Robert J. Hartsock

Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy: A southwest oncology group study

Between 1974 and 1977, 652 patients with non‐Hodgkins lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP‐bleomycin (180 patients), CHOP‐bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow‐up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular “histiocytic”) and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP‐BCG was 68% compared to 48% in 61 patients treated with CHOP‐bleomycin (P = 0.02) (two‐tailed test) or 44% for 45 patients treated with COP‐bleomycin (P = 0.02). CR duration for both CHOP‐based regimens was similar and superior to that produced by COP‐bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP‐BCG was better than that observed with CHOP‐bleomycin (P = 0.02) or COP‐Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other “biologic response modifiers” is warranted for patients with lymphoma.

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.

Comparison of adriamycin‐containing chemotherapy (MOP‐BAP) with MOPP‐bleomycin in the management of advanced Hodgkin‐s disease a southwest oncology group study

Between 1974 and 1978, 315 eligible patients with advanced Hodgkin‐s disease (HD) without prior chemotherapy were randomized to MOPP plus low‐dose bleomycin or the same agents plus Adriamycin (in 1 of 2 schedules). The results of the two Adriamycin‐containing schedules were similar and were, therefore, combined as „MOP‐BAP and compared to MOPP‐Bleo. All patients completed remission induction therapy with a median time on study of 47 months. Of 291 evaluable patients, the complete remission rate was 77% for 166 patients treated with MOP‐BAP compared to 67% for 125 patients receiving MOPP‐Bleo (P = 0.05, one‐sided test). Among patients with more favorable pretreatment prognostic factors, MOP‐BAP produced a higher CR rate than MOPP‐Bleo (patients with hemoglobin ≥ 12 g/dl, 85 versus 67%, P = 0.01; those with a performance status of 70‐100%, 81 versus 70%, P = 0.03; those without bone marrow involvement, 81 versus 68%, P = 0.03, those older than age of 40 years, 79 versus 62%, P = 0.03; those who were asymptomatic [A], 94 versus 77%, P = 0.04; and those without any prior therapy, 75 versus 63%, P = 0.04). CR duration and overall survival were similar for the two treatments. However, survival was better for patients with favorable pretreatment prognostic factors treated with MOP‐BAP compared to MOPP‐Bleo (those who were asymptomatic [P = 0.08], without bone marrow involvement [P = 0.04], and with nearly normal initial hemoglobin levels [P = 0.02]). MOP‐BAP was associated with less nausea and vomiting and significantly less thrombocytopenia than MOPP‐Bleo (P = 0.01). For patients with prognostically more favorable types of HD, the use of an initial Adriamycin‐containing MOPP regimen (MOP‐BAP) offers a higher complete remission rate, less acute toxicity and improved survival compared to MOPP‐Bleo.

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.

Alternated Versus Syncopated CHOP-PVB: Two Studies for the Treatment of Non-Hodgkin's Lymphoma by the Southwest Oncology Group

Based on a preliminary trial that suggested that CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and PVB (cisplatinum, vinblastine, bleomycin), are at least partially non-cross-resistant, the Southwest Oncology Group treated patients with unfavorable histology, non-Hodgkins lymphoma with CHOP and PVB. In the first study, 76 eligible patients were given three courses of CHOP, with complete or partial responders receiving three courses of PVB followed by three further courses of CHOP. Nonresponders after the initial three cycles of CHOP, received six courses of PVB. In the second study, 154 eligible patients were treated with alternating cycles of the two drug regimens. The overall objective antitumor response (CR + PR) was 77% for the first study and 58% for the second. The complete remission rates were 48% and 38%, respectively. The overall survival for both studies is similar. These results are interpreted in terms of the Goldie-Coldman hypothesis.

Comparative studies on the steroid metabolism in mammals: I. Characterization of 17β-hydroxysteroid dehydrogenase from monkey liver

Abstract 17β-Hydroxysteroid dehydrogenase preparation was obtained from soluble fraction of monkey liver by ammonium sulfate fractionation and heat-treatment. The activity of 17β-hydroxysteroid dehydrogenase was localized in the 50–80% ammonium sulfate fraction and was found to be stable at 37° for 25 hr. This enzyme preparation catalyzed the reduction of dehydroepiandrosterone (DHEA) to androst-5-ene-3β, 17β-diol (Adiol), estrone (E 1 ) to estradiol-17β (E 2 ), and androstenedione (A) to testosterone (T). The Michaelis constants ( K m ) for each substrate were: DHEA, 50 μ M ; E 1 , 20 μ M ; and A, 13 μ M . The activity of 17β-hydroxysteroid dehydrogenase was activated by either NADH or NADPH, NADPH, however, was found to be more effective than NADH. The K m values for NADPH were 170, 120, and 30 μ M , respectively, for the reduction of the 17-oxo group of DHEA, E 1 , and A. NADP inhibited the activity of 17β-hydroxysteroid dehydrogenase for all three substrates. Both DHEA and E 1 served as competitive substrates for the enzyme. The inhibitor constants were 26 μ M for DHEA and 50 μ M for E 1 . A acted as a competitive inhibitor of the enzyme for DHEA, but it acted as a noncompetitive inhibitor of the enzyme for E 1 .