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Stage III nonsmall cell lung cancer: Still a challenge for the radiation oncologist
Int. J. Radiation
Oncology
Biol.
Phys., Vol. 39, No. 3, pp. 533-535, 1997 Copyright 0 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0360.3016/97 $17.00 + .OO
PI1 SO360-3016(97)00363-S
l
Clinical STAGE
Investigation/Editorial III
NONSMALL
CELL LUNG CANCER: STILL THE RADIATION ONCOLOGIST
A CHALLENGE
FOR
P. VAN HOUTTE, M.D. Department Radiotherapy, Institut Jules Bordet, Brussels, Belgium Inoperable lung cancers still remain a major challenge in spite of the small but real progress made during the last years. The article of Komaki et al. illustrates the possible benefit obtained with a combined approach but also our frustrations (5). This RTOG trial was designed both to test a hyperfractionated radiation schedule with two fractions a day and to confirm the results of a CALGB trial published in 1990 by Dillman et al. testing the role of two cycles of cisplatin and vinblastine given before a definitive course of radiation (2). The latter was prematurely stopped after an interim analysis showing a significant difference in favor of the induction chemotherapy arm. The current RTOG trial clearly confirms the results of the CALGB with figures very close to the one reported by Dillman et al. and those of a French trial by R. Arriagada et al. using an induction and maintenance chemotherapy (1). Furthermore, a recent metaanalysis including data from 22 trials showed a significant benefit in favor of chemotherapy administered in a sequential way: this was particularly true for a cisplatin-based chemotherapy with an absolute benefit of 4% at 2 years and 2% at 5 years (6). Should induction chemotherapy followed by thoracic radiotherapy become the treatment for all inoperable but localized nonsmall cell lung tumors? The available data suggest a small but definitive benefit in favor of the combined approach, but those results are largely based on a select subset of patients with very favorable prognostic factors (a weight loss less than 5%, performance status above 70 for the CALGB and RTOG trials) and after a careful staging procedure. Patients included in randomized trials represent a very small proportion of all lung cancer patients treated (1%). Extending this approach to all patients may probably produce considerable unnecessary toxicity and morbidity jeopardizing the small possible benefit from combining drugs and radiation, especially in less healthy or less meticulously staged patients. More intensive treatments do not necessarely translate to better survival or better quality of life. As radiation oncologists, we may feel frustrated by the negative results of the hyperfractionated arm both in terms of survival and local control. Several explanations have been put forward to try to justify the absence of benefit including a possible repopulation, suggesting then that an
accelerated hyperfractionated radiation course such as the CHART protocol may be the right answer (7). Indeed, in this randomized trial, the benefit was mainly observed for squamous cell cancers, and there was a trend for CHART to be more effective with increasing tumor stage. However, this trial included a large number of T2 tumors (44%) and of No disease (49%). In contrast, classical hyperfractionated schedules were able to improve the local control and the survival for some head and neck cancers: in the EORTC trial including T2, T3 tonsil tumors, two daily fractions of 1.15 Gy to a total dose of 80.5 Gy led to an improved 5-year local control from 38% for the conventional arm of 70 Gy to 56% for the hyperfractionated schedule (4). Interestingly, this benefit was only observed in T3 but not in T2 tumors. Tumor size is often not reported when dealing with lung cancer: in the current article of Komaki et al., the average tumor size was about 5 cm (5). In contrast with the head and neck trial, the tumor sizes of lung cancer are in most trials often larger and the radiation doses lower. Radiation doses commonly used to treat lung cancer, in the range of 60 to 65 Gy, are certainly inadequate to achieve a high rate of local tumor control. Doses in excess of 75 Gy are probably required to control tumors larger than 3 cm. Therefore, the small increase in the total physical dose used in the hyperfractionated schedule of the RTOG (16%) was unlikely to produce a dramatic increase in local control and, of course, in survival in spite of the promizing results of the large Phase 11 trial. Nevertheless, the absence of any difference in the patterns of failure is very disappointing, but we should keep in mind that the survival curve for the hyperfractionated schedule is always above the classic treatment with one daily fraction. Patterns of failure analyses are an important endpoints to design new studies and strategies. In the article of Komaki et al., induction chemotherapy reduced the incidence of distant metastases other than brain for squamous cell carcinoma, but this did not translate in improving survival, whereas the reverse sentence was true for nonsquamous histology (5). In contrast, Arriagada et al. clearly observed a reduction in distant metastases after an induction chemotherapy program without any difference in local control, and this reduction translated into a survival benefit (1). Furthermore, those two trials also 533
534
1. J. Radiation Oncology 0 Biology
l
Physics
