- Email: [email protected]
The German multinational GPOH-HD 95 trial: Treatment results and analysis of failures in pediatric Hodgkins disease using combination chemotherapy with and without radiation
Proceedings of the 46th Annual ASTRO Meeting
selection of patients based on these low risk factors may be associated with such a small risk of breast relapse that the benefit of partial breast radiation may be very modest.
3
The German Multinational GPOH-HD 95 Trial: Treatment Results and Analysis of Failures in Pediatric Hodgkins Disease Using Combination Chemotherapy With and Without Radiation
U. Ruhl,1 M. R. Albrecht,1 H. Lueders,2 H. Marciniak,3 W. Doerffel2 1 Radiation Oncology, Moabit Hospital Berlin, Berlin, Germany, 2Pediatric Oncology, Klinikum Buch Berlin, Berlin, Germany, 3Diagnostic Radiology, Klinikum Buch Berlin, Berlin, Germany Purpose/Objective: Aim of the multicenter trial GPOH-HD 95 was to maintain the excellent treatment results of previous protocols in pediatric Hodgkins disease(HD), however to reduce the risk of potential late effects caused by radiation therapy(RT). Materials/Methods: Patients (pts.) below the age of 18 years were treated within 3 different treatment groups (TG 1–3) according to risk factors (stage, B-symptoms, extranodal extension) with 2, 4 or 6 cycles of combination chemotherapy (CTx). When a complete clinical remission (CR) was achieved no consolidating RT followed. In the case of a tumor reduction of ⬎75% the RT-dose to initially involved areas was 20Gy, otherwise 30Gy, to remaining lymphomas of ⬎50ml 35Gy. General treatment planning, quality assessment and analysis of treatment failures were done in the Trial Control Center in Berlin. Results: From August 1995 to July 2001 a total of 1018 eligible patients were registered from 107 institutions in 7 European countries. At a median follow-up of 50 months (in February 2004) overall survival is excellent with 97% for all pts., 99% for TG1 (stage I/IIA) and 93% for TG3 (advanced disease). 211 patients (22%) were in CR after CTx and therefore did not get RT. 916 pts are in continiously complete remission. 102 events occurred (10%), 95 of them due to treatment failures (38 progressive disease during CTx, before, during or shortly after RT and 57 relapses after achieving complete tumor control initially. Disease free survival (DFS) for the low risk group TG1 is 96%. For the intermediate and high risk groups (TG2 ⫹ 3) DFS is 92% when CTx induced PR was followed by adjuvant RT, however in cases with CR and no consolidating RT the incidence of relapses is significantly higher (DFS 69% and 77%, p ⫽ 0.006). Nevertheless until now there is no difference in survival for pts. with or without RT after induction CTx . Risk factors for early failures were advanced disease and unfavorable histology, in relapses they are different for irradiated and non-irradiated patients. Protocol violations with regard to radiotherapy volumes and the time lag between end of CTx and start of RT seem to be of importance. Conclusions: Overall results of the HD95 trial are excellent. The omission of RT after achieving a CR with CTx causes an increased risk of treatment failures in advanced cases, however the total incidence of failures is rather low and has no impact on survival. The potential gain by reducing radiation dose and volume with respect to treatment induced long term toxicity might be considerable for the young patient population.
4
A Randomized Trial Comparing Conventional Dose (70.2GyE) and High-Dose (79.2GyE) Conformal Radiation in Early Stage Adenocarcinoma of the Prostate: Results of an Interim Analysis of PROG 95– 09
A. L. Zietman,1 M. DeSilvio,3 J. D. Slater,2 C. J. Rossi,2 L. T. Yonemoto,2 J. M. Slater,2 B. Berkey,3 J. A. Adams,1 W. U. Shipley1 1 Radiation Oncology, Massachusetts General Hospital, Boston, MA, 2Radiation Oncology, Loma Linda University Medical Center, Loma Linda, CA, 3American College of Radiology, Philadelphia, PA Purpose/Objective: This trial was designed to test the hypothesis that increasing the radiation dose delivered conformally to men with early stage prostate cancer above conventional levels improves disease free outcome. Materials/Methods: From January 1996 to December 1999 393 patients with biopsy proven T1b-T2b prostate cancer and a PSA of ⬍15ng/ml were recruited at two centers onto an IRB approved protocol. 75.3% had Gleason scores of 6 or less, 15.3% Gleason 7, and 8.4% Gleason 8 –10. 61.2% had T1c tumors. The median age at diagnosis was 67 years and the median PSA was 6.3. Patients were randomized to receive an initial boost to the prostate alone using conformal protons (either lateral or perineal fields) of either 19.8 or 28.8 Gray equivalent (GyE). All patients then received 50.4Gy at 1.8Gy per fraction using 3-D conformal photons to the prostate, seminal vesicles, and peri-prostatic tissues. 