- Email: [email protected]
Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial
Proceedings of the 52nd Annual ASTRO Meeting
PLENARY
1
The TME Trial after a Median Follow-up of 11 Years
C. A. Marijnen1, W. van Gijn1, I. D. Nagtegaal2, E. Klein Kranenbarg1, H. Putter1, T. Wiggers3, H. J. T. Rutten4, L. Pahlman5, B. Glimelius5, C. J. H. van de Velde1 1
Leiden University Medical Center, Leiden, Netherlands, 2University Medical Center St. Radboud, Nijmegen, Netherlands, University Medical Center Groningen, Groningen, Netherlands, 4Catharina Hospital, Eindhoven, Netherlands, 5Uppsala University Hospital, Uppsala, Sweden 3
Purpose/Objective(s): Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 11 years. Materials/Methods: One thousand eight hundred sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 x 5 Gy radiotherapy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. Results: Ten-year local recurrence rate is 6.4% in the irradiated group and 13.3% in the surgery alone group (p \ 0.001). While overall recurrence is significantly lower in the irradiated group (28.8% vs. 33.6%, p = 0.042), there is no difference in overall survival. For patients with a negative circumferential resection margin (CRM), cancer specific survival is higher in the irradiated group. In subgroup analysis, radiotherapy only reduces local recurrence in CRM negative patients, lymph node positive patients and patients with a tumor more than 5 cm from the anal verge. In a subgroup with lymph node positive patients with a negative CRM, preoperative radiotherapy improves 10 year survival from 41% to 51%, p = 0.02. Conclusions: Preoperative short-term radiotherapy for patients with resectable rectal cancer reduces the local recurrence rate with more than 50%. In subgroup analyses, radiotherapy seems only effective in patients with a negative CRM, patients with TNM stage III and a tumor height above 5 cm. There is no difference in survival when the entire trial population is analyzed on an intention to treat basis. However, future staging techniques will offer possibilities to select patient groups that will obtain a survival benefit. Author Disclosure: C.A. Marijnen, None; W. van Gijn, None; I.D. Nagtegaal, None; E. Klein Kranenbarg, None; H. Putter, None; T. Wiggers, None; H.J.T. Rutten, None; L. Pahlman, None; B. Glimelius, None; C.J.H. van de Velde, None.
PLENARY
2
Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial
H. T. Eich1, R. P. Mueller1, V. Diehl2, H. Go¨rgen2, H. Mueller-Hermelink3, B. Schmidt4, A. Grosu5, J. Karstens6, N. Willich7, A. Engert2 1 Department of Radiation Oncology, University of Cologne, Cologne D-50937, Germany, 2Clinic I for Internal Medicine, University of Cologne, Cologne D-50937, Germany, 3Institute of Pathology, University of Wu¨rzburg, Wu¨rzburg, Germany, 4 Department of Radiation Oncology, Katharinenhospital Stuttgart, Stuttgart, Germany, 5Department of Radiation Oncology, University of Freiburg, Freiburg, Germany, 6Department of Radiation Oncology, University of Hannover, Hannover, Germany, 7 Department of Radiation Oncology, University of Mu¨nster, Mu¨nster, Germany
Purpose/Objective(s): Combined modality treatment consisting of 4-6 cycles of chemotherapy (CT) followed by involved field radiotherapy (IF-RT) is the standard treatment for early unfavorable HL. However, the optimal CT regimen and adequate radiation dose is unclear. The previous trial for this group of patients (HD8), revealed an overall survival (OS) and freedom from treatment failure (FFTF) at 5 years of 91% and 83%, respectively. The HD11 trial thus addressed two major questions: (1) improving outcome by intensifying CT (4xABVD vs. 4xBEACOPPbaseline; Bbas) and (2) defining the best radiation dose (30 Gy vs. 20 Gy IFRT). Materials/Methods: Between May 1998 and January 2003, 1395 eligible patients aged 16-75 years with untreated early unfavorable stage HL (CS I, IIA with at least one of the risk factors large mediastinal mass (a), extranodal disease (b), elevated ESR (c) or $ 3 nodal areas (d); IIB with risk factors c and/or d) were randomized into one of the following 