate
occult micrometastases before or after concomitant chemoradiotherapy that improves local control
has the potential to improve survival in locally advanced NSCLC.
Giving full dose systemic chemotherapy prior to concomitant chemoradiotherapy treats
micrometastatic disease immediately before it has the opportunity to progress or become resistant to
the lower doses of chemotherapy that are typically given concomitantly with radiation. In addition
compared to consolidation therapy, induction chemotherapy is delivered at a time when the patient
will better tolerate side effects and bone marrow suppression. CALGB 9431 is a randomized phase II
trial in which all patients received two cycles cisplatin based induction doublet chemotherapy and 2
cycles of cisplatin based doublet chemotherpay concurrent with daily radiation 2 Gy per fraction to a
total dose 66 Gy [123]. Patients were randomized to receive gemcitabine, paclitaxel or navelbine as
the second chemotherapeutic agent. The median survival for all patients was 17 months and there
was no clear superiority to any of the recent generation chemotherapy agents. A phase II trial that
evaluated induction chemotherapy with paclitaxel and carboplatin followed by concomitant
chemoradiotherapy with weekly paclitaxel, carboplatin and conformal radiation therapy to a dose of
74 Gy had a median survival of 26 months with 1-, 2-, 3- and 4-year survival rates of 71, 52, 40, and
36%, respectively [124]. CALGB 30105 is an ongoing randomized phase II trial with one arm being
the above regimen and the other consisting of induction carboplatin and gemcitabine followed by
concomitant chemoradiation with twice weekly gemcitabine 35 mg/m2 also with conformal thoracic
radiation to a dose of 74 Gy.
Beginning therapy with concomitant chemoradiotherapy utilizes what appears to be the most
important component of the combination immediately before the often bulky local tumor can become
larger or become chemoradioresistant. Southwest Oncology Group (SWOG) 9019 gave concurrent
chemoradiation with cisplatin and etoposide followed by consolidation with 2 cycles of cisplatin and
etoposide. In 50 patients with stage IIIB NSCLC the median survival was 15 months [125]. SWOG
9504 used the same concomitant chemoradiotherapy as SWOG 9019 but replaced two cycles of
cisplatin and etoposide consolidation with two cycles of docetaxel. SWOG 9504 had an encouraging
median survival of 27 months, with 1- and 2-year survivals of 76 and 53%, respectively [126].
The Locally Advanced Multimodality Project or LAMP trial is a randomized phase II trial with three
arms of paclitaxel and carboplatin chemoradiation: arm 1 induction chemotherapy followed by
radiotherapy alone, arm 2 induction chemotherapy followed by concomitant chemoradiotherapy, and
arm 3 concomitant chemoradiotherapy followed by consolidation [127]. The reported median
Radiotherapy in lung cancer. Dr. V. Kouloulias
28
survivals for the three arms of the LAMP trial are arm one 13 months, arm two 12.8 months, and arm
three 16.1 months.
Conclusions
• Chemoradiotherapy is superior to radiation alone for locally advanced unresectable stage III.
NSCLC.
• Concomitant chemoradiotherapy appears to be superior to sequential chemoradiotherapy for
good performance status patients.
• Encouraging results from phase II trials suggest that induction or consolidation chemotherapy
added to concomitant chemoradiation may improve outcome
II.6. Superior vena cava syndrome
Superior vena cava syndrome is a medical emergency that requires immediate therapeutic action.
The syndrome is produced by extrinsic compression of the superior vena cava or intracaval
thrombosis which is seen in approximately 40-50% of patients with this syndrome. Although it is
generally believed that these patients have an extremely poor prognosis approximately 10% - 20%
survive longer than 2 years [128]. Therefore in the absence of distant metastases, aggressive
management and support are indicated. Radiotherapy should be initiated as soon as possible. Patients
should initially be given high dose fractions (4Gy per fraction) for 2-3 days, followed by
conventional radiotherapy [129]. The recommended total dose for patients with localized
bronchogenic carcinoma should be 60-70Gy while in patients with malignant lymphoma should be
40-45Gy. Radiation therapy portals (fig. 8) should include the mediastinal, hilar, supraclavicular
nodal areas and any adjacent parenchymal pulmonary lesions.