differed in terms of local control: 32 to 42% of patients had a local failure in the RTOG trial compared to 83% in the French trial. This only reflects differences in definition and evaluation procedures: in the French trial, repeated fiberbronchoscopy with biopsies was part of the restaging procedure. Furthermore, thoracic tumor control is a rather vague definition, going from an absence of tumor progression to a complete clearance of all signs of thoracic tumor including a negative fiberbronchoscopy with negative biopsies; this explains the wide variation in reported local control for doses in the range of 60 to 65 Gy: from 17 to 65%. Furthermore, an analysis of local failure is quite a complicated issue for lung cancers due to the procedures used to evaluate the tumor response, and to make the difference between the fibrosis and remaining tumor. Moreover, local control should be reported taking into account the time frame and/or specific date points. Another problem is the absenceof restaging procedure at the time of a first failure: only the most striking event will be reported. This probably explains the high rate of brain relapsesreported in most series.Indeed, the key question is not to know the number of brain metastasiscases,but rather the number of patients failing solely in the brain. Brain metastasismay only be the first sign of a systemic spreadof the cancer, announcing other sites of possible metastastic deposit discovered through a restaging procedure or occurring a few weeks later. The use of a common language appearsas an important issueto understandthe resultsof all trials. The endpoints for multimodal clinical trials were largely discussedduring a workshop of the International Association for the Study of Lung Cancer on Controversies in Staging and Treatment of Locally Advanced Nonsmall Cell Lung Cancersheld in Bruges in 1993. Definitions were proposedboth for local control and local failure after radiotherapy. Furthermore, there was a general agreement to recommend to repeat a minimal restaging procedure at the time of first failure to searcheither for distant metastasisin caseof a local progressionor to assessthe local statusat the time of documentation of distant metastasis(3). This restaging procedure applies especially for studies dealing with patterns of failure. Improving local control remainsan important issuewhen dealing with Stage III lung cancers. Several approachesare possibleincluding surgery, conformal radiotherapy, altered
Volume 39, Number 3, 1997
fractionated radiation schedules,and combining drugs and radiation. As radiation oncologists, we should try to capitalize on our treatment procedures in an attempt to define the optimal approach as well as the limits of the technique. This also implies a high quality control of all our procedure including adequate treatment planning to avoid any geographic errors: in the already coted CALGB trial, the tumor was not completely encompassedwithin the radiation field in 33 out of the 151 reviewed caseseither for the large fields (12 patients) or for the small fields (21 patients) (2). Chemotherapy must not be used to compensate for a weak technique. Then, hyperfractionated schedules, conformal radiotherapy may in a secondstep be introduced in a combined approach either with chemotherapy or even surgery. The latter approachis becoming more and more popular for Stage III diseaseand is not only restricted for Stage IIIa tumor but also for some selected Stage IIIb tumors. The current AJC and UICC classifications are certainly not a very efficient tool to discriminate patients who may or may not benefit from suchan aggressiveapproach. Indeed, many series included patients with tumors considered by some surgeonsas initially resectableand by other as definitively not suitable for surgery. Large-scale randomized trials will be the only way to answer the question and to avoid too toxic treatments. Combining drugs and radiation, especially in a concurrent approach, is one of the most promising ways to be explored in the near future: this approach offers the theoretical advantages to act both on the primary tumor and the possible microscopic spread, but there is a clear risk of increased toxicities requiring strict criteria to select patients for such an aggressive treatment. New drugs with radiosensitizing effect (taxane, gemcitabine, tirapazamine) are being tested in feasability studies but only well-designed Phase III trials including a large number of patients will help to answer the question of their efficacy or not. Furthermore, additional studies also necessary to test the potential benefit of more classical drugs such as cisplatin, etoposide. We should encourage large Phase III trials such as the one conducted by the RTOG, even if they are time-consuming procedures. They will have a greater impact on our daily practice and are the only way to justify our treatment policy and to convince our authorities in this era of budget cuts.
REFERENCES 1. Arriagada, R.: Le Chevalier, T.; Quoix, E.; Ruffie, P.; De Cremoux, H.; Douillard, J. Y.; Tarayre, M.; Pignon, J. P.; Laplanche, A. Effect of chemotherapy on locally advanced non-small lung carcinoma: a randomized study of 353 patients. Int. J. Radiat. Oncol. Biol. Phys. 20:1183-l 190; 1991. 2. Dillman, R. 0.; Seagren, S. L.: Propert, K. J.; Guerra, J.; Eaton, W. L.; Perry. M. C.; Carey, R. W.; Frei, E. F.: Green, M. R. A randomized trial of induction chemotherapy plus high-dose versus radiation alone in stage III non-small cell lung cancer. N. Engl. J. Med. 323:940-945; 1990.
