Dennis O. Dixon

High-Dose Glucocorticoid Treatment of Resistant Myeloma

Intermittent, high-dose dexamethasone treatment was given to 49 consecutive patients with refractory multiple myeloma. In patients who were unresponsive to previous treatment, the response rate of 27% was similar to that achieved with the VAD regimen, which combines the same schedule of dexamethasone with vincristine and doxorubicin given by continuous infusion. Among patients with relapses, VAD chemotherapy induced remissions in 11 of 17 patients (65%), whereas dexamethasone alone induced remissions in 4 of 19 (21%). The median survival of all patients responding to either treatment, 22 months, was longer than that from any previous program for treatment of resistant myeloma. These findings indicate the value of frequent dexamethasone administration in patients unresponsive to standard therapy and show the major role of vincristine and doxorubicin given by continuous infusion in patients with relapses. They also suggest different mechanisms for primary and secondary resistance to chemotherapy.

Alternating Combination Chemotherapy and Levamisole Improves Survival in Multiple Myeloma A Southwest Oncology Group Study

Previously untreated patients with multiple myeloma were entered on a randomized clinical trial to determine whether the use of alternating combination chemotherapy, including vincristine, doxorubicin, alkylating agents, and prednisone (160 patients) was more effective than conventional chemotherapy with melphalan and prednisone (77 patients), and whether the addition of the immunomodulating agent levamisole to maintenance chemotherapy enhanced the survival of patients achieving remission. The treatment groups were well matched for all major factors. The more aggressive chemotherapy was more effective at inducing remission, with a significantly higher proportion of patients achieving at least 75% tumor mass regression (53% with alternating combinations versus 32% with melphalan-prednisone, p = 0.002). Furthermore, the median survival was increased to 43 months with alternating combination chemotherapy as compared to 23 months with melphalan-prednisone (p = 0.004). After six to 12 months of induction therapy, 84 patients achieving remission were rerandomized to receive maintenance chemotherapy alone or with the addition of levamisole. The survival from the start of maintenance therapy was longer in patients receiving the added levamisole than with chemotherapy alone (p = 0.01). These findings support the use of aggressive multiagent chemotherapy for remission induction in patients with advanced-stage multiple myeloma.

Stage III follicular lymphoma: Durable remissions with a combined chemotherapy-radiotherapy regimen

From 1975 to 1982, 74 patients with stage III follicular lymphoma were treated with a combined modality protocol which included chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo), and radiotherapy to involved regions. This program resulted in a complete remission (CR) rate of 81%, a 5-year survival of 75%, and 5-year relapse-free survival (RFS) of 52% for all patients. Analysis of potential factors affecting treatment outcome revealed a significantly better CR rate for patients with small cleaved cell type (97%) than for patients with mixed (73%) or large-cell (57%) histologies. The 5-year survival was significantly better for patients with small cleaved (91%) and mixed (84%) cell types than for large cell (40%). In addition, bulky abdominal disease and elevated serum lactate dehydrogenase (LDH) were significant adverse prognostic factors for CR and for survival. Toxicity was moderate. No secondary leukemias have occurred. This combined modality regimen resulted in prolonged remission and potential cure for over half of patients who achieved CR, and is particularly encouraging for those with follicular small cleaved and mixed histologies.

Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study.

Four hundred forty previously untreated patients with active multiple myeloma were entered into a randomized trial (Southwest Oncology Group [SWOG] study 7927/28) comparing vincristine, melphalan, Cytoxan (Mead Johnson & Company, Evansville, Ind), and prednisone (VMCP) alternating with vincristine, BCNU, Adriamycin (Adria Laboratories, Columbus, Ohio) and prednisone (VBAP) with or without levamisole with vincristine, Cytoxan, and prednisone (VCP) with or without levamisole for induction therapy. The treatment groups were well balanced for all of the known major prognostic factors. Patients receiving VMCP-VBAP responded (greater than or equal to 75% regression) more frequently to induction therapy, both without (54%) and with (44%) levamisole v VCP without (28%) or with (28%) levamisole (P less than .001). In addition, patients receiving VMCP-VBAP (+/- levamisole) had a survival duration determined to be significantly increased by all forms of analysis: 48 and 33 months for VMCP-VBAP without and with levamisole v 29 and 26 months for VCP without and with levamisole (P = .011 overall). Levamisole did not improve response rates or survival duration (P greater than or equal to .1), nor did it prolong remission in the maintenance phase (P = .85). Analysis of SWOG study 7704/05 (updated April 1985) confirmed improved survival for combination therapy v MP, but no benefit for levamisole. The overall findings support the use of VMCP-VBAP as an excellent treatment option for remission induction in patients with active myeloma of all stages and prognostic categories.