4 treatment arms: 4xABVD + 30 Gy (A), 4xABVD + 20 Gy (B), 4x Bbas + 30 Gy (C) or 4x Bbas + 20 Gy (D). Since there are strong indications for an interaction between CT- and RT-doses, a comparison of pooled treatment arms (A+B vs. C+D for comparison of 4xABVD vs. 4x Bbas and A+C vs. B+D for comparison of 30 Gy IF-RT vs. 20 Gy IF-RT) would be misleading. Therefore, all treatment arms were analyzed separately. Results: Patient characteristics were well balanced between the 4 arms (median age 33 years; 49% male; 6% stage I; 29% B-symptoms). CT- and RT-related acute toxicity occurred significantly more often in the arms with the more intensive therapy (CT: 74.1% vs. 51.8%; RT: 12.3% vs. 5.5%). The complete remission rate 3 months after end of therapy was 94.1% for the whole group and did not differ significantly between the 4 arms. The 5-year estimate of FFTF (primary endpoint) is 85.0% (OS 94.5%, PFS 86.0%). Bbas is more effective than ABVD if followed by 20 Gy IF-RT (5y-FFTF difference 5.7%, 95%-CI [0.1%; 11.3%]). This effect does not exist in combination with 30 Gy IF-RT (5y-FFTF difference 1.6% [-3.6%; 6.9%]). Similar results are observed for the RTquestion: After 4 cycles of Bbas, 20 Gy is not inferior to 30 Gy (5y-FFTF difference -0.1%, 95%-CI [-5.1%; 4.9%]), whereas after 4xABVD, a relevant inferiority of 20 Gy cannot be excluded (-4.0% [-9.5%; 1.4%]). Conclusions: A reduction of RT dose from 30 Gy to 20 Gy IF-RT seems to be justified only in combination with Bbas, but not with a less effective chemotherapy such as 4xABVD. Four cycles of ABVD followed by 30 Gy IFRT is the standard of care for HL patients in early unfavorable stages. Author Disclosure: H.T. Eich, None; R.P. Mueller, None; V. Diehl, None; H. Go¨rgen, None; H. Mueller-Hermelink, None; B. Schmidt, None; A. Grosu, None; J. Karstens, None; N. Willich, None; A. Engert, None.
S1
PLENARY
1
The TME Trial after a Median Follow-up of 11 Years
C. A. Marijnen1, W. van Gijn1, I. D. Nagtegaal2, E. Klein Kranenbarg1, H. Putter1, T. Wiggers3, H. J. T. Rutten4, L. Pahlman5, B. Glimelius5, C. J. H. van de Velde1 1
Leiden University Medical Center, Leiden, Netherlands, 2University Medical Center St. Radboud, Nijmegen, Netherlands, University Medical Center Groningen, Groningen, Netherlands, 4Catharina Hospital, Eindhoven, Netherlands, 5Uppsala University Hospital, Uppsala, Sweden 3
Purpose/Objective(s): Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 11 years. Materials/Methods: One thousand eight hundred sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 x 5 Gy radiotherapy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. Results: Ten-year local recurrence rate is 6.4% in the irradiated group and 13.3% in the surgery alone group (p \ 0.001). While overall recurrence is significantly lower in the irradiated group (28.8% vs. 33.6%, p = 0.042), there is no difference in overall survival. For patients with a negative circumferential resection margin (CRM), cancer specific survival is higher in the irradiated group. In subgroup analysis, radiotherapy only reduces local recurrence in CRM negative patients, lymph node positive patients and patients with a tumor more than 5 cm from the anal verge. In a subgroup with lymph node positive patients with a negative CRM, preoperative radiotherapy improves 10 year survival from 41% to 51%, p = 0.02. Conclusions: Preoperative short-term radiotherapy for patients with resectable rectal cancer reduces the local recurrence rate with more than 50%. In subgroup analyses, radiotherapy seems only effective in patients with a negative CRM, patients with TNM stage III and a tumor height above 5 cm. There is no difference in survival when the entire trial population is analyzed on an intention to treat basis. However, future staging techniques will offer possibilities to select patient groups that will obtain a survival benefit. Author Disclosure: C.A. Marijnen, None; W. van Gijn, None; I.D. Nagtegaal, None; E. Klein Kranenbarg, None; H. Putter, None; T. Wiggers, None; H.J.T. Rutten, None; L. Pahlman, None; B. Glimelius, None; C.J.H. van de Velde, None.
