- Email: [email protected]
Effect of Low-Dose Chest Irradiation Before Chemotherapy on the Rate of Local Failure in Small-Cell Lung Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 41, No. 2, pp. 287–289, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/98 $19.00 1 .00
PII S0360-3016(98)00049-2
●
Clinical Investigation EFFECT OF LOW-DOSE CHEST IRRADIATION BEFORE CHEMOTHERAPY ON THE RATE OF LOCAL FAILURE IN SMALL-CELL LUNG CANCER PIERRE HO¨ SLI, M.D.,* HERVE´ BONNEFOI, M.D.,* RENE´ -OLIVIER MIRIMANOFF, M.D.,† BERNADETTE MERMILLOD, B.SC.‡ AND PIERRE ALBERTO, M.D.* *Division d’Oncologie, Hôpital Cantonal Universitaire, Geneva, Switzerland; †Service de Radio-oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and ‡Division d’Informatique Me´dicale, Hôpital Cantonal Universitaire, Geneva, Switzerland Purpose: To evaluate the rate of tumor recurrence within the irradiated volume after initial low-dose irradiation of limited-stage small-cell lung cancer (SCLC), to assess the tolerance of a sequential combination of low-dose chest irradiation followed by chemotherapy, and to confirm the responsiveness of limited-stage SCLC to low-dose irradiation. Methods and Materials: In this pilot study, 26 patients with limited-stage SCLC were treated by first-line 20-Gy thoracic irradiation followed 3 weeks later by chemotherapy (cisplatin, doxorubicin, and etoposide for six cycles). Results: We present our final results with a median follow-up of surviving patients of 7 years. The response rate to this low-dose irradiation was 83%, with an overall response rate to radiochemotherapy of 96% and a median survival of 21 months. No unexpected early or late toxicity was observed. The rate of initial isolated local failure was 8%, which compares favorably with other published series using higher doses of radiochemotherapy. Conclusion: An initial chest irradiation of 20 Gy before chemotherapy could be sufficient to reduce the risk of local failure during the time of survival of patients with limited-stage SCLC. Potential advantages of this treatment may be the prevention of resistance mechanisms to radiotherapy induced by preliminary chemotherapy and a reduced radiation-induced toxicity. © 1998 Elsevier Science Inc. Neoplasms, Carcinoma, Small cell, Radiotherapy, Drug therapy, Combination.
INTRODUCTION
ond, at least in vitro, SCLC is highly sensitive to RT (7). Third, the tumor response to radiation may be better when given up front than after the initial effect of CT that could already have increased potential resistance mechanisms. Fourth, 20 Gy in conventional fractionation is likely to be associated with far less acute and late toxicity than 50 – 60 Gy. The aims of this pilot study were (a) to evaluate the effect of initial low-dose irradiation on the rate of tumor recurrence within the irradiated volume, (b) to assess the tolerance of a sequential combination of low-dose chest irradiation followed by CT, and (c) to confirm the responsiveness of SCLC to low-dose irradiation. Preliminary results have been published (8) indicating that the rate of first local relapse was as low as that generally observed with higher doses of radiation. The present update is a final report with a median follow-up of surviving patients of 7 years.
There is ample evidence that chest irradiation in combination with chemotherapy improves local control and survival in patients with limited-stage small-cell lung cancer (SCLC) (1– 4). However, the most efficient dose and timing of radiotherapy (RT) when delivered as an adjuvant to chemotherapy (CT) has not yet been adequately defined. In a randomized study by the National Cancer Institute of Canada (5), the overall and progression-free survival time was longer when thoracic irradiation took place early (3 weeks) than when the same RT dose and fractionation were administered late (15 weeks) after initiation of CT. Recent metaanalyses (1, 2) could not determine a significant difference in the outcome when CT and RT were delivered concurrently or sequentially. Although radiation doses as high as $50 Gy have been used for the local treatment of limited-stage SCLC (6), it has not been demonstrated that such high doses are necessary for the purpose of concomitant irradiation during CT of SCLC. Early low-dose concomitant irradiation may be preferred for four reasons. The first is that low-dose concomitant RT would not compromise the tolerance to CT. Sec-
METHODS AND MATERIALS This study was initiated in March 1986. Patients with histologically proven limited-stage SCLC and a World Health Organization (WHO) performance status of 0 –3
Reprint requests to: Dr. P. Ho¨sli, Division of Hematology, University Hospital, CH-1011 Lausanne-CHUV, Switzerland.