3. Green, M.; Cox, J. D.; Ardizzoni, A.; Arriagada, R.; Bureau, G.; Darwish, S.; Deneffe, G.; Fukuoka, M.; Joseph, R.; Komaki, R.; Mirimanoff, R. 0.; Mornex, F.; Palazzi, M.; Pastorino, U.; Pavy, J. J.; Postmus, P. E.; Roth, J.; Rubin, P.; Saijo, N.; Saunders, M.; Stout, R.; Sutedja, T. G.; Trove, M. G. Endpoints for multimodal clinical trials in Stage III non-small cell lung cancer (NSCLC): A consensus report. Lung Cancer 1 l(Supp1. 3):Sl l-S13; 1994. 4. Horiot, J. C.; LeFur, R.; Schraub, S.; Van Den Bogaert, W.; Van Glabbeke. M.; Pierart, M.; Begg, A. C. Status of the
Stage III nonsmall ceil lung cancer 0 P. VAN Hour-m experience of the EORTC Cooperative Group of Radiotherapy with hyperfractionated and accelerated radiotherapy regimes. Semin. Radiat. Oncol. 2:34-37; 1992. 5. Komaki, R.; Scott, C. B.; Sause, W. T.; Johnson, D. H.; Taylor, S.; Lee, J. S.; Emami, B.; Byhardt, R. W.; Curran, W. J.; Dar, A. R.; Cox, J. D. Induction cisplatin/vinblastine and irradiation vs irradiation in unresectable squamous cell lung cancer: Faillure patterns by cell type in RTOG 8%OUECOG 4.588. Int. J. Radiat. Oncol. Biol. Phys. 39: 537-544.
535
6. Non-small Cell Lung Cancer Collaborative Group. Chemotherapoy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br. Med. J. 311:899-909; 1995. 7. Saunders, M. I.: Dische, S.; Barrett, A.; Parmar, M. K. B.; Harvey, A.; Gibson, D.; on behalf of the CHART Steering Committee. Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small cell lung cancer: An interim report. Br. J. Cancer 73:1455-1462; 1996.
Oncology
Biol.
Phys., Vol. 39, No. 3, pp. 533-535, 1997 Copyright 0 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0360.3016/97 $17.00 + .OO
PI1 SO360-3016(97)00363-S
l
Clinical STAGE
Investigation/Editorial III
NONSMALL
CELL LUNG CANCER: STILL THE RADIATION ONCOLOGIST
A CHALLENGE
FOR
P. VAN HOUTTE, M.D. Department Radiotherapy, Institut Jules Bordet, Brussels, Belgium Inoperable lung cancers still remain a major challenge in spite of the small but real progress made during the last years. The article of Komaki et al. illustrates the possible benefit obtained with a combined approach but also our frustrations (5). This RTOG trial was designed both to test a hyperfractionated radiation schedule with two fractions a day and to confirm the results of a CALGB trial published in 1990 by Dillman et al. testing the role of two cycles of cisplatin and vinblastine given before a definitive course of radiation (2). The latter was prematurely stopped after an interim analysis showing a significant difference in favor of the induction chemotherapy arm. The current RTOG trial clearly confirms the results of the CALGB with figures very close to the one reported by Dillman et al. and those of a French trial by R. Arriagada et al. using an induction and maintenance chemotherapy (1). Furthermore, a recent metaanalysis including data from 22 trials showed a significant benefit in favor of chemotherapy administered in a sequential way: this was particularly true for a cisplatin-based chemotherapy with an absolute benefit of 4% at 2 years and 2% at 5 years (6). Should induction chemotherapy followed by thoracic radiotherapy become the treatment for all inoperable but localized nonsmall cell lung tumors? The available data suggest a small but definitive benefit in favor of the combined approach, but those results are largely based on a select subset of patients with very favorable prognostic factors (a weight loss less than 5%, performance status above 70 for the CALGB and RTOG trials) and after a careful staging procedure. Patients included in randomized trials represent a very small proportion of all lung cancer patients treated (1%). Extending this approach to all patients may probably produce considerable unnecessary toxicity and morbidity jeopardizing the small possible benefit from combining drugs and radiation, especially in less healthy or less meticulously staged patients. More intensive treatments do not necessarely translate to better survival or better quality of life. As radiation oncologists, we may feel frustrated by the negative results of the hyperfractionated arm both in terms of survival and local control. Several explanations have been put forward to try to justify the absence of benefit including a possible repopulation, suggesting then that an