PLENARY
2
Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial
H. T. Eich1, R. P. Mueller1, V. Diehl2, H. Go¨rgen2, H. Mueller-Hermelink3, B. Schmidt4, A. Grosu5, J. Karstens6, N. Willich7, A. Engert2 1 Department of Radiation Oncology, University of Cologne, Cologne D-50937, Germany, 2Clinic I for Internal Medicine, University of Cologne, Cologne D-50937, Germany, 3Institute of Pathology, University of Wu¨rzburg, Wu¨rzburg, Germany, 4 Department of Radiation Oncology, Katharinenhospital Stuttgart, Stuttgart, Germany, 5Department of Radiation Oncology, University of Freiburg, Freiburg, Germany, 6Department of Radiation Oncology, University of Hannover, Hannover, Germany, 7 Department of Radiation Oncology, University of Mu¨nster, Mu¨nster, Germany
Purpose/Objective(s): Combined modality treatment consisting of 4-6 cycles of chemotherapy (CT) followed by involved field radiotherapy (IF-RT) is the standard treatment for early unfavorable HL. However, the optimal CT regimen and adequate radiation dose is unclear. The previous trial for this group of patients (HD8), revealed an overall survival (OS) and freedom from treatment failure (FFTF) at 5 years of 91% and 83%, respectively. The HD11 trial thus addressed two major questions: (1) improving outcome by intensifying CT (4xABVD vs. 4xBEACOPPbaseline; Bbas) and (2) defining the best radiation dose (30 Gy vs. 20 Gy IFRT). Materials/Methods: Between May 1998 and January 2003, 1395 eligible patients aged 16-75 years with untreated early unfavorable stage HL (CS I, IIA with at least one of the risk factors large mediastinal mass (a), extranodal disease (b), elevated ESR (c) or $ 3 nodal areas (d); IIB with risk factors c and/or d) were randomized into one of the following 4 treatment arms: 4xABVD + 30 Gy (A), 4xABVD + 20 Gy (B), 4x Bbas + 30 Gy (C) or 4x Bbas + 20 Gy (D). Since there are strong indications for an interaction between CT- and RT-doses, a comparison of pooled treatment arms (A+B vs. C+D for comparison of 4xABVD vs. 4x Bbas and A+C vs. B+D for comparison of 30 Gy IF-RT vs. 20 Gy IF-RT) would be misleading. Therefore, all treatment arms were analyzed separately. Results: Patient characteristics were well balanced between the 4 arms (median age 33 years; 49% male; 6% stage I; 29% B-symptoms). CT- and RT-related acute toxicity occurred significantly more often in the arms with the more intensive therapy (CT: 74.1% vs. 51.8%; RT: 12.3% vs. 5.5%). The complete remission rate 3 months after end of therapy was 94.1% for the whole group and did not differ significantly between the 4 arms. The 5-year estimate of FFTF (primary endpoint) is 85.0% (OS 94.5%, PFS 86.0%). Bbas is more effective than ABVD if followed by 20 Gy IF-RT (5y-FFTF difference 5.7%, 95%-CI [0.1%; 11.3%]). This effect does not exist in combination with 30 Gy IF-RT (5y-FFTF difference 1.6% [-3.6%; 6.9%]). Similar results are observed for the RTquestion: After 4 cycles of Bbas, 20 Gy is not inferior to 30 Gy (5y-FFTF difference -0.1%, 95%-CI [-5.1%; 4.9%]), whereas after 4xABVD, a relevant inferiority of 20 Gy cannot be excluded (-4.0% [-9.5%; 1.4%]). Conclusions: A reduction of RT dose from 30 Gy to 20 Gy IF-RT seems to be justified only in combination with Bbas, but not with a less effective chemotherapy such as 4xABVD. Four cycles of ABVD followed by 30 Gy IFRT is the standard of care for HL patients in early unfavorable stages. Author Disclosure: H.T. Eich, None; R.P. Mueller, None; V. Diehl, None; H. Go¨rgen, None; H. Mueller-Hermelink, None; B. Schmidt, None; A. Grosu, None; J. Karstens, None; N. Willich, None; A. Engert, None.
S1