Accepted for publication 29 December 1997. 287
288
I. J. Radiation Oncology
●
Biology
●
Physics
were eligible. No patients with pleural effusion or susclavicular lymph node were included in the trial. Initial evaluation included chest X ray, thoracic, abdominal, and brain CT scan, bone scintigraphy, and bone marrow aspiration and needle biopsy. The accrual was slow because our center was simultaneously participating in another randomized multicentric study using higher doses of RT and requiring the administration as rapidly as possible of six cycles of alternating chemotherapy (9). Patients included in this pilot trial were only those who could not participate, or refused to do so, in the randomized multicentric study. Among all patients included in one of these two concomitant trials, 52% were enrolled in our pilot study. There was no significant age difference between the two groups of patients: The median ages were 57 years (range 45–74) in the pilot study and 59 years (range 42– 67) in the multicentric study. Radiotherapy was delivered first (day 1) with a dose of 20 Gy by anterior and posterior parallel opposed fields to the primary tumor in 10 daily fractions of 2 Gy, 5 days/week (6 –10-MV linear accelerator). The target volume included the primary tumor site, ipsilateral hilar nodes, mediastinal nodes, and thoracic inlet. The protocol required leaving at least a 2-cm margin around the primary tumor and grossly involved lymph nodes, and at least a 1-cm margin around sites at risk (i.e., mediastinum and thoracic inlet). The dose was prescribed at the midplane, with isocentric techniques. CT started on day 21 and was repeated every 4 weeks for six cycles. It consisted of cisplatin 30 mg/m2 on days 1–3, doxorubicin 40 mg/m2 on day 1, and etoposide 100 mg/m2, intravenously (i.v.) on days 1–3 (PAV). Response was assessed with a chest X ray before chemotherapy on day 21, and with a thoracoabdominal CT scan after completion of the whole treatment program using WHO criteria. As the response rate was only a secondary end point of the study, patients did not undergo repeat bronchoscopy for response assessment. For the same reason, response appraisal was not systematically repeated after 4 weeks.
Volume 41, Number 2, 1998
Table 1. Results of 20-Gy chest irradiation before chemotherapy in 26 patients with limited-stage SCLC Response rate to radiotherapy Overall response rate Overall complete response rate Median time to first event Median survival time Rate of initial isolated local relapse
83% 96% 68% 13 mo. (95% CI 11–30) 21 mo. (95% CI 14–38) 8%
SCLC 5 small-cell lung cancer; CI - confidence interval.
was 31% at 6 years (95% CI 16 –50). Seven patients (27%) were alive after 6 –9 years (Fig. 1). Six of them were initially considered to have a complete response, and one was assessed as having a partial response. One patient with an initial complete response was lost to follow-up after a period of 4.2 years. Fifteen relapses occurred among responders, and 14 patients died of their relapse. The first site of relapse was the chest alone for two patients, chest and brain for one, brain alone for seven, bone for two, soft tissues for one, pleura for one, and liver for one. Of the two patients with a local first failure, one died of thoracic progression. In the second one, the local recurrence was treated with complementary irradiation, laser desobstruction, and second-line CT; after 4 years of full remission, he presented with a second local relapse, which was treated with CT. There were four further local recurrences in patients with first failure outside the irradiation field. In addition, two local recurrences were documented postmortem. The acute toxicity was detailed in a previous publication (8). The most significant toxicities were leukopenia and thrombocytopenia (occasional vomiting, alopecia, peripheral neuropathy, and renal or hepatic toxicity). In two patients, the toxicity implied the use of carboplatin instead of cisplatin or an interruption of CT. One patient developed
RESULTS Twenty-six eligible patients entered the study: 21 males and 5 females, median age 57 years (range 45–74). Response to RT was evaluated before day 21 in 24 patients (in two patients, thoracic X rays were not done before the beginning of CT). Twenty of 24 patients (83%) responded to up-front RT within 21 days; five (21%) had a complete response. The overall response was assessable in 25 patients (one patient refused further treatment after one cycle of CT), with an overall response rate of 96% (24 of 25 patients). A complete response was observed in 17 of 25 patients (68%). One patient progressed during treatment (Table 1). The median time to the first event was 13 months [95% confidence interval (CI) 11–30) and the median survival time was 21 months (95% CI 14 –38). The overall survival
Fig. 1. Kaplan–Meier survival curve and cumulative number of deaths.
