Don V. Jackson

Phase III Study of Fluorouracil, Leucovorin, and Levamisole in High-Risk Stage II and III Colon Cancer: Final Report of Intergroup 0089

PURPOSE In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients. PATIENTS AND METHODS From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year. RESULTS After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival. CONCLUSION The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.

Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial.

Adriamycin is of noteworthy efficacy in the treatment of metastatic breast cancer. Its role in combination regimens is under investigation. One hundred seventy‐five women with advanced breast cancer were entered into a prospectively randomized trial comparing two five‐drug regimens. Regimen CMFVP consisted of cyclophosphamide (C), methotrexate (M), 5‐fluorouracil (F), vincristine (V), and prednisone (P). Regimen CAFVP was identical but substituted Adriamycin (A) for methotrexate. Twenty‐seven patients were disqualified; 148 were evaluable. With CMFVP the complete response rate (CR) was 11%, and the partial response rate (PR) was 46%; with CAFVP, CR was 13% and PR was 45%. Duration of response tended to be slightly longer for patients on the Adriamycin arm. The median survival for CR and PR patients with CMFVP was 20.2 months, which was shorter (p =.07) than the 33 month median survival with CAFVP. Although statistical significance was not reached at the 5% level, the increased survival of responders on the Adriamycin regimen supports the data of other studies which suggest that first line combination chemotherapy in advanced breast cancer should include Adriamycin. Cancer 42:2141–2148, 1978.

A randomized comparative trial of chemotherapy and irradiation therapy for stage ii breast cancer

One hundred fifty‐eight evaluable patients with Stage II carcinoma of the breast with positive lymph nodes were treated either with adjuvant chemotherapy or irradiation therapy followed by chemotherapy. Patients were randomized to test the effectiveness of L‐phenylalanine mustard (L‐PAM) with and without postoperative irradiation therapy (R.T.) against cyclophosphamide, 5‐fluorouracil, and methotrexate (CMF) with and without postoperative irradiation therapy in decreasing the frequency of recurrence. No significant difference was observed between L‐PAM as compared with R.T. plus L‐PAM (P = 0.85). The difference between CMF and R.T. plus CMF was significant in support of CMF alone (P = 0.04). The frequency of recurrence between R.T. plus L‐PAM and R.T. plus CMF showed no difference. A comparison of the chemotherapy only regimens showed an advantage of CMF over L‐PAM (P = 0.05). Both the delay in starting chemotherapy and the significant decrease in percent optimal drug dosage during the first six cycles of therapy are factors that may influence the high frequency of relapse observed in the R.T. plus chemotherapy groups. Of the four treatments, CMF has the lowest frequency of recurrence.

Biliary excretion of vincristine

A patient with pancreatic carcinoma and a choledochal T tube was given tritiated vincristine sulfate ([3H]‐VCR) intravenously. Peak biliary excretion occurred in 2 to 4 hr and this sample contained 9.7% of the injected radioactivity. The first 24‐hr bile sample contained 21.7% of the dose and 76.4% of the cumulative 72‐hr biliary excretion. During a 3‐day period of observation, 4.2%, 45.6%, and 49.6% of the excreted radiolabel was present in the feces, urine, and bile, respectively. Products of VCR metabolism and decomposition appeared in the bile rapidly; only 46.5% of the drug was present in the parent form in the 2‐hr collection. Since significant amounts of these products were also identified in control specimens of bile, blood, plasma, and buffer alone after brief periods of incubation, the origin and nature of the species appearing in the bile remain unclear. Observing the fecal route to be the major source of elimination of radio label following intravenous injection of [3H]‐VCR in our patients previously, we now conclude the biliary system to be the principal route of excretion of VCR and its products. Hepatic dysfunction might therefore alter elimination kinetics and increase the exposure to VCR and its products which might augment toxicity and require dose modification.

Spinal cord compression due to extramedullary hematopoiesis in thalassemia: long-term follow-up after radiotherapy.

Spinal cord compression as a consequence of mass lesions due to extramedullary hematopoiesis is a well-described but rare syndrome occurring in thalassemia and some other hematologic conditions. After low-dose radiotherapy alone, a rapid and durable response occurred in a patient with thalassemia. No side effects were encountered and the patient has been stable neurologically for over 7 years since treatment. The results of the current case, and those previously reported in which radiotherapy alone was given, suggest that low-dose radiotherapy should be considered as a primary treatment modality for the management of this syndrome, at least in patients with thalassemia.

Treatment of advanced non-Hodgkin's lymphoma with vincristine infusion

Twenty‐five patients with a variety of histologic types of advanced non‐Hodgkins lymphoma refractory to previous chemotherapy were entered into a trial of vincristine infusion. Patients received 5‐day courses of vincristine 0.25 mg/m2/day by continuous intravenous infusion after an initial 0.5 mg intravenous bolus injection. Courses were repeated every 3 weeks. Objective responses were observed in nine patients (36%), all of whom had previously received vincristine given by conventional bolus injection. A complete response occurred in a patient with diffuse mixed histiocytic lymphocytic lymphoma, and partial responses were observed in eight patients with the following histologic types: diffuse poorly differentiated lymphocytic (4); nodular poorly differentiated lymphocytic (2); diffuse mixed histiocytic lymphocytic (1); and diffuse histiocytic (1). Duration of response lasted from 1.2 to 16.2 months (mean, 4.4 months). The principal complication of therapy was mild‐to‐moderate neurotoxicity; this occurred in 12 patients (48%) who received a total of 54 courses of vincristine infusion. Hematologic toxicity was minimal and nausea/vomiting did not occur. Vincristine infusion may afford palliation for patients with advanced non‐Hodgkins lymphomas who have become refractory to standard chemotherapeutic regimens even if they have received prior vincristine by conventional bolus injection. These data suggest the possibility of enhancing the therapeutic efficacy of vincristine in the treatment of non‐Hodgkins lymphoma by use of an infusion technique.