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.

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.

Effect of latency on calculated complication rates

Late complications of radiation therapy and other cancer therapies may not always be expressed because of the shortened survival of cancer patients. Methods for estimating the true complication rate must account for censoring of the data. Actuarial methods give the time-dependent probability of remaining free of the injury. However, these methods fail when the last surviving patient develops a complication. This study describes a different method for calculating the corrected complication rate. One advantage is that the method does not produce estimates of 100% for the complication rate that occur using the actuarial method when the last survivor suffers a complication. To use the method presented here, the distribution of latent periods of the injury and the survival function for the patients at risk must be identified.

Follicular large cell lymphoma: analysis and prognostic factors in 62 patients.

Sixty-two patients with follicular large cell lymphoma were treated between 1973 and 1981. The overall median survival was 78 months with a five-year survival of 62%. The complete remission rate was 76%, with a median relapse-free interval of 72 months for responders. Complete remission produced a significantly longer survival than partial response and failure. Patients who tolerated therapy with an intensive doxorubicin-containing regimen had a significantly longer relapse-free interval and survival. Patients with stage I-II disease treated with radiation therapy alone had a higher relapse rate than those treated with radiation and combination chemotherapy. The addition of radiation therapy to combination chemotherapy in stage III-IV disease decreased the incidence of relapse at irradiated sites, but did not translate into improved survival. Pretreatment prognostic factors associated with poor response were thrombocytosis and stage III-IV disease; those associated with shortened survival were thrombocytosis, elevated lactic dehydrogenase level, stage III-IV disease, and bulky abdominal disease. Follicular large cell lymphoma is an aggressive lymphoma. Treatment should be curative in intent, and should include intensive combination chemotherapy even in stage I-II disease. Knowledge of important prognostic factors can be useful for analysis of future trials and planning therapeutic strategies.

Chemoimmunotherapy for multiple myeloma.

The effect of chemoimmunotherapy consolidation treatment using alternating courses of alkylating agents and BCG was studied in 105 responding patients with multiple myeloma. The survival time of these patients was similar to that of responding patients treated on previous maintenance programs, indicating no apparent value from BCG for myeloma. The duration of unmaintained remission was longest in those with low numbers of residual plasma cells, and relapse usually developed within one year in patients with persistent serum myeloma peaks. Disease recontrol was achieved in 50% of relapsing patients whose median survival from retreatment was 20 months. Patient follow‐up without chemotherapy until relapse was justified mainly for those responding patients with disappearance of myeloma proteins.

Erythrocyte polyamine levels during intravenous feeding of patients with colorectal carcinoma

Changes in erythrocyte (RBC) polyamines were studied during total parenteral nutrition (TPN) in 16 colorectal carcinoma patients and six patients with noncancerous diseases. RBC putrescine (PTC), spermidine (SPD), and spermine (SPM) were analyzed before and at the completion of preoperative TPN in each patient. Before TPN, nutritional status, based on a history of weight loss and plasma albumin, prealbumin and retinol-binding protein levels, were similar for the two groups. Initial RBC PTC, SPD, and SPM levels were also similar for both groups. Preoperative TPN induced significant increases in RBC PTC levels (P less than 0.001) and RBC PTC:SPD ratios (P less than 0.005) of the cancer patients while no significant polyamine changes were observed in the other group. Host response to nutritional therapy was monitored with plasma prealbumin and retinol-binding protein levels which did not change significantly in either group.