Low-dose irradiation in SCLC
acute FAB M1 myeloid leukemia 2 years after the end of CT. A sudden nontoxic death after one cycle of PAV was most probably due to suicide. There was no late complication or toxicity (particularly concerning ischemic cardiopathy, heart failure, respiratory insufficiency, or secondary solid tumor) at the time of this publication. DISCUSSION We confirm the high responsiveness of SCLC to radiation with 83% response to 20 Gy irradiation within 3 weeks, which is probably too soon for an optimal evaluation. This irradiation of 20 Gy did not add any significant toxicity to what would have been expected of CT alone. No unexpected late toxicity was observed. Of 24 patients who responded, only two (8%) had an initial isolated local relapse. This low rate of first solitary local failure compares favorably with results observed in other published studies using much higher doses of RT
●
P. HO¨SLI et al.
289
(10 –14). All further local relapses happened in patients already symptomatic of distant metastases elsewhere, or were discovered postmortem. The overall results of our pilot study (complete response rate of 68%, median survival time of 21 months, and overall survival of 31% at 6 years) are equivalent to those obtained in other recent published series (10 –14) with more intensive RT. In this final report, we conclude that initial irradiation with 20 Gy could be sufficient to delay or reduce the risk of locoregional recurrence during the time of survival of patients with limited-stage SCLC. These results confirm in our opinion the speculation that limited-stage SCLC, a highly radiosensitive tumor, does not require a high dose of locoregional irradiation if the objective is to delay the risk of local recurrence, provided RT is given prior to CT. This low-dose irradiation was administered first with the assumption that it could have been less efficient after CT because of a possible cross-resistance. This remains speculative in the absence of a comparative trial.
REFERENCES 1. Warde, P.; Payne, D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J. Clin. Oncol. 10:890 – 895; 1992. 2. Pignon, J. P.; Arriagada, R.; Ihde, D. C.; Johnson, D. H.; Perry, M. C.; Souhami, R. L.; Brodin, O.; Joss, R. A.; Kies, M. S.; Lebeau, B.; Onoshi, T.; Osterlind, K.; Tattersall, M. H. N.; Wagner, H. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N. Engl. J. Med. 327:1618 – 1624; 1992. 3. Bunn, P., Jr.; Lichter, A. S.; Makuch, R. W.; Cohen, M. H.; Veach, S. R.; Matthews, M. J.; Johnston Anderson, A.; Edison, M.; Glatstein, E; Minna, J. D.; Ihde, D. C. Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. Ann. Intern. Med. 106:655– 662; 1987. 4. Perry, M. C.; Eaton, W. L.; Propert, K. J.; Ware, J. H.; Zimmer, B.; Chahinian, P.; Skarin, A.; Carey, R. W.; Kreisman, H.; Faulkner, C.; Comis, R.; Green, M. R. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N. Engl. J. Med. 316:912–918; 1987. 5. Murray, N.; Coy, P.; Pater, J. L.; Hodson, I.; Arnold, A.; Zee, B. C.; Payne, D.; Kostashuk, E. C.; Evans, W. K.; Dixon, P.; Sadura, A.; Feld, R.; Levitt, M.; Wierzbicki, R.; Ayoub, J.; Maroun, J. A.; Wilson, K. S. Importance of timing for thoracic irradiation in the combined modality treatment of limited stage small-cell lung cancer. J. Clin. Oncol. 11:336 –344; 1993. 6. Choi, N. C.; Carey, R. W. Importance of radiation dose in achieving loco-regional tumor control in limited stage smallcell lung carcinoma: An update. Int. J. Radiat. Oncol. Biol. Phys. 17:307–310; 1989. 7. Malaise, E. P.; Fertil, B.; Chavaudra, N.; Guichard, M. Distribution of radiation sensitivities for human tumor cells of specific histological types: Comparison of in vitro and in vivo data. Int. J. Radiat. Oncol. Biol. Phys. 12:617– 624; 1986. 8. Bonnefoi, H.; Zulian, G. B.; Mirimanoff, R. O.; Mermillod, B.; Alberto, P. Priming low-dose chest radiotherapy followed
9.
10.
11.
12.
13.
