Authors: Bonnet C, Fillet G, Mounier N, et al.
Source: Journal of Clinical Oncology, 2007, 25:787-792
- The optimal treatment for limited-stage non-Hodgkin’s lymphoma remains uncertain, particularly with regards to the role of radiotherapy despite 4 controlled randomized clinical trials.
- An early report by SWOG had suggested improved overall survival with 3 cycles of CHOP chemotherapy with involved-field radiotherapy (IFRT) when compared to 8 cycles of CHOP alone.1 However, a more recent update of this study has failed to confirm these findings, and instead suggest worse outcomes with reduced cycles of chemotherapy.2
- Patients enrolled on this SWOG study were heterogenous with regard to recognized prognostic factors, and thus questions regarding risk stratification with regards to the role of radiotherapy also remains unanswered.
- To address these issues, a prospective randomized study was undertaken to compare 4 cycles of standard CHOP alone with 4 cycles of CHOP followed by IFRT in a homogenous population of elderly patients without adverse prognostic factors as defined by the age-adjusted International Prognostic Index.
- The Groupe d’Etude des Lymphomes de l’Adulte ( GELA) initiated in 1993 a prospective randomized study with or without radiotherapy and enrolled patients with the following criteria:
- Patients older than 60 years with newly diagnosed aggressive non-Hodgkin’s lymphoma without any adverse factors of the age-adjusted International Prognostic Index (elevated LDH, performance status >1, and Ann Arbor III or IV). Histologies included diffuse mixed, diffuse large-cell (DLBCL), immunoblastic, and anaplastic.
- Exclusion criteria included infection with either HIV or HTLV-I, transformation of previous indolent lymphoma, primary cerebral lymphoma, previous organ transplantation, concomitant or previous cancer, liver or kidney failure, and cardiac contraindication to doxorubicin. Patients with intestinal lymphoma whose treatment could not be encompassed safely into a radiation field were also excluded.
- Staging included CT of the chest, abdomen and pelvis, CSF examination, bone marrow biopsy.
- Bulky disease was defined as any mass >10 cm in maximal diameter.
- There was central pathology review
- Patients were randomized to one of two treatment arms according to participating centers and presence or absence of bulky disease.
- Chemotherapy consisted of 4 cycles of CHOP at 3 week intervals (doxorubicin 60 mg/m 2, cyclophosphamide 750 mg/m 2, vincristine 1.4 mg/m 2 [max dose 2 mg] on day 1, and prednisone 60 mg/m 2 on days 1-5). Dose reductions were not planned according to toxicity, but courses were postponed until leukocyte and platelet counts increased >2,000 and 1000,000/uL , respectively
- Patients randomized to 4 cycles of CHOP followed by IFRT were subsequently treated only if they had achieved either a complete or partial response (CR, PR). Radiotherapy was to commence 1 month after the last cycle of CHOP. The prescribed dose of radiation was 40 Gy in 22 fractions of 1.8 Gy 5 days per week. Irradiated volumes encompassed involved nodal or extranodal sites and adjacent uninvolved nodes. Technical factors were determined by the treating radiation oncologist. There was central review for radiation therapy delivery.
- Response was evaluated 1 month after completion of treatment.
- A “confirmed CR” was defined as 100% disappearance of all clinical and radiographic abnormalities.
- An “unconfirmed CR” was defined as at least >75% disappearance of all radiographic abnormality.
- PR was defined as 50-75% regression
- Stable disease (SD) was defined as <25% regression
- Progressive disease (PD) was defined as >25% growth, or appearance of a new lesion during treatment.
- The primary end-point was event-free survival (EFS). Secondary end-points were response rates and OS
- Analysis was by intent-to-treat principle. Patient characteristics and response rates were compared using Chi-Squared and Fisher’s exact tests. Event-free survival was measured from date of randomization to primary failure, relapse, or death from any cause. OS was measured from randomization to date of death from any cause. Survival functions were estimated using the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were performed using the Cox model for survival data.
- 576 patients were enrolled between 1993-2002 at 65 centers. There was no difference in patient characteristics. Median age was 68 years (range 60-85). Bulky disease was present in 8% of patients. 65% of patients had Stage I disease. Extranodal disease was found in half of patients. 80% of patients had DLBCL.