A randomized trial of chemotherapy (L-PAM vs CMF) and irradiation for node positive breast cancer Eleven year follow-up of a Piedmont Oncology Association trial

Summary158 evaluable patients with stage II, lymph node positive, carcinoma of the breast were randomized to adjuvant therapy with either melphalan (L-PAM) or cyclophosphamide, methotrexate, and fluorouracil (CMF) after mastectomy. In addition, patients were randomized to be treated with or without post-operative irradiation therapy (RT) in addition to their chemotherapy. At a median follow-up time of 11 years, there is no difference in time to relapse (P=0.69) or survival (P=0.55) among the four treatment groups. Multivariate analysis including treatment arm, age, race, tumor size, histologic type, performance status, time to onset of treatment, menopausal status, and number of positive nodes, revealed that only the number of positive nodes (<4 vs ≥ 4) was related to disease-free and overall survival. Ten year relapse-free survival for patients with <4 positive nodes compared to those with ≥4 positive nodes was 63% versus 30%, and overall survival 63% versus 41%, respectively. Patients who received post-operative radiation therapy had significantly less local recurrence than those treated with chemotherapy alone (P=0.03) but without improvement in relapse-free or overall survival. In this trial, post-operative radiation therapy when added to chemotherapy decreased the risk of local recurrence without adverse effects on survival. Treatment outcome was not influenced by chemotherapy regimen, but differences may have been obscured by the small sample size.

VP-16-213 in combination chemotherapy with chest irradiation for small-cell lung cancer: a randomized trial of the Piedmont Oncology Association.

The role of etoposide epipodophyllotoxin (VP-16-213) in a combined modality treatment program incorporating local chest irradiation and combination chemotherapy with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and vincristine has been evaluated in a randomized trial of 165 patients with small-cell lung cancer. The overall response rate (complete response [CR] plus partial response [PR]) was significantly greater in the VP-16-213 arm (85% v 64%, P = .005) primarily as a consequence of improved response in patients with extensive disease (85% v 38%, P = .002 and 30% v 8% for CR only, P = .045). No differences in the response rates were observed in limited disease. The duration of response (months) was greater in the VP-16-213 arm (8.6 v 7.0 overall and 14.4 v 11.5 for CR) but not significantly so. Median survival times (months) were consistently greater in the group receiving VP-16-213 when analyzed according to extent of disease and response (10.6 v 9.5 overall; 15.0 v 13.6 for limited disease; 9.0 v 6.7 for extensive disease; 18.5 v 16.2 for CR overall; and 18.6 v 16.1 for CR in limited disease); the results were not statistically significant. The median survival of extensive disease patients attaining a CR was 15.3 months (range 3.2 to 34.3 + months) in the VP-16-213 arm and 7.4+ and 8.1+ months for the two patients with CR in the other group. Anemia and leukopenia occurred to a greater degree in the four-drug regimen, but no unusual or significant compounding toxicity (ie, neurotoxicity) was observed otherwise. Further investigation of this agent in combination chemotherapy programs for small-cell lung cancer appears to be warranted.

Cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil in advanced prostatic cancer: A randomized trial

Thirty‐two evaluable patients with metastatic carcinoma of the prostate were entered into a prospective randomized trial comparing cyclophosphamide (CYC) with a combination of cyclophosphamide, methotrexate, and fluorouracil (CMF). Progressive disease after endocrine manipulation was noted in 97% (31/32) of patients before entry. Stable disease (S) was observed in 9 of 17 patients treated with CYC. One partial response (PR) and seven stable responses occurred in the 15 CMF patients. Median duration of stable response was 4.5 months for CYC and 4.5 months on CMF. Median survival of patients with PR and S receiving CYC was 10.1 and for CMF 8.8 months. Patients with progressive disease survived a median 1.7 and 2.6 months with CYC and CMF, respectively. Toxicity was moderate, and no deaths were attributable to sepsis or bleeding. Almost all patients in this study had bone lesions as the dominant site of disease; this made objective assessment of response difficult. There was no significant improvement in response conferred by the combination regimen. Although patients with metastatic prostatic cancer may benefit from chemotherapy, impressive clinical responses are uncommon.

A randomized trial of adjuvant chemotherapy and immunotherapy in stage I and stage II cutaneous melanoma. An interim report

Seventy patients with Stage I and II malignant melanoma were randomized to treatment with either intravenous dacarbazine alone or intravenous dacarbazine plus intradermal injection of the methanol‐extracted residue of bacillus Calmette‐Guerin (BCG). Analysis of treatment failed to reveal a statistically significant difference between these two forms of treatment in Stage I and II patients. It is possible that chemoimmunotherapy may increase survival in Stage II patients, but this possibility should be interpreted with caution.