Alternatively, superior vena cava syndrome secondary to malignant disease is preferentially
treated by endovascular stenting with highly palliative effect [130]. Adjuvantly, external beam
radiation and/or chemotherapy would also be administered for tumor mass reduction.
Radiotherapy in lung cancer. Dr. V. Kouloulias
29
Figure 8. Typical portal of RT for vena cava syndrome.
II.7. Palliative RT
According to all publications and most of the radiation oncologists agree that patients with
low PS must be treated palliatively with short hypofractionated RT schedules. In every day clinical
practice radiation oncologist is called to treat patients with local disease too extensive for radical
treatment. According to MRC studies an effective palliative treatment could be a 2 x 8.5 Gy one-
week apart regimen [131]. In case of a low PS a single fraction of 10 Gy could be administered
[132]. These studies have significantly influenced clinical practice in the UK and other countries
[133], since they offer fast and effective palliation. It should be emphasized that the large dose per
fraction does not produce unacceptable toxicity; especially for the widely used 2x8.5 Gy scheme the
risk of radiation myelitis is extremely low if the spinal cord is blocked in the posterior field of the
second fraction [134].
A third MRC study [135] comparing 2x8.5 Gy with 13x3 Gy for patients with good PS
showed no difference in palliation, more severe and prolonged oesophagitis and a small but
statistically significant increase in 2-year survival for the higher dose regimen (13 vs 9%). It is
concluded that it is difficult to decide the trade-off between the increased toxicity and relative
inconvenience against a modest increase in survival for an individual patient. The option between
radical and palliative treatment may be based on the presence of the unfavorable patient and disease
characteristics. Low PS (<60), WL >5%, positive pleural effusion, TNM stage of T4 or N3 and
intensive symptomatology advocate the use of short course-palliative RT schemes. Nevertheless the
10x3 Gy course is widely used in the USA as the schedule of choice with palliative intent.
CTV
Radiotherapy in lung cancer. Dr. V. Kouloulias
30
Particularly for patients with supraclavicular node metastases (when there is lack of other adverse
prognostic factors) Machtay et al. [136] reported that when treated with modern chemoradiotherapy
these patients appear to have similar prognosis to other stage IIIb patients. Platinum-based
chemotherapy is also recommended for patients with metastatic NSCLC and good performance
status, while short term hypofractionated radiation therapy should also be considered for symptoms
relief in these patients [137].
Conclusions
• CTV to PTV margins are 2cm around GTV and 1cm around regional lymphnodes.
• Spinal cord dose should be kept below 45Gy.
• 3D conformal should be the treatment of choice for irradiation. Traditional anterior-posterior
fields should be used only for phase I of irradiation schedule or palliative radiotherapy.
• The lung volume received dose of 20Gy (V20) should not exceed the 30% of total lung volume
in order to minimize the radiation induced pneumonitis.
• The most important unfavorable characteristics of patients with NSCLC are: low KPS, weight
loss>5%, positive pleural effusion, intensive symptomatology and distant metastases.
• For patients with unresectable stage IIIa,b and a PS of 70–100, a radical treatment should be
given in terms of combined chemo-radiotherapy.
• Results from randomized clinical trials advocate the use of intensive RT (e.g. CHART or
HFXRT).
• In case of radical RT alone the general recommendation is to administer as high dose as
possible in as short as possible overall treatment time.
• The dose of 60 Gy in 30 fractions should be the least therapeutic dose to eradicate such a bulky
disease, while it is the recommended RT schedule for patients over the age of 70 years.
• A high dose hyperfractionated RT scheme, or the CHART (in case of squamous cell
carcinoma) could be employed.
• In all randomized clinical trials it is always reproduced that combined RT+CHT gives better
therapeutic results that RT alone, and that HFX/ACCRT yields better results than STDRT
alone.
