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Intensive chemotherapy and thoracic irradiation as induction treatment in small cell lung cancer (SCLC)
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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
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had a partial response to the first cycle had an additional response to the second. Relapse free interval and proportion relapsing in the thorax were similar to the first study. Overall survival (median 49 weeks) was rather worse due to difficulty in giving further chemotherapy on relapse due to haematological toxicity. In the 3rd study 15 patients were treated with CP 200 mg/kg after an attempt had been made to reduce the tumour mass with 2 cycles of chemotherapy using vincristine 2 mg and doxorubicin 50 mg/m2 on day 1 with etoposide 120 mg/m2 days l3. The high dose CP converted 4 partial responders to CR but overall response rate lo/15 was the same as after the preliminary 2 cycles. Thoracic irradiation (54 Gy in 27 fractions) was given after CP. Median survival was 44 weeks. In the present study high dose combination chemoherapy is given (carboplatin 600 mg/m2, etoposide 120 mg/m2 days l4, cyclophosphamide 40 mg/kg days l-4) as initial treatment followed 4-5 weeks later by thoracic irradiation (54 Gy 27 fractions). All patients have responded so far, but only 9 have yet been treated. High dose chemotherapy and irradiation are feasible, but toxic, as induction treatment in SCLC in highly selected patients. The treatment related mortality has been 4/14. In this patient group the results are so far no better than conventional treatment, but the high response rate encourages the belief that intensive treatment (in this or other forms) may yet increase the cure rate in limited stage SCLC. MAJOR EFFECT ON SURVIVAL OF THE FIRST COURSE OF CHEMOTHERAPY IN LIMITED SMALL CELL LUNG CANCER. H. De The, R. Arriagada, F. Thomas, P. Ruffie, H. De Cremoux, H. SanchoGarnier, T. Le Chavalier. Analysis of two consecutive phase II trials showed that the intensity of the first course of chemotherapy in limited small cell lung cancer (SCLC) was a major prognostic factor. The induction treatment consisted of 6 cycles of chemotherapy (doxorubicin, VP16213, either cyclophosphamide and (protocol 002) or methotrexate cisplatinum (protocol 004) alternating thoracic 3 courses of with radiotherapy. trial (002, 28 In the first patients), haematological toxicity of the first course of chemotherapy was significantly associated to a longer survival (p = 0.03). In the second trial (004, 48 patients) a Cox multivariate analysis detected 3 independent prognostic factors for survival: T stage (TNM) and the doses square meter of per cisplatinum and cyclophosphamide actually administered during the first course of chemotherapy. The observed dispersion in drug doses/m2 was caused by standard drug prescription, unadjusted for body surface area. Corrected drug doses/m2 were unrelated to
patient's or tumor characteristics. Age, sex, performance status, delayed hematological toxicity had no independent prognostic value in this multivariate analysis. Among the 39 patients with completely responsive tumors, high initial drug doses were significantly associated to a longer metastasis free survival (p < 0.001). This effect was of great magnitude, since an increase of 100 mg/m2 for cyclophosphamide and for cisplatinum 10 mg/m2 decreased metastasis rate by 1.43 and 2.5, respectively. No prognostic factor was found for local control. These retrospective analyses underline the importance of delivering full initial doses and favor initially aggressive therapeutic approaches in limited SCLC. THE INTEGRATION OF MULTIFRACTIONATED INTO COMBINED RADIOTHERAPY APCHEMOTHERAPEUTIC-RADIOTHERAPEUTIC PROACHES TO LUNG CANCER TREATMENT.=.2 W.B. Looney, H.A. Hopkins. Division of Radiobiology & Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, U.S.A. The rationale for multiple fractions per day (MFD) radiation is that normal tissue recovers more rapidly than the tumor. Marked improvement in tumor cure rates was achieved in our experimental cancer treatment studies by the alternation of cyclophosphamide (CP) with intermittent MFD radiation schedules compared to the alternation of CP with daily fraction schedules. The magnitude of the increased effectiveness was demonstrated by the fact that only 60 Gy were needed for a 50% cure rate with MFD as opposed to 112.5 Gy with daily radiation schedules alternated with chemotherapy. A plan for evaluation of clinical further chemotherapy and radiotherapy is based on holding the dose and schedule of chemotherapy constant for 6 cycles of induction therapy and increasing the total radiation dose by a factor of three by increasing the fraction number from one to two and three fractions per day. Total radiation doses can be adjusted upward or downward by increasing or decreasing fraction size or number if the proposed total radiation dose range is considered to be too small for effective tumor control or too large for normal tissue toxicity. The exresults provide the perimental framework for further clinical evaluation of multi-fractionated radiotherapy alternated with chemotherapy in the management of patients with lung cancer. lsupported in part by Public Health Service grant CA-35372, "Cross Resistance or Sensitivity in Multimodal from the National Cancer Therapy", Institutes of Institute, National Health, Department of Health and Human Services. 2For presentation at the International Association for the Study of Lung Cancer workshop on Combined Radiothera- py and Chemotherapy Modalities in Lung
