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180 Postoperative adjuvant therapy for resected lung cancer: chemotherapy or radiotherapy
Symposia
arm are as follows. Overall response rate = 59% (95% CI = 48-69%), with 27% complete and 32% partial responses, intention to treat basis. Estimated median time to treatment failure = 3.2 months (95% CI = 2.1 - 5.1 me), estimated median survival 5.1 me (95% CI = 4,2 - 7.2 me). (Int J Radiat Oncol Biol Phys 2000; 46:975-81). Conclusion - There is a role for RT in neuropathic bone pain with about 3 out of 5 patients obtaining pain relief which is maintained for a significant proportion of their remaining lifespan. If available, the results of the second interim analysis (180 patients) will be presented at the symposium.
LUNG C A N C E R (NON S M A L L CELL) 179 H o w r e l e v a n t is TNM staging for the radiotherapeutic management of non-small cell lung cancer ? D. Ball Peter Mac Callum Cancer Institute, Melbourne, Australia The TNM staging system [NSCLC], last revised in 1997, is recognised as a major prognostic factor in non-small cell lung cancer . Until recently, surgery was regarded as the only treatment capable of significantly altering the natural history of NSCLC, and the staging system therefore placed heavy emphasis not only on disease extent, but also on resectability. Hence a very small tumour could be classified T4 if it were involving the trachea, and therefore unresectable. For most epithelial cancers treated with radiotherapy, tumour size is an important determinant of outcome. One study has shown little correlation between lung tumour size and stage [Martel et al, Radiotherapy and Oncology 1997; 44:23]. Now that there is convincing evidence that the combination of cisplatin-based chemotherapy and radiotherapy does alter the natural history of NSCLC, there is a need to re-evaluate the prognostic importance of tumour volume in patients receiving non-surgical treatments. This presentation will critically review the prognostic value of TN staging in NSCLC patients treated with radiotherapy _+chemotherapy, referring to recent studies in which its prognostic value has not been validated. Issues relating to reproducible volume measurement using 3D CT software will also be discussed. 180
Postoperative adjuvant therapy for resected lung cancer: chemotherapy or radiotherapy P. Van Houtte Institut J. Bordet, Department of Radiotherapy, Brussels, Belgium The results of surgery remains over the years poor with only one patient out of 3 alive 5 years after the resection outlining the needs for adjuvant treatments. Pattern of failure analysis after a complete resection has shown the different challenge facing the oncologist: the local control of the disease, the metastatic spread and the problem of second cancer. The risk of local failure increases with the tumor extent (from less than 10% for stage I to 30% or more for stage III). For stage I, the challenge is more to control the metastatic spread and to avoid second cancer (chemoprevention). Until today, adjuvant chemotherapy failed to improve significantly the survival of resected patients. The large metaanalysis demonstrated a negative effect with alkylating agents and suggested a small benefit with cisplatine based chemotherapy. Large trials are ongoing but their size outlines the limited benefit expected with this approach. Chemoprevention also failed to change the outcome. Postoperative radiotherapy was showed in a recent metaanalysis including the different randomized trials to have a negative impact on survival; this effect was more pronounced for stage I disease. This negative effect disappeared for stage III disease suggesting perhaps a possible therapeutic effect compensating for a poor radiation technique. The technique used in most trials conducted in the past was certainly not optimal due to the size of the fields used, the dose or the fractionation. Postop Rt improved the local control of the disease in several trials including N1 and/or N2 disease. Post. Rt. requires a very precise technique to avoid inducing lifethreatening complication and is an area for 3D conformal radiotherapy particularly after a pneumectomy. Conclusions If surgery remains the keystone of the treatment of early lung cancer, adjuvant treatment remains more a question of belief. Postop.Rt. may be considered for stage selected stage Ill disease but requires a precise technique.