• Results from randomized trials advocate the use of combined RT-CHT as a continuous way as
possible. Platinum based chemotherapy can be combined to radiation therapy as inductive,
concurrent or in consolidation.
Radiotherapy in lung cancer. Dr. V. Kouloulias
31
• If the above-mentioned therapeutic modalities are not available a tumor dose of at least 60 Gy
in 6 weeks (or shorter) or its radiobiological equivalent could be employed.
• For patients with PS of 70 with either locally too advanced disease or positive pleural effusion,
a palliative (e.g. 2 x 8.5 Gy or 13 x 3Gy) RT regimen can be given.
• Concurrent CHT+RT and intensified RT schedules (hyperfractionated-accelerated) should be
administered for radical irradiation.
• In terms of 3D conformal, positive are regional lymphnodes with diameter more than 1.5cm
(probability 90% of having pathological involvement).
• The GTV – CTV margins are depending on the histology: 6mm for adenocarcinoma and 8mm
for squamous cell.
• The acute side effects after RT are: acute pneumonitis, acute esophagitis, cough, Lhermitte
syndrome. The management consists of bed/rest-bronchodilators-corticosteroid-O2
(pneumonitis), mucosal anesthetics-liquid antacids (esophagitis), antitusive therapy (cough),
antibiotics (secondary infection), antifungal medication (esophagitis). In severe esophagitis,
nasogastic tube or intravenous hyperalimentation. In severe acute pneumonitis, hospitalization
due to high percent of mortality.
• Spinal cord myelopathy with doses >45
• Esophagitis as a late complication (stenosis, ulceration, perforation, fistula) occurs in 5% or
more of patients with 60Gy dose delivery in esophagus. Very careful with cis-platin combined
with RT, since the previous incidence is higher.
• Doxorubicin plus RT have synergistic effect with RT for the induction of cardiotoxicity.
Figure 9. Decision tree for radiotherapy in non small cell lung cancer [3,125].
Radiotherapy in lung cancer. Dr. V. Kouloulias
32
The general outcome to the treatment of lung cancer according to stage is shown in table 9.
Table 9. General approach to the treatment of lung cancer and outcome [21,126].
Local recurrence
NSCLC
S tage I - II
Good PS
Poor PS
Stage IIIa
Good PS
Poor PS
S urgery
Thoracic RT (50Gy )
Surgery
No surgery (medically inoperable)
Thoracic RT ( >60 Gy)
No surgery
Good PS
Palliative RT
Stage IIIb Thoracic RT (>60Gy)
Palliative RT + supportive care
Poor PS
Stage IV
(+) margins
( - ) margins Local Recurrence Thoracic RT ( >60 Gy )
No Local Recurrence
N o distant Metastases
No RT
Asymptomatic bone metastases in no - weight - bearing bones Symptomatic bone metastases Local RT
Brain metastases
Brain RT
Thoracic RT ( ≤ 60Gy, or palliative )
N0,N1
(+) m argins Thoracic RT (50Gy )
(-) margins
Thoracic RT ( >60 Gy )
No Local Recurrence
No distant Metastases No RT
Asymptomatic bone metastases in no - weight - bearing bones
Local RT
Brain metastases
Brain RT
Thoracic RT (50Gy )
N>1
Symptomatic bone metastases
Thoracic RT ( >60 Gy )
Thoracic RT
(≤60Gy, or palliative)
No Local Recurrence
No RT
Asymptomatic bone metastases in no - weight - bearing bones
Symptomatic bone metastases Local RT
Brain metastases
Brain RT
No Local Recurrence
platinum based chemotherapy: Induction, concomitant or consolidation
platinum based chemotherapy: i nduction , concomitant , or consolidation hyperfractionated RT
Supportive care
Thorasic RT (50Gy) Surgery IIIA,N2
Good PS
IIIA,N2 Poor PS
Operable Inoperable Chemotherapy
Radiotherapy in lung cancer. Dr. V. Kouloulias
33
Stage Treatment Outcome
Non small cell cancer
I Surgical resection, ±
chemotherapy
5-year survival >60-70%
II Surgical resection, ±
chemotherapy
5-year survival >40-50%
IIIA Surgical resection, +chemo-
irradiation
IIIA,N2 Chemo-irradiation ± surgery
IIIB without pleural effusion Chemo-irradiation
5-year survival >15-30%
IIIIB with pleural effusion or IV Chemo-irradiation Median survival 8-10mo
1-year survival 30-35%
2-year survival 10-15%
Small Cell Cancer
Limited stage Chemo-irradiation 5-year survival 15-25%
Extensive disease Chemotherapy + palliative
irradiation
5-year survival <5%
Section III. Radiation induced pneumonitis
Radiation pneumonitis (RP), which manifests within a period of 1–8 months after radiotherapy (RT),
is one of the most significant complications. RT-induced pulmonary symptoms occur in about 20%
of all PTs irradiated for lung cancer or other thoracic neoplasms, while subclinical functional and
radiological changes are seen in an even larger fraction of patients [140-143].
