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Predictors of survival for patients with brain metastases: results of a randomized phase III trial
Proceedings of the 44th Annual ASTRO Meeting
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93
Predictors of Survival for Patients with Brain Metastases: Results of a Randomized Phase III Trial
W.J. Curran1, M. Mehta2, P. Rodrigus3, C. Terhaard4, A. Rao5, J. Suh6, W. Roa7, L. Souhami8, A. Bezjak9, M. Leibenhaut10, R. Komaki11, C. Schultz12, R. Timmerman13, T. Illidge14, S. Phan15, J. Smith15, A. DeVault15, R. Miller15, M.F. Renschler15 1 Thomas Jefferson University, Philadelphia, PA, 2University of Wisconsin, Madison, WI, 3Verbeeten Institute, Tilburg, Netherlands, 4Academisch Hospital, Utrecht, Netherlands, 5Kaiser Permanente, Los Angeles, CA, 6Cleveland Clinic, Cleveland, OH, 7Cross Cancer Institute, Edmonton, AB, Canada, 8Montreal General Hospital, Montreal, QC, Canada, 9 Princess Margaret Hospital, Toronto, ON, Canada, 10Radiological Association of Sacramento, Sacramento, CA, 11UTMD Anderson, Houston, TX, 12Medical College of Wisconsin, Milwaukee, WI, 13Indiana University, Indianapolis, IN, 14Wessex Cancer Center, Southampton, United Kingdom, 15Pharmacyclics, Sunnyvale, CA Purpose/Objective: A commonly used prognostic classification for brain metastasis patients is the Recursive Partitioning Analysis (RPA) classification developed with data from patients enrolled in RTOG trials from 1979 to 1993 (Gaspar, et al, IJROBP, Vol 37:745-751, 1997). To determine if the RPA classification applies to good performance status patients with brain metastases managed at the present time, prognostic factors for survival were collected and analyzed in the phase III trial of motexafin gadolinium (MGd, Xcytrin威). Materials/Methods: A prospective, international, randomized phase III trial of MGd and whole brain radiation therapy (WBRT) vs. WBRT was conducted. Patients with unresected brain metastases from any primary cancer and good performance status (KPSⱖ70) were eligible. Excluded were patients with liver metastases, 2 or more sites of extracranial metastasis (except for breast cancer), small cell lung cancer, lymphoma and germ cell tumors. Results: 401 patients with brain metastases from lung cancer (62.6%), breast cancer (18.7%), melanoma (6%) or other cancers (12.7%), RPA class 1 (16%) or 2 (84%) were randomized to MGd ⫹ WBRT (MGd, N⫽193) or WBRT (Ctrl, N⫽208) between April 1999 and March 2001. All patients had a minimum follow-up of 6 months. At study termination in September 2001, 345 patients had died, 55 patients were alive, and one patient was lost to follow-up. The patient characteristics were as follows: median age 58 yrs, 45% male, 35% presenting with brain metastases, 51% primary tumor controlled, 49% extracranial metastases present, 55% KPS of 90 –100, 28.7% single brain metastasis, and 8.5 months median time from diagnosis of the primary cancer to brain metastases. Overall median survival was 5.0 months, 4.4 months for lung cancer patients, 7.2 months for breast cancer patients, and 5.0 months for patients with other primaries, including primary of unknown origin. RPA class was not prognostic for survival. Median survival for RPA class 1 was 5.4 months and for RPA class 2 was 4.9 months (p⫽0.88). In a multivariate analysis, performance status, gender, breast cancer, low albumin, low LDH (defined as below the lower limit of normal (LLN) and elevated LDH (defined as above the LLN) remained significant independent predictors of survival. The RTOG database differed from this trial in several factors. Data from 1200 patients was available for comparison. 32% had prior brain surgery, 42% had single brain metastasis, and the whole brain radiation ranged from 30 Gy to 70.4 Gy. Conclusions: In the phase III trial of motexafin gadolinium for the treatment of patients with brain metastases, RPA class was not a predictor of survival. Independent predictors of survival were performance status, gender, breast cancer, low albumin, low LDH, and elevated LDH. Significant Multivariate Predictors of Time to All-Cause Mortality (Cox Model) Factor