accelerated hyperfractionated radiation course such as the CHART protocol may be the right answer (7). Indeed, in this randomized trial, the benefit was mainly observed for squamous cell cancers, and there was a trend for CHART to be more effective with increasing tumor stage. However, this trial included a large number of T2 tumors (44%) and of No disease (49%). In contrast, classical hyperfractionated schedules were able to improve the local control and the survival for some head and neck cancers: in the EORTC trial including T2, T3 tonsil tumors, two daily fractions of 1.15 Gy to a total dose of 80.5 Gy led to an improved 5-year local control from 38% for the conventional arm of 70 Gy to 56% for the hyperfractionated schedule (4). Interestingly, this benefit was only observed in T3 but not in T2 tumors. Tumor size is often not reported when dealing with lung cancer: in the current article of Komaki et al., the average tumor size was about 5 cm (5). In contrast with the head and neck trial, the tumor sizes of lung cancer are in most trials often larger and the radiation doses lower. Radiation doses commonly used to treat lung cancer, in the range of 60 to 65 Gy, are certainly inadequate to achieve a high rate of local tumor control. Doses in excess of 75 Gy are probably required to control tumors larger than 3 cm. Therefore, the small increase in the total physical dose used in the hyperfractionated schedule of the RTOG (16%) was unlikely to produce a dramatic increase in local control and, of course, in survival in spite of the promizing results of the large Phase 11 trial. Nevertheless, the absence of any difference in the patterns of failure is very disappointing, but we should keep in mind that the survival curve for the hyperfractionated schedule is always above the classic treatment with one daily fraction. Patterns of failure analyses are an important endpoints to design new studies and strategies. In the article of Komaki et al., induction chemotherapy reduced the incidence of distant metastases other than brain for squamous cell carcinoma, but this did not translate in improving survival, whereas the reverse sentence was true for nonsquamous histology (5). In contrast, Arriagada et al. clearly observed a reduction in distant metastases after an induction chemotherapy program without any difference in local control, and this reduction translated into a survival benefit (1). Furthermore, those two trials also 533
534
1. J. Radiation Oncology 0 Biology
l
Physics
differed in terms of local control: 32 to 42% of patients had a local failure in the RTOG trial compared to 83% in the French trial. This only reflects differences in definition and evaluation procedures: in the French trial, repeated fiberbronchoscopy with biopsies was part of the restaging procedure. Furthermore, thoracic tumor control is a rather vague definition, going from an absence of tumor progression to a complete clearance of all signs of thoracic tumor including a negative fiberbronchoscopy with negative biopsies; this explains the wide variation in reported local control for doses in the range of 60 to 65 Gy: from 17 to 65%. Furthermore, an analysis of local failure is quite a complicated issue for lung cancers due to the procedures used to evaluate the tumor response, and to make the difference between the fibrosis and remaining tumor. Moreover, local control should be reported taking into account the time frame and/or specific date points. Another problem is the absenceof restaging procedure at the time of a first failure: only the most striking event will be reported. This probably explains the high rate of brain relapsesreported in most series.Indeed, the key question is not to know the number of brain metastasiscases,but rather the number of patients failing solely in the brain. Brain metastasismay only be the first sign of a systemic spreadof the cancer, announcing other sites of possible metastastic deposit discovered through a restaging procedure or occurring a few weeks later. The use of a common language appearsas an important issueto understandthe resultsof all trials. The endpoints for multimodal clinical trials were largely discussedduring a workshop of the International Association for the Study of Lung Cancer on Controversies in Staging and Treatment of Locally Advanced Nonsmall Cell Lung Cancersheld in Bruges in 1993. Definitions were proposedboth for local control and local failure after radiotherapy. Furthermore, there was a general agreement to recommend to repeat a minimal restaging procedure at the time of first failure to searcheither for distant metastasisin caseof a local progressionor to assessthe local statusat the time of documentation of distant metastasis(3). This restaging procedure applies especially for studies dealing with patterns of failure. Improving local control remainsan important issuewhen dealing with Stage III lung cancers. Several approachesare possibleincluding surgery, conformal radiotherapy, altered