Several studies have investigated the relationship between a number of clinical factors including age,
gender, performance status, pulmonary comorbidity, tumour site, changes in plasma, cytokine
transforming growth factor-β levels, histology and the development of severe RP [144-147]. Some
authors have focused their analyses on patients treated with combined modality treatment
(chemoradiotherapy), for which an increased risk of RP has been postulated [98,107,108,148-150].
However, most of these studies did not take into account 3D dosimetry data.
Some reports have identified `simple' dosimetric risk factors for RP [150]. Based on the detailed
dosimetric information provided by three-dimensional (3D) treatment planning tools, other
researchers have related the risk and severity of RP to specific Dose Volume Histogram (DVH)
Radiotherapy in lung cancer. Dr. V. Kouloulias
34
parameters [151-155], and a few studies have characterised the dose–response curve for RP
following RT by means of biological models [156-158].
While there is a number of differences in the published reports, there is some consensus about
the association between a few of the dosimetric factors (mainly the mean lung dose Dmean) and the
incidence of RP [152,159]. Most lung cancer patients showed poor pre-treatment pulmonary function
and among those patients, chronic obstructive pulmonary disease (COPD) was not an uncommon
clinical finding. However, the role of pre-treatment lung function and the influence of covariates
such as chemotherapy agents are still under debate. According to several publications, the incidence
of clinical pneumonitis is correlated with parameters from the DVH of the total lung volume (figure
10).
Figure 10. Representative DVH for total lung. The indices of V20 and V30 are
shown.
In general, the most statistically significant factor predicting pneumonitis seems to be the percent
volume of the total lung exceeding 20 Gy (V20). According to Graham et al. [151], there was a strong
correlation between V20 and the severity of pneumonitis (table 10). When the V20 was less than 22%
there was no pneumonitis. When the V20 was 22–31% there was an 8% Grade 2 pneumonitis, but no
higher severity. It was not until >32% V20 where high-grade pneumonitis ( Grade 3) was
encountered. The highest incidence of severe ( Grade 3) pneumonitis was in patients with a V20 >
40%, where there was a 23% crude incidence of Grade 3–5 pneumonitis and 3 patients died of
unequivocal radiation-induced pneumonitis.
V30
V20
Radiotherapy in lung cancer. Dr. V. Kouloulias
35
Table 10. Correlation between V20 and severity of pneumonitis
V20 (%) Grade 2 (%) Grade 3-5 (%)
<22 0 0
22-31 8 8
32-40 13 5(1 fatal)
>40 19 23(3 Fatal)
It seems that there is little correlation between the tumor size (measured by the GTV in cc) and the
V20 [151]. This implies that the potential ability to give escalated radiation doses is not limited to
small tumors, but rather to the patient's unique anatomy and the treatment planning in order to keep
the V20 as low as possible. The V20 parameter is easily identified on all treatment planning systems
and can be quickly utilized as a parameter to judge whether a plan is acceptable or whether the plan
is better than a computing plan.
