British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin's disease--long term results

From 1979-1983, 299 patients with stage III or IV Hodgkin's disease (HD) were randomised to receive cyclical chemotherapy with MOPP (mustine, Oncovin, procarbazine, prednisone) or LOPP (Leukeran substituted for mustine). Two hundred and ninety patients were evaluable. There was no statistically significant difference between the complete remission (CR) rates (63% for MOPP, 57% for LOPP), percentage of patients remaining disease free at 5 years (38% for MOPP, 35% for LOPP) and overall survival at 5 years (65% for MOPP, 64% for LOPP). On multivariate analysis younger age, grade I histopathology, absence of systemic symptoms, and normal albumin level were favourable prognostic factors for survival. Acute toxicity in the form of nausea/vomiting, myelosuppression, and phlebitis were less with LOPP than MOPP. Deaths in both groups were usually due to disseminated Hodgkin's disease; there were no infective deaths in the absence of Hodgkin's disease. Second malignancies occurred in six patients treated with MOPP--three acute myeloid leukaemia (AML), one non-Hodgkin's lymphoma (NHL), two carcinomas (Ca); with LOPP, four second malignancies occurred (one AML, one NHL, two Ca). These long term results confirm that LOPP is as effective as MOPP, and less toxic, in the treatment of advanced Hodgkin's disease.     

ChlVPP alternating with PABlOE is superior to PABlOE alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation/Central Lymphoma Group randomized controlled trial

The purpose of this randomized trial was to compare the efficacy of 6 cycles of prednisolone, Adriamycin (doxorubicin), bleomycin, vincristine (Oncovin) and etoposide (PABlOE) with 3 cycles of PABIOE that alternate with 3 cycles of chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) in patients with advanced Hodgkin's disease. Between October 1992 and April 1996, 679 patients were entered onto the study. 41 of these did not match the protocol requirements on review and were excluded from further analysis, most of these being reclassified as NHL on histological review. Of the remaining 638 patients, 319 were allocated to receive PABIOE and 319 were allocated to receive ChlVPP/PABlOE. The complete remission (CR) rates were 78% and 64%, for ChlVPP/PABlOE and PABIOE respectively after initial chemotherapy (P< 0.0001). 124 patients were re-evaluated subsequently following radiotherapy to residual masses. The CR rates changed from 78% to 88% for ChlVPP/PABlOE and from 64% to 77% for PABlOE when re-evaluated in this manner (treatment difference still significant, P = 0.0002). The treatment associated mortality in the PABlOE arm was 2.2% (7 deaths), while there were no such deaths in the ChlVPP/PABlOE arm (P = 0.015). The failure-free survival was significantly greater in the ChlVPP/PABlOE arm (P< 0.0001) as was the overall survival (P = 0.01). The failure-free and overall survival rates at 3 years were 77% and 91% in the ChlVPP/PABlOE arm, compared with 58% and 85% in the PABIOE arm, respectively. These results indicate that ChlVPP alternating with PABIOE is superior to PABIOE alone as initial treatment for advanced Hodgkin's disease.     

Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study.

PURPOSE: To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkin's disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT. PATIENTS AND METHODS: From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkin's disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44). RESULTS: All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02). CONCLUSION: We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.     

Evaluation of therapeutic modalities in the control of Hodgkin's disease

The results achieved in three different studies carried out on patients affected by Hodgkin's disease are discussed. In study No. 1, 58 patients with pathological Stage I-II were treated with only a "Mantle" field irradiation. The complete remission (CR) rate was 98% with an actuarial overall survival of 90%, and a median of follow-up of 80 months. Thirty-one percent of patients relapsed. In study No. 2, 42 patients were randomly allocated to receive only MOPP chemotherapy versus extended field irradiation; CR rate was 68 and 95%, respectively (p less than 0.05). The overall survival rate was 100% in the radiotherapy group and 82% in the MOPP group. No relapses have been observed in patients treated with MOPP. In study No. 3, 218 patients affected by advanced Stage HD were randomly treated with 6 cycles of MOPP chemotherapy versus 6 cycles of ABVD chemotherapy. In the MOPP group the CR rate, the relapse-free survival rate (RFS), and overall survival (OS) rates at 60 months were 77, 68, and 76% respectively, whereas, in the ABVD group the CR, the RFS, and OS rates at 60 months were 75, 77 and 80% respectively, (p less than 0.05). These data and statistical comparisons are analyzed.     

