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Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma
Lung Cancer 10 Suppl. 1 (1994) S239-S244
Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma Thierry Le Chevalier * a, Rodrigo Arriagada”, Elizabeth Quoixb, Pierre Ruffieayc, Michel Martinc, Jean-Yves Douillardd, Michkle Tarayrea, Marie-Jo& Lacombe-Terrier”, Agnks Laplanche” “Institut Gustaw-Roussy, 94805 Wleju~ France bCentre Hospitalier Rt!gional, Strasbourg, France ‘Centre Hospitalier Intercommunal, C&teil, France dCentre Renl Gauducheau, Nantes, France
Abstract We report the results observed in a large randomized study comparing radiotherapy alone to combined radiotherapy and chemotherapy in unresectable squamous cell and large cell lung carcinoma. Radiation dose was 65 Gy in both groups and chemotherapy included vindesine, cyclophosphamide, cisplatin and lomustine. One hundred seventy-seven patients received radiotherapy alone, and 176 received the combined treatment. The 2-year survival rate was 14% for patients receiving radiotherapy vs. 21% for patients receiving the combined treatment 0’ = 0.02). The distant metastasis rate was significantly lower in the group receiving the combined treatment (P < 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively) and remains a major problem in locally advanced non-small cell lung cancer. Key words: Randomized cell lung carcinoma
study; Chemotherapy;
Radiotherapy;
Locally advanced non-small
1. Introduction The therapeutic approach of locally advanced NSCLC has been widely discussed. Extensive literature has reported the possibility of improving survival with thoracic 0169-5002/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0169-5002(93)00285-H
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et al. /Lung
Cancer 10 Suppl. 1 (1994) S239-S244
irradiation and this treatment can be considered as standard therapy for this type of presentation in spite of a poor median survival not exceeding lo-12 months [l,lO]. However, the high incidence of local relapses and/or distant metastases calls for systemic treatment [3] and the combination of these two modalities has to be clearly evaluated. In 1980, we conducted a Phase II study combining radical radiotherapy and a four-drug chemotherapy regimen including vindesine, cisplatin, lomustine and cyclophosphamide: we observed a 42% objective response rate after initial CT and 54.5% complete remission rate after combined modality treatment with a median survival of 15.9 months [5]. On the basis of these results, we designed a Phase III study comparing such a combined schedule to radiotherapy alone given at the same doses. We report here updated results of this large multicentric randomised trial which included 353 patients [7]. 2. Patients and methods Patients entered in this study were previously untreated and had histologically proven squamous cell or large cell carcinoma of the lung. All patients were deemed unresectable but free of metastasis after physical examination and bronchoscopic, radiologic and nuclear work-up. Eligibility criteria included: age I 70 years, Karnofsky Index performance status 2 50%, measurable or evaluable disease, no prior chemotherapy or radiation therapy, no previous history of malignant disease (except basal cell skin carcinoma), no haematologic, cardiac, renal or liver abnormalities contraindicating the combined modality therapy; no esophageal or chest wall involvement; no pleural effusion except for those with biopsy-proven negative histology; no superior vena cava syndrome requiring urgent radiation therapy. Patients underwent the following investigations: chest X-ray and fiberoptic bronchoscopy; bone scan, brain scintigraphy or computerized axial tomographic (CAT) scan, liver CAT scan or ultrasound. Disease had to be limited to one hemithorax, the mediastinum and supra-clavicular nodes, provided all nodes could be included in the same radiotherapy fields as the primary tumor. Patients fulfilling inclusion criteria were randomized to one of the following regimens: Group A received radiotherapy alone given to a volume including primary tumor, mediastinum and bilateral supraclavicular nodes by: (a) Two large opposed anteroposterior/posteroanterior complex shaped beams to irradiate the whole target volume including tumor volume, homolateral hilar, mediastinal and supraclavicular lymph nodes with a free margin of l-l.5 cm. The dose delivered with this first-beam arrangement was limited to 40 Gy in 16 fractions and 28 days. (b) Two opposed lateral beams including the tumor, hilar and mediastinal lymph nodes. The dose delivered with this second-beam arrangement was 15 Gy in six fractions and 10 days.