Marks et al. [150] reviewed the results of 100 patients after 3D CRT for the development of
pneumonitis, pulmonary fibrosis, and/or pulmonary symptoms. Although the authors looked at
additional biologic (transforming growth factor-β [TGF-β]) and functional (PFTs and ventilation–
perfusion scans) parameters, the best predictors of "pulmonary symptoms" after radiation therapy
(RT) were the V30 and the Normal Tissue Complication Probability (NTCP, Lyman model). This is
most consistent with our presented data in this paper. The V20 and V30 parameters may be nearly
identical parameters particularly when "traditional" plans are used. They may differ in the future if
new treatment modalities are created that use nonconventional beam arrangements, or intensity
modulation.
In a study involving the pooled data of five institutions with 540 patients, Kwa et al. [158]
reported that the mean lung dose, (NTDmean) was a useful predictor of the risk of pneumonitis. Future
studies are indicated to further identify and refine these DVH data in predicting not just "risks" of
pneumonitis, but who exactly will develop pneumonitis. It is anticipated that there are unique and
individual biologic/physiologic responses to radiation that will not be well predicted by this empiric
dose–volume relationship. Further modeling taking into account other biologic markers, such as
cytokine changes [159-164] underlying lung function, may be necessary.
In addition, it is clear that there are other pulmonary outcomes worth evaluating after 3D
treatment, such as lung fibrosis, long symptomatic pulmonary function, and quality of life as it
relates to lung function. However, because the V20 seems to be the most important predictor of
Radiotherapy in lung cancer. Dr. V. Kouloulias
36
pneumonitis, this implies to us that the volume effect in the development of acute pneumonitis is a
much more important factor than the physiologic lung function and response to radiation of the
affected parts of the lung.
Until further investigations of this nature can be performed, we recommend that the total lung
volume DVH be assessed when evaluating the "goodness" of a 3D radiation plan in the treatment of
NSCLC patients. In the clinic of Carlos Perez, some practical guidelines are used for the routine lung
radiotherapy:
Conclusions and recommendations
• When the total lung V20 is <25%, we might be comfortable with tumor dose escalation and
the very low risk of pneumonitis. These plans are considered "acceptable."
• If a plan has a total lung V20 of >25% to 37%, alternative plans should be made with an
attempt at reducing the V20. This may be achieved by different beam arrangements,
noncoplanar beams, less or no elective nodal irradiation, or smaller margins around the target
volumes. This last technique is applied only as a last resort and should be carried out with
great caution as it may decrease the dose delivered to the tumor.
• If a treatment plan gives a V20 of >35–40%, we do not use that plan for treatment. All fatal
pneumonitis occurred in patients with a V20 35%.
• Similarly, all high-grade pneumonitis occurred in patients with a V20 of 32%. The risk of
pneumonitis seems too great. Options for treatment then include: (1) changing the plan, as
outlined above, (2) administering neoadjuvant chemotherapy in an attempt to reduce the
volume of the tumor and treat the postchemotherapy tumor volume, and (3) treating the
patient palliatively with lower doses.
As we move into the era of intensity-modulated radiation therapy (IMRT) and potentially more
unconstrained beam arrangements, these data may not be valid. Further work in confirming these
data with higher doses and IMRT is indicated.
Section IV. Cyttoprotection – Amifostine
Efforts to develop pharmacologic agents that protect normal tissues from the effects of radiation are
long-standing. One very promising radioprotector that has emerged from these efforts is amifostine,
Radiotherapy in lung cancer. Dr. V. Kouloulias
37
an organic thiophosphate developed by the United States Army (WR [Walter Reed]-2721) in the
post–World War II era to protect against the possible effects of radioactive fallout. The active
metabolite (WR-1065) is a free thiol that is thought to provide an alternative target for reactive
species from alkylating agents that would otherwise target DNA. The free thiol is also believed to
scavenge the free radicals released during the interaction of ionizing radiation and water. With regard
to its tissue selectivity, amifostine has been shown to protect both the salivary glands from the
damaging effects of RT [165] and the kidneys from the nephrotoxic effects of cisplatin [166].