14.
by chemotherapy for limited small-cell lung cancer. Ann. Oncol. 5:771–772; 1994. Joss, R. A.; Bacchi, M.; Hu¨rny, C.; Bernhard, J.; Cerny, T.; Martinelli, G.; Leyvraz, S.; Senn, H. J.; Stahel, R.; Siegenthaler, P.; Ludwig, C.; Alberto, P. Early versus late alternating chemotherapy in small-cell lung cancer. Ann. Oncol. 6:157– 166; 1995. Johnson, B. E.; Bridges, J. D.; Sobczeck, M.; Gray, J.; Linnoila, R. I.; Gazdar, A. F.; Hankins, L.; Steinberg, S. M.; Edison, M.; Frame, J. N.; Pass, H.; Nesbitt, J.; Holden, D.; Mulshine, J. L; Glatstein, E.; Ihde, D. C. Patients with limited small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J. Clin. Oncol. 14:806 – 813; 1996. Mc Cracken, J. D.; Janaki, L. M.; Crowley, J. J.: Taylor, S. A.; Shankir Giri, P. G.; Weiss, G. B.; Gordon, W., Jr.; Baker, H. B.; Mansouri, A.; Kuebler, J. P. Concurrent chemotherapy/ radiotherapy for limited small-cell lung carcinoma: A Southwest Oncology Group study. J. Clin. Oncol. 8:892– 898; 1990. Arriagada, R.; Le Chevalier, T.; Ruffie, P.; Baldeyrou, P.; De Cremoux, H.; Martin, M.; Chomy, P.; Cerrina, M. L.; PellaeCosset, B.; Tarayre, M.; Sancho-Garnier, H. Alternating radiotherapy and chemotherapy in 173 consecutive patients with limited small-cell lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 19:1135–1138; 1990. Mornex, F.; Trillet, V.; Chauvin, F.; Ardiet, J. M.; Schmitt, T.; Romestaing, P.; Carrie, C.; Mahe, M.; Mornex, J. F.; Fournel, P.; Souquet, P. J.; Boniface, E.; Vincent, M.; Piperno, D.; Rebattu, P.; Gerard, J. P. Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 19:23–30; 1990. Turrisi, A. T.; Glover, D. J. Thoracic radiotherapy variables: Influence on local control in small-cell lung cancer limited disease. Int. J. Radiat. Oncol. Biol. Phys. 19:1473–1479; 1990.
PII S0360-3016(98)00049-2
●
Clinical Investigation EFFECT OF LOW-DOSE CHEST IRRADIATION BEFORE CHEMOTHERAPY ON THE RATE OF LOCAL FAILURE IN SMALL-CELL LUNG CANCER PIERRE HO¨ SLI, M.D.,* HERVE´ BONNEFOI, M.D.,* RENE´ -OLIVIER MIRIMANOFF, M.D.,† BERNADETTE MERMILLOD, B.SC.‡ AND PIERRE ALBERTO, M.D.* *Division d’Oncologie, Hôpital Cantonal Universitaire, Geneva, Switzerland; †Service de Radio-oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and ‡Division d’Informatique Me´dicale, Hôpital Cantonal Universitaire, Geneva, Switzerland Purpose: To evaluate the rate of tumor recurrence within the irradiated volume after initial low-dose irradiation of limited-stage small-cell lung cancer (SCLC), to assess the tolerance of a sequential combination of low-dose chest irradiation followed by chemotherapy, and to confirm the responsiveness of limited-stage SCLC to low-dose irradiation. Methods and Materials: In this pilot study, 26 patients with limited-stage SCLC were treated by first-line 20-Gy thoracic irradiation followed 3 weeks later by chemotherapy (cisplatin, doxorubicin, and etoposide for six cycles). Results: We present our final results with a median follow-up of surviving patients of 7 years. The response rate to this low-dose irradiation was 83%, with an overall response rate to radiochemotherapy of 96% and a median survival of 21 months. No unexpected early or late toxicity was observed. The rate of initial isolated local failure was 8%, which compares favorably with other published series using higher doses of radiochemotherapy. Conclusion: An initial chest irradiation of 20 Gy before chemotherapy could be sufficient to reduce the risk of local failure during the time of survival of patients with limited-stage SCLC. Potential advantages of this treatment may be the prevention of resistance mechanisms to radiotherapy induced by preliminary chemotherapy and a reduced radiation-induced toxicity. © 1998 Elsevier Science Inc. Neoplasms, Carcinoma, Small cell, Radiotherapy, Drug therapy, Combination.
