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Radiotherapy of NSCLC: current challenges and future directions
Abstracts reduction in the risk of death was observed, suggesting an absolute benefit of 5% with adjuvant chemotherapy at five years. Chemotherapy was randomly added to surgery and radiotherapy in a total of 807 patients. This led to a 6% reduction in the risk of death, suggesting a 2% absolute benefit at five years. The above findings constitute the rationale for large scale trials and several new generation adjuvant studies have recently been initiated worldwide. The role of adjuvant radiotherapy has been recently revised by the PORT Meta-analysis Trialist Group. This meta-analysis, using individual data from randomized clinical trials, showed a significant adverse effect of post-operative radiotherapy on survival with a 22% relative increase in the risk of death, equivalent to an absolute detriment of 7% at 2 years, reducing overall survival from 55% to 48% (5). In conclusion, in totally resected NSCLC patients, available data do not support the use of post-operative radiotherapy, while a potential advantage in survival can be obtained with post-operative CDDP-based chemotherapy. Ongoing trials will clarify the exact role of chemotherapy in this setting. References: 1. Girling DJ, Stott H, Stephens RJ, et al. Fifteen-year follow-up of all patients in a study of post-operative chemotherapy for bronchial carcinoma. Br J Cancer 1985;52:867-873 2. Feld R, Rubinstein L, Thomas PA, and the Lung Cancer Study Group. Adjuvant chemotherapy with cyclophosphamide, doxorubicin and cisplatin in patients with completely resected stage I non-small cell lung cancer. J Natl Cancer Inst 1993;85:299-306 3. Holmes E, Gail M. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 1986;4:710-715. 4. Non-small cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995 ;311:899-909. 5. Stewart LA, Burdett S, Souhami RL, on behalf of the PORT Meta-analysis Trialist Group. Post-operative radiotherapy (PORT) in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTS). Proc Am Soc Clin Oncol 1998;17:1760 (abstract) Radiotherapy of NSCLC: current challenges and future directions Allan Price, Department of Oncology, University of Edinburgh, Edinburgh, UK Patients with inoperable non-small cell lung cancer (NSCLC) have a 20-30% chance of surviving 2 years if fit for radical radiotherapy, and a similar chance of surviving 1 year if not. No contemporary randomized trial has examined the role of radical radiotherapy in these outcomes. Radical Radiotherapy: Following RTOG 73-01, the standard radical radiotherapy regime for NSCLC has been 60 Gy in 30 daily fractions over 6 weeks. Hyperfractionated treatment without acceleration has not shown consistent benefit in randomized clinical trials, but CHART, delivering 54 Gy in 36 fractions over 12 days increased survival by 9% over standard therapy at 2 years5. CHART has proved logistically difficult to implement. CHARTWEL, delivering 60 Gy in 40 fractions over 17 days excluding weekends, is being studied as an alternative. No randomized trial has examined what volume should be irradiated. The standard has been the primary tumour, hilar and mediastinal lymph nodes with a 1-2 cm margin. Retrospective comparisons have not shown an advantage over smaller volumes treating involved areas only. It has become clear in conformal therapy dose escalation studies that elective nodal irradiation may constrain
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the dose delivered to the primary tumour. Omitting uninvolved nodal groups does not appear to increase the local relapse rate4. The NSCLC Collaborative Group overview suggested a 2% increase in 5-year survival with cisplatin-based chemotherapy added to radical radiotherapy2. Two further trials, MIC I and RTOG 88-08, have reinforced this result. Chemotherapy delivered synchronously with standard radiotherapy has not increased survival in randomized trials, but does increase toxicity. Even with CHART, local control is only about 20%. Dose escalation with conformal therapy is being explored to improve this. Using normal tissue complication probabilities to estimate a ÔsafeÕ dose, up to 92.4 Gy has been delivered to small volumes without significant toxicity4. Randomized trials have not yet been completed. Future developments are likely to involve the integration of CHART, conformal dose escalation and chemotherapy, possibly combining synchronous and adjuvant treatment as in oesophageal cancer, reserving neo-adjuvant chemotherapy for tumours too large for immediate radical treatment. Alternative methods of reducing overall treatment time, such as CHARTWEL and concomitant boosts will need to be compared to CHART. Clinical research will need to define the maximum dose which can be delivered safely with conformal techniques, identify which chemotherapy regimes can be combined with radiotherapy without limiting the radiation dose, particularly with accelerated and hyperfractionated regimes, and demonstrate improved local control and survival with toxicities acceptable to patients. Postoperative Radiotherapy: A meta-analysis of post-operative radiotherapy suggested that survival is reduced by radiotherapy in stage I and II NSCLC3. Individual studies have suggested improved local control in patients with N2 disease. Palliative radiotherapy: Most patients with NSCLC are not suitable for aggressive treatment. Palliative radiotherapy is effective for haemoptysis, chest pain, dyspnoea and cough. UK