Copynghl
0360-3016191 $3.00 + .oO 0 I99 I Pergamon Press plc
l Brief Communication
LIMITED SMALL CELL LUNG CANCER: THE EFFECT OF RADIOTHERAPY ON LOCAL CONTROL FOLLOWING RESPONSE TO CHEMOTHERAPY S. NGAN, FRCS,’ D. BALL, FRACR,’ C. BULL, FRCR, FRACR,2 J. BISHOP, M.D., FRACP, FRCPA,’ P. DUVAL, FRCR, FRACR,3 C. LAIDLAW, B.Sc. (Hons)’ AND J. MATTHEWS, B.Sc. (Hons), PH.D.’ ‘Peter MacCallum
Cancer Institute,
Melbourne;
‘Westmead
Centre,
Sydney; and ‘Royal Prince Alfred Hospital, Sydney
The survival and rate of chest infield relapse was examined in 48 patients with limited disease small cell lung cancer (LSCLC)who had achieved complete (CR) or partial response (PR)following three courses of chemotherapy. During 1985-1986 chemotherapy consisted of carboplatin and etoposide and during 1986-1987, of etoposide, carboplatin, cyclophosphamide, and vincristine (ECCO). After three courses of chemotherapy, chest irradiation (50 Gy in 25 fractions over 5 weeks) was given to encompass the original tumor volume. Complete responders were also given prophylactic cranial irradiation, 30 Gy in 10 fractions over 2 weeks. Overall median survival of all patients receiving chest irradiation was 17 months from commencement of radiotherapy. The infield relapse-free survival at 24 months was 49% (95% confidence interval: 32-66%). Patients who had only achieved a PR at the time of irradiation were more likely to relapse in the chest than complete responders (p = 0.09). We conclude that local relapse remains a major cause of failure in patients with LSCLC in spite of sequential high dose radiotherapy given to patients who have responded to chemotherapy. Small cell lung cancer, Thoracic irradiation, Local control.
INTRODUCTION
prospective Canadian trial, in which patients responding to chemotherapy were randomized to two different dose levels of locoregional thoracic irradiation, showed no difference in survival between the high and low dose groups, although the median progression-free survival was shorter in the low dose group (6). However, the dose schedules used were low (25 Gy in 10 fractions versus 37.5 Gy in 15 fractions) and the local progression rates at 2 years high (80% and 69%, respectively). To define better the relationship of dose to locoregional control in patients with LSCLC, we examined the rates of infield failure in patients treated in two prospective Phase II studies in which chemotherapy and high dose radiotherapy were standardized.
The role of thoracic radiotherapy in patients with limited small cell lung cancer (LSCLC) is controversial. Some randomized trials have shown a survival benefit for patients given thoracic irradiation as well as chemotherapy compared with those treated with chemotherapy alone (4, 12, 13), whereas others have not (8, 10, 11, 14). A comparison of the radiotherapy schedules used in these trials reveals considerable variation in terms of total dose, dose per fraction, and duration and timing of treatment (whether concurrent or sequential in relation to chemotherapy, or whether given at diagnosis or on completion of chemotherapy), indicating that there is no consensus on the optimum schedule and timing of radiotherapy which maximizes the likelihood of local control. In one retrospective study (5) locoregional control was significantly better in patients receiving 50 Gy compared with those receiving 35 Gy; however, the type of chemotherapy used as primary treatment changed over the study period and it is not clear from the report whether radiotherapy was given to nonresponders as well as to responders. A
METHODS
AND
MATERIALS
All patients had histologically or cytologically proven SCLC. All patients had limited disease defined as disease confined to one hemithorax and/or ipsilateral supraclavicular fossa. The presence of a pleural effusion was clas-
preparing the illustrations manuscript. Accepted for publication
Reprint requests to: D. Ball, Peter MacCallum Cancer Institute, 481 Little Lonsdale St., Melbourne, Victoria 3000, Australia. Acknowledgements-We wish to thank the Department of Medical Photography, Peter MacCallum Cancer Institute for
459
and Cathy 3 January
Girardi 199 1.
