William Costello

BCVPP Chemotherapy for Advanced Hodgkin's Disease: Evidence for Greater Duration of Complete Remission, Greater Survival, and Less Toxicity Than with a MOPP Regimen: Results of the Eastern Cooperative Oncology Group Study

Two chemotherapy regimens for treatment of patients with advanced Hodgkins disease, BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone) and MOPP (mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone), were compared in a randomized prospective study. Two hundred ninety-three patients were evaluable in the induction phase of this study. The complete remission rate with BCVPP was 76% (112/147) and with MOPP, 73% (106/146) (p = 0.51). The duration of complete remissions for previously untreated patients given BCVPP was significantly longer than that for previously untreated patients given MOPP (p = 0.02). Although hematologic toxicities were similar, BCVPP caused less gastrointestinal (p = 0.0001) and neurologic toxicity (p = 0.01) than MOPP. Previously untreated patients achieving complete remission with BCVPP survived significantly longer than those receiving MOPP (p = 0.03). As primary induction chemotherapy for advanced Hodgkins disease, BCVPP is an effective alternative to MOPP, having equal or greater therapeutic benefit with less toxicity.

Nodular histiocytic lymphoma: Factors influencing prognosis and implications for aggressive chemotherapy

Twenty‐five patients with Stage III and IV nodular histiocytic lymphoma (NH), entered on three different Eastern Cooperative Oncology Group protocols from 1972–78, were analyzed for response and survival. A complete response (CR) rate of 44% was observed, with 40% partial responders (PR). Four of the 11 CRs are continuing in their original remission. Median survival for CRs was 52 months; for PRs it was 30 months. The six patients treated with cyclophosphamide‐prednisone had a median survival of 18 months versus 51 months for the 19 patients treated with more aggressive combination chemotherapy programs. No significant difference in survival was noted between those patients with both nodular and diffuse histology and those with a pure nodular pattern. The median survival of the 25 NH patients was 47 months and is similar to a group of 101 patients with nodular mixed lymphoma (NM) entered on the same ECOG protocols during this time. This survival is intermediate between the nodular lymphocytic poorly differentiated subtype and diffuse histiocytic lymphoma. It suggests that patients with NH histologies be treated with aggressive combination chemotherapy programs designed to achieve complete remission and prolonged disease‐free survival.

Eastern Cooperative Oncology Group experience with the rappaport classification of non-Hodgkin's lymphomas.

Eastern Cooperative Oncology Group experience in the cinical application of the Rappaport Classification of Non‐Hodgkins lymphomas (NHL) is reviewed in 670 cases studied since 1972. The diagnoses of institutional pathologists were reviewed by the Pathology Panel and Repository Center for Lymphoma Clinical Studies. Diagnostic agreement in regard to histologic pattern (nodular versus diffuse) was excellent (90%) but was less favorable when concurrence as to both pattern and cell type was assessed (82% in NLPD and 60% or less in other subtypes). Disagreement in regard to NHL diagnosis is related to the complexity of present nomenclature and to the lack of support of pathology activities within cooperative groups. It is suggested that patients entered into group NHL studies be randomized into favorable and unfavorable groups, primarily on the basis of histological pattern. Cancer 43:544–550, 1979.

Survival of nodular versus diffuse pattern lymphocytic poorly differentiated lymphoma

Response and survival were analyzed in 97 patients with NLPD (Nodular Lymphocytic Poorly Differentiated Lyphoma) and 77 with DLPD (Diffuse Lymphocytic Poorly Differentiated) treated by intensive versus moderate chemotherapy regimens. The complete and overall response rate in NLPD of 47% and 81% was significantly superior to 25% and 59% obtained in DLPD. The estimated two year survival of 83% in NLPD was also significantly superior to 47% two year survivorship of DLPD (p < .001). The chemotherapy responsiveness had a significantly favorable effect on DLPD survivorship with two year survivals of 84% for CR, 58% for PR and 17% for PD. In NLPD the effect of chemotherapy responsiveness on survival was less striking (CR 91%, PR 85%, and PD 72% surviving two years). The data, in our opinion, confirm the rationale for the use of aggressive multiple agent chemotherapy regimens in DLPD where achievement of complete response appears to be the single most important factor in improving survivorship. On the other hand NLPD, with excellent survival rates which appear to be only partially dependent on chemotherapy responsiveness might serve as an ideal model for moderate intensity or single agent chemotherapy trials.