Trials in advanced Hodgkin's disease: more than 30 years experience of the British National Lymphoma Investigation

Hodgkin's disease demonstrates an exquisite sensitivity to chemotherapy and radiation therapy. This necessitates investigation of modes of delivering these modalities in the best possible fashion to improve outcomes. The British National Lymphoma Investigation (BNLI) has conducted randomized trials in advanced Hodgkin's disease for > 30 years. The results of BNLI studies have demonstrated that MOPP (mechlorethamine/vincristine/procarbazine/prednisone) chemotherapy is superior to MOP (mechlorethamine/vincristine/procarbazine) chemotherapy; that there are no significant differences between MOPP and B-MOPP (MOPP plus bleomycin); that there is no significant benefit from maintenance therapy with lomustine/vinblastine/bleomycin; that LOPP (chlorambucil/vincristine/procarbazine/prednisone) is as effective as MOPP and has less acute toxicity; that alternating therapy with LOPP and EVAP (etoposide/vinblastine/doxorubicin/prednisolone) is superior to EVAP alone or hybrid LOPP and EVA (etoposide/vinblastine/doxorubicin); that alternating therapy with ChlVPP (a substitute for MOPP) and prednisolone/doxorubicin/bleomycin/vincristine/etoposide regimens is superior to the latter regimen alone; that the Stanford V regimen (doxorubicin/vinblastine/mechlorethamine/vincristine/bleomycin/etoposide/prednisone) combined with disciplined radiation therapy is safe and effective; that hybrid therapy with ChlVPP and EVA and alternating therapy with ChlVPP and prednisolone/doxorubicin/bleomycin/vincristine/etoposide are as effective as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) alone; and that there is no additional benefit from total nodal irradiation or combined-modality therapy compared with MOPP; and that treatment with high-dose BEAM (carmustine/etoposide/cytarabine/melphalan) and autologous bone marrow transplantation is superior to mini-BEAM (lower-dose BEAM not requiring bone marrow rescue) for poor-risk relapsed and refractory disease.     

Intermediate stage Hodgkin's disease: preliminary results on 210 patients treated with four ABVD chemotherapy cycles plus extended versus involved field radiotherapy

BACKGROUND: To improve long-term survival by reducing toxicity in intermediate stage Hodgkin's disease patients, we compared the effects of involved field (IF) versus extended field (EF) irradiation administered after four cycles of ABVD regimen. MATERIALS AND METHODS: Two hundred and ten Hodgkin's disease patients, at clinical stage II with risk factors and III without risk factors, were enrolled in the randomized study HD94. After four courses of ABVD regimen, patients who achieved complete remission (CR) or partial remission (PR) were randomly assigned to the IF or EF arm. The Kaplan-Meier method was adopted to estimate overall survival (OS) and relapse-free survival (RFS). RESULTS: After a median follow-up of 78 months (range 13-111 months), OS was 98% and 96%, respectively, in the EF and IF arms; RFS was 94% and 91%, respectively, in the EF and IF arms. Conclusion: We confirm the efficacy of four cycles of ABVD regimen, with suitable dose intensity, and radiotherapy as consolidation therapy, in intermediate stage Hodgkin's disease patients (CR = 99.5% and OS = 95%). We also found that involved field radiotherapy results were as effective as extended field, without acute toxicity.     

ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study.

BACKGROUND: In 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. PATIENTS AND METHODS: Patients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). RESULTS: Ninety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT) + RT] were 93% and 92% for ABVD and EVE arms, respectively (P = NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P < 0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P < 0.05). No differences in terms of overall survival (OS) were observed for the two study arms. CONCLUSIONS: In unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as initial treatment for HL.     

Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin's lymphoma

PURPOSE: The use of radiotherapy in patients with advanced Hodgkin's lymphoma (HL) is controversial. The purpose of this study was to describe the role of radiotherapy in patients with advanced HL who were in partial remission (PR) after chemotherapy. METHODS: In a prospective randomized trial, patients <70 years old with previously untreated Stage III-IV HL were treated with six to eight cycles of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycine, vinblastine hybrid chemotherapy. Patients in complete remission (CR) after chemotherapy were randomized between no further treatment and involved-field radiotherapy (IF-RT). Those in PR after six cycles received IF-RT (30 Gy to originally involved nodal areas and 18-24 Gy to extranodal sites with or without a boost). RESULTS: Of 739 enrolled patients, 57% were in CR and 33% in PR after chemotherapy. The median follow-up was 7.8 years. Patients in PR had bulky mediastinal involvement significantly more often than did those in CR after chemotherapy. The 8-year event-free survival and overall survival rate for the 227 patients in PR who received IF-RT was 76% and 84%, respectively. These rates were not significantly different from those for CR patients who received IF-RT (73% and 78%) or for those in CR who did not receive IF-RT (77% and 85%). The incidence of second malignancies in patients in PR who were treated with IF-RT was similar to that in nonirradiated patients. CONCLUSION: Patients in PR after six cycles of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicine, bleomycine, vinblastine treated with IF-RT had 8-year event-free survival and overall survival rates similar to those of patients in CR, suggesting a definite role for RT in these patients.     

Predictive value of the early response to chemotherapy in high-risk stages II and III Hodgkin's disease

A series of 60 patients with "high risk" Stage II and III Hodgkin's disease (B symptoms, or large mediastinal mass, or E lung disease) were staged without laparotomy and treated with combined modality treatment: mechlorethamine, vincristine, procarbazine, and prednisone (6 MOPP) plus radiotherapy. Patients were restaged after the first three courses of MOPP and the status of response to therapy at that time was called early response to chemotherapy (ERC). The rate of nitrogen mustard and procarbazine delivery (MRD) during the first three cycles of chemotherapy also was assessed. At the completion of the therapy patients were restaged and the final response was assessed. Fifty-two (86.7%) patients entered complete remission (CR). Forty-eight percent of the complete responders achieved CR in the first three courses of MOPP. Eight-year survival and disease-free survival (DFS) rates of the patients achieving CR were 71% and 73%, respectively. Survival and DFS were significantly better for the patients who achieved CR in the first three cycles of chemotherapy than for patients who entered CR at a later stage of therapy: 8-year survival 90% versus 55% (P = 0.00); 8-year DFS 87% versus 59% (P = 0.01). The attainment of a complete ERC was adversely affected by lymphocyte depletion (LD) histologic type (P = 0.01) and MRD less than 65% (P = 0.04). However, when a multivariate regression analysis was used, ERC was the only significant prognostic variable for survival and DFS and its predictive value was confirmed even after correction by MRD. These data suggest that the rapidity of response to chemotherapy could be an important prognostic factor in high-risk Stage II and III Hodgkin's disease.     

Impact of adjuvant radiation on the patterns and rate of relapse in advanced-stage Hodgkin's disease treated with alternating chemotherapy combinations

The role of adjuvant radiation therapy (RT) in the management of advanced-stage Hodgkin's disease (HD) was analyzed in 222 patients who attained a complete remission (CR) with alternating chemotherapy combinations. Mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) or MOPP/ABV alternating with the lomustine, melphalan, and vindesine combination (MOPP/ABV/CAD) were similarly effective in inducing a CR in 222 of 270 (83%) patients. These patients were scheduled to receive consolidative RT to bulky disease or other critical sites of initial nodal involvement to a total dose of 2,000 cGy, with an optional additional boost of 1,000 cGy. However, only 125 (56%) patients received radiation to all initial nodal sites of disease. In 69 (31%) patients, only selected nodal sites were included in the radiation fields, and 28 (13%) did not receive any RT. Of the 222 CR patients, 42 (19%) relapsed during a median follow-up period of 6.5 years (range, 2 to 15 years). Of these, 26 (62%) patients relapsed exclusively in unirradiated nodal sites, six (14%) within irradiated sites, and 10 (24%) both within and outside irradiated fields. The actuarial 10-year relapse-free survival (RFS) and overall survival (OS) for patients receiving radiation to all initially involved nodal sites were 89% and 94%, respectively, compared with 68% and 71% (P less than .0001) for patients who had only partial or no RT. Cox proportional hazards regression analysis showed that RT to all sites of initial disease was the most significant independent covariate (P less than .005) affecting RFS and OS. These data demonstrate that residual microscopic disease is relatively frequent in patients with apparent CR after alternating combination chemotherapy, and that irradiation of all sites of initial nodal involvement decreases relapse and improves survival in advanced-stage HD.     

