Cary A. Presant

A randomized prospective clinical trial of adjuvant C. parvum immunotherapy in 260 patients with clinically localized melanoma (Stage I): Prognostic factors analysis and preliminary results of immunotherayp

A total of 260 patients with clinically localized melanoma (Stage I) from 18 medical institutions in the Southeastern Cancer Study Group were randomized to receive either surgical treatment alone, or surgery plus Corynebacterium parvum immunotherapy. A multivariant analysis (Cox regression model) of nine prognostic factors was performed on 110 patients with a minimum of two years follow‐up. The dominant prognostic variables were thickness (P = 0.0007) and anatomic location of the melanoma (trunk versus other, P = 0.015). Disease‐free survival curves were then calculated for 204 surgically evaluable patients. Overall, there was no significant difference in three‐year survival for the two‐treatment arms, which was 81% for the adjuvant immunotherapy group compared to 67% for the surgical control group (P = 0.10). The median follow‐up period was 24 months (range, 1‐60 months). However, when the data was subgrouped by tumor thickness, an apparent benefit of immunotherapy was observed in 49 patients with melanomas greater than 3 mm in thickness. Only five of 23 such patients relapsed after receiving C. parvum. Their three‐year disease‐free survival was 73%. In contrast, 13 of 26 patients who did not receive immunotherapy have relapsed so far and their three‐year disease‐free survival was only 33% (P = 0.01). In the 175 patients with melanomas less than 3 mm in thickness, both treatment arms had identical three‐year disease‐free survival rates of 83%. No significant differences between the treatment arms were observed using other prognostic variables, including the level of invasion. Toxicity to C. parvum injections was minimal in most patients. It is concluded that a prognostic factors analysis is critically important in adjunctive trials of melanoma to determine which dominant variables should be used for analyzing patient subgroups; that C. parvum immunotherapy appears to be associated with an improved disease‐free survival rate in the subgroup of patients with melanomas >3 mm thickness (this early encouraging data must still be confirmed with continued patients accrual and a longer observation period); and that patients with melanomas less than 3 mm thick have a relatively favorable prognosis after appropriate surgical treatment, and immunotherapy does not improve their survival rates.

Prospective randomized reappraisal of 5-fluorouracil in metastatic colorectal carcinoma. A comparative trial with 6-thioguanine.

In order to redefine the effectiveness of 5‐fluorouracil (5‐FU) as palliative therapy in patients with metastatic colorectal carcinoma, and to compare the effectiveness of 6‐thioguanine (6‐TG) with that of 5‐FU, we studied 176 patients with metastatic colorectal carcinoma in a randomized prospective trial (SEG 79GI268). The pretreatment performance status of all patients was greater than 50% (ambulatory), and there was an equal distribution of patients with favorable pretreatment characteristics into each of the treatment regimens. Complete responses were only seen to 5‐FU, but were obtained in only 3% of instances. The overall complete plus partial response rates were not different for 5‐FU (8%) versus 6‐TG (3%), or for patients who had shown prior progression on chemotherapy and who then received 6‐TG in a nonrandomized fashion (7%). The time to tumor progression on each of the treatment programs was similar, 1.0 months. Survival was also similar in each regimen in the randomized study (6.3 months for 5‐FU versus 7.9 months for 6‐TG). However, survival was only 4.8 months for patients with previously drug‐resistant tumors treated with 6‐TG in the nonrandomized arm. in 16 patients failing 6‐TG who then received 5‐FU, there were no objective responses. Similarly, in patients failing 5‐FU on this study who then received 6‐TG, there were no responses in nine patients. Dose‐limiting toxicity was observed in 40% to 51% of patients, and consisted of myelosuppression, vomiting, or diarrhea. It is concluded that 5‐FU is a minimally effective agent in a very small number of patients with metastatic colorectal carcinoma. The drug 6‐TG is equally ineffective in this setting. Alternative treatment programs to the systemic use of 5‐FU should be considered in patients requiring palliative chemotherapy.

Metastatic sarcomas: Chemotherapy with adriamycin, cyclophosphamide, and methotrexate alternating with actinomycin D, DTIC, and vincristine

Two‐hundred‐thirty‐two evaluable patients with metastatic sarcomas received a palliative experimental treatment program consisting of Adriamycin, 60 mg/m2, Cyclophosphamide, 600 mg/m2, and methotrexate, 25 mg/m2 intravenously every three weeks for two courses. This program was followed by a randomization to maintenance therapy consisting of either the same regimen (ACM), an alternative regimen ADV (actinomycin‐D, 1 mg/m2, DTIC, 250 mg/m2, and vincristine, 1.4 mg/m2 intravenously weekly), or alternating ACM and ADV. Twenty percent of patients had complete (6%) or partial (14%) responses, and an additional 41% of patients were stable throughout the remission and maintenance regimens. Response rates were similar regardless of the degree of toxicity observed during induction therapy. Although improved quality of responses after maintenance therapy was more frequent on ACM‐ADV (19%) than on ADV (3%) or ACM (10%) maintenance therapy, the durations of response were similar for the three regimens (25 weeks, 19.7 weeks, and 19.6 weeks, respectively). Complete responses lasted a median of 44.5 weeks versus 19 weeks for partial responses. Although the length of survival depended upon the quality of response ultimately achieved (16 months for complete responders, 13.6 for partial responders, 11.6 months for patients with stable disease versus 4.0 months with progressive disease), median survival was similar for patients on each of the three randomized maintenance regimens (12 months for ACM, 13 months for ADV, and ten months for ACM‐ADV). Toxicity was significantly worse on either of the regimens containing ADV, particularly peripheral neuropathy and gastrointestinal toxicity. Therefore, the ACM regimen for remission induction and remission maintenance is the most desirable of the treatment programs tested.