INTRODUCTION
ond, at least in vitro, SCLC is highly sensitive to RT (7). Third, the tumor response to radiation may be better when given up front than after the initial effect of CT that could already have increased potential resistance mechanisms. Fourth, 20 Gy in conventional fractionation is likely to be associated with far less acute and late toxicity than 50 – 60 Gy. The aims of this pilot study were (a) to evaluate the effect of initial low-dose irradiation on the rate of tumor recurrence within the irradiated volume, (b) to assess the tolerance of a sequential combination of low-dose chest irradiation followed by CT, and (c) to confirm the responsiveness of SCLC to low-dose irradiation. Preliminary results have been published (8) indicating that the rate of first local relapse was as low as that generally observed with higher doses of radiation. The present update is a final report with a median follow-up of surviving patients of 7 years.
There is ample evidence that chest irradiation in combination with chemotherapy improves local control and survival in patients with limited-stage small-cell lung cancer (SCLC) (1– 4). However, the most efficient dose and timing of radiotherapy (RT) when delivered as an adjuvant to chemotherapy (CT) has not yet been adequately defined. In a randomized study by the National Cancer Institute of Canada (5), the overall and progression-free survival time was longer when thoracic irradiation took place early (3 weeks) than when the same RT dose and fractionation were administered late (15 weeks) after initiation of CT. Recent metaanalyses (1, 2) could not determine a significant difference in the outcome when CT and RT were delivered concurrently or sequentially. Although radiation doses as high as $50 Gy have been used for the local treatment of limited-stage SCLC (6), it has not been demonstrated that such high doses are necessary for the purpose of concomitant irradiation during CT of SCLC. Early low-dose concomitant irradiation may be preferred for four reasons. The first is that low-dose concomitant RT would not compromise the tolerance to CT. Sec-
METHODS AND MATERIALS This study was initiated in March 1986. Patients with histologically proven limited-stage SCLC and a World Health Organization (WHO) performance status of 0 –3
Reprint requests to: Dr. P. Ho¨sli, Division of Hematology, University Hospital, CH-1011 Lausanne-CHUV, Switzerland.
Accepted for publication 29 December 1997. 287
288
I. J. Radiation Oncology
●
Biology
●
Physics
were eligible. No patients with pleural effusion or susclavicular lymph node were included in the trial. Initial evaluation included chest X ray, thoracic, abdominal, and brain CT scan, bone scintigraphy, and bone marrow aspiration and needle biopsy. The accrual was slow because our center was simultaneously participating in another randomized multicentric study using higher doses of RT and requiring the administration as rapidly as possible of six cycles of alternating chemotherapy (9). Patients included in this pilot trial were only those who could not participate, or refused to do so, in the randomized multicentric study. Among all patients included in one of these two concomitant trials, 52% were enrolled in our pilot study. There was no significant age difference between the two groups of patients: The median ages were 57 years (range 45–74) in the pilot study and 59 years (range 42– 67) in the multicentric study. Radiotherapy was delivered first (day 1) with a dose of 20 Gy by anterior and posterior parallel opposed fields to the primary tumor in 10 daily fractions of 2 Gy, 5 days/week (6 –10-MV linear accelerator). The target volume included the primary tumor site, ipsilateral hilar nodes, mediastinal nodes, and thoracic inlet. The protocol required leaving at least a 2-cm margin around the primary tumor and grossly involved lymph nodes, and at least a 1-cm margin around sites at risk (i.e., mediastinum and thoracic inlet). The dose was prescribed at the midplane, with isocentric techniques. CT started on day 21 and was repeated every 4 weeks for six cycles. It consisted of cisplatin 30 mg/m2 on days 1–3, doxorubicin 40 mg/m2 on day 1, and etoposide 100 mg/m2, intravenously (i.v.) on days 1–3 (PAV). Response was assessed with a chest X ray before chemotherapy on day 21, and with a thoracoabdominal CT scan after completion of the whole treatment program using WHO criteria. As the response rate was only a secondary end point of the study, patients did not undergo repeat bronchoscopy for response assessment. For the same reason, response appraisal was not systematically repeated after 4 weeks.