Friday, 2 February 2001
$53
181
Current status of chemoradiotherapy for non-small cell lung cancer and its goals in the new millennium K. Havakawa Department of Radiology,Kitasato Univ< School of Medicine, Kanagawa, Japan Radiation therapy (RT) has been frequently used for the patients with locally advanced unresectabte non-small cell lung cancer (NSCLC). Although RT has proven of benefit to local control, the 5-year survival rate is 10% or less in patients treated with RT alone because both local and distant failure are common in these patients. The addition of chemotherapy to RT, therefore, aims at enhancing radiosensitivity of tumor cells and at early eradication of distant micrometastases. The majority of the recent data have suggested that the survival rate for selected favorable patients with locally advanced NSCLC will be improved by cisplatin-based chemotherapy combined with sequential or concurrent RT (1). In the current status, however, the benefit of the combined use of chemotherapy with RT seems marginal because most patients are not candidates for these aggressive treatment schedules. The results of the phase III trial in regionally advanced unresectable NSCLC by RTOG, ECOG and SWOG(2) demonstrated that in the elderly patients standard thoracic RT alone had the most favorable benefit on survival compared with sequential chemoradiotherapy and hyperfractionated radiatiotherapy. In the elderly patients, therefore, the addition of chemotherapy to radiation therapy may have little benefit due to adverse effects of cytotoxic agents, and potential toxicity of chemoradiotherapy must be carefully evaluated. Immediate concurrent use of chemotherapy and radiation appears to represent an additional step forward in overall survival. Recent treatment results(3) have indicated that concurrent chemoradiotherapy is feasible and that the overall survival appears more favorable than sequential combination, while acute toxicities are increased but acceptable in concurrent integrating. In Japan, JCOG western group conducted an important randomized trial of concurrent versus sequential chemoradiotherapy (4). In the concurrent arm, the radiation schedule was splitcourse, whereas in the sequential arm, the radiation schedule was continuous 2Gy once daily treatment. Nevertheless the results showed that concurrent schedule had a statistically significant survival advantage. The variables of radiation dose, fractionation and treatment volume seem to be important in the successful management of the disease. In the combined chemoradiotherapy, reducing treatment volumes may permit increasing doses without enhancing normal tissue damage. The Clinical Practice Guidelines of ASCO (5) outlined that definitive dose of radiation therapy should be no less than 60 Gy. However, since the dose of 60 Gy yields a local control rate of only tess than 30%, higher dose or more intensive treatment has been increasingly investigated. In a UK trial (6), continuous hyperfractionated accelerated radiotherapy (CHART), that was a locally intensive treatment, produced a statistical improvement in survival for all patients. But This more aggressive treatment could not reduce the relative risk of death for nonsquamous tumors but had an absolute survival benefit for squamous cell carcinoma only. The biological characteristics of tumors are very important for chemoradiotherapy. In our series (7) of patients treated with RT alone for inoperable or unresectable NSCLC, the majority of patients with squamous cell carcinoma, who had no progression of disease at the end of two years after RT, were alive free of disease after 5 years from RT. On the other hand, the majority of adenocarcinoma patients without tumor progression after 2 years from RT had distant failures later. The final results of a large phase III trial in regionally advanced disease (RTOG 8808, ECOG 4588, SWOG 8992) (2) demonstrated that chemoradiotherapy schedule had the greatest benefit on overall survival in patients with nonsquamous tumors. The survival of patients with squamous cell carcinoma, however, was not significantly improved by the addition of chemotherapy to RT. Chemoradiotherapy, therefore, may have the real benefit in patients with tumors of nonsquamous histology, but little benefit in patients with squamous cell carcinoma. Recently, a better understanding of tumor biology has opened many new ways of clinical investigation of lung cancer (8). Many reports suggested that tumor response to the treatment may be correlated with p53 mutations resulting in abnormalities in apoptosis. Individual tumors will have multiple therapeutic targets. In the new century, therefore, individualized treatment strategies based on molecular biological discoveries will be needed and we should make every effort to offer more rational therapy to NSCLC patients.
