Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced squamous bronchogenic carcinoma: A randomized study

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RADIOTHERAPY ALTERNATING AND CHEMOTHERAPY SCHEDULES AS INDUCTION TREATMENT IN LIMITED SMALL CELL LUNG CARCINOMA. Arriagada, P. T. Le Chevalier, R. Baldeyrou, P. Ruffie, F. Thomas, H. De Cremoux, M. Martin, M.L. Cerrina, H. De The, M. Tarayre, H. Sancho-Garnier and the GROP. Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif, France. From 1980 to 1986, 156 patients with limited small cell lung carcinoma were pilot included in three consecutive studies of inductin therapy using an alternating thoracic radiotherapy CRT) and chemotherapy (CT) protocol. The schedule was as follows: CT---CT-RT-CT-RT-CT-RTCT---CT, where (-1 represents 1 week interval. 28 In the first protocol (002; oatients): CT included doxorubicin 40 mg/m2 dl; VP 16213 75 mg/m2 d1,2,3: cyclophosphamide 300 mg/m' d3,4,5,6 and methotrexate 400 mg/m2 d2 - plus folinic acid rescue. Each of the 3 courses of RT delivered 15 Gy/ fractions/lo days by anterior-posterior (AP) fields (total dose: 45 Gy). In the second protocol (004; 81 patients); cis platinum at the dose of 100 mg/m2 d2 was substituted for methotrexate. The first 2 courses of RT delivered 20 Gy/% fractions/l2 days by AP fields and the third course delivered 15 GY/6 fractions/lo days by lateral fields avoiding the spinal cord (total dose: 55 Gvl. In the third protocol (006; 47 patients); doses of VP 16213 were increased uw to 100 ma/m' d1.2.3 and cisplatinum up to 120 mg/m2 d2 in the first 2 cycles. The dose of the third course of RT was increased up to 25 Gy/lO fractions/l7 days delivered by lateral and oblique fields (total dose: 65 Gy). Prophylactic cranial irradiation (PCI) was given in all patients after the second chemotherapy cycle in 002 and 004 (30 Gy/lO fractions/l2 days). Comnlete reswonders were randomized after &ompletion* of induction therapy to receive or not PC1 (24 Gy/8 fractions/l2 days) in 006. The complete remission rate was 79% in 002 + 004; and 85% in 006. Isolated local recurrence rate was 15% in 002-004 and 11.5% in 006. Tolerance was acceptable but bone marrow toxicity was seen in all natients (lethal in 3%). Analvsis of long-term effects is presented in another abstract. Results of the first two protocols were similar and they were pooled: disease free survival rate was 33% at 18 months and 21% at 36 months in 002 and 004. It was 44% at 18 months in 006. These 3 consecutive protocols gave reproducible results in terms of survival. New trends in our ongoing studies include increased initial doses of CT, early alternation of RT-CT and use of multifractionated RT. z-----

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ANTITUMOR ACTIVITY OF RADIATION THERAPY IN PATIENTS WITH NON-SMALL CELL LUNG CANCER REFRACTORY TO VINDESINE + CISPLATIN THERAPY. Takashi Ota, Nagahiro Saijo, Tetsu Shinkai, Kenji Eguchi, Yasutsuna Sasaki, Tomohide Tamura, Masanori Sakurai. Dept. Int. Med. National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104 Japan. The antitumor and adverse effects of radiation after combination therapy chemotherapy of vindesine and cisplatin were analyzed in patients with advanced NSCLC. Seventy four patients with non small cell lung cancer received a combination chemotherapy of cisplatin (80 mg/m2 every 3 weeks) and vindesine (3 mg/m2 every week) from July 1982 to March 1985 in The National Cancer Center Hospital. All patients received two courses of combination chemotheranv. and chemotherapy was continued until--there was evidence of progressive disease or unacceptable toxicity. There were 28 watients who received radiation therawv bn the primary site and mediastinal and hilar lymph nodes. Twenty six patients were evaluable for response. Radiation therapy was performed by linac or microtron in each of 13 patients. Average dose of 59 Gy radiation was 59 The effect of radiotherapy was GY. evaluated by the WHO criteria. The definition of radiation fibrosis was the consolidation of irregular fibrotic shadows in the irradiated area. 26 patients receiving radiation In therapy, three responders were observed (response rate: 11.5%). Two had squamous cell carcinoma and one had a large cell carcinoma. No responder was observed in the fifteen patients with adenocarcinoma. Radiation of out fibrosis was observed in 24 out of 28 patients (85.7%). Two patients died (both of them had pulmonary emphysema as basic disease). These results suggest that patients who receive radiation therapy after the failure of chemotherapy can not experience high response rate. The schedules, dose and timing of radiation therapy should carefully be evaluated by randomized controlled trial in non-small cell lung cancer. COMBINED RADIOTHERAPY AND CHEMOTHERAPY VERSUS RADIOTHERAPY ALONE IN LOCALLY ADVANCED SQUAMOUS BRONCHOGENIC CARCINOMA: A RANDOMIZED STUDY. M.G. Trove, M. Roncadin, E. Minatel, A. Veronesi", A. De Paoli, G. Franchin, G. Boz, M. Arcicasa, R. Bortolus, C. Gobitti, E. Grigoletto. Radiotherapy Dept., C.R.O. Aviano Pordenone."Medical Oncology Dept., C.R.O. Aviano-Pordenone. The therapeutic value of combined radiotherapy (RT) and chemotherapy (CT) in non-small cell carcinoma of the lung remains unclear and a great uncertainty still characterizes the bases of this