for typing
the
460
I. J. Radiation Oncology 0 Biology0 Physics
sified as extensive disease. Details of pretreatment staging investigations, chemotherapy, response rates, and survival have all been published previously (2, 3). From 1985 to 1986, patients were given carboplatin 100 mg/m* IV days 1, 2, and 3 (300 mg/m* per course) and etoposide 120 mg/m2 IV days 1,2, and 3 (360 mg/ m2 per course). Chemotherapy was repeated every 28 days. From 1986 to 1987 patients were given etoposide and carboplatin as above, as well as cyclophosphamide 750 mg/m2 IV day 1 and vincristine 1.4 mg/m* IV day 1 (ECCO), every 28 days. Patients achieving complete (CR) or partial response (PR) as defined by the WHO criteria (9) after three cycles of chemotherapy were then given chest irradiation, 50 Gy in 25 fractions over 5 weeks. The target volume was selected to include the known original extent of disease. The supraclavicular fossa was only covered if it had been involved at the outset. Treatment planning was performed using CT images on a computer planning system, correcting for tissue inhomogeneities. Parallel opposed anterior and posterior fields were used to give the first 40 Gy; the final 10 Gy were given via lateral or oblique fields, placed so as to avoid the spinal cord, the dose to which did not exceed 45 Gy. Complete responders were given cranial irradiation 30 Gy in 10 fractions if CR was achieved after 3 or 6 courses of chemotherapy. After completion of radiotherapy, a further three cycles of chemotherapy were administered. On completion of treatment, patients were seen and assessed at regular intervals with physical examination and chest X ray. Sites of thoracic relapse were correlated with the simulator films to determine if progression was in or outside the treatment field. Overall survival and chest infield relapse-free survival were calculated from the commencement of chest irradiation. All analyses were performed using the BMDP statistical package (7). The product limit (Kaplan-Meier) method was used to obtain estimates of the survival distribution. Percentages quoted in the survival context refer to these estimates. The log-rank test was used in the comparison of survival curves. p values quoted are two-sided.
July 1991, Volume 2 1, Number 2 OVERALL SURVIVAL Carboplatm-Etoposlde vs ECCO
_
ECCO 28 pahmts CoboplafnEtoposlde 20 pahents
0
6
12 MONTHS
24
18 FOLLOWING
30
36
RADIOTHERAPY
Fig. 2. Survival according to chemotherapy
regimen.
RESULTS
A total of 184 patients were entered on the two studies: 94 patients were treated with carboplatin and etoposide and 90 patients with the ECCO regimen. Fifty-four patients received chest irradiation after three courses of chemotherapy. Six of these patients were excluded from further analysis since they were considered to have extensive disease on review of their pretreatment investigations: all had ipsilateral pleural effusions at commencement of treatment. Of the 48 remaining patients, 24 were male and 24 female. The mean age of these patients was 6 1 years (range 4 l-77). Twenty patients had been treated with carboplatin and etoposide and 28 with ECCO. Seventeen patients had achieved a CR and 31 a PR before thoracic irradiation. The median time from commencement of chemotherapy to commencement of radiotherapy was 12 weeks, range 10 to 15 weeks. Although all patients were planned to receive 50 Gy thoracic target volume, three patients ceased treatment at 46 Gy and one at 44 Gy. These patients have been included in the analysis. The median survival of the 48 patients was 17 months from the commencement of chest irradiation (Fig. 1). There was no difference in survival between the two chemotherapy regimens (Fig. 2). The median overall relapse-free survival was 13 months, with 25% of patients disease free at 24 months (Fig. 3). Patients OVERALL RELAPSE FREE SURVIVAL
OVERALL SURVIVAL _
_ All pchents 46 patients
CR’ n potmts
PR 3t pahents
PR
0
0
m
cl21
6
12 MONTHS
ml)
(VI
(6)
(21
18
24
30
36
FOLLOWING
RADIOTHERAPY
Fig. 1. Survival of patients receiving chest irradiation following chemotherapy induced CR or PR.
All potlents 48 patmts CR t7 pahents
0
6
12
t8
MONTHS
FOLLOWING
24
30
36
RADIOTHERAPY
Fig. 3. Relapse free survival of patients receiving thoracic irmdiation, including survival of complete (CR) and partial rewonders (PR).
Limited small cell lung cancer 0 S. NCAN et al.