Nonetheless, amifostine's ability to protect normal tissue is not well understood, and the dosage
required to reduce specific toxicities has not been established [167]. However, it appears to protect
normal tissues, including the esophagus, lung, kidney, liver, bone marrow, immune system, skin,
colon, small bowel, salivary glands, oral mucosa, and testes, from radiation damage; the brain and
spinal cord, however, were not protected. In addition, no evidence has shown that it caused tumors to
be spared the effects of RT or chemotherapy. Also in its favor, amifostine has been shown to protect
normal tissues against the toxic effects of several classes of cytotoxic agents, including the alkylating
and organo-platinum agents, anthracyclines, and taxanes [168]. All these qualities, therefore, indicate
amifostine's potentially broad applicability as a cytoprotective agent. Amifostine is already approved
for use as a radioprotector in the United States as the result of an international multi-institutional
Phase III comparative trial that showed a significant reduction in the severity of acute and late
xerostomia in patients given intravenous amifostine before each fraction of RT [165].
Several prospective randomized comparative studies of RT with and without amifostine have been
published all these years. Komaki et al. [169] in a study conducted in M. D. Anderson Cancer Center
reported a significant radioprotective effect of amifostine against radiation induced pneumonitis and
esophagitis. All the randomized studies are shown in table 11.
Table 11. Randomized trials with amifostine in lung cancer
Reference Radiation dose Chemotherapy Amifostine dose Comment
Movsas et al. (n = 242)
[170]
69.6 Gy at 1.2 Gy (hyperfractionation)
Induction PC 500 mg i.v. 4_/wk between RT fractions
No difference by NCI-CTC esophagitis, Swallowing diaries (p < 0.03) and weight loss (p < 0.05) favour amifostine (median survival, 15.6 and 15.8 mo)
Leong et al. (n = 60)
[171]
60–66 Gy at 2.0 Gy Induction PC 740 mg/m2 with each
chemo (Days 1, 22, 43, 50, 57,64, 71, 78)
Esophagitis Grade 2–3: 43% in amifostine, 70% in control (not significant) (median survival, 12.5 and 14.5 mo)
Senzer et al. (n = 63)
[172]
64.8 Gy at 1.8 Gy Concurrent PC, gemcitabine and cisplatin X 3 after
500 mg i.v. before weekly chemo; 200 mg i.v. daily before RT
No difference in toxicity, no survival data (ongoing trial)
Radiotherapy in lung cancer. Dr. V. Kouloulias
38
chemoradiation
Antonadou et al. (n = 146), [173]
55–60 Gy at 2.0 Gy. None 340 mg/m2/d before RT ↓Pneumonitis ↓Esophagitis (no survival data)
Antonadou et al. (n = 73), [174]
55–60 Gy at 2.0Gy. Concurrent weekly Por C
300 mg/m2/d before chemoradiation and RT
↓esophagitis (p <0.001) ↓pneumonitis (p = 0.009) (no survival data)
Komaki et al. (n = 62),
[169]
69.6 Gy at 1.2 Gy (hyperfractionation)
Concurrent i.v. cisplatin Days 1, 8,29, 36; Oral etoposide Days1–5 8–12, 29–33,36–40
500 mg i.v. 1st, 2nd day each wk before chemo and 1st RT fraction
↓Degree of esophagitis, ↓Pneumonitis, ↓Neutropenic fever (median survival,19 and 20 mo)
Abbreviations: P = paclitaxel; C = carboplatin; RT = radiotherapy; NCI-CTC = National Cancer Institute-Common Toxicity Criteria.
As general guidelines:
• Amifostine should be administered only to patients with good performance status, no
cardiovascular diseases, no severe hypotension, normal kidney and liver function and age up
to 70 years.
• Amifostine as intravenous infusion should be administered with an intermediate time from Rt
15 minutes (maximum).
• In case of concomitant chemotherapy-radiotherapy, amifostine should be administered before
chemotherapy.
Radiotherapy in lung cancer. Dr. V. Kouloulias
39
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