Effect of the degree of nodularity on the survival of patients with nodular lymphomas.

The survival of patients with favorable lymphoma entered on various Eastern Cooperative Oncology Group (ECOG) studies was analyzed according to the degree of nodularity. A pure nodular pattern (NN), defined as nodularity involving 75% or more of the cross-sectional area, was found to be an important favorable prognostic indicator as compared with a nodular-diffuse pattern (ND). The median survival in 336 patients with NN of 68.2 months was significantly better than the 39.6 months in 87 patients with ND (P less than .003). The median survival in NN-lymphocytic poorly differentiated (LPD) was 77.2 months v 44.3 months for ND-LPD. NN-M median survival of 56.4 months contrasted with only 25.5 months for ND-mixed lymphocytic and histiocytic (M). The degree of nodularity as defined in this study appears to have significant prognostic implication and should be more widely used by pathologists.

Moderate versus intensive chemotherapy of prognostically favorable non-Hodgkin's lymphoma a progress report

Two hundred and fifty‐two patients with advanced stages of favorable non‐Hodgkins lymphoma (NHL) subtypes (nodular histiocytic (NH), and diffuse well‐differentiated lymphocytic (DLWD)) were analyzed for response and survival to moderate (cyclophosphamide‐prednisone (CP)) vs. intensive (BCVP or COPP) chemotherapy regimens. The overall complete response (CR) rate was 57%. The median duration of remission for the entire group was 88 weeks and 65% of complete responders were in remission at one year. Survival rates at one year were 87% for BCVP, 86% for COPP, and 91% for CP. The response rate, response duration, and survival rate differences between the groups were not significant. Severe and life threatening hematologic toxicity rates were significantly higher with BCVP and COPP as compared to CP (P < 0.001). The highest CR rate was obtained in NM (74%) and CP gave the highest CR rate in DLWD (60%). Survival rates at one year for NM (97%) and NLPD (90%) were comparable whereas the one‐year survival rate for DLWD was significantly lower (75%) than that for NLPD (P < 0.005) or NM (P < 0.001). We conclude that in favorable NHL subtypes, cyclophosphamide‐prednisone combination is an effective regimen with minimal toxicity. Cancer 46:29–33, 1980.

Treatment of histiocytic and mixed lymphomas: a comparison of two, three and four drug chemotherapy.

The Eastern Cooperative Oncology Group has studied 187 patients with generalized progressive malignant lymphoma classified as having the histologic sub‐types histiocytic or mixed. Histology review by the Pathology Panel for Lymphoma Clinical Trials demonstrated a 31% disparity with contributing institutions pathologists in regard to cell type, but good agreement with interpretation of nodular or diffuse nodal pattern. Patients were assigned at random to treatment with cyclophosphamide 1 g/m2 on day 1 and prednisone 100 mg/m2 daily for five days (CP); CP plus vincristine 1 mg/m2 on day 1 (CVP); or CVP plus BCNU 60 mg/m2 on day 1 (BCVP). Chemotherapy was given for nine, twenty‐one day cycles. The observed complete remission rates were CP‐21%, CVP 34%, BCVP 34%. Both CVP and BCVP had significantly more complete remissions than CP, but survival following CVP (118 weeks) was significantly longer than that following either BCVP (76 weeks) or CP (74 weeks). Histologic sub‐type, lymph node pattern, response to chemotherapy, performance status and stage of disease were also found to influence survival.

Nodular mixed lymphocytic-histiocytic lymphoma (NM) response and survival

Eighty patients with nodular mixed lymphocytic‐histiocytic lymphoma (NM) entered on four different Eastern Cooperative Oncology Group chemotherapy studies were analyzed for response and survival. They were compared with 249 patients with nodular lymphocytic poorly differentiated lymphoma (NLPD), who were treated similarly. The response rates in NM were: CR 45%, PR 30%, NC‐PD 25%. In NLPD the quality of response had little effect on survival (CR 91%, PR 90%, NC‐PD 76%), whereas in NM the two year survivorship of 85% for CR dropped drastically to 33% for the partial responders (P <.01). Ninety percent of the previously untreated NLPD, but only 59% of the comparable group of NM, survived 2 years. In 23 patients with NM in which the pattern was reported as both nodular and diffuse (ND‐M), the 2‐year survival of 35% was markedly inferior to a 66% 2‐year survivorship observed in 57 patients with the pure nodular pattern (P < 0.05). It appears that NM is a less favorable lymphoma type than NLPD. In NM achievement of a CR affects survival favorably; consequently, the use of aggressive chemotherapy regimens in an attempt to achieve high rates of CR are recommended. In NLPD, on the other hand, since survival curves of partial and complete responders are almost identical, suboptimal treatments may be justified.