461
CHEST IN-FIELDRELAPSEFREESURVIVAL lapse-free survival rates-63% _
All patients 48 potmts
PR 31 patients
0
6
12
18
MONTHS FOLLOWING
24
30
36
RADIOTHERAPY
Fig. 4. Chest infield relapse free survival following commencement of thoracic radiotherapy, including survival of complete (CR) and partial responders (PR). achieving CR before radiotherapy had better relapse-free survival than patients achieving PR (p = 0.04) (Fig. 3). Twenty-three patients (48%) failed within the thoracic irradiation treatment volume. This number includes all infield relapses whether sites of first or subsequent relapses. The chest infield relapse-free survival at 24 months was 49% (95% confidence interval 32-66%) (Fig. 4). Patients in PR at the time of irradiation tended to have a higher rate of infield relapse than patients who had achieved CR (p = 0.09) (Fig. 4). Only one patient appeared to relapse as a result of a geographic miss. Recurrence occurred in the supraclavicular fossa immediately outside the margin of the neck field without relapse in the thorax. Of the four patients receiving less than 50 Gy, one patient relapsed infield after receiving 46 Gy and the remainder relapsed outside the treatment volume. Nineteen patients failed first within the radiotherapy treatment volume. Of these, 12 (25%) relapsed in the chest alone. Eleven patients (23%) relapsed in the brain; 7 at the time of first relapse, and in 4 of these patients the brain was the only site of relapse. Four patients relapsing in brain as first site had received prophylactic cranial irradiation. Overall 68% (95% confidence interval 50%-85%) were CNS relapse-free 24 months after commencing chest irradiation. DISCUSSION
The wide variation in radiotherapy schedules in terms of total dose, fractionation, and timing that have been used for thoracic irradiation in SCLC is testimony to the fact that there is no consensus as to the ideal regimen associated with the best rates of local control. Of six recently published randomized trials (4, 10-14) in which chest irradiation was the treatment variable, only two studies used identical radiation schedules (40 Gy in 20 fractions) ( 10, 14) and only two reported 2-year chest re-
(4) and 54% ( 13). The Canadian study (6) in which two dose levels of thoracic irradiation were compared reported very low rates of chest relapse-free survival at 2 years viz 20% for 25 Gy in 10 fractions and 31% for 37.5 Gy in 15 fractions. Choi and Carey (5) have demonstrated better relapse-free survival at 2.5 years in patients receiving 50 Gy (63%) compared with those receiving 35 Gy (21%). This study provides some useful information about the value of thoracic irradiation in patients who have responded to chemotherapy for small cell lung cancer. All patients were treated in the context of two prospective Phase II trials in which the chemotherapy and radiotherapy were standardized. Although two different chemotherapy regimens were used in sequential studies, there was no difference in patient survival between the two studies. All patients included in this analysis had limited disease and had achieved a complete or partial response before radiotherapy. Patients who had achieved CR had at most clinically undetectable microscopic disease at the time of radiotherapy, yet in spite of a dose of 50 Gy, only 66% of these remained infield relapse-free at 24 months, although the 95% confidence interval (C.I.) was wide (4 l9 1%). Only 38% (95% C.I. 16-6 1%) of partial responders remained infield relapse-free at 24 months. These data suggest that radiotherapy delayed until the patient has achieved CR or PR and given in a dose of 50 Gy is of limited efficacy in achieving local control (especially in partial responders), since all the failures occurred within the target volume. Our experience is in keeping with the 40-50% locoregional failure rate reported by others (4, 5, 12). The volume of lung to be irradiated after chemotherapy is also controversial. Marginal failure was not, however, a problem in this analysis, occurring in only one patient. This suggests that the high thoracic failure rate results from inadequacy of dose rather than the treatment volume. We conclude that in patients with chemotherapy-responsive limited small cell lung cancer, high doses of conventionally fractionated chest irradiation (50 Gy) given sequentially after chemotherapy are associated with significant rates of infield failure. Local control may be important for survival since 25% of patients in this analysis relapsed in the chest alone. To improve local control, the options are to increase the dose of chest irradiation, or to try innovative approaches such as alternating chemotherapy/radiotherapy using conventional fractionation ( 1) or multiple fractions per day ( 15). This last approach appears to hold the most promise, but it needs to be tested against what can be achieved with conventional fractionation.
REFERENCES 1. Arriagada, R.; Le Chevalier, T.; Baldeyrou, P.; Pica, J. L.; Ruffie, P.; Martin, M.; El Bakry, H. M.; Duroux, P.; Bignon,
J.; Lenfant, B.; Hayat, M.; Rouesse, J. G.; Sancho-Garnier, H.; Tubiana, M. Alternating radiotherapy and chemother-
462
2.
3.
4.
5.
6.
7. 8.