Risk Ratio1
P-Value
1.420 0.658 0.645 1.708 0.324 1.868
0.0038 0.0016 0.0224 0.0001 0.0025 0.0001
KPS (70-80) Female Breast Cancer Albumin (⬍ LLN) LDH (⬍ LLN) LDH (⬎ LLN) 1
Risk ratio ⬍ 1 indicates protective effect on all-cause mortality
156
Whole Brain Radiotherapy Alone or in Combination with Temozolomide for Brain Metastases. A Phase III Study
D. Antonadou1, N. Coliarakis2, M. Paraskevaidis2, H. Athanasiou3, G. Sarris1, M. Synodinou1, I. Skarlatos3, A. Sagriotis1, G. Georgakopoulos4, C. Beroukas3, P. Karageorgis2, N. Throuvalas1 1 1st Radiation Oncology Department, Metaxas Cancer Hospital, Pireus, Greece, 22nd Radiation Oncology Department, Metaxas Cancer Hospital, Pireus, Greece, 31st Radiation Oncology Department, Ag. Savas Cancer Hospital, Athens, Greece, 4Radiation Oncology Department, G.Genimatas Hospital, Athens, Greece Purpose/Objective: Based on our previous phase II study, where radiographic response was significantly higher in the group receiving temozolomide (TMZ) with whole brain radiotherapy (WBRT), we conducted a confirmatory phase III multicenter randomized trial. Materials/Methods: Patients with previously untreated brain metastases from various primary tumors were randomly allocated to receive WBRT with or without TMZ. TMZ 75mg/sqm was administered daily during WBRT (10 fractions of 3Gy) and 1 month after WBRT 200mg/sqm from days 1-5 every 28 days for 6 consecutive cycles. Objective response was evaluated with computerized tomography or magnetic resonance imaging. Response rate was further evaluated with respect to prognostic factors, e.g age and Karnofsky performance status. Results: 134 eligible patients were randomized, 82% with lung primaries. The two arms did not differ significantly in primary tumor sites, age, gender and performance status. A significantly higher response rate was observed between the two arms, a
155
93
Predictors of Survival for Patients with Brain Metastases: Results of a Randomized Phase III Trial
W.J. Curran1, M. Mehta2, P. Rodrigus3, C. Terhaard4, A. Rao5, J. Suh6, W. Roa7, L. Souhami8, A. Bezjak9, M. Leibenhaut10, R. Komaki11, C. Schultz12, R. Timmerman13, T. Illidge14, S. Phan15, J. Smith15, A. DeVault15, R. Miller15, M.F. Renschler15 1 Thomas Jefferson University, Philadelphia, PA, 2University of Wisconsin, Madison, WI, 3Verbeeten Institute, Tilburg, Netherlands, 4Academisch Hospital, Utrecht, Netherlands, 5Kaiser Permanente, Los Angeles, CA, 6Cleveland Clinic, Cleveland, OH, 7Cross Cancer Institute, Edmonton, AB, Canada, 8Montreal General Hospital, Montreal, QC, Canada, 9 Princess Margaret Hospital, Toronto, ON, Canada, 10Radiological Association of Sacramento, Sacramento, CA, 11UTMD Anderson, Houston, TX, 12Medical College of Wisconsin, Milwaukee, WI, 13Indiana University, Indianapolis, IN, 14Wessex Cancer Center, Southampton, United Kingdom, 15Pharmacyclics, Sunnyvale, CA Purpose/Objective: A commonly used prognostic classification for brain metastasis patients is the Recursive Partitioning Analysis (RPA) classification developed with data from patients enrolled in RTOG trials from 1979 to 1993 (Gaspar, et al, IJROBP, Vol 37:745-751, 1997). To determine if the RPA classification applies to good performance status patients with brain metastases managed at the present time, prognostic factors for survival were collected and analyzed in the phase III trial of motexafin gadolinium (MGd, Xcytrin威). Materials/Methods: A prospective, international, randomized phase III trial of MGd and whole brain radiation therapy (WBRT) vs. WBRT was conducted. Patients with unresected brain metastases from any primary cancer and good performance status (KPSⱖ70) were eligible. Excluded were patients with liver metastases, 