197 patients were randomized to a total dose of 70.2 GyE (conventional dose) and 196 to 79.2 GyE (high dose). Of those assigned to high dose 12 received less than 77 GyE (5.6%). Of those assigned to conventional dose only 5 received doses above 71 GyE (2%). Median follow-up is 4 years. No patient received adjunctive androgen suppression therapy with their radiation. Local failure was defined using both direct and surrogate criteria: clinically through palpation, histologically after rebiopsy of a clinically benign prostate with a rising PSA, or biochemically by a PSA of ⬎1ng/ml 2 or more years after treatment without rebiopsy. Biochemical failure was determined using the ASTRO definition. This trial originated with the Proton Radiation Oncology Group and received statistical and data management support from the American College of Radiology. Results: The distribution of PSA nadirs of either ⬍0.5 or ⬍1.0ng/ml was 36.7% and 73% after 70.2 GyE and 50% and 79.9% after 79.2 GyE. The cumulative incidence estimates of the five-year local failure rate using the surrogate of a PSA ⬎1ng/ml 2 or more years after radiation were 63.6% (95% CI ⫽ 54.5% to 72.8%) for the 70.2 GyE group and 36.3% (95% CI ⫽ 26.5% to 46.0%) for the 79.2 GyE group (p ⱕ 0.0001). The five-year biochemical failure rates were 37.3% (95% CI ⫽ 28.4% to 46.3%) for the conventional dose group and 19.1% (95% CI ⫽ 11.1% to 27.1%) for the high dose group (p ⫽ 0.00001). This difference held true when only those with low risk disease were examined (T1b-2a, PSA ⬍10, Gleason ⬍6, n ⫽ 227, 58% of total). The 5-year biochemical failure rate was 34.9% in the conventional dose arm and only 17.2% in the high dose arm (p ⫽ 0.002). It was also significant for intermediate risk patients (39.5% vs 21.3% p ⫽ 0.01). At this time, there was no difference in the overall survival rates between the treatment arms (p ⫽ 0.83). Only 2% of patients receiving conventional dose and 1.5% receiving high dose radiation experienced acute urinary or rectal morbidity of RTOG grade ⬎3. The respective proportions for those experiencing any grade 2 acute morbidity was 62 and 69%. So far only 1.5% and 0.5% respectively have experienced late morbidity of RTOG grade ⬎3.
S131
selection of patients based on these low risk factors may be associated with such a small risk of breast relapse that the benefit of partial breast radiation may be very modest.
3
The German Multinational GPOH-HD 95 Trial: Treatment Results and Analysis of Failures in Pediatric Hodgkins Disease Using Combination Chemotherapy With and Without Radiation
U. Ruhl,1 M. R. Albrecht,1 H. Lueders,2 H. Marciniak,3 W. Doerffel2 1 Radiation Oncology, Moabit Hospital Berlin, Berlin, Germany, 2Pediatric Oncology, Klinikum Buch Berlin, Berlin, Germany, 3Diagnostic Radiology, Klinikum Buch Berlin, Berlin, Germany Purpose/Objective: Aim of the multicenter trial GPOH-HD 95 was to maintain the excellent treatment results of previous protocols in pediatric Hodgkins disease(HD), however to reduce the risk of potential late effects caused by radiation therapy(RT). Materials/Methods: Patients (pts.) below the age of 18 years were treated within 3 different treatment groups (TG 1–3) according to risk factors (stage, B-symptoms, extranodal extension) with 2, 4 or 6 cycles of combination chemotherapy (CTx). When a complete clinical remission (CR) was achieved no consolidating RT followed. In the case of a tumor reduction of ⬎75% the RT-dose to initially involved areas was 20Gy, otherwise 30Gy, to remaining lymphomas of ⬎50ml 35Gy. General treatment planning, quality assessment and analysis of treatment failures were done in the Trial Control Center in Berlin. Results: From August 1995 to July 2001 a total of 1018 eligible patients were registered from 107 institutions in 7 European countries. At a median follow-up of 50 months (in February 2004) overall survival is excellent with 97% for all pts., 99% for TG1 (stage I/IIA) and 93% for TG3 (advanced disease). 211 patients (22%) were in CR after CTx and therefore did not get RT. 916 pts are in continiously complete remission. 102 events occurred (10%), 95 of them due to treatment failures (38 progressive disease during CTx, before, during or shortly after RT and 57 relapses after achieving complete tumor control initially. Disease free survival (DFS) for the low risk group TG1 is 96%. For the intermediate and high risk groups (TG2 ⫹ 3) DFS is 92% when CTx induced PR was followed by adjuvant RT, however in cases with CR and no consolidating RT the incidence of relapses is significantly higher (DFS 69% and 77%, p ⫽ 0.006). Nevertheless until now there is no difference in survival for pts. with or without RT after induction CTx . Risk factors for early failures were advanced disease and unfavorable histology, in relapses they are different for irradiated and non-irradiated patients. Protocol violations with regard to radiotherapy volumes and the time lag between end of CTx and start of RT seem to be of importance. Conclusions: Overall results of the HD95 trial are excellent. The omission of RT after achieving a CR with CTx causes an increased risk of treatment failures in advanced cases, however the total incidence of failures is rather low and has no impact on survival. The potential gain by reducing radiation dose and volume with respect to treatment induced long term toxicity might be considerable for the young patient population.