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approach. Even if a combined treatment with RT and CT with the intent of controlling both local and distant disease could seem logical in limited epidermoid bronchogenic carcinoma (EBC), the results of combined modality treatment have been so far disappointing. This could be due to the inadequacy of CT regimens so far used. The encouraging results obtained in a previous pilot study (Int. J. Radiat. Oncol. Biol. Phys. 8: 1051-1054, followed by CAMP 1982) with RT (cyclophosphamide 300 mg/m2 i.v., doxorubicin 20 mg/m2 i.v., methotrexate 15 mg/m* i.v. days 1, 8 and procarbazine 100 mg/m2 orally, days 1, 10, every 4 weeks) in patients with UICC Stage III EBC, suggested a randomized comparison of RT (45 Gy/15 fract./3 weeks) to be followed by CAMP for 12 cycles versus RT alone at the same dosage with CAMP at progression. All patients completed RT treatment. The median number of cycles of CAMP administered was 4.5 (range 1 - 12). From November 1980 to December 1983, 111 patients entered the study. Response, site of relapse, median time to progression (MTP) and median survival time (MST are as follows:

Prognostic factors affecting survival were initial performance status score and weight loss in the previous 6 months. No difference in MTP and MST was noted at a multivariate analysis performed in December 1986. In our hands, adjuvant CAMP did not improve the results obtained with RT alone in patients with Stage III EBC. UNCONVENTIONAL COMBINATIONS Chairman: R. Arriagada ROLE OF SMALL DOSES OF RADIOTHERAPY COMBINED TO CHEMOTHERAPY IN NON SMALL CELL LUNG CANCER. Claude Dionet, Pierre Verrelle, Dominique Roux, Pierre Fraisse, JeanLouis Achard, Raymond Rozan. Centre Jean Perrin, Place Henri Dunant, B.P. 392, 63011 Clermong-Ferrand Cedex, France. We have shown on murine tumours and organotypic cultures (lung cancer) the synergistic action of 5-Fluorouracil (5FU), cisplatinum (DDP) and low doses of x-rays. From previous studies on tolerance to the drugs and their pharmacokinetics the following therapeutic protocol was used in non-small cell lung cancers: - days 1 to 6: 5FU 400 mg sq.m. IV per day; - days 1,2,5,6: DDP 20 mg sq.m. IV per day;

- days 1,2,5,6: VP16 50 mg sq.m. IV per day; - days 3 and 4: x-rays: 3 grays per day (6 Gy per course). There was a 21-day rest period beThe number of tween each course. courses depended on the renal tolerance (6 to 9). 25 patients entered the protocol since 1986. good: Early tolerance was very since tetracosactide was used there were no digestive side effects greater than grade 1. Biological tolerance was good provided that Karnofsky index was greater than 50%. Thrombopenia may occur but with a short duration. Renal insufficiency is the limiting factor after 6 courses (15% grade 1; 5% grade 2). After completion of 3 courses and 6 courses results are respectively: - complete response: 12% and 45%, - Partial response >50%: 59% and 28%, - minor response <50%: 23% and 18%, - no response: 6% and 9%. The follow-up is too short (longest months) to draw conclusions on 18 survival. Nevertheless, results suggest a good early tolerance and an improvement in response rate compared to conventional treatments.

INTENSIVE CHEMOTHERAPY AND THORACIC IRRADIATION AS INDUCTION TREATMENT IN SMALL CELL LUNG CANCER (SCLC). R.L. Souhami, C.M. Ash, H.M. Earl, P.G. Harper, D. Geddes, J.S. Tobias, S.G. Spiro. Dept. of Clinical Oncology, University College and Middlesex School of Medicine, Faculty of Clinical Sciences, University Street, London, WClE 6AU. Brompton Hospital, London, SW3 6HP. London Chest Hospital, London E2 9JX. Guy's Hospital, London, SE1 9RT. 74 Since 1980 we have treated patients in 4 consecutive studies using very high dose chemotherapy as induction treatment in limited stage SCLC. The aim was to determine a) if a clinical dose-response relationship existed for cyclophosphamide (CP), b) if a long disease-free interval could be obtained without further chemotherapy, c) if in combination with thoracic irradiation there would be a proportion of long term survivors. In the first study 25 patients were treated with a cycle of CP (160-200 mg/kg divided over 4 days] followed by thoracic radiation (40 Gy in 20 fractions). 84% of patients responded to the chemotherapy with 56% CR. The median survival was 74 weeks. In the second study 26 patients were treated with 2 high dose cycles (18 CP alone, 200 mg/kg, 8 CP 160 mg/kg and etoposide 120 mg/m2 days l-4) followed by thoracic irradiation (40 Gy, 20 fractions). The response rate was similar (83%) but only 3 patients who