2 or more sites of extracranial metastasis (except for breast cancer), small cell lung cancer, lymphoma and germ cell tumors. Results: 401 patients with brain metastases from lung cancer (62.6%), breast cancer (18.7%), melanoma (6%) or other cancers (12.7%), RPA class 1 (16%) or 2 (84%) were randomized to MGd ⫹ WBRT (MGd, N⫽193) or WBRT (Ctrl, N⫽208) between April 1999 and March 2001. All patients had a minimum follow-up of 6 months. At study termination in September 2001, 345 patients had died, 55 patients were alive, and one patient was lost to follow-up. The patient characteristics were as follows: median age 58 yrs, 45% male, 35% presenting with brain metastases, 51% primary tumor controlled, 49% extracranial metastases present, 55% KPS of 90 –100, 28.7% single brain metastasis, and 8.5 months median time from diagnosis of the primary cancer to brain metastases. Overall median survival was 5.0 months, 4.4 months for lung cancer patients, 7.2 months for breast cancer patients, and 5.0 months for patients with other primaries, including primary of unknown origin. RPA class was not prognostic for survival. Median survival for RPA class 1 was 5.4 months and for RPA class 2 was 4.9 months (p⫽0.88). In a multivariate analysis, performance status, gender, breast cancer, low albumin, low LDH (defined as below the lower limit of normal (LLN) and elevated LDH (defined as above the LLN) remained significant independent predictors of survival. The RTOG database differed from this trial in several factors. Data from 1200 patients was available for comparison. 32% had prior brain surgery, 42% had single brain metastasis, and the whole brain radiation ranged from 30 Gy to 70.4 Gy. Conclusions: In the phase III trial of motexafin gadolinium for the treatment of patients with brain metastases, RPA class was not a predictor of survival. Independent predictors of survival were performance status, gender, breast cancer, low albumin, low LDH, and elevated LDH. Significant Multivariate Predictors of Time to All-Cause Mortality (Cox Model) Factor
Risk Ratio1
P-Value
1.420 0.658 0.645 1.708 0.324 1.868
0.0038 0.0016 0.0224 0.0001 0.0025 0.0001
KPS (70-80) Female Breast Cancer Albumin (⬍ LLN) LDH (⬍ LLN) LDH (⬎ LLN) 1
Risk ratio ⬍ 1 indicates protective effect on all-cause mortality
156
Whole Brain Radiotherapy Alone or in Combination with Temozolomide for Brain Metastases. A Phase III Study
D. Antonadou1, N. Coliarakis2, M. Paraskevaidis2, H. Athanasiou3, G. Sarris1, M. Synodinou1, I. Skarlatos3, A. Sagriotis1, G. Georgakopoulos4, C. Beroukas3, P. Karageorgis2, N. Throuvalas1 1 1st Radiation Oncology Department, Metaxas Cancer Hospital, Pireus, Greece, 22nd Radiation Oncology Department, Metaxas Cancer Hospital, Pireus, Greece, 31st Radiation Oncology Department, Ag. Savas Cancer Hospital, Athens, Greece, 4Radiation Oncology Department, G.Genimatas Hospital, Athens, Greece Purpose/Objective: Based on our previous phase II study, where radiographic response was significantly higher in the group receiving temozolomide (TMZ) with whole brain radiotherapy (WBRT), we conducted a confirmatory phase III multicenter randomized trial. Materials/Methods: Patients with previously untreated brain metastases from various primary tumors were randomly allocated to receive WBRT with or without TMZ. TMZ 75mg/sqm was administered daily during WBRT (10 fractions of 3Gy) and 1 month after WBRT 200mg/sqm from days 1-5 every 28 days for 6 consecutive cycles. Objective response was evaluated with computerized tomography or magnetic resonance imaging. Response rate was further evaluated with respect to prognostic factors, e.g age and Karnofsky performance status. Results: 134 eligible patients were randomized, 82% with lung primaries. The two arms did not differ significantly in primary tumor sites, age, gender and performance status. A significantly higher response rate was observed between the two arms, a