Volume 41, Number 2, 1998
Table 1. Results of 20-Gy chest irradiation before chemotherapy in 26 patients with limited-stage SCLC Response rate to radiotherapy Overall response rate Overall complete response rate Median time to first event Median survival time Rate of initial isolated local relapse
83% 96% 68% 13 mo. (95% CI 11–30) 21 mo. (95% CI 14–38) 8%
SCLC 5 small-cell lung cancer; CI - confidence interval.
was 31% at 6 years (95% CI 16 –50). Seven patients (27%) were alive after 6 –9 years (Fig. 1). Six of them were initially considered to have a complete response, and one was assessed as having a partial response. One patient with an initial complete response was lost to follow-up after a period of 4.2 years. Fifteen relapses occurred among responders, and 14 patients died of their relapse. The first site of relapse was the chest alone for two patients, chest and brain for one, brain alone for seven, bone for two, soft tissues for one, pleura for one, and liver for one. Of the two patients with a local first failure, one died of thoracic progression. In the second one, the local recurrence was treated with complementary irradiation, laser desobstruction, and second-line CT; after 4 years of full remission, he presented with a second local relapse, which was treated with CT. There were four further local recurrences in patients with first failure outside the irradiation field. In addition, two local recurrences were documented postmortem. The acute toxicity was detailed in a previous publication (8). The most significant toxicities were leukopenia and thrombocytopenia (occasional vomiting, alopecia, peripheral neuropathy, and renal or hepatic toxicity). In two patients, the toxicity implied the use of carboplatin instead of cisplatin or an interruption of CT. One patient developed
RESULTS Twenty-six eligible patients entered the study: 21 males and 5 females, median age 57 years (range 45–74). Response to RT was evaluated before day 21 in 24 patients (in two patients, thoracic X rays were not done before the beginning of CT). Twenty of 24 patients (83%) responded to up-front RT within 21 days; five (21%) had a complete response. The overall response was assessable in 25 patients (one patient refused further treatment after one cycle of CT), with an overall response rate of 96% (24 of 25 patients). A complete response was observed in 17 of 25 patients (68%). One patient progressed during treatment (Table 1). The median time to the first event was 13 months [95% confidence interval (CI) 11–30) and the median survival time was 21 months (95% CI 14 –38). The overall survival
Fig. 1. Kaplan–Meier survival curve and cumulative number of deaths.
Low-dose irradiation in SCLC
acute FAB M1 myeloid leukemia 2 years after the end of CT. A sudden nontoxic death after one cycle of PAV was most probably due to suicide. There was no late complication or toxicity (particularly concerning ischemic cardiopathy, heart failure, respiratory insufficiency, or secondary solid tumor) at the time of this publication. DISCUSSION We confirm the high responsiveness of SCLC to radiation with 83% response to 20 Gy irradiation within 3 weeks, which is probably too soon for an optimal evaluation. This irradiation of 20 Gy did not add any significant toxicity to what would have been expected of CT alone. No unexpected late toxicity was observed. Of 24 patients who responded, only two (8%) had an initial isolated local relapse. This low rate of first solitary local failure compares favorably with results observed in other published studies using much higher doses of RT
●
P. HO¨SLI et al.
289
(10 –14). All further local relapses happened in patients already symptomatic of distant metastases elsewhere, or were discovered postmortem. The overall results of our pilot study (complete response rate of 68%, median survival time of 21 months, and overall survival of 31% at 6 years) are equivalent to those obtained in other recent published series (10 –14) with more intensive RT. In this final report, we conclude that initial irradiation with 20 Gy could be sufficient to delay or reduce the risk of locoregional recurrence during the time of survival of patients with limited-stage SCLC. These results confirm in our opinion the speculation that limited-stage SCLC, a highly radiosensitive tumor, does not require a high dose of locoregional irradiation if the objective is to delay the risk of local recurrence, provided RT is given prior to CT. This low-dose irradiation was administered first with the assumption that it could have been less efficient after CT because of a possible cross-resistance. This remains speculative in the absence of a comparative trial.