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(c) Two opposed oblique beams including the tumor and homolateral hilar and mediastinal lymph nodes. The dose delivered with this third-beam arrangement was 10 Gy in four fractions and 7 days. Group B received 3 monthly cycles of VCPC (vindesine, 1.5 mg/m* on days 1 and 2; lomustine 50 mg/m2 on day 2,25 mg/m* on day 3; cisplatin 100 mg/m2 on day 2; cyclophosphamide 200 mg/m2 on days 2-4). Radiographic, fiberoptic and histologic examinations were performed just before the third cycle in order to determine the response to initial chemotherapy. All patients received thoracic radiotherapy identical to group A, starting 2-3 weeks after the third chemotherapy cycle. Three additional VCPC cycles were administered after completion of radiotherapy to patients who had not progressed after initial chemotherapy. A final assessment identical to the pre-randomization one was performed 3 months after completion of radiotherapy in order to determine final response rates in both groups. Response and toxicity were evaluated according to the WHO criteria [ 161. It was estimated that a minimum of 175 patients per group would be necessary to demonstrate a minimum difference of 15% in a 2-year survival between the two groups with a Type I error of 5% and a Type II error of 10%. A comparison of the two groups of patients was made using the chi-square test, Student f-test and the Fisher exact test. The Kaplan Meier method [4] and the logrank test 1111were used for the estimation and comparison of survival curves for all patients and local control curves for complete responders. 3. Results From June 1983 to February 1989,353 patients were entered from 22 cooperating centers. Patient characteristics are presented in Table 1. There were significantly more males in group B (P = 0.05) and performance status was slightly better in the combined arm (P = 0.06). No patient was lost to follow-up and all are available for survival rate estimations. Twenty-nine patients (16%) had an incomplete radiation course in group A. In group B, seven patients did not receive initial chemotherapy, 15 patients received only one cycle, and 20 patients received two cycles. Fifty-seven patients (33%) had an incomplete RT course and 74 patients received one to three additional VCPC cycles after completion of radiotherapy. Twenty-seven percent of patients had an objective radiologic and endoscopic response after two VCPC cycles in Group B; 44% had a response < 50% or stable disease and 29% progressed locally or distantly. At the time of final assessment (i.e. with a mean delay of 5.6 months after randomization in Group A and 7.7 months in Group B), a complete response was observed in 33 patients (20%) a partial response in 26, a stabilization in 33 and a progression in 75 in Group A versus 26 (16%), 25, 27 and 87, respectively in Group B. Survival was calculated from the date of patient randomization to the date of death or last follow-up. The time between randomization and the analysis ranges
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Table 1 Patient characteristics
Males (%) Mean age (years) Pathology (o/o) Squamous cell carcinoma Well differentiated Mod. differentiated Poorly differentiated Large cell carcinoma Kamofsky index 2 80 (%) Abnormal CEA (o/o)
Group A (RT ALONE) 177 pts
Group B (RT + CT) 176 pts
95 59
99 58
47 15 24 14 76 22
37 16 32 15 84 16
RT, radiotherapy; CT, chemotherapy.
from 26 to 94 months; the mean follow-up time is 61 months. Median survival was 10 months in Group A and 12 months in Group B. The survival rate was 41% at 1 year, 14% at 2 years and 4% at 3 years for group A vs. 51%, 21% and 12%, respectively for group B. A comparison of survival between the two arms yielded a P value of 0.02 using the logrank test. Comparison of survival remained statistically significant when adjusted on center, performance status and sex. As local control was not the main goal of the study, the best local response was not determined but local control at 1 year was poor in both groups (17% and 15%, respectively). There was no statistical difference between the two groups. The metastasis rate was significantly lower in group B (P < 0.001). This difference remained significant when adjusted on center, performance status and sex. Toxicity was mainly haematological and digestive after chemotherapy. Grade III and IV neutropenia toxicities were observed in 8% of cycles. One patient had Grade IV neurologic toxicity after the first VCPC cycle and chemotherapy was discontinued. One patient had Grade V renal toxicity after the second VCPC cycle. Radiation-related toxicity was observed in 121 of the 313 patients who received the first RT course and in 67 of the 280 patients who received the second RT course. Toxic effects were mild to moderate in most cases and the discontinuation of treatment was never necessary. There were eight treatment-related fatal toxicities, two pneumonitis and one pericarditis in group A, four aplasia and one renal failure in group B. 4. Discussion The present study included a large number of patients with locally advanced squamous cell and large cell lung cancer. Adenocarcinoma were excluded because