1. J. Radiation Oncology 0 Biology 0 Physics
apy schedules in small cell lung cancer, limited disease. Int. J. Radiat. Oncol. Biol. Phys. 11:1461-1467; 1985. Bishop, J. F.; Raghavan, D.; Stuart-Harris, R.; Morstyn, G.; Aroney, R.; Kefford, R.; Yeun, K.; Lee, J.; Gianoutsos, P.; Olver, I.; Zalcberg, J.; Ball, D. L.; Bull, C.; Fox, R. Carboplatin and VP 16 in previously untreated patients with small cell lung cancer. J. Clin. Oncol. 5: 1574- 1578; 1987. Bishop, J. F.; Kefford, R.; Raghavan, D.; Zalcberg, J.; StuartHarris, R.; Ball, D. L.; Olver, I. N.; Friedlander, M.; Bull, C.; Yuen, K.; Matthews, J. P.; Zimet, A. Etoposide, carboplatin, cyclophosphamide and vincristine (ECCO) in previously untreated patients with small cell lung cancer. Cancer Chemother. Pharmacol. 25:367-370; 1990. Bunn, P. A.; Lichter, A. S.; Makuch, R. W.; Cohen, M. H.; Veach, S. R.; Matthews, M. J.; Anderson, A. J.; Edison, M.; Glatstein, E.; Minna, J.; Ihde, D. C. Chemotherapy alone or chemotherapy with chest irradiation therapy in limited stage small cell lung cancer. Ann. Int. Med. 106:655-662; 1987. Choi, N. C.; Carey, R. W. Importance of radiation dose in achieving improved locoregional control in limited stage small cell lung cancer: an update. Int. J. Radiat. Oncol. Biol. Phys. 17:307-310; 1989. Coy, P.; Hudson, I.; Payne, D. G.; Evans, W. K.; Feld, R.; MacDonald, A. S.; Osoba, D.; Pater, J. L. The effect of dose of thoracic irradiation on recurrence in patients with limited stage small cell lung cancer. Initial results of a Canadian multicentre trial. Int. J. Radiat. Oncol. Biol. Phys. 14:219226; 1988. Dixon, W. J., Ed BMDP Statistical software 198 1. University of California, Berkely: California Press; 1981:557-575. Fox, R. M.; Woods, R. L.; Brodie, G. N.; Tattersall, M. N. A randomised study: small cell anaplastic lung cancer treated by combination chemotherapy and adjuvant radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 6:1083-1085; 1980.
July I99 1, Volume 2 I, Number 2
9. Miller, A. B.; Hoogstraten, B.; Staquet, M.; Winkler, A. Reporting results of cancer treatment. Cancer 47:207-214; 1981. 10. Nou, E.; Brodin, 0.; Bergh, J. A random&d study of radiation treatment in small cell bronchial carcinoma treated with two types of fourdrug chemotherapy regimens. Cancer 62:1079-1090; 1988. 11. Osterhnd, K.; Hansen, H. H.; Hansen, H. J.; Dombernowsky, P.; Hansen, M.; Rorth, M. Chemotherapy versus chemotherapy plus irradiation in limited small cell lung cancer. Results of a controlled trial with 5 years follow-up. Br. J. Cancer 54:7-17; 1986. 12. Perez, C. A.; Einhorn, L.; Oldham, R. K.; Greco, F. A.; Cohen, M. J.; Silberman, M.; Krauss, J.; Hornback, N.; Comas, F.; Omura, G.; Salter, M.; Keller, J. W.; McLaren, J.; Kellermeyer, R.; Storaasli, J.; Birch, R.; Dandy, M. Randomised trial of radiotherapy to the thorax in limited small cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report. J. Clin. Oncol. 2:1200-1208; 1984. 13. Perry, M. C.; Eaton, W. L.; Propert, K. J.; Wake, J. H.; Zimmer, B.; Chahnian, 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. 3 I6:9 12-9 18; 1987. 14. Souhami, R. L.; Geddes, D. M.; Spiro, S. G.; Harper, P. G.; Tobias, J. S.; Mantell, B. J.; Fearon, F.; Bradbury, I. Radiotherapy in small cell cancer of the lung treated with combination chemotherapy: a controlled trial. Br. Med. J. 288: 1643-1646; 1984. 15. Tunisi, A. T.; Glover, D. J.; Mason, B. A. A preliminary report: concurrent twice daily radiotherapy plus cisplatinetoposide chemotherapy for limited small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15:183-187; 1988.