- Data regarding treatment compliance and tolerance were as follows.
- In each arm, 94% of patients received at least 80% of the theoretical dose-intensity of doxorubicin and cyclophosphamide.
- 12% of patients allocated to IFRT did not receive chemotherapy due to poor response, death after CHOP, medical decision, and refusal. 69% of irradiated patients received a dose of 36-44 Gy and 77% received the recommended dose of 40Gy.
- Among 7 deaths occurring during treatment, 5 resulted from chemotherapy-related toxicity, 2 from lymphoma progression, and none from acute toxicity of radiotherapy. There were a total of 18 grade 3 infections reported, equally balanced at 3% in each treatment arm.
- There was no difference seen in complete response rates (confirmed or unconfirmed) between the CHOP alone or CHOP + IFRT arms (89% vs 91%, respectively).
- After a median follow-up of 7 years, the primary endpoint of EFS also did not differ between groups with 5 year estimates of 61 and 64%, respectively.
- Median time to relapse was 14 and 17 months, respectively. Failure in the primary site occurred in 47 vs 37% of patients, respectively, with no difference in distant sites of failure which was reported at 15%.
- Among patients who received IFRT and experience failure, 21% were in-field, 66% were out of field, and 13% were both.
- The secondary end-point of OS was also not different with 5 year estimates of 72 vs 68%, respectively.
- An analysis was performed restricted to patients who met eligible histologic criteria, and once again, the 5 year EFS and OS were not statistically different.
- In multivariate analysis, OS was affected by Stage II disease (p<0.001, risk ratio 1.9) and male sex (p=0.03, risk ratio 1.4), but not by bulky disease (p=0.3). EFS was affected only by stage II disease (p<0.001, risk ratio 1.8).
- Causes of death were able to be evaluated in 99% of patients.
- 64% were related to lymphoma progression, 15% from secondary cancers, 4% from toxicity that occurred during or after primary treatment, and 1% from toxicity related to salvage treatment after relapse.
- Secondary cancers were the cause of death in 5% of all patients enrolled in the study, all of whom were in remission from their lymphoma at the time of death. These included 9 patients treated with CHOP-alone and 20 with CHOP+IFRT.
- Other causes of death included equally balanced numbers of cardiovascular disease (16 in each arm), infection in 2, suicide in 2, and hypereosinophilic syndrome in 1.
- There was a 36% rate of persistent xerostomia in patients with Waldeyer’s ring lymphoma. Other toxicities included 3 patients with gastritis, and 2 with ileitis.
- This is the only randomized trial comparing brief chemotherapy alone with 4 cycles of CHOP vs 4 cycles of CHOP+IFRT.
- The study consisted of a homogenous group of elderly patients with aggressive NHL that were limited stage disease and had no adverse age-adjusted IPI factors. This is in contrast to the recent Miller et. al. SWOG study which enrolled a heterogenous mix of patients of whom half were < 61 years, 20 % had elevated baseline LDH levels, tow-thirds had stage I disease, and bulky stage II was excluded.
- IFRT after 4 cycles of CHOP influenced the pattern of localization of relapses, but did not decrease EFS or OS compared with 4 cycles of CHOP alone in this homogenous group of elderly patients with aggressive limited-stage NHL who are otherwise low-risk as defined by the absence of any adverse factors according to age-adjusted IPI factors.
- There was no benefit seen in patients with bulky disease, which is a factor often believed to be best controlled with the addition of adjuvant radiotherapy. The authors do advise this latter finding should be interpreted cautiously because of small numbers as only 8% of patients had bulky disease.
- Second malignancies and cardiovascular disease remained significant causes of subsequent death in these patients which is consistent with other reports of moderate risks following brief CHOP followed by IFRT.
- The authors recommend future studies evaluating rituximab or radiolabled antibodies to CHOP to provide further improvements in outcomes
- It is important to note this study was designed before publication of the SWOG randomized clinical trial, or subsequent negative update.
- PET scanning was not used for staging or evaluation of response, thus it may be difficult to interpret these data with regards to current clinical management.
1 Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339:21-26, 1998
2 Miller TP et al (Abstract), Blood, 2001