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of the dilemma concerning the unknown origin of the primary in a large subset of patients [6]. The rationale for combining radiotherapy and chemotherapy in the present trial was: (i) to improve the local control rate by delivering radiation at adequate doses, i.e. 65 Gy in 6.5 weeks; (ii) to not exceed this dose in order to avoid toxicity to normal tissues in the thorax; and (iii) to decrease the distant metastasis rate by acting on micrometastases existing at the time of presentation in more than 50% of cases. The response rate observed in this study after chemotherapy is modest but it concerns patients with bulky disease, included in a multicentric study, with a fiberoptic control examination and systematic biopsies performed after two chemotherapy cycles. The l-year local control rate was particularly poor in both groups. It can be explained by our restrictive definition of local control concerning only patients in complete remission. The most dramatic effect shown in the present trial is the significant impact of chemotherapy on the rate of distant metastases. This fact is of critical importance as it demonstrates that chemotherapy can significantly decrease the metastasis rate in locally advanced disease and allow a marginal but significant effect on survival
@I. Our results have a clear impact on future protocol designs according to the new UICC classification [9] which takes into account two different subsets of patients with locally advanced NSCLC:
(1) More recent chemotherapy
regimen will probably be able to increase the complete response rate and so improve the control of micrometastases. (2) Patients presenting with marginally operable disease (Stage IIIA) can potentially benefit from preoperative chemotherapy as suggested by many Phase II studies [2,12,15]. Randomized trials able to adequately define the subset of patients likely to benefit from the effect of chemotherapy on both local and distant disease are urgently required. (3) Patients with definitively unresectable tumor (Stage IIIB patients) can be considered for new combined modality strategies including multifractionated radiotherapy 1141and concurrent chemotherapy and radiotherapy [13] in an attempt to improve local control.
5. References 1 Cox JD, Komaki R and Byhardt RW. Is immediate chest radiotherapy obligatory for any or all patients with limited-stage non-small cell carcinoma of the lung? Yes. Cancer Treat Rep 1983; 67: 327-31. 2 Gralla RJ. Preoperative and adjuvant chemotherapy in non-small cell lung cancer. Semin Oncol 15: suppl. 1988; 7: 8-12. 3 Greco FA. Rationale for chemotherapy for patients with advanced non-small cell lung cancer. Semin Oncol 13: suppl. 1986; 3: 92-6. 4 Kaplan EL, Meier P. Non parametric estimations from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.
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Le Chevalier T, Arriagada R, Baldeyrou P, Martin M, Duroux P, Jacquotte A, Sancho-Garnier H and Rouesse J. Combined chemotherapy (vindesine, lomustine, cisplatin and cyclophosphamide) and radical radiotherapy in inoperable non-metastatic squamous cell carcinoma of the lung. Cancer Treat Rep 1985; 69: 469-72. Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G, Spielmann M, Rouesse J. Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients. Arch Intern Med 1988; 148: 2035-9. Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, Lacombe-terrier MJ, Douillard JY, Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer. First analysis of a randomized trial in 353 patients. J Nat1 Cancer Inst 1991; 83: 417-23. Le Chevalier T, Arriagada R, Quoix E et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung cancer. J Nat1 Cancer Inst 1992; 84: 58. Mountain CF. A new international staging system for lung cancer. Chest 1986; 89: 225-33. Perez CA, Stanley K, Grunay G et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat-cell carcinoma of the lung. Cancer 1982; 50: 1091-9. Peto R, Pike MC, Armitage P et al. Design and analysis of randomized clinical trials requiring prolonged observations of each patient. II. Analysis and examples. Br J Cancer 1977; 35: l-39. Pujol JL, Rossi JF, Le Chevalier T, Daures JP, Rouanet P, Douillard JY, Dubois JB, Arriagada R, Mary P, Godart P, Michel FB. Pilot study of neoadjuvant Ifosfamide, Cisplatin and Etoposide in locally advanced non-small cell lung cancer. Eur J Cancer 1990; 26: 798-801. Schaake-Koning C, Van Den Bogaert W, Dalesio 0 et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326: 524-30. Thames HD, Hendry JM. Fractionation in radiotherapy. London, New York, Philadelphia: Taylor and Francis, 1987. Vokes EE, Bitran JD, Hoffman PC et al. Neoadjuvant vindesine, etoposide and cisplatin for locally advanced non-small cell lung cancer. Chest 1989; 96: 110-13. WHO Handbook for reporting results of cancer treatment. WHO Offset Publication No. 48, 1979, Geneva.
Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma Thierry Le Chevalier * a, Rodrigo Arriagada”, Elizabeth Quoixb, Pierre Ruffieayc, Michel Martinc, Jean-Yves Douillardd, Michkle Tarayrea, Marie-Jo& Lacombe-Terrier”, Agnks Laplanche” “Institut Gustaw-Roussy, 94805 Wleju~ France bCentre Hospitalier Rt!gional, Strasbourg, France ‘Centre Hospitalier Intercommunal, C&teil, France dCentre Renl Gauducheau, Nantes, France
Abstract We report the results observed in a large randomized study comparing radiotherapy alone to combined radiotherapy and chemotherapy in unresectable squamous cell and large cell lung carcinoma. Radiation dose was 65 Gy in both groups and chemotherapy included vindesine, cyclophosphamide, cisplatin and lomustine. One hundred seventy-seven patients received radiotherapy alone, and 176 received the combined treatment. The 2-year survival rate was 14% for patients receiving radiotherapy vs. 21% for patients receiving the combined treatment 0’ = 0.02). The distant metastasis rate was significantly lower in the group receiving the combined treatment (P < 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively) and remains a major problem in locally advanced non-small cell lung cancer. Key words: Randomized cell lung carcinoma
study; Chemotherapy;
Radiotherapy;
Locally advanced non-small
1. Introduction The therapeutic approach of locally advanced NSCLC has been widely discussed. Extensive literature has reported the possibility of improving survival with thoracic 0169-5002/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0169-5002(93)00285-H
S240
T. Le Chedier
et al. /Lung
Cancer 10 Suppl. 1 (1994) S239-S244
irradiation and this treatment can be considered as standard therapy for this type of presentation in spite of a poor median survival not exceeding lo-12 months [l,lO]. However, the high incidence of local relapses and/or distant metastases calls for systemic treatment [3] and the combination of these two modalities has to be clearly evaluated. In 1980, we conducted a Phase II study combining radical radiotherapy and a four-drug chemotherapy regimen including vindesine, cisplatin, lomustine and cyclophosphamide: we observed a 42% objective response rate after initial CT and 54.5% complete remission rate after combined modality treatment with a median survival of 15.9 months [5]. On the basis of these results, we designed a Phase III study comparing such a combined schedule to radiotherapy alone given at the same doses. We report here updated results of this large multicentric randomised trial which included 353 patients [7]. 2. Patients and methods Patients entered in this study were previously untreated and had histologically proven squamous cell or large cell carcinoma of the lung. All patients were deemed unresectable but free of metastasis after physical examination and bronchoscopic, radiologic and nuclear work-up. Eligibility criteria included: age I 70 years, Karnofsky Index performance status 2 50%, measurable or evaluable disease, no prior chemotherapy or radiation therapy, no previous history of malignant disease (except basal cell skin carcinoma), no haematologic, cardiac, renal or liver abnormalities contraindicating the combined modality therapy; no esophageal or chest wall involvement; no pleural effusion except for those with biopsy-proven negative histology; no superior vena cava syndrome requiring urgent radiation therapy. Patients underwent the following investigations: chest X-ray and fiberoptic bronchoscopy; bone scan, brain scintigraphy or computerized axial tomographic (CAT) scan, liver CAT scan or ultrasound. Disease had to be limited to one hemithorax, the mediastinum and supra-clavicular nodes, provided all nodes could be included in the same radiotherapy fields as the primary tumor. Patients fulfilling inclusion criteria were randomized to one of the following regimens: Group A received radiotherapy alone given to a volume including primary tumor, mediastinum and bilateral supraclavicular nodes by: (a) Two large opposed anteroposterior/posteroanterior complex shaped beams to irradiate the whole target volume including tumor volume, homolateral hilar, mediastinal and supraclavicular lymph nodes with a free margin of l-l.5 cm. The dose delivered with this first-beam arrangement was limited to 40 Gy in 16 fractions and 28 days. (b) Two opposed lateral beams including the tumor, hilar and mediastinal lymph nodes. The dose delivered with this second-beam arrangement was 15 Gy in six fractions and 10 days.