Volume 39, Number 3, 1997
fractionated radiation schedules,and combining drugs and radiation. As radiation oncologists, we should try to capitalize on our treatment procedures in an attempt to define the optimal approach as well as the limits of the technique. This also implies a high quality control of all our procedure including adequate treatment planning to avoid any geographic errors: in the already coted CALGB trial, the tumor was not completely encompassedwithin the radiation field in 33 out of the 151 reviewed caseseither for the large fields (12 patients) or for the small fields (21 patients) (2). Chemotherapy must not be used to compensate for a weak technique. Then, hyperfractionated schedules, conformal radiotherapy may in a secondstep be introduced in a combined approach either with chemotherapy or even surgery. The latter approachis becoming more and more popular for Stage III diseaseand is not only restricted for Stage IIIa tumor but also for some selected Stage IIIb tumors. The current AJC and UICC classifications are certainly not a very efficient tool to discriminate patients who may or may not benefit from suchan aggressiveapproach. Indeed, many series included patients with tumors considered by some surgeonsas initially resectableand by other as definitively not suitable for surgery. Large-scale randomized trials will be the only way to answer the question and to avoid too toxic treatments. Combining drugs and radiation, especially in a concurrent approach, is one of the most promising ways to be explored in the near future: this approach offers the theoretical advantages to act both on the primary tumor and the possible microscopic spread, but there is a clear risk of increased toxicities requiring strict criteria to select patients for such an aggressive treatment. New drugs with radiosensitizing effect (taxane, gemcitabine, tirapazamine) are being tested in feasability studies but only well-designed Phase III trials including a large number of patients will help to answer the question of their efficacy or not. Furthermore, additional studies also necessary to test the potential benefit of more classical drugs such as cisplatin, etoposide. We should encourage large Phase III trials such as the one conducted by the RTOG, even if they are time-consuming procedures. They will have a greater impact on our daily practice and are the only way to justify our treatment policy and to convince our authorities in this era of budget cuts.
REFERENCES 1. Arriagada, R.: Le Chevalier, T.; Quoix, E.; Ruffie, P.; De Cremoux, H.; Douillard, J. Y.; Tarayre, M.; Pignon, J. P.; Laplanche, A. Effect of chemotherapy on locally advanced non-small lung carcinoma: a randomized study of 353 patients. Int. J. Radiat. Oncol. Biol. Phys. 20:1183-l 190; 1991. 2. Dillman, R. 0.; Seagren, S. L.: Propert, K. J.; Guerra, J.; Eaton, W. L.; Perry. M. C.; Carey, R. W.; Frei, E. F.: Green, M. R. A randomized trial of induction chemotherapy plus high-dose versus radiation alone in stage III non-small cell lung cancer. N. Engl. J. Med. 323:940-945; 1990.
3. Green, M.; Cox, J. D.; Ardizzoni, A.; Arriagada, R.; Bureau, G.; Darwish, S.; Deneffe, G.; Fukuoka, M.; Joseph, R.; Komaki, R.; Mirimanoff, R. 0.; Mornex, F.; Palazzi, M.; Pastorino, U.; Pavy, J. J.; Postmus, P. E.; Roth, J.; Rubin, P.; Saijo, N.; Saunders, M.; Stout, R.; Sutedja, T. G.; Trove, M. G. Endpoints for multimodal clinical trials in Stage III non-small cell lung cancer (NSCLC): A consensus report. Lung Cancer 1 l(Supp1. 3):Sl l-S13; 1994. 4. Horiot, J. C.; LeFur, R.; Schraub, S.; Van Den Bogaert, W.; Van Glabbeke. M.; Pierart, M.; Begg, A. C. Status of the
Stage III nonsmall ceil lung cancer 0 P. VAN Hour-m experience of the EORTC Cooperative Group of Radiotherapy with hyperfractionated and accelerated radiotherapy regimes. Semin. Radiat. Oncol. 2:34-37; 1992. 5. Komaki, R.; Scott, C. B.; Sause, W. T.; Johnson, D. H.; Taylor, S.; Lee, J. S.; Emami, B.; Byhardt, R. W.; Curran, W. J.; Dar, A. R.; Cox, J. D. Induction cisplatin/vinblastine and irradiation vs irradiation in unresectable squamous cell lung cancer: Faillure patterns by cell type in RTOG 8%OUECOG 4.588. Int. J. Radiat. Oncol. Biol. Phys. 39: 537-544.
535
6. Non-small Cell Lung Cancer Collaborative Group. Chemotherapoy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br. Med. J. 311:899-909; 1995. 7. Saunders, M. I.: Dische, S.; Barrett, A.; Parmar, M. K. B.; Harvey, A.; Gibson, D.; on behalf of the CHART Steering Committee. Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small cell lung cancer: An interim report. Br. J. Cancer 73:1455-1462; 1996.