Geoffrey Falkson

Locoregional Failure 10 Years After Mastectomy and Adjuvant Chemotherapy With or Without Tamoxifen Without Irradiation: Experience of the Eastern Cooperative Oncology Group

PURPOSE To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy

A prospective randomized trial was conducted comparing the clinical response of 78 previously untreated patients with advanced metastatic breast cancer to a combination of cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) or to a combination of cyclophosphamide, adriamycin, and 5‐fluorouracil (CAF). Sixty‐two percent of the patients receiving CMF responded to treatment compared to an 82% response rate for the patients receiving CAF. Although within acceptable limits, hematologic and GI toxicity was greater with CAF. There was no significant difference in the duration of response to the two regimens. Therefore, the therapeutic difference between the two therapies is a higher initial response rate to the adriamycin containing regimen.

Eastern cooperative oncology group experience with chemotherapy for inoperable gallbladder and bile duct cancer

In a prospective randomized Eastern Cooperative Oncology Group (ECOG) study, 53 eligible and evaluable patients with advanced gallbladder carcinoma and 34 with advanced bile duct carcinoma were treated with oral 5‐fluorouracil (5‐FU) or with oral 5‐FU plus streptozotocin (Stz) or oral 5‐FU + Methyl‐CCNU (MeCCNU). Severe toxicity occurred in 2 of 30 patients receiving 5‐FU (7%), in 14 of 26 receiving 5‐FU + Stz (54%), and in 12 of 31 receiving 5‐FU + MeCCNU (39%). Five of 53 patients with gallbladder carcinoma (2/18 [11%] on 5‐FU, 2/16 [12%] on 5‐FU + Stz, and 1/19 [5%] on 5‐FU + MeCCNU) had objective response to treatment. There was no significant difference between treatments with respect to response or survival. Three of 34 patients with bile duct cancer (1/12 [8%] on 5‐FU, 0/10 on 5‐FU + Stz, and 2/12 on 5‐FU + MeCCNU) had objective response to treatment. There was no significant difference between treatments with respect to response or survival. Patients with prior chemotherapy were randomized between MeCCNU alone and Stz alone. Among such patients, only 1 of 17 patients who had prior chemotherapy with other agents responded to MeCCNU alone, and none of 14 patients responded to Stz alone.

Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma.

Sixty-four patients with histologically confirmed metastatic malignant melanoma were entered on a prospectively controlled randomized trial. Patients received dacarbazine (DTIC) alone or DTIC plus interferon (IFN) alfa-2b. Patients were reasonably balanced with respect to age, sex, performance status (PS), site of metastases, and number of metastatic sites. Objective response (complete plus partial remission [CR + PR]) was documented in six patients on DTIC and in 16 patients on DTIC plus IFN alfa-2b. Median time to treatment failure (TTF) and median survival are significantly better on the combination arm, with some long-term CRs observed. More toxicity was encountered in the combination arm, which was acceptable except in three patients where treatment was discontinued because of IFN toxicity.

A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin‐D, and cyclophosphamide for advanced sarcoma

This randomized study, conducted by the Eastern Cooperative Oncology Group, compared Adriamycin (doxorubicin) (70 mg/m2) versus vincristine (1.4 mg/m2) and Adriamycin (50 mg/m2); and cyclophosphamide (750 mg/m2) versus vincristine (1.4 mg/m2), actinomycin‐D, (0.4 mg/m2), and cyclophosphamide (750 mg/m2) for treatment of metastatic mesenchymal malignancies. The respective response rate seen in 200 evaluable patients to the treatments were, 27, 19, and 11%. The response rate to Adriamycin was significantly better than the response to vincristine, actinomycin‐D, and cyclophosphamide (P = 0.03, two‐sided). The respective median survivals on the three treatments were 37, 34, and 41 weeks and were not significantly different. Moderate or severe vomiting occurred in 60% of patients receiving vincristine—cyclophosphamide—adriamycin, a greater frequency than in Adriamycin alone (P = .09 two‐sided). Severe or life‐threatening hematologic toxicity (leukocytes <2000, platelets <50,000) occurred in 30% of patients receiving the Adriamycin combination, a markedly increased frequency when compared to the other two regimens (P = 0.07, P = 0.02, two‐sided). This trial establishes that Adriamycin has a better response rate than the combination of vincristine—actinomycin‐D—cyclophosphamide in advanced sarcomas. The combination of vincristine, Adriamycin, and cyclophosphamide increased toxicity and did not add to the therapeutic effect achieved with Adriamycin alone.

Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer.

Carcinoma of the prostate gland is one of the most common malignancies in males. This study was undertaken to determine which factors predict the course and outcome of patients treated with first line hormonal manipulation. A total of 144 patients with Stage D2 prostate cancer who received androgen deprivation therapy were studied. Pretreatment parameters analyzed were age, performance status, analgesia usage, concurrent disease, histologic differentiation, hemoglobin, leukocyte and platelet count, serum creatinine, alkaline phosphatase, lactate dehydrogenase, prostate specific antigen, total and prostatic acid phosphatase, serum testosterone, follicle stimulating and luteinizing hormone levels, number of metastatic sites and bone scan grade. Only initial serum testosterone (> 10 nmol/l) had a positive impact on response (p = 0.0304), whereas age older than 60 years had a positive impact on time to progression (16 vs. 11 months, p = 0.0414). Both serum testosterone (26 vs. 20 months, p = 0.003), and age (28 vs. 17 months, p = 0.036) had a significant influence on overall survival. Low testosterone, indicating androgen independence, and a younger age, seem to result in a more aggressive disease and a poorer prognosis in advanced prostate cancer.

Malignant mesothelioma. The eastern cooperative oncology group (ECOG) experience

The Eastern Cooperative Oncology Group has conducted a retrospective review of their experience of 96 patients with a tissue diagnosis of malignant mesothelioma treated between 1972 and 1980 on four separate sarcoma chemotherapy protocols. Thirty‐two of the 96 patients were diagnosed and treated in South Africa. There were 75 males and 21 females with an age range of 27 to 78 with a median of 58.1 years. All, except for 28 patients, had some form of prior therapy. The median time from the onset of symptoms to diagnosis was 12 weeks; from the diagnosis to randomization was 15.1 weeks. Only 12 of the 96 patients demonstrated an objective regression. The responses were 7/51 on Adriamycin with 2 complete responses (complete responses—38 weeks and 52 weeks), 2/24 on Adriamycin combinations, 2/7 on cycloleucine, 1/3 on bleomycin, and 0/10 on non‐Adriamycin combinations. Only 1/28 responded to a cross‐over therapy (Adriamycin). The median survival from the start of protocol chemotherapy was 7.4 months and 7.5 months for Adriamycin treated patients. The median survival for responders was 29.9 months, compared to 6.3 months for nonresponders. The median survival for this entire series from the time of first symptoms was 15.2 months. The median survival for the 7 patients with abdominal mesothelioma was 12 weeks. There was a slight improvement in survival for the South Africans as compared to the Americans. Malignant mesothelioma in this series, was a rapidly lethal, nonresponsive disease whose treatment will require new therapies. Cancer 52:1981‐1985, 1983.

Prevalence and management of cancer pain in South Africa

&NA; Inadequate relief from cancer pain is an international health problem. The aim of this study was to document the prevalence and patterns of cancer pain management in the Republic of South Africa. The first phase of this study consisted of screening 263 patients to document the prevalence of cancer pain in varying settings. A total of 94 patients were experiencing cancer‐related pain; this comprised 35.7% of the sample. Inpatients had a higher prevalence than outpatients, which is likely due to the fact that these patients are more acutely ill. Blacks (56.1%) had a higher prevalence of pain than whites (29.4%, P<0.005); this difference was most pronounced in the outpatient setting. Phase 2 consisted of asking 426 patients with cancer pain from different settings to complete a questionnaire that included the brief pain inventