M Henry-Amar

Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors.

The H5 program in clinical stage (CS) I to II supradiaphragmatic Hodgkins disease (HD) was tailored to prognostic factors identified in former European Organization for the Research and Treatment of Cancer (EORTC) studies. Among the 494 adult patients included in the study, the 237 patients belonging to the favorable group (H5F) underwent a staging laparotomy (Sx) in order to select the patients who could be treated with limited radiotherapy (RT) only. Thus, 198 patients (84%) with negative laparotomy were treated with RT alone and randomized to either mantle irradiation (M) or extended field mantle plus para-aortic (M + PA) irradiation. Complete remission (CR) was achieved in 99% of the patients. There was no difference in the 6-year relapse-free survival (RFS) rate (74% and 72%, respectively) or survival rate (96% and 89%). Therefore, Sx helped to define those patients who could be treated with M alone in contrast to those who required more aggressive therapy. The 39 patients with positive laparotomy were treated as the unfavorable group (H5U) from onset and randomized to either total/subtotal nodal irradiation (TNI/STNI) or a sandwiched mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) X 3, M irradiation, MOPP X 3 protocol (3M). Although the RFS rate was higher in the 3M arm (100% v 53%; P = .002), the 6-year survival was not significantly different between the two arms (overall, 92%). In the 257 patients with initial unfavorable disease, the Sx was avoided. They were randomized to either TNI/STNI or 3M. In complete responders (96%), the 6-year RFS was 91% in the 3M arm and 77% in the TNI/STNI arm (P = .02). The pattern of failure differed in the two arms: the inverted Y and spleen irradiation controlled occult infradiaphragmatic disease better than MOPP; conversely, less patients begun on MOPP recurred in the involved mantle areas. The difference in 6-year actuarial total survival (TS) (89% and 82%; P = .05 in favor of the 3M arm) was not retrieved after exclusion of the unrelated deaths from the analysis. The two arms produced similar TS in patients under 40 years of age. TNI retains interest, especially in young men wishing to preserve fertility. The overall result shows that when treatment is tailored to initial prognostic factors, excellent results can be obtained in all patient subgroups at minimal morbidity and toxic cost.

A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial.

PURPOSE We report a prospective randomized study comparing the relative efficacy of alternating chemotherapy mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) with the standard MOPP chemotherapy in patients with stage IIIB and IV Hodgkins disease (HD). The purpose is to study the influence of time of remission on clinical outcome. PATIENTS AND METHODS After two courses of MOPP, patients were randomized to receive six further courses of MOPP, or two courses of ABVD followed by two courses of MOPP and two courses of ABVD. Radiotherapy was given to areas presenting with masses > or = 5 cm and to residual masses after course no. 4. Evaluation of response (complete remission [CR]) took place after two courses (CR2), after four courses (CR4), at the end of chemotherapy (CR8), and after additional radiotherapy (CR(CT + RT)). Logistic regression analysis was used to study prognostic factors for response at the end of chemotherapy. Cox analysis was used to study prognostic factors for survival. Two hundred seven patients were registered, 192 (93%) of whom were randomized. RESULTS The CR rate at the end of chemotherapy (CR8) was similar in both arms (57% v 59%). However, there were more progressions in the MOPP arm compared with the MOPP/ABVD arm (23% v 8%, P = .014). A significantly higher failure-free survival (FFS) rate was found in the MOPP/ABVD arm (60% v 43% at 6 years, P = .025). There was no difference in the relapse-free survival (RFS) or survival rate. Of patients not in CR4, only 28% still reached a CR8. RFS at 6 years of patients with CR4 (69%) was not different from that of patients with CR8 (68%); patients with a CR(CT + RT)) had a lower RFS rate (48%). CR4 (P < .001) predicted strongly for final remission at the end of chemotherapy. Cox analysis showed that age more than 50 years, six or more involved lymph node areas, no CR by the fourth cycle, chemotherapy with MOPP alone, and no radiotherapy were unfavorable factors for survival. CONCLUSION MOPP/ABVD chemotherapy significantly improved response and FFS rates, but had no influence on RFS and survival rates. Early CR (CR4) is an important factor for final remission and might be used to select a group of patients with a good prognosis.

Prognostic significance of the number of involved areas in the early stages of Hodgkin's disease

An analysis of 1059 patients with clinical stage (CS) I and II Hodgkins disease was undertaken to determine the prognostic significance of the number of involved sites. In this group of patients the number of involved lymph node areas was highly correlated with the probability of dissemination of occult disease. In the subgroup of patients with involvement of two lymph node sites (CS II2) approximately 50% demonstrated occult dissemination on the other side of the diaphragm as evidenced by subsequent relapse in the untreated subdiaphragmatic region. However, only 15% to 20% of this group had unsuspected disease in regions other than the spleen or the paraaortic lymph nodes. In CS I and II2 supradiaphragmatic patients, who underwent a staging laparotomy, splenic involvement was a powerful prognostic indicator. When the spleen was not involved, less than 10% of patients had disease elsewhere below the diaphragm, whereas, when the spleen was involved as many as 40% of patients had additional subdiaphragmatic sites involved. In the subgroup with three or more lymph node areas involved (CS II3), the proportion of patients with extension of disease on the other side of the diaphragm, as evidenced by later relapse was also about 50%. But in these patients, unlike the CS II2 patients, analysis of relapse patterns showed that occult disease had already disseminated to the pelvic nodes or to extra nodal sites. Furthermore, splenic involvement was of much less prognostic significance because CS II3 patients who did not demonstrate splenic involvement at staging laparotomy had similar relapse incidence and similar relapse patterns as those with positive spleens.

Late relapse in early-stage Hodgkin's disease patients enrolled on European Organization for Research and Treatment of Cancer protocols.

PURPOSE The great majority of relapses after the treatment for early-stage Hodgkins disease are observed within 4 to 5 years after treatment completion. This study describes the characteristics and outcome of patients who had late relapses, which was defined as relapses that occurred 5 or more years after initial treatment start. PATIENTS AND METHODS A total of 1,082 adult patients with early clinical stage Hodgkins disease were enrolled on three consecutive European Organization for Research and Treatment of Cancer (EORTC) protocols (H1, H2, and H5 trials) from 1964 to 1981. Of these, 1,044 patients satisfied the eligibility criteria with a supradiaphragmatic localization, age greater than 15 years, and initial complete remission. Overall, 341 patients (32.6%) relapsed, 304 (29.1%) early and 37 (3.5%) late. For each of these 37 late relapsers, questionnaires were sent to the participating centers and detailed information for 34 relapses was obtained. Cumulative probabilities for developing a late relapse were estimated using the Kaplan and Meier method. Quantification of the relationship between late relapse and several confounding variables was performed using the Coxs proportional hazards model. RESULTS The 10- and 15-year cumulative probabilities of late relapse in patients who were disease-free at 5 years were 4.8% and 8.3%, respectively. Patients treated on more recent protocols had a higher incidence of late relapse, possibly due to an attempt to tailor therapy to the specific prognostic factors (10-year cumulative probabilities, 4.6%, 2.6%, and 7.5% in trials H1, H2, and H5, respectively). Incidence of late relapses significantly correlated with male sex, B symptoms, mediastinal involvement, and treatment modality. Salvage treatment induced a complete response in 27 patients (79%) and a prolonged complete remission in 24 patients (71%). Twenty years after initial treatment start, similar overall survival rates were observed for late relapsing (72%) and nonrelapsing patients (75%). CONCLUSION Late relapses of Hodgkins disease are uncommon, but may be more frequent with recent protocols tailored to specific prognostic factors. If treated, their outcome is favorable. Late relapse is therefore another factor indicating that careful, long-term follow-up is needed for patients with Hodgkins disease.