Reference 1) Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small cell lung cancer. A meta-analysis, Ann Intern Med 125: 723-29, 1996.
arm are as follows. Overall response rate = 59% (95% CI = 48-69%), with 27% complete and 32% partial responses, intention to treat basis. Estimated median time to treatment failure = 3.2 months (95% CI = 2.1 - 5.1 me), estimated median survival 5.1 me (95% CI = 4,2 - 7.2 me). (Int J Radiat Oncol Biol Phys 2000; 46:975-81). Conclusion - There is a role for RT in neuropathic bone pain with about 3 out of 5 patients obtaining pain relief which is maintained for a significant proportion of their remaining lifespan. If available, the results of the second interim analysis (180 patients) will be presented at the symposium.
LUNG C A N C E R (NON S M A L L CELL) 179 H o w r e l e v a n t is TNM staging for the radiotherapeutic management of non-small cell lung cancer ? D. Ball Peter Mac Callum Cancer Institute, Melbourne, Australia The TNM staging system [NSCLC], last revised in 1997, is recognised as a major prognostic factor in non-small cell lung cancer . Until recently, surgery was regarded as the only treatment capable of significantly altering the natural history of NSCLC, and the staging system therefore placed heavy emphasis not only on disease extent, but also on resectability. Hence a very small tumour could be classified T4 if it were involving the trachea, and therefore unresectable. For most epithelial cancers treated with radiotherapy, tumour size is an important determinant of outcome. One study has shown little correlation between lung tumour size and stage [Martel et al, Radiotherapy and Oncology 1997; 44:23]. Now that there is convincing evidence that the combination of cisplatin-based chemotherapy and radiotherapy does alter the natural history of NSCLC, there is a need to re-evaluate the prognostic importance of tumour volume in patients receiving non-surgical treatments. This presentation will critically review the prognostic value of TN staging in NSCLC patients treated with radiotherapy _+chemotherapy, referring to recent studies in which its prognostic value has not been validated. Issues relating to reproducible volume measurement using 3D CT software will also be discussed. 180
Postoperative adjuvant therapy for resected lung cancer: chemotherapy or radiotherapy P. Van Houtte Institut J. Bordet, Department of Radiotherapy, Brussels, Belgium The results of surgery remains over the years poor with only one patient out of 3 alive 5 years after the resection outlining the needs for adjuvant treatments. Pattern of failure analysis after a complete resection has shown the different challenge facing the oncologist: the local control of the disease, the metastatic spread and the problem of second cancer. The risk of local failure increases with the tumor extent (from less than 10% for stage I to 30% or more for stage III). For stage I, the challenge is more to control the metastatic spread and to avoid second cancer (chemoprevention). Until today, adjuvant chemotherapy failed to improve significantly the survival of resected patients. The large metaanalysis demonstrated a negative effect with alkylating agents and suggested a small benefit with cisplatine based chemotherapy. Large trials are ongoing but their size outlines the limited benefit expected with this approach. Chemoprevention also failed to change the outcome. Postoperative radiotherapy was showed in a recent metaanalysis including the different randomized trials to have a negative impact on survival; this effect was more pronounced for stage I disease. This negative effect disappeared for stage III disease suggesting perhaps a possible therapeutic effect compensating for a poor radiation technique. The technique used in most trials conducted in the past was certainly not optimal due to the size of the fields used, the dose or the fractionation. Postop Rt improved the local control of the disease in several trials including N1 and/or N2 disease. Post. Rt. requires a very precise technique to avoid inducing lifethreatening complication and is an area for 3D conformal radiotherapy particularly after a pneumectomy. Conclusions If surgery remains the keystone of the treatment of early lung cancer, adjuvant treatment remains more a question of belief. Postop.Rt. may be considered for stage selected stage Ill disease but requires a precise technique.