Sequential cyclophosphamide‐prednisone and vincristine‐bleomycin (CPOB). An effective, schedule‐dependent treatment for advanced diffuse histiocytic lymphoma

In an Eastern Cooperative Oncology Group non‐Hodgkins lymphoma clinical trial, 90 patients with Stage III or IV diffuse histiocytic lymphoma (DHL) were treated with one of four chemotherapy regimens. All patients were previously untreated with chemotherapy, and careful restaging was required to document responses. Each treatment included cyclophosphamide, vincristine and prednisone (COP) plus Adriamycin (COPA), BCNU (BCVP) or bleomycin (COPB and CPOB). The two bleomycincontaining regimens differed only in the schedule of drug administration. CPOB‐treated patients received cyclophosphamide on day 1, prednisone on days 1 to 5 and vincristine and bleomycin on day 15 of each 21‐day cycle. COPB‐treated patients received the same four drugs in the same dosage; however, the schedule was changed so that vincristine and bleomycin were given on day 1. Treatment of responders was continued for 8 cycles. Those with a complete response (CR) were randomized to maintenance therapy with BCVP or no treatment. Treatment with CPOB yielded a CR rate of 55% compared to 25% for COPB (P = 0.07). In contrast to COPB, treatment with CPOB was associated with a significantly longer median duration of CR (26.5 versus 5.7 months; P < 0.05) and median survival (27.7 versus 11.2 months; P < 0.02). The CR rate was 31% for BCVP and 45% for COPA, and the median survivals were 10.7 months and 14.4 months, respectively. One half of the CPOB‐treated patients who achieved CR remained alive in continuous CR after 30 to 72 months. No advantage for maintenance therapy was observed. Myelotoxicity was greater with CPOB than COPB, but comparable to COPA. This trial demonstrated that the results of treatment of DHL with COP plus bleomycin were strikingly dependent upon the schedule of administration of bleomycin and vincristine. Bleomycin effectively combined with COP, as in CPOB, yielded results comparable to those obtained when Adriamycin was added to COP. CPOB appears to be an effective treatment for DHL that should be considered as an alternative to other regimens, particularly for patients who cannot receive Adriamycin.

Cyclophosphamide, cytosine arabinoside and methotrexate versus cytosine arabinoside and thioguanine for acute non-lymphocytic leukemia in adults.

One‐hundred and fifty‐one adults with acute non‐lymphocytic leukemia (ANLL) were entered into an Eastern Cooperative Oncology Group protocol (EST‐1473) comparing twice daily cytosine arabinoside and thioguanine (AT) with weekly cyclophosphamide, cytosine arabinoside, and methotrexate (CAM) for remission induction. Of 111 evaluable patients, 16 treated with CAM and 16 treated with AT entered complete remission (CR) on their initial therapy and 5 additional patients entered CR on crossover for a total of 37 or 33% of the evaluable patients. Of the 71 patients who survived three weeks or longer, the overall CR rate was 52%. Cytochemical studies were performed on 85% of the evaluable cases. Minor disagreements between morphologic subtypes of ANLL occurred in 50% of cases. There was no difference in response rates between the major subtypes of ANLL regardless of whether the investigators diagnosis or the cytochemical reference laboratory diagnosis was used. The median survival of all evaluable patients was 4.9 weeks; those patients who responded with a CR had a median survival of 60 weeks, while those who did not have a median survival of <3 weeks. Age <60, ambulatory performance status, or fewer than 50% marrow blasts were also associated with a better response rate and longer survival. CAM had more severe mucositis and vomiting associated with it than did AT, but toxicities were otherwise comparable. Weekly CAM and AT appear to be equally effective regimens in the treatment of ANLL.