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
30
had a partial response to the first cycle had an additional response to the second. Relapse free interval and proportion relapsing in the thorax were similar to the first study. Overall survival (median 49 weeks) was rather worse due to difficulty in giving further chemotherapy on relapse due to haematological toxicity. In the 3rd study 15 patients were treated with CP 200 mg/kg after an attempt had been made to reduce the tumour mass with 2 cycles of chemotherapy using vincristine 2 mg and doxorubicin 50 mg/m2 on day 1 with etoposide 120 mg/m2 days l3. The high dose CP converted 4 partial responders to CR but overall response rate lo/15 was the same as after the preliminary 2 cycles. Thoracic irradiation (54 Gy in 27 fractions) was given after CP. Median survival was 44 weeks. In the present study high dose combination chemoherapy is given (carboplatin 600 mg/m2, etoposide 120 mg/m2 days l4, cyclophosphamide 40 mg/kg days l-4) as initial treatment followed 4-5 weeks later by thoracic irradiation (54 Gy 27 fractions). All patients have responded so far, but only 9 have yet been treated. High dose chemotherapy and irradiation are feasible, but toxic, as induction treatment in SCLC in highly selected patients. The treatment related mortality has been 4/14. In this patient group the results are so far no better than conventional treatment, but the high response rate encourages the belief that intensive treatment (in this or other forms) may yet increase the cure rate in limited stage SCLC. MAJOR EFFECT ON SURVIVAL OF THE FIRST COURSE OF CHEMOTHERAPY IN LIMITED SMALL CELL LUNG CANCER. H. De The, R. Arriagada, F. Thomas, P. Ruffie, H. De Cremoux, H. SanchoGarnier, T. Le Chavalier. Analysis of two consecutive phase II trials showed that the intensity of the first course of chemotherapy in limited small cell lung cancer (SCLC) was a major prognostic factor. The induction treatment consisted of 6 cycles of chemotherapy (doxorubicin, VP16213, either cyclophosphamide and (protocol 002) or methotrexate cisplatinum (protocol 004) alternating thoracic 3 courses of with radiotherapy. trial (002, 28 In the first patients), haematological toxicity of the first course of chemotherapy was significantly associated to a longer survival (p = 0.03). In the second trial (004, 48 patients) a Cox multivariate analysis detected 3 independent prognostic factors for survival: T stage (TNM) and the doses square meter of per cisplatinum and cyclophosphamide actually administered during the first course of chemotherapy. The observed dispersion in drug doses/m2 was caused by standard drug prescription, unadjusted for body surface area. Corrected drug doses/m2 were unrelated to
patient's or tumor characteristics. Age, sex, performance status, delayed hematological toxicity had no independent prognostic value in this multivariate analysis. Among the 39 patients with completely responsive tumors, high initial drug doses were significantly associated to a longer metastasis free survival (p < 0.001). This effect was of great magnitude, since an increase of 100 mg/m2 for cyclophosphamide and for cisplatinum 10 mg/m2 decreased metastasis rate by 1.43 and 2.5, respectively. No prognostic factor was found for local control. These retrospective analyses underline the importance of delivering full initial doses and favor initially aggressive therapeutic approaches in limited SCLC. THE INTEGRATION OF MULTIFRACTIONATED INTO COMBINED RADIOTHERAPY APCHEMOTHERAPEUTIC-RADIOTHERAPEUTIC PROACHES TO LUNG CANCER TREATMENT.=.2 W.B. Looney, H.A. Hopkins. Division of Radiobiology & Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, U.S.A. The rationale for multiple fractions per day (MFD) radiation is that normal tissue recovers more rapidly than the tumor. Marked improvement in tumor cure rates was achieved in our experimental cancer treatment studies by the alternation of cyclophosphamide (CP) with intermittent MFD radiation schedules compared to the alternation of CP with daily fraction schedules. The magnitude of the increased effectiveness was demonstrated by the fact that only 60 Gy were needed for a 50% cure rate with MFD as opposed to 112.5 Gy with daily radiation schedules alternated with chemotherapy. A plan for evaluation of clinical further chemotherapy and radiotherapy is based on holding the dose and schedule of chemotherapy constant for 6 cycles of induction therapy and increasing the total radiation dose by a factor of three by increasing the fraction number from one to two and three fractions per day. Total radiation doses can be adjusted upward or downward by increasing or decreasing fraction size or number if the proposed total radiation dose range is considered to be too small for effective tumor control or too large for normal tissue toxicity. The exresults provide the perimental framework for further clinical evaluation of multi-fractionated radiotherapy alternated with chemotherapy in the management of patients with lung cancer. lsupported in part by Public Health Service grant CA-35372, "Cross Resistance or Sensitivity in Multimodal from the National Cancer Therapy", Institutes of Institute, National Health, Department of Health and Human Services. 2For presentation at the International Association for the Study of Lung Cancer workshop on Combined Radiothera- py and Chemotherapy Modalities in Lung