Friday, 2 February 2001
$53
181
Current status of chemoradiotherapy for non-small cell lung cancer and its goals in the new millennium K. Havakawa Department of Radiology,Kitasato Univ< School of Medicine, Kanagawa, Japan Radiation therapy (RT) has been frequently used for the patients with locally advanced unresectabte non-small cell lung cancer (NSCLC). Although RT has proven of benefit to local control, the 5-year survival rate is 10% or less in patients treated with RT alone because both local and distant failure are common in these patients. The addition of chemotherapy to RT, therefore, aims at enhancing radiosensitivity of tumor cells and at early eradication of distant micrometastases. The majority of the recent data have suggested that the survival rate for selected favorable patients with locally advanced NSCLC will be improved by cisplatin-based chemotherapy combined with sequential or concurrent RT (1). In the current status, however, the benefit of the combined use of chemotherapy with RT seems marginal because most patients are not candidates for these aggressive treatment schedules. The results of the phase III trial in regionally advanced unresectable NSCLC by RTOG, ECOG and SWOG(2) demonstrated that in the elderly patients standard thoracic RT alone had the most favorable benefit on survival compared with sequential chemoradiotherapy and hyperfractionated radiatiotherapy. In the elderly patients, therefore, the addition of chemotherapy to radiation therapy may have little benefit due to adverse effects of cytotoxic agents, and potential toxicity of chemoradiotherapy must be carefully evaluated. Immediate concurrent use of chemotherapy and radiation appears to represent an additional step forward in overall survival. Recent treatment results(3) have indicated that concurrent chemoradiotherapy is feasible and that the overall survival appears more favorable than sequential combination, while acute toxicities are increased but acceptable in concurrent integrating. In Japan, JCOG western group conducted an important randomized trial of concurrent versus sequential chemoradiotherapy (4). In the concurrent arm, the radiation schedule was splitcourse, whereas in the sequential arm, the radiation schedule was continuous 2Gy once daily treatment. Nevertheless the results showed that concurrent schedule had a statistically significant survival advantage. The variables of radiation dose, fractionation and treatment volume seem to be important in the successful management of the disease. In the combined chemoradiotherapy, reducing treatment volumes may permit increasing doses without enhancing normal tissue damage. The Clinical Practice Guidelines of ASCO (5) outlined that definitive dose of radiation therapy should be no less than 60 Gy. However, since the dose of 60 Gy yields a local control rate of only tess than 30%, higher dose or more intensive treatment has been increasingly investigated. In a UK trial (6), continuous hyperfractionated accelerated radiotherapy (CHART), that was a locally intensive treatment, produced a statistical improvement in survival for all patients. But This more aggressive treatment could not reduce the relative risk of death for nonsquamous tumors but had an absolute survival benefit for squamous cell carcinoma only. The biological characteristics of tumors are very important for chemoradiotherapy. In our series (7) of patients treated with RT alone for inoperable or unresectable NSCLC, the majority of patients with squamous cell carcinoma, who had no progression of disease at the end of two years after RT, were alive free of disease after 5 years from RT. On the other hand, the majority of adenocarcinoma patients without tumor progression after 2 years from RT had distant failures later. The final results of a large phase III trial in regionally advanced disease (RTOG 8808, ECOG 4588, SWOG 8992) (2) demonstrated that chemoradiotherapy schedule had the greatest benefit on overall survival in patients with nonsquamous tumors. The survival of patients with squamous cell carcinoma, however, was not significantly improved by the addition of chemotherapy to RT. Chemoradiotherapy, therefore, may have the real benefit in patients with tumors of nonsquamous histology, but little benefit in patients with squamous cell carcinoma. Recently, a better understanding of tumor biology has opened many new ways of clinical investigation of lung cancer (8). Many reports suggested that tumor response to the treatment may be correlated with p53 mutations resulting in abnormalities in apoptosis. Individual tumors will have multiple therapeutic targets. In the new century, therefore, individualized treatment strategies based on molecular biological discoveries will be needed and we should make every effort to offer more rational therapy to NSCLC patients.
Reference 1) Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small cell lung cancer. A meta-analysis, Ann Intern Med 125: 723-29, 1996.