0360-3016191 $3.00 + .oO 0 I99 I Pergamon Press plc
l Brief Communication
LIMITED SMALL CELL LUNG CANCER: THE EFFECT OF RADIOTHERAPY ON LOCAL CONTROL FOLLOWING RESPONSE TO CHEMOTHERAPY S. NGAN, FRCS,’ D. BALL, FRACR,’ C. BULL, FRCR, FRACR,2 J. BISHOP, M.D., FRACP, FRCPA,’ P. DUVAL, FRCR, FRACR,3 C. LAIDLAW, B.Sc. (Hons)’ AND J. MATTHEWS, B.Sc. (Hons), PH.D.’ ‘Peter MacCallum
Cancer Institute,
Melbourne;
‘Westmead
Centre,
Sydney; and ‘Royal Prince Alfred Hospital, Sydney
The survival and rate of chest infield relapse was examined in 48 patients with limited disease small cell lung cancer (LSCLC)who had achieved complete (CR) or partial response (PR)following three courses of chemotherapy. During 1985-1986 chemotherapy consisted of carboplatin and etoposide and during 1986-1987, of etoposide, carboplatin, cyclophosphamide, and vincristine (ECCO). After three courses of chemotherapy, chest irradiation (50 Gy in 25 fractions over 5 weeks) was given to encompass the original tumor volume. Complete responders were also given prophylactic cranial irradiation, 30 Gy in 10 fractions over 2 weeks. Overall median survival of all patients receiving chest irradiation was 17 months from commencement of radiotherapy. The infield relapse-free survival at 24 months was 49% (95% confidence interval: 32-66%). Patients who had only achieved a PR at the time of irradiation were more likely to relapse in the chest than complete responders (p = 0.09). We conclude that local relapse remains a major cause of failure in patients with LSCLC in spite of sequential high dose radiotherapy given to patients who have responded to chemotherapy. Small cell lung cancer, Thoracic irradiation, Local control.
INTRODUCTION
prospective Canadian trial, in which patients responding to chemotherapy were randomized to two different dose levels of locoregional thoracic irradiation, showed no difference in survival between the high and low dose groups, although the median progression-free survival was shorter in the low dose group (6). However, the dose schedules used were low (25 Gy in 10 fractions versus 37.5 Gy in 15 fractions) and the local progression rates at 2 years high (80% and 69%, respectively). To define better the relationship of dose to locoregional control in patients with LSCLC, we examined the rates of infield failure in patients treated in two prospective Phase II studies in which chemotherapy and high dose radiotherapy were standardized.
The role of thoracic radiotherapy in patients with limited small cell lung cancer (LSCLC) is controversial. Some randomized trials have shown a survival benefit for patients given thoracic irradiation as well as chemotherapy compared with those treated with chemotherapy alone (4, 12, 13), whereas others have not (8, 10, 11, 14). A comparison of the radiotherapy schedules used in these trials reveals considerable variation in terms of total dose, dose per fraction, and duration and timing of treatment (whether concurrent or sequential in relation to chemotherapy, or whether given at diagnosis or on completion of chemotherapy), indicating that there is no consensus on the optimum schedule and timing of radiotherapy which maximizes the likelihood of local control. In one retrospective study (5) locoregional control was significantly better in patients receiving 50 Gy compared with those receiving 35 Gy; however, the type of chemotherapy used as primary treatment changed over the study period and it is not clear from the report whether radiotherapy was given to nonresponders as well as to responders. A
METHODS
AND
MATERIALS
All patients had histologically or cytologically proven SCLC. All patients had limited disease defined as disease confined to one hemithorax and/or ipsilateral supraclavicular fossa. The presence of a pleural effusion was clas-
preparing the illustrations manuscript. Accepted for publication
Reprint requests to: D. Ball, Peter MacCallum Cancer Institute, 481 Little Lonsdale St., Melbourne, Victoria 3000, Australia. Acknowledgements-We wish to thank the Department of Medical Photography, Peter MacCallum Cancer Institute for
459
and Cathy 3 January
Girardi 199 1.