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(c) Two opposed oblique beams including the tumor and homolateral hilar and mediastinal lymph nodes. The dose delivered with this third-beam arrangement was 10 Gy in four fractions and 7 days. Group B received 3 monthly cycles of VCPC (vindesine, 1.5 mg/m* on days 1 and 2; lomustine 50 mg/m2 on day 2,25 mg/m* on day 3; cisplatin 100 mg/m2 on day 2; cyclophosphamide 200 mg/m2 on days 2-4). Radiographic, fiberoptic and histologic examinations were performed just before the third cycle in order to determine the response to initial chemotherapy. All patients received thoracic radiotherapy identical to group A, starting 2-3 weeks after the third chemotherapy cycle. Three additional VCPC cycles were administered after completion of radiotherapy to patients who had not progressed after initial chemotherapy. A final assessment identical to the pre-randomization one was performed 3 months after completion of radiotherapy in order to determine final response rates in both groups. Response and toxicity were evaluated according to the WHO criteria [ 161. It was estimated that a minimum of 175 patients per group would be necessary to demonstrate a minimum difference of 15% in a 2-year survival between the two groups with a Type I error of 5% and a Type II error of 10%. A comparison of the two groups of patients was made using the chi-square test, Student f-test and the Fisher exact test. The Kaplan Meier method [4] and the logrank test 1111were used for the estimation and comparison of survival curves for all patients and local control curves for complete responders. 3. Results From June 1983 to February 1989,353 patients were entered from 22 cooperating centers. Patient characteristics are presented in Table 1. There were significantly more males in group B (P = 0.05) and performance status was slightly better in the combined arm (P = 0.06). No patient was lost to follow-up and all are available for survival rate estimations. Twenty-nine patients (16%) had an incomplete radiation course in group A. In group B, seven patients did not receive initial chemotherapy, 15 patients received only one cycle, and 20 patients received two cycles. Fifty-seven patients (33%) had an incomplete RT course and 74 patients received one to three additional VCPC cycles after completion of radiotherapy. Twenty-seven percent of patients had an objective radiologic and endoscopic response after two VCPC cycles in Group B; 44% had a response < 50% or stable disease and 29% progressed locally or distantly. At the time of final assessment (i.e. with a mean delay of 5.6 months after randomization in Group A and 7.7 months in Group B), a complete response was observed in 33 patients (20%) a partial response in 26, a stabilization in 33 and a progression in 75 in Group A versus 26 (16%), 25, 27 and 87, respectively in Group B. Survival was calculated from the date of patient randomization to the date of death or last follow-up. The time between randomization and the analysis ranges
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Table 1 Patient characteristics
Males (%) Mean age (years) Pathology (o/o) Squamous cell carcinoma Well differentiated Mod. differentiated Poorly differentiated Large cell carcinoma Kamofsky index 2 80 (%) Abnormal CEA (o/o)
Group A (RT ALONE) 177 pts
Group B (RT + CT) 176 pts
95 59
99 58
47 15 24 14 76 22
37 16 32 15 84 16
RT, radiotherapy; CT, chemotherapy.
from 26 to 94 months; the mean follow-up time is 61 months. Median survival was 10 months in Group A and 12 months in Group B. The survival rate was 41% at 1 year, 14% at 2 years and 4% at 3 years for group A vs. 51%, 21% and 12%, respectively for group B. A comparison of survival between the two arms yielded a P value of 0.02 using the logrank test. Comparison of survival remained statistically significant when adjusted on center, performance status and sex. As local control was not the main goal of the study, the best local response was not determined but local control at 1 year was poor in both groups (17% and 15%, respectively). There was no statistical difference between the two groups. The metastasis rate was significantly lower in group B (P < 0.001). This difference remained significant when adjusted on center, performance status and sex. Toxicity was mainly haematological and digestive after chemotherapy. Grade III and IV neutropenia toxicities were observed in 8% of cycles. One patient had Grade IV neurologic toxicity after the first VCPC cycle and chemotherapy was discontinued. One patient had Grade V renal toxicity after the second VCPC cycle. Radiation-related toxicity was observed in 121 of the 313 patients who received the first RT course and in 67 of the 280 patients who received the second RT course. Toxic effects were mild to moderate in most cases and the discontinuation of treatment was never necessary. There were eight treatment-related fatal toxicities, two pneumonitis and one pericarditis in group A, four aplasia and one renal failure in group B. 4. Discussion The present study included a large number of patients with locally advanced squamous cell and large cell lung cancer. Adenocarcinoma were excluded because