Effects of amphotericin B on combination chemotherapy of metastatic sarcomas

Ninety‐four evaluable patients with metastatic soft tissue and bone sarcomas entered into a prospective randomized trial (SEG 78SAR327) to determine whether amphotericin B (AMB), a membrane‐permeabilizing and immunopotentiating agent, could increase either the response rates or the survival of patients treated with a three‐drug combination chemotherapy regimen consisting of Adriamycin, cyclophosphamide, and methotrexate (ACM). Pretreatment patient characteristics were similar in each arm. In patients treated with ACM there were 4% complete responses and 34% partial responses, compared with only 5% partial responses on ACM + AMB (P < 0.05). However, there was no difference in the median time to progression (5.0 months on either arm) or in survival (7.0 months on ACM, and 6.0 months on ACM + AMB). Myelosuppression was the dose‐limiting toxicity, and was equal in each treatment arm. The addition of AMB to dactinomycin during maintenance therapy did not result in any complete or partial responses. It is concluded that despite definite biologic activity in experimental tumor models, AMB is not useful clinically in potentiating chemotherapeutic drug activity in patients with metastatic sarcomas, and actually results in a decrease in the frequency of objective responses.

Reversal of cancer chemotherapeutic resistance by amphotericin B—A broad phase I–II pilot study

In order to determine if it was possible to reverse clinically evident chemotherapeutic drug-resistance, 51 evaluable patients received chemotherapy (in doses and schedules on which they had previously demonstrated tumor progression) together with amphotericin B (AMB). AMB was given in 1-, 2-, or 4-day courses. There was 1 complete response (2%), and 5 partial responses (10%). Response rates tended to be higher in the 4-day treatment program (23%) than in the 1- or 2-day AMB treatment schedules (8%). Toxicity was that expected with chemotherapy (myelosuppression), or AMB alone (fever, chills, and reversible mild azotemia). We conclude that AMB is only infrequently able to reverse clinical drug-resistance, but that this might have palliative effects in a small number of patients in whom other standard chemotherapeutic drugs lack clinical effectiveness.

A randomized comparison of cyclophosphamide, DTIC with or without piperazinedione in metastatic malignant melanoma

One hundred and ninety‐five patients with metastic malignant melanoma were randomized to receive either cyclophosphamide 600 mg/m2 IV plus DTIC 600 mg/m2 IV day 1 (CD); or cyclophosphamide 400 mg/m2 IV, DTIC 400 mg/m2 IV, and piperazinedione 4 mg/m2 IV on day 1 (PCD). Therapy was repeated every 21 days. Patient groups were similar regarding pretreatment performance status, evaluability, and site of metastases. The overall response rate was low, 11% on CD and 12% on PCD. Paradoxically, patients with visceral disease responded at least as frequently as patients with skin and lymph node metastases only (12% and 6% respectively for CD, and 15% and 5% for PCD). Survival was identical on each treatment program, with medians of six months. The major dose‐limiting toxicity was myelosuppression, which was similar on each treatment program. We conclude that the addition of piperazinedione to cyclophosphamide plus DTIC does not improve the response rate in patients with metastatic malignant melanoma. Both of the treatment programs (CD and PCD) utilizing one‐day DTIC produced response rates slightly (but not meaningfully) lower than those previously obtained with cyclophosphamide plus five‐day DTIC.

Chemotherapy of advanced prostatic cancer with adriamycin, BCNU, and cyclophosphamide

A phase II trial of Adriamycin, BCNU, and cyclophosphamide was performed in 29 patients with advanced prostatic carcinoma (Southeastern Cancer Study Group protocol SEG 76 PR 0102P). Therapy consisted of BCNU 100 mg/m2, plus cyclophosphamide, 300 mg/m2 i.v., on day 1, followed by Adriamycin, 30 mg/m2 i.v., on day 2. Therapy was repeated every four weeks. In 27 evaluable patients refractory to prior estrogen therapy, one patient had a complete response, six patients had partial responses, and two patients had objective improvement (complete plus partial response rate 26%, and overall response rate 33%). Responders had a median time to progression of disease of 5.5 months, compared with a median time to progression of 4.0 months for those patients with stable disease. The median survival of responders was 9.3 months, compared with 6.7 months for stable disease and 3.9 months for patients with progression. Patients with higher pretreatment performance status did not have higher response rates. No life‐threatening toxicity was observed. Only five patients had nadir platelet counts below 50,000/mm3, and only six patients had nadir granulocyte counts below 750/mm3. This regimen palliates the effects of hormone‐resistant metastatic prostatic carcinoma.