for typing
the
460
I. J. Radiation Oncology 0 Biology0 Physics
sified as extensive disease. Details of pretreatment staging investigations, chemotherapy, response rates, and survival have all been published previously (2, 3). From 1985 to 1986, patients were given carboplatin 100 mg/m* IV days 1, 2, and 3 (300 mg/m* per course) and etoposide 120 mg/m2 IV days 1,2, and 3 (360 mg/ m2 per course). Chemotherapy was repeated every 28 days. From 1986 to 1987 patients were given etoposide and carboplatin as above, as well as cyclophosphamide 750 mg/m2 IV day 1 and vincristine 1.4 mg/m* IV day 1 (ECCO), every 28 days. Patients achieving complete (CR) or partial response (PR) as defined by the WHO criteria (9) after three cycles of chemotherapy were then given chest irradiation, 50 Gy in 25 fractions over 5 weeks. The target volume was selected to include the known original extent of disease. The supraclavicular fossa was only covered if it had been involved at the outset. Treatment planning was performed using CT images on a computer planning system, correcting for tissue inhomogeneities. Parallel opposed anterior and posterior fields were used to give the first 40 Gy; the final 10 Gy were given via lateral or oblique fields, placed so as to avoid the spinal cord, the dose to which did not exceed 45 Gy. Complete responders were given cranial irradiation 30 Gy in 10 fractions if CR was achieved after 3 or 6 courses of chemotherapy. After completion of radiotherapy, a further three cycles of chemotherapy were administered. On completion of treatment, patients were seen and assessed at regular intervals with physical examination and chest X ray. Sites of thoracic relapse were correlated with the simulator films to determine if progression was in or outside the treatment field. Overall survival and chest infield relapse-free survival were calculated from the commencement of chest irradiation. All analyses were performed using the BMDP statistical package (7). The product limit (Kaplan-Meier) method was used to obtain estimates of the survival distribution. Percentages quoted in the survival context refer to these estimates. The log-rank test was used in the comparison of survival curves. p values quoted are two-sided.
July 1991, Volume 2 1, Number 2 OVERALL SURVIVAL Carboplatm-Etoposlde vs ECCO
_
ECCO 28 pahmts CoboplafnEtoposlde 20 pahents
0
6
12 MONTHS
24
18 FOLLOWING
30
36
RADIOTHERAPY
Fig. 2. Survival according to chemotherapy
regimen.
RESULTS
A total of 184 patients were entered on the two studies: 94 patients were treated with carboplatin and etoposide and 90 patients with the ECCO regimen. Fifty-four patients received chest irradiation after three courses of chemotherapy. Six of these patients were excluded from further analysis since they were considered to have extensive disease on review of their pretreatment investigations: all had ipsilateral pleural effusions at commencement of treatment. Of the 48 remaining patients, 24 were male and 24 female. The mean age of these patients was 6 1 years (range 4 l-77). Twenty patients had been treated with carboplatin and etoposide and 28 with ECCO. Seventeen patients had achieved a CR and 31 a PR before thoracic irradiation. The median time from commencement of chemotherapy to commencement of radiotherapy was 12 weeks, range 10 to 15 weeks. Although all patients were planned to receive 50 Gy thoracic target volume, three patients ceased treatment at 46 Gy and one at 44 Gy. These patients have been included in the analysis. The median survival of the 48 patients was 17 months from the commencement of chest irradiation (Fig. 1). There was no difference in survival between the two chemotherapy regimens (Fig. 2). The median overall relapse-free survival was 13 months, with 25% of patients disease free at 24 months (Fig. 3). Patients OVERALL RELAPSE FREE SURVIVAL
OVERALL SURVIVAL _
_ All pchents 46 patients
CR’ n potmts
PR 3t pahents
PR
0
0
m
cl21
6
12 MONTHS
ml)
(VI
(6)
(21
18
24
30
36
FOLLOWING
RADIOTHERAPY
Fig. 1. Survival of patients receiving chest irradiation following chemotherapy induced CR or PR.
All potlents 48 patmts CR t7 pahents
0
6
12
t8
MONTHS
FOLLOWING
24
30
36
RADIOTHERAPY
Fig. 3. Relapse free survival of patients receiving thoracic irmdiation, including survival of complete (CR) and partial rewonders (PR).
Limited small cell lung cancer 0 S. NCAN et al.