T. Le Chewlier et al. /Lung
Cancer 10 Suppl. 1 (1994) S239-S244
S243
of the dilemma concerning the unknown origin of the primary in a large subset of patients [6]. The rationale for combining radiotherapy and chemotherapy in the present trial was: (i) to improve the local control rate by delivering radiation at adequate doses, i.e. 65 Gy in 6.5 weeks; (ii) to not exceed this dose in order to avoid toxicity to normal tissues in the thorax; and (iii) to decrease the distant metastasis rate by acting on micrometastases existing at the time of presentation in more than 50% of cases. The response rate observed in this study after chemotherapy is modest but it concerns patients with bulky disease, included in a multicentric study, with a fiberoptic control examination and systematic biopsies performed after two chemotherapy cycles. The l-year local control rate was particularly poor in both groups. It can be explained by our restrictive definition of local control concerning only patients in complete remission. The most dramatic effect shown in the present trial is the significant impact of chemotherapy on the rate of distant metastases. This fact is of critical importance as it demonstrates that chemotherapy can significantly decrease the metastasis rate in locally advanced disease and allow a marginal but significant effect on survival
@I. Our results have a clear impact on future protocol designs according to the new UICC classification [9] which takes into account two different subsets of patients with locally advanced NSCLC:
(1) More recent chemotherapy
regimen will probably be able to increase the complete response rate and so improve the control of micrometastases. (2) Patients presenting with marginally operable disease (Stage IIIA) can potentially benefit from preoperative chemotherapy as suggested by many Phase II studies [2,12,15]. Randomized trials able to adequately define the subset of patients likely to benefit from the effect of chemotherapy on both local and distant disease are urgently required. (3) Patients with definitively unresectable tumor (Stage IIIB patients) can be considered for new combined modality strategies including multifractionated radiotherapy 1141and concurrent chemotherapy and radiotherapy [13] in an attempt to improve local control.
5. References 1 Cox JD, Komaki R and Byhardt RW. Is immediate chest radiotherapy obligatory for any or all patients with limited-stage non-small cell carcinoma of the lung? Yes. Cancer Treat Rep 1983; 67: 327-31. 2 Gralla RJ. Preoperative and adjuvant chemotherapy in non-small cell lung cancer. Semin Oncol 15: suppl. 1988; 7: 8-12. 3 Greco FA. Rationale for chemotherapy for patients with advanced non-small cell lung cancer. Semin Oncol 13: suppl. 1986; 3: 92-6. 4 Kaplan EL, Meier P. Non parametric estimations from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.
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Le Chevalier T, Arriagada R, Baldeyrou P, Martin M, Duroux P, Jacquotte A, Sancho-Garnier H and Rouesse J. Combined chemotherapy (vindesine, lomustine, cisplatin and cyclophosphamide) and radical radiotherapy in inoperable non-metastatic squamous cell carcinoma of the lung. Cancer Treat Rep 1985; 69: 469-72. Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G, Spielmann M, Rouesse J. Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients. Arch Intern Med 1988; 148: 2035-9. Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, Lacombe-terrier MJ, Douillard JY, Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer. First analysis of a randomized trial in 353 patients. J Nat1 Cancer Inst 1991; 83: 417-23. Le Chevalier T, Arriagada R, Quoix E et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung cancer. J Nat1 Cancer Inst 1992; 84: 58. Mountain CF. A new international staging system for lung cancer. Chest 1986; 89: 225-33. Perez CA, Stanley K, Grunay G et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat-cell carcinoma of the lung. Cancer 1982; 50: 1091-9. Peto R, Pike MC, Armitage P et al. Design and analysis of randomized clinical trials requiring prolonged observations of each patient. II. Analysis and examples. Br J Cancer 1977; 35: l-39. Pujol JL, Rossi JF, Le Chevalier T, Daures JP, Rouanet P, Douillard JY, Dubois JB, Arriagada R, Mary P, Godart P, Michel FB. Pilot study of neoadjuvant Ifosfamide, Cisplatin and Etoposide in locally advanced non-small cell lung cancer. Eur J Cancer 1990; 26: 798-801. Schaake-Koning C, Van Den Bogaert W, Dalesio 0 et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326: 524-30. Thames HD, Hendry JM. Fractionation in radiotherapy. London, New York, Philadelphia: Taylor and Francis, 1987. Vokes EE, Bitran JD, Hoffman PC et al. Neoadjuvant vindesine, etoposide and cisplatin for locally advanced non-small cell lung cancer. Chest 1989; 96: 110-13. WHO Handbook for reporting results of cancer treatment. WHO Offset Publication No. 48, 1979, Geneva.