4
A Randomized Trial Comparing Conventional Dose (70.2GyE) and High-Dose (79.2GyE) Conformal Radiation in Early Stage Adenocarcinoma of the Prostate: Results of an Interim Analysis of PROG 95– 09
A. L. Zietman,1 M. DeSilvio,3 J. D. Slater,2 C. J. Rossi,2 L. T. Yonemoto,2 J. M. Slater,2 B. Berkey,3 J. A. Adams,1 W. U. Shipley1 1 Radiation Oncology, Massachusetts General Hospital, Boston, MA, 2Radiation Oncology, Loma Linda University Medical Center, Loma Linda, CA, 3American College of Radiology, Philadelphia, PA Purpose/Objective: This trial was designed to test the hypothesis that increasing the radiation dose delivered conformally to men with early stage prostate cancer above conventional levels improves disease free outcome. Materials/Methods: From January 1996 to December 1999 393 patients with biopsy proven T1b-T2b prostate cancer and a PSA of ⬍15ng/ml were recruited at two centers onto an IRB approved protocol. 75.3% had Gleason scores of 6 or less, 15.3% Gleason 7, and 8.4% Gleason 8 –10. 61.2% had T1c tumors. The median age at diagnosis was 67 years and the median PSA was 6.3. Patients were randomized to receive an initial boost to the prostate alone using conformal protons (either lateral or perineal fields) of either 19.8 or 28.8 Gray equivalent (GyE). All patients then received 50.4Gy at 1.8Gy per fraction using 3-D conformal photons to the prostate, seminal vesicles, and peri-prostatic tissues. 197 patients were randomized to a total dose of 70.2 GyE (conventional dose) and 196 to 79.2 GyE (high dose). Of those assigned to high dose 12 received less than 77 GyE (5.6%). Of those assigned to conventional dose only 5 received doses above 71 GyE (2%). Median follow-up is 4 years. No patient received adjunctive androgen suppression therapy with their radiation. Local failure was defined using both direct and surrogate criteria: clinically through palpation, histologically after rebiopsy of a clinically benign prostate with a rising PSA, or biochemically by a PSA of ⬎1ng/ml 2 or more years after treatment without rebiopsy. Biochemical failure was determined using the ASTRO definition. This trial originated with the Proton Radiation Oncology Group and received statistical and data management support from the American College of Radiology. Results: The distribution of PSA nadirs of either ⬍0.5 or ⬍1.0ng/ml was 36.7% and 73% after 70.2 GyE and 50% and 79.9% after 79.2 GyE. The cumulative incidence estimates of the five-year local failure rate using the surrogate of a PSA ⬎1ng/ml 2 or more years after radiation were 63.6% (95% CI ⫽ 54.5% to 72.8%) for the 70.2 GyE group and 36.3% (95% CI ⫽ 26.5% to 46.0%) for the 79.2 GyE group (p ⱕ 0.0001). The five-year biochemical failure rates were 37.3% (95% CI ⫽ 28.4% to 46.3%) for the conventional dose group and 19.1% (95% CI ⫽ 11.1% to 27.1%) for the high dose group (p ⫽ 0.00001). This difference held true when only those with low risk disease were examined (T1b-2a, PSA ⬍10, Gleason ⬍6, n ⫽ 227, 58% of total). The 5-year biochemical failure rate was 34.9% in the conventional dose arm and only 17.2% in the high dose arm (p ⫽ 0.002). It was also significant for intermediate risk patients (39.5% vs 21.3% p ⫽ 0.01). At this time, there was no difference in the overall survival rates between the treatment arms (p ⫽ 0.83). Only 2% of patients receiving conventional dose and 1.5% receiving high dose radiation experienced acute urinary or rectal morbidity of RTOG grade ⬎3. The respective proportions for those experiencing any grade 2 acute morbidity was 62 and 69%. So far only 1.5% and 0.5% respectively have experienced late morbidity of RTOG grade ⬎3.
S131