461
CHEST IN-FIELDRELAPSEFREESURVIVAL lapse-free survival rates-63% _
All patients 48 potmts
PR 31 patients
0
6
12
18
MONTHS FOLLOWING
24
30
36
RADIOTHERAPY
Fig. 4. Chest infield relapse free survival following commencement of thoracic radiotherapy, including survival of complete (CR) and partial responders (PR). achieving CR before radiotherapy had better relapse-free survival than patients achieving PR (p = 0.04) (Fig. 3). Twenty-three patients (48%) failed within the thoracic irradiation treatment volume. This number includes all infield relapses whether sites of first or subsequent relapses. The chest infield relapse-free survival at 24 months was 49% (95% confidence interval 32-66%) (Fig. 4). Patients in PR at the time of irradiation tended to have a higher rate of infield relapse than patients who had achieved CR (p = 0.09) (Fig. 4). Only one patient appeared to relapse as a result of a geographic miss. Recurrence occurred in the supraclavicular fossa immediately outside the margin of the neck field without relapse in the thorax. Of the four patients receiving less than 50 Gy, one patient relapsed infield after receiving 46 Gy and the remainder relapsed outside the treatment volume. Nineteen patients failed first within the radiotherapy treatment volume. Of these, 12 (25%) relapsed in the chest alone. Eleven patients (23%) relapsed in the brain; 7 at the time of first relapse, and in 4 of these patients the brain was the only site of relapse. Four patients relapsing in brain as first site had received prophylactic cranial irradiation. Overall 68% (95% confidence interval 50%-85%) were CNS relapse-free 24 months after commencing chest irradiation. DISCUSSION
The wide variation in radiotherapy schedules in terms of total dose, fractionation, and timing that have been used for thoracic irradiation in SCLC is testimony to the fact that there is no consensus as to the ideal regimen associated with the best rates of local control. Of six recently published randomized trials (4, 10-14) in which chest irradiation was the treatment variable, only two studies used identical radiation schedules (40 Gy in 20 fractions) ( 10, 14) and only two reported 2-year chest re-
(4) and 54% ( 13). The Canadian study (6) in which two dose levels of thoracic irradiation were compared reported very low rates of chest relapse-free survival at 2 years viz 20% for 25 Gy in 10 fractions and 31% for 37.5 Gy in 15 fractions. Choi and Carey (5) have demonstrated better relapse-free survival at 2.5 years in patients receiving 50 Gy (63%) compared with those receiving 35 Gy (21%). This study provides some useful information about the value of thoracic irradiation in patients who have responded to chemotherapy for small cell lung cancer. All patients were treated in the context of two prospective Phase II trials in which the chemotherapy and radiotherapy were standardized. Although two different chemotherapy regimens were used in sequential studies, there was no difference in patient survival between the two studies. All patients included in this analysis had limited disease and had achieved a complete or partial response before radiotherapy. Patients who had achieved CR had at most clinically undetectable microscopic disease at the time of radiotherapy, yet in spite of a dose of 50 Gy, only 66% of these remained infield relapse-free at 24 months, although the 95% confidence interval (C.I.) was wide (4 l9 1%). Only 38% (95% C.I. 16-6 1%) of partial responders remained infield relapse-free at 24 months. These data suggest that radiotherapy delayed until the patient has achieved CR or PR and given in a dose of 50 Gy is of limited efficacy in achieving local control (especially in partial responders), since all the failures occurred within the target volume. Our experience is in keeping with the 40-50% locoregional failure rate reported by others (4, 5, 12). The volume of lung to be irradiated after chemotherapy is also controversial. Marginal failure was not, however, a problem in this analysis, occurring in only one patient. This suggests that the high thoracic failure rate results from inadequacy of dose rather than the treatment volume. We conclude that in patients with chemotherapy-responsive limited small cell lung cancer, high doses of conventionally fractionated chest irradiation (50 Gy) given sequentially after chemotherapy are associated with significant rates of infield failure. Local control may be important for survival since 25% of patients in this analysis relapsed in the chest alone. To improve local control, the options are to increase the dose of chest irradiation, or to try innovative approaches such as alternating chemotherapy/radiotherapy using conventional fractionation ( 1) or multiple fractions per day ( 15). This last approach appears to hold the most promise, but it needs to be tested against what can be achieved with conventional fractionation.
REFERENCES 1. Arriagada, R.; Le Chevalier, T.; Baldeyrou, P.; Pica, J. L.; Ruffie, P.; Martin, M.; El Bakry, H. M.; Duroux, P.; Bignon,
J.; Lenfant, B.; Hayat, M.; Rouesse, J. G.; Sancho-Garnier, H.; Tubiana, M. Alternating radiotherapy and chemother-
462
2.
3.
4.
5.
6.
7. 8.
