Clarence B. Vaughn

Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes. A southwest oncology group study

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP to two years of intermittent L‐PAM in women with operable breast cancer with histologically positive axillary lymph nodes. In fully evaluable patients with a 42‐month median and 30‐month minimum follow‐up, treatment failures have occurred in 26% of 145 receiving CMFVP and 47% of 167 women given L‐PAM (P = 0.002). Disease‐free survival times were significantly longer with CMFVP than with L‐PAM in the following subgroups: premenopausal women (P = 0.002), postmenopausal women (P = 0.002), women with 1–3 involved axillary nodes (P = 0.003), and women with four or more involved axillary nodes (P = 0.002). CMFVP was effective in pre‐ and postmenopausal women. There is a significant difference in survival in favor of CMFVP compared to L‐PAM (P = 0.005). The life table estimates of survival at 42 months are 86% for women on the CMFVP treatment arm and 73% for women on the L‐PAM treatment arm. There was no correlation between the interval from mastectomy to onset of chemotherapy (between one and six weeks) and recurrence rates. Acute toxicity with both treatment arms was moderate and reversible. These results show that continuous CMFVP is superior to intermittent L‐PAM in decreasing recurrences and increasing survival in both pre‐ and postmenopausal women with operable breast cancer with histologically involved axillary nodes.

Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study.

Patients with advanced breast cancer who had not previously received chemotherapy were treated on a three‐arm prospective study: adriamycin day 1 plus 5‐FU on day 1 and 8 (AF), adriamycin day 1, plus 5‐FU day 1 and 8, and cyclophosphamide day 1 (AFC), and adriamycin day 1 plus 5‐FU day 1 and 8, cyclophosphamide day 1 and methotrexate day 1 (AFCM). These courses were repeated every 21 days. The response rate was 44/105(42%) AF, 44/103(43%) AFC and 52/105 (49%) AFCM. The length of response was 22, 33 and 35 weeks, respectively, for AF, AFC and AFCM (P =0.21). The median survival, 64 weeks, was equal in all three limbs. The major toxicity was leukopenia. Twenty‐eight percent developed a WBC of less than 2,000/μ1, which resulted in seven deaths (2.2%).

Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group Study

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first‐line management of recurrent breast cancer.

Adriamycin combinations in advanced breast cancer. A Southwest Oncology Group Study.

The Southwest Oncology Group tested three combinations of drugs with Adriamycin to identify a best regimen for treatment of advanced breast cancer. Adriamycin, cyclophosphamide, and 5‐fluorouracil (5FU)(FAC); Adriamycin and cyclosphosphamide (AC); and Adriamycin followed by cyclophosphamide, vincristine, methotrexate, 5FU, and prednisone (A + COMFP) were used in a prospective randomized study of 497 patients with previously untreated metastatic breast cancer.

Tissue ferritin concentration and prognosis in carcinoma of the breast

SummarySeven year follow-up data were available on 36 of 40 breast carcinoma patients in whom breast tissue ferritin concentrations at the time of surgery were known. 18 patients were alive and free of recurrence or second tumor (Group 1) and 11 died with breast cancer (Group 2). Patients with lower tissue ferritin concentrations defined as < 319 ng/mcp (nanograms of ferritin/milligram of cytosol protein) were at reduced risk: 86% of patients with low tissue ferritin concentration survived free of recurrence or second tumor vs. 40% of patients with high tissue ferritin concentration (P = 0.0056). Mean breast carcinoma tissue ferritin concentration was 295 ± 52 ng/mcp in Group 1 and 444 ± 55 ng/mcp in Group 2 (P = 0.036).Lymph node involvement was predictive of mortality from breast carcinoma (P = 0.0003), but did not correlate with mean tissue ferritin concentration (P = 0.082). 10/10 (100%) patients who had both low tissue ferritin concentration and absence of lymph node involvement were in Group 1.The correlation of breast tissue ferritin concentration with histopathologic dedifferentiation and with prognosis suggests tumor tissue ferritin as a marker of malignant potential.

Ferritin Content in Human Cancerous and Noncancerous Colonic Tissue

Tumor tissue samples from 25 patients with adenocarcinoma of the colon, twelve related samples of normal colons as well as five serum specimens from the same patients were analyzed for ferritin. The average ferritin content of the tumor tissue was 788 ng/mcp with a range of 47-1,745 ng/mcp. The average ferritin content of normal colon mucosa was 115 ng/mcp with a range of 32-230 ng/mcp. Two specimens of metastatic colon cancer taken from the retroperitoneal space and liver, respectively, contained 3,867 and 2,827 ng/mcp of ferritin. The ferritin content of the tumor tissue was higher than that of the normal colon in 8 of 9 patients who had specimens obtained from both sites. The amount of ferritin found in tumor tissue was independent of sex, age, and the site of the original tumor. This study shows that the ferritin content of colon neoplasms is elevated and indicates that the tumor tissue may be the direct source of elevated serum levels of ferritin previously observed in cancer patients.

Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study

Over a 24‐month period, the Southwest Oncology Group (SWOG) conducted a randomized prospective chemotherapeutic trial in 158 patients with advanced prostatic cancer. Patients were initially randomized to receive either a combination of Adriamycin and cyclophosphamide (AC) or a single agent, hydroxyurea (H), and then crossed over to the other treatment on failure. Of the 137 evaluable patients, 43 (31%) had classically measurable metastatic disease in the lymph nodes, skin, chest, or liver. Focusing their efforts on this subset of patients with measurable disease, the authors of this report found the combination AC to have a superior response rate to the single agent, hydroxyurea. Objective response to AC was seen in 6 of 19 (32%) and in only one of 24 (4%) patients randomized to hydroxyurea (P = 0.06, Fishers exact test). However, in the larger group of 137 evaluable patients, a survival advantage was not seen for those individuals treated with AC. Failure to demonstrate a survival advantage for an objectively superior drug combination would suggest the need for more active phase II agents in this disease.

A randomized trial of doxorubicin, mitoxantrone and bisantrene in advanced breast cancer (A South West Oncology Group Study)

SummaryNew agents with increased activity and/or reduced toxicity are needed for the treatment of advanced breast cancer. The anthracene derivatives mitoxantrone and bisantrene had significant activity and acceptable toxicity in phase II trials. In an ongoing phase III trial we have now randomized 150 patients with advanced breast cancer to either doxorubicin (60 mg/m2), mitoxantrone (14 mg/m2) or bisantrene (260 mg/m2) i.v. q 3 weeks with re-randomization for cross-over at the time of progression to determine the relative efficacy and toxicity of these three agents. To be eligible, patients must have had only one previous chemotherapy regimen. ER positive patients must have failed endocrine therapy. Patients with CHF or severe cardiac disease were ineligible. In this preliminary evaluation, 117 patients are evaluable for response and 110 for toxicity. Median age for all patients is 58 years (range 26–78). The majority (86%) are postmenopausal. Fifty-nine percent of the patients have visceral dominant disease. Estrogen receptor is positive in 37%, negative in 39% and unknown in 24% of patients. Median performance status (SWOG) is 1, range 0–2. Objective responses have been observed on each arm (doxorubicin 9/35, mitoxantrone 6/38, bisantrene 6/44). Thirty-two patients are evaluable for cross-over response (doxorubicin 2/13, mitoxantrone 1/11, bisantrene 0/8). The predominant toxicity is leukopenia with a nadir WBC count <2000 in 45% of all courses administered. Leukopenia is similar with the three drugs. Significant nausea, vomiting and alopecia are common with doxorubicin and uncommon with the other agents. Congestive heart failure has been observed in one patient (doxorubicin). Definitive conclusions regarding the efficacy and toxicity of these agents await the completion of this trial.

VP-16 and adriamycin in patients with advanced breast cancer.

Twenty-eight patients with advanced adenocarcinoma of the breast were treated with a combination of VP-16 and adriamycin (VAD). Two complete (CR), and eight partial (PR) remissions were observed. The CR plus PR produced a 36% response rate in this study. Nine additional patients had stable disease for at least 2 months. No drug deaths were seen with this combination, but thrombocytopenia, leukopenia, and vomiting were observed. Alopecia was seen in 100% of the patients treated with the above combination. This study suggests that the combination of adriamycin and VP-16 may be a good second-line therapy for patients with adenocarcinoma of the breast who failed and/or relapsed to CMFVP.

Combination Chemotherapy in Advanced Gastrointestinal Malignancy

This study compares two combinations of drugs with proven activity in gastrointestinal malignancy. The drugs utilized are 5-fluorouracil (5FU), mitomycin C (Mito C), and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU). All 57 patients received 5FU 25 mg/kg as a 24-hour infusion for 5 days every 4 weeks. One group received Mito C 20 mg/m2 IV bolus every 8 weeks. The second group received MeCCNU 150 mg/m2 orally every 8 weeks. These combinations are tolerable, and the toxicities are acceptable. The response to 5FU/Mito C is more efficacious at 47% than 5FU/MeCCNU at 25% in the treatment of evaluable patients with colorectal malignancy.