High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy.

PURPOSE: To determine whether high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) should be included in the initial consolidative treatment of patients with advanced, unfavorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: One hundred sixty-three patients achieving complete remission (CR) or partial remission (PR) with four initial courses of doxorubicin, bleomycin, vinblastine, and dacarbazine, or other doxorubicin-containing regimens, were randomly assigned to receive HDT plus ASCT (83 patients) versus four courses of conventional chemotherapy (80 patients). Unfavorable HL was defined as the presence of at least two of the following poor prognostic factors: high lactate dehydrogenase level, large mediastinal mass (greater than at least 33% of the thoracic diameter), more than one extranodal site, low hematocrit level, and inguinal involvement. RESULTS: At the end of the treatment program, 92% of patients in arm A and 89% in arm B achieved a CR (P =.6). After a median follow-up of 48 months, the 5-year failure-free survival rates were 75% (95% confidence interval [CI], 65 to 85) in arm A and 82% (95% CI, 73 to 90) in arm B (P =.4). The 5-year overall survival rates were 88% (95% CI, 80 to 96) in arm A and 88% (95% CI, 79 to 96) in arm B (P =.99). The 5-year relapse-free survival rates were 88% in arm A (95% CI, 80 to 96) and 94% in arm B (95% CI, 88 to 100), and the difference was not significant (P =.3). CONCLUSION: Patients with advanced unfavorable HL achieving CR or PR after four courses of doxorubicin-containing regimens have a favorable outcome with conventional chemotherapy. No benefit from an early intensification with HDT and ASCT was shown.     

Treatment of indolent B-Cell nonfollicular lymphomas: final results of the LL01 randomized trial of the Gruppo Italiano per lo Studio dei Linfomi.

PURPOSE: To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. PATIENTS AND METHODS: A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFNalpha-2a; 3 MU, three times weekly) for 12 months or observation. RESULTS: There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P =.07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P =.45), failure-free survival (P =.07), or progression-free survival (PFS; P =.5). Eighty-eight patients were randomly assigned to either IFNalpha-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. CONCLUSION: HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFNalpha maintenance treatment did not prolong response duration.     

Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies.

BACKGROUND: This randomized study compared the efficacy and safety of fludarabine-mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m(2) i.v.), days 1-5, plus mitoxantrone (10 mg/m(2) i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m(2) i.v. infusion), doxorubicin (25 mg/m(2) i.v.) and vindesine (3 mg/m(2) i.v.) on day 1, and prednisone (50 mg/m(2)) on days 1-5. RESULTS: FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P = 0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. CONCLUSION: FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.     

Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study.

BACKGROUND: Chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine and darcarbacine) schedule is the standard treatment for advanced Hodgkin's lymphoma. Certain facts, including a low toxicity compared with MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin and vinblastine) and minimal potential for inducing second neoplasias or patient sterility, support the use of ABVD to treat early disease stages. In the present study, we prospectively evaluated the long-term efficacy and toxicity of six cycles of ABVD as treatment for early-stage Hodgkin's lymphoma. PATIENTS AND METHODS: From January 1990 to June 2002, 95 patients with stage I and II Hodgkin's lymphoma were treated with six ABVD cycles. Fifteen patients who met the criteria for mediastinal bulky disease also received further radiotherapy on the mediastinum. RESULTS: After six cycles, 89 patients (94%) showed a complete response (CR) and six patients (6%) showed a partial response (PR). These PRs became CRs after radiotherapy. After a median follow-up of 78 months, 14 patients had relapsed and three had died. Overall survival and progression-free survival rates at 7 years were 96% and 84%, respectively. For patients with stage IA and IIA without mediastinal bulky disease, the survival rates were 97% and 88%, respectively. CONCLUSIONS: The administration of six ABVD cycles is an effective and safe treatment in patients with stage I and II Hodgkin's lymphoma.     

Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group.

PURPOSE: We report results of a randomized trial comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy alone with treatment that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma. PATIENTS AND METHODS: Patients with nonbulky clinical stage I to IIA Hodgkin's lymphoma were stratified into favorable and unfavorable risk cohorts. Patients allocated to radiation-containing therapy received subtotal nodal radiation if favorable risk or combined-modality therapy if unfavorable risk. Patients allocated to ABVD received four to six treatment cycles. RESULTS: We evaluated 399 patients. Median follow-up is 4.2 years. In comparison with ABVD alone, 5-year freedom from disease progression is superior in patients allocated to radiation therapy (P = .006; 93% v 87%); no differences in event-free survival (P = .06; 88% v 86%) or overall survival (P = .4; 94% v 96%) were detected. In a subset analyses comparing patients stratified into the unfavorable cohort, freedom from disease progression was superior in patients allocated to combined-modality treatment (P = .004; 95% v 88%); no difference in overall survival was detected (P = .3; 92% v 95%). Of 15 deaths observed, nine were attributed to causes other than Hodgkin's lymphoma or acute treatment-related toxicity. CONCLUSION: In patients with limited-stage Hodgkin's lymphoma, no difference in overall survival was detected between patients randomly assigned to receive treatment that includes radiation therapy or ABVD alone. Although 5-year freedom from disease progression was superior in patients receiving radiation therapy, this advantage is offset by deaths due to causes other than progressive Hodgkin's lymphoma or acute treatment-related toxicity.     

A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer

After primary surgery, 125 patients with epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] 1c + IIb + IIc = 22 patients, FIGO III = 82 patients, FIGO IV = 21 patients) were randomly allocated to receive PC (cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 on day 1 every 28 days) (corrected) or PAC (PC + doxorubicin 45 mg/m2). After six cycles, patients clinically disease-free or with resectable residual disease were submitted to second-look surgery. After restaging, patients in surgical complete response (CR) stopped treatment while those responding partially (PR) received six more courses; patients whose disease progressed were excluded from the study. Among patients with measurable disease, the following clinical response rates were observed: PC = 20% CR, 34.3% PR, 14.3% stable disease, and 31.4% progression; PAC = 40.6% CR, 15.6% PR, 12.5% stable disease, and 31.3% progression. In the 75 patients submitted to second look, the results have been the following: PC = 39.5% CR, 36.8% PR, 7.9% stable disease, and 15.8% progression; PAC = 62.2% CR, 18.9% PR, 10.8% stable disease, and 8.1% progression. The difference in surgical complete response in favor of the PAC regimen is significant (P less than .05). Median survival and progression-free survival were 800 and 400 days, respectively, for PAC arm; median survival and progression-free survival were 680 and 380 days, respectively, for PC. These differences are not significant. Probability of survival was affected by FIGO stage, amount of residual disease, histology, performance status, and response at second look, while no influence was observed according to grade of tumor differentiation and age. Our results demonstrate the usefulness of doxorubicin in terms of surgical CR.     

Three cycles of ABDV plus extended field radiotherapy in patients with poor prognosis early-intermediate stage Hodgkin's disease

The aim of the study was to verify the possibility of treating patients with poor prognosis early-intermediate Hodgkin's disease with a combined modality therapy consisting of three cycles of ABVD followed by extended field irradiation (EFRT). No patient had bulky mediastinum or had previously been administered chemo- or radiotherapy. At pathological restaging, 40/44 (91%) evaluable patients achieved complete responses (CR). After a ten-year followup, freedom from progression (FFP), relapse-free survival (RFS) and overall survival (OS) were 80%, 83% and 81%, respectively. Of the prognostic factors, univariate analysis showed that only stage III negatively influenced RFS, but not OS. Toxicity was mild except for subclinical mediastinal fibrosis in 32.5% of CR patients. No patient reported reduced fertility. Two cases of second neoplasms were recorded: one ameboid glioma and one thymoma, both occurring within five years after discontinuing chemo-radiotherapy. Our data suggest that three cycles of ABVD preceeding EFRT is an effective treatment for poor prognosis early-intermediate stage Hodgkin's disease; nevertheless, stage III patients and some stage II patients with unfavorable prognostic factors should be treated with a more aggressive approach.     

Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin's lymphoma: final results of the German Hodgkin's Lymphoma Study Group Trial HD5.

PURPOSE: To investigate whether treatment results in intermediate-stage Hodgkin's lymphoma can be improved by rapid application of non-cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks. PATIENTS AND METHODS: From January 1988 to January 1993, 996 patients in stage I or II Hodgkin's lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkin's lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy. RESULTS: Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P =.010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each). CONCLUSION: Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkin's lymphoma and produce excellent long-term treatment results.     

Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin's disease: the experience of the French Society of Pediatric Oncology.

PURPOSE: With the aim of decreasing undesirable side effects of therapy, we investigated the reduction of both chemotherapy and radiation therapy (RT) in children with Hodgkin's disease, and compared Adriamycin (doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France), bleomycin, vinblastine, and dacarbazine (ABVD) alone to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and ABVD in favorable cases and assessed the effectiveness of low-dose RT (20 Gy) after good response to chemotherapy. PATIENTS AND METHODS: A French national study began in 1982 that included 238 pediatric patients with Hodgkin's disease. Initial staging was clinical and without laparotomy. In patients with localized disease (IA-IIA), an equivalence trial compared the effectiveness of four cycles of ABVD with two cycles of ABVD that were alternated with two cycles of MOPP. Patients with more advanced disease (IB-IIB-III-IV) received three courses of MOPP that was alternated with three courses of ABVD. All of the patients who achieved a good remission after chemotherapy were administered 20 Gy RT, which was limited to the initially involved areas for localized disease, and encompassed the paraaortic nodes and the spleen as well for more advanced stages. When a good remission was not obtained, 40 Gy RT was administered. RESULTS: At the completion of chemotherapy, 227 patients (97%) were considered good responders, whereas 11 did not achieve a good remission. With a median follow-up of 6 years, the 6-year actuarial survival was 92% and the disease-free survival was 86%. The relapse-free survival in favorable stages was 90% in the ABVD arm and was 87% in the MOPP and ABVD arm. In June 1987, inclusion of stage IV patients was discontinued because of poor results. CONCLUSIONS: Present findings indicate that (1) in favorable stages, ABVD alone and alternating MOPP and ABVD are equivalent, and (2) chemotherapy followed by 20 Gy RT represents a valid therapeutic approach in the vast majority of children with Hodgkin's disease.     

Comparison of total nodal irradiation versus combined sequence of mantle irradiation with mechlorethamine, vincristine, procarbazine, and prednisone in clinical stages I and II Hodgkin's disease: experience of the European Organization for Research and Treatment of Cancer

The H5 study of supradiaphragmatic Hodgkin's disease in clinical stages I-II consisted of two controlled trials adapted to patients considered to have either favorable or unfavorable characteristics, based on prognostic factors identified in two former studies by the European Organization for Research and Treatment of Cancer. Of 494 patients, 257 who were classified as having unfavorable prognosis qualified for the more intensive treatment and consequently were spared a staging laparotomy. They were randomized either to total nodal irradiation (TNI) (132 patients) or to treatment with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternated with mantle irradiation (MOPP X 3-mantle irradiation-MOPP X 3; 3M) (125 patients). In complete responders (96%), the 6-year relapse-free survival was 77% in the TNI arm and 91% in the 3M arm (P = .02). Relapses in the initially involved and irradiated mantle area were less frequent in patients started on MOPP. The 6-year actuarial total survival (TS) (TNI, 82%, and 3M, 89%; P = .05) appeared to favor the 3M arm, but this difference disappeared when patients dying from causes unrelated to cancer were excluded from analysis. In men less than or equal to 40 years old, there was no difference in relapse-free survival, freedom from disease progression, or TS between the groups receiving TNI and 3M. Thus, TNI is a short and appealing treatment, especially because it preserves fertility. The same observation was true in women less than or equal to 40 years old. In addition, even irradiation less than TNI, which is meant to spare the ovaries, provided a TS similar to that for 3M.