MRC trials have shown equivalent results for short and long regimes, making 1 or 2 fraction courses the most common treatment for symptom control in advanced NSCLC in the UK. However, these short schedules are associated with pain and flu-like symptoms in up to 40% of patients, a transient reduction in peak expiratory flow rates and moderate to severe oesophagitis. The third MRC trial suggested that high dose palliation using 39 Gy in 13 fractions over 2.5 weeks did offer a survival advantage for good performance status patients with large tumours, comparable to that seen with cisplatin-based combination chemotherapy1, and was associated with reduced psychological distress. Further trials are needed to clarify the most effective palliation for these patients. References 1. MRC Lung Cancer Working Party (1996) Clin Oncol 8:167-175. 2. NSCLC Collaborative Group (1995) Br Med J 311:899-909. 3. PORT TriallistsÕ Group, (1998) The Lancet. 4. Robertson, JM, et al., (1997) Int J Radiat Oncol Biol Phys 37: 1079-1086. 5. Saunders, M, et al., (1997) The Lancet 350:161-165 The impact of new agents in the management of stage III and IV non-small cell lung cancer. An overview Heine H. Hansen, Finsen Centre, National University Hospital, Rigshospitalet, Copenhagen, Denmark. In the early 1990s a number of new active agents was introduced against non-small cell lung cancer, such as navelbine, gemcitabine, taxenes (taxol and taxotere), topoisomeraseinhibitors (topotecan and irinotecan), and tirapazamine. In phase II trials each of these agents yielded response rates of 15-25 % in untreated selected groups of patients with stage III and IV NSCLC and the median and 1-year survival data were superior to historical results. When com-
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the dose delivered to the primary tumour. Omitting uninvolved nodal groups does not appear to increase the local relapse rate4. The NSCLC Collaborative Group overview suggested a 2% increase in 5-year survival with cisplatin-based chemotherapy added to radical radiotherapy2. Two further trials, MIC I and RTOG 88-08, have reinforced this result. Chemotherapy delivered synchronously with standard radiotherapy has not increased survival in randomized trials, but does increase toxicity. Even with CHART, local control is only about 20%. Dose escalation with conformal therapy is being explored to improve this. Using normal tissue complication probabilities to estimate a ÔsafeÕ dose, up to 92.4 Gy has been delivered to small volumes without significant toxicity4. Randomized trials have not yet been completed. Future developments are likely to involve the integration of CHART, conformal dose escalation and chemotherapy, possibly combining synchronous and adjuvant treatment as in oesophageal cancer, reserving neo-adjuvant chemotherapy for tumours too large for immediate radical treatment. Alternative methods of reducing overall treatment time, such as CHARTWEL and concomitant boosts will need to be compared to CHART. Clinical research will need to define the maximum dose which can be delivered safely with conformal techniques, identify which chemotherapy regimes can be combined with radiotherapy without limiting the radiation dose, particularly with accelerated and hyperfractionated regimes, and demonstrate improved local control and survival with toxicities acceptable to patients. Postoperative Radiotherapy: A meta-analysis of post-operative radiotherapy suggested that survival is reduced by radiotherapy in stage I and II NSCLC3. Individual studies have suggested improved local control in patients with N2 disease. Palliative radiotherapy: Most patients with NSCLC are not suitable for aggressive treatment. Palliative radiotherapy is effective for haemoptysis, chest pain, dyspnoea and cough. UK MRC trials have shown equivalent results for short and long regimes, making 1 or 2 fraction courses the most common treatment for symptom control in advanced NSCLC in the UK. However, these short schedules are associated with pain and flu-like symptoms in up to 40% of patients, a transient reduction in peak expiratory flow rates and moderate to severe oesophagitis. The third MRC trial suggested that high dose palliation using 39 Gy in 13 fractions over 2.5 weeks did offer a survival advantage for good performance status patients with large tumours, comparable to that seen with cisplatin-based combination chemotherapy1, and was associated with reduced psychological distress. Further trials are needed to clarify the most effective palliation for these patients. References 1. MRC Lung Cancer Working Party (1996) Clin Oncol 8:167-175. 2. NSCLC Collaborative Group (1995) Br Med J 311:899-909. 3. PORT TriallistsÕ Group, (1998) The Lancet. 4. Robertson, JM, et al., (1997) Int J Radiat Oncol Biol Phys 37: 1079-1086. 5. Saunders, M, et al., (1997) The Lancet 350:161-165 The impact of new agents in the management of stage III and IV non-small cell lung cancer. An overview Heine H. Hansen, Finsen Centre, National University Hospital, Rigshospitalet, Copenhagen, Denmark. In the early 1990s a number of new active agents was introduced against non-small cell lung cancer, such as navelbine, gemcitabine, taxenes (taxol and taxotere), topoisomeraseinhibitors (topotecan and irinotecan), and tirapazamine. In phase II trials each of these agents yielded response rates of 15-25 % in untreated selected groups of patients with stage III and IV NSCLC and the median and 1-year survival data were superior to historical results. When com-