1. J. Radiation Oncology 0 Biology 0 Physics
apy schedules in small cell lung cancer, limited disease. Int. J. Radiat. Oncol. Biol. Phys. 11:1461-1467; 1985. Bishop, J. F.; Raghavan, D.; Stuart-Harris, R.; Morstyn, G.; Aroney, R.; Kefford, R.; Yeun, K.; Lee, J.; Gianoutsos, P.; Olver, I.; Zalcberg, J.; Ball, D. L.; Bull, C.; Fox, R. Carboplatin and VP 16 in previously untreated patients with small cell lung cancer. J. Clin. Oncol. 5: 1574- 1578; 1987. Bishop, J. F.; Kefford, R.; Raghavan, D.; Zalcberg, J.; StuartHarris, R.; Ball, D. L.; Olver, I. N.; Friedlander, M.; Bull, C.; Yuen, K.; Matthews, J. P.; Zimet, A. Etoposide, carboplatin, cyclophosphamide and vincristine (ECCO) in previously untreated patients with small cell lung cancer. Cancer Chemother. Pharmacol. 25:367-370; 1990. Bunn, P. A.; Lichter, A. S.; Makuch, R. W.; Cohen, M. H.; Veach, S. R.; Matthews, M. J.; Anderson, A. J.; Edison, M.; Glatstein, E.; Minna, J.; Ihde, D. C. Chemotherapy alone or chemotherapy with chest irradiation therapy in limited stage small cell lung cancer. Ann. Int. Med. 106:655-662; 1987. Choi, N. C.; Carey, R. W. Importance of radiation dose in achieving improved locoregional control in limited stage small cell lung cancer: an update. Int. J. Radiat. Oncol. Biol. Phys. 17:307-310; 1989. Coy, P.; Hudson, I.; Payne, D. G.; Evans, W. K.; Feld, R.; MacDonald, A. S.; Osoba, D.; Pater, J. L. The effect of dose of thoracic irradiation on recurrence in patients with limited stage small cell lung cancer. Initial results of a Canadian multicentre trial. Int. J. Radiat. Oncol. Biol. Phys. 14:219226; 1988. Dixon, W. J., Ed BMDP Statistical software 198 1. University of California, Berkely: California Press; 1981:557-575. Fox, R. M.; Woods, R. L.; Brodie, G. N.; Tattersall, M. N. A randomised study: small cell anaplastic lung cancer treated by combination chemotherapy and adjuvant radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 6:1083-1085; 1980.
July I99 1, Volume 2 I, Number 2
9. Miller, A. B.; Hoogstraten, B.; Staquet, M.; Winkler, A. Reporting results of cancer treatment. Cancer 47:207-214; 1981. 10. Nou, E.; Brodin, 0.; Bergh, J. A random&d study of radiation treatment in small cell bronchial carcinoma treated with two types of fourdrug chemotherapy regimens. Cancer 62:1079-1090; 1988. 11. Osterhnd, K.; Hansen, H. H.; Hansen, H. J.; Dombernowsky, P.; Hansen, M.; Rorth, M. Chemotherapy versus chemotherapy plus irradiation in limited small cell lung cancer. Results of a controlled trial with 5 years follow-up. Br. J. Cancer 54:7-17; 1986. 12. Perez, C. A.; Einhorn, L.; Oldham, R. K.; Greco, F. A.; Cohen, M. J.; Silberman, M.; Krauss, J.; Hornback, N.; Comas, F.; Omura, G.; Salter, M.; Keller, J. W.; McLaren, J.; Kellermeyer, R.; Storaasli, J.; Birch, R.; Dandy, M. Randomised trial of radiotherapy to the thorax in limited small cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report. J. Clin. Oncol. 2:1200-1208; 1984. 13. Perry, M. C.; Eaton, W. L.; Propert, K. J.; Wake, J. H.; Zimmer, B.; Chahnian, 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. 3 I6:9 12-9 18; 1987. 14. Souhami, R. L.; Geddes, D. M.; Spiro, S. G.; Harper, P. G.; Tobias, J. S.; Mantell, B. J.; Fearon, F.; Bradbury, I. Radiotherapy in small cell cancer of the lung treated with combination chemotherapy: a controlled trial. Br. Med. J. 288: 1643-1646; 1984. 15. Tunisi, A. T.; Glover, D. J.; Mason, B. A. A preliminary report: concurrent twice daily radiotherapy plus cisplatinetoposide chemotherapy for limited small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15:183-187; 1988.