REFERENCES 1. Warde, P.; Payne, D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J. Clin. Oncol. 10:890 – 895; 1992. 2. Pignon, J. P.; Arriagada, R.; Ihde, D. C.; Johnson, D. H.; Perry, M. C.; Souhami, R. L.; Brodin, O.; Joss, R. A.; Kies, M. S.; Lebeau, B.; Onoshi, T.; Osterlind, K.; Tattersall, M. H. N.; Wagner, H. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N. Engl. J. Med. 327:1618 – 1624; 1992. 3. Bunn, P., Jr.; Lichter, A. S.; Makuch, R. W.; Cohen, M. H.; Veach, S. R.; Matthews, M. J.; Johnston Anderson, A.; Edison, M.; Glatstein, E; Minna, J. D.; Ihde, D. C. Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. Ann. Intern. Med. 106:655– 662; 1987. 4. Perry, M. C.; Eaton, W. L.; Propert, K. J.; Ware, J. H.; Zimmer, B.; Chahinian, P.; Skarin, A.; Carey, R. W.; Kreisman, H.; Faulkner, C.; Comis, R.; Green, M. R. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N. Engl. J. Med. 316:912–918; 1987. 5. Murray, N.; Coy, P.; Pater, J. L.; Hodson, I.; Arnold, A.; Zee, B. C.; Payne, D.; Kostashuk, E. C.; Evans, W. K.; Dixon, P.; Sadura, A.; Feld, R.; Levitt, M.; Wierzbicki, R.; Ayoub, J.; Maroun, J. A.; Wilson, K. S. Importance of timing for thoracic irradiation in the combined modality treatment of limited stage small-cell lung cancer. J. Clin. Oncol. 11:336 –344; 1993. 6. Choi, N. C.; Carey, R. W. Importance of radiation dose in achieving loco-regional tumor control in limited stage smallcell lung carcinoma: An update. Int. J. Radiat. Oncol. Biol. Phys. 17:307–310; 1989. 7. Malaise, E. P.; Fertil, B.; Chavaudra, N.; Guichard, M. Distribution of radiation sensitivities for human tumor cells of specific histological types: Comparison of in vitro and in vivo data. Int. J. Radiat. Oncol. Biol. Phys. 12:617– 624; 1986. 8. Bonnefoi, H.; Zulian, G. B.; Mirimanoff, R. O.; Mermillod, B.; Alberto, P. Priming low-dose chest radiotherapy followed
9.
10.
11.
12.
13.
14.
by chemotherapy for limited small-cell lung cancer. Ann. Oncol. 5:771–772; 1994. Joss, R. A.; Bacchi, M.; Hu¨rny, C.; Bernhard, J.; Cerny, T.; Martinelli, G.; Leyvraz, S.; Senn, H. J.; Stahel, R.; Siegenthaler, P.; Ludwig, C.; Alberto, P. Early versus late alternating chemotherapy in small-cell lung cancer. Ann. Oncol. 6:157– 166; 1995. Johnson, B. E.; Bridges, J. D.; Sobczeck, M.; Gray, J.; Linnoila, R. I.; Gazdar, A. F.; Hankins, L.; Steinberg, S. M.; Edison, M.; Frame, J. N.; Pass, H.; Nesbitt, J.; Holden, D.; Mulshine, J. L; Glatstein, E.; Ihde, D. C. Patients with limited small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J. Clin. Oncol. 14:806 – 813; 1996. Mc Cracken, J. D.; Janaki, L. M.; Crowley, J. J.: Taylor, S. A.; Shankir Giri, P. G.; Weiss, G. B.; Gordon, W., Jr.; Baker, H. B.; Mansouri, A.; Kuebler, J. P. Concurrent chemotherapy/ radiotherapy for limited small-cell lung carcinoma: A Southwest Oncology Group study. J. Clin. Oncol. 8:892– 898; 1990. Arriagada, R.; Le Chevalier, T.; Ruffie, P.; Baldeyrou, P.; De Cremoux, H.; Martin, M.; Chomy, P.; Cerrina, M. L.; PellaeCosset, B.; Tarayre, M.; Sancho-Garnier, H. Alternating radiotherapy and chemotherapy in 173 consecutive patients with limited small-cell lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 19:1135–1138; 1990. Mornex, F.; Trillet, V.; Chauvin, F.; Ardiet, J. M.; Schmitt, T.; Romestaing, P.; Carrie, C.; Mahe, M.; Mornex, J. F.; Fournel, P.; Souquet, P. J.; Boniface, E.; Vincent, M.; Piperno, D.; Rebattu, P.; Gerard, J. P. Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 19:23–30; 1990. Turrisi, A. T.; Glover, D. J. Thoracic radiotherapy variables: Influence on local control in small-cell lung cancer limited disease. Int. J. Radiat. Oncol. Biol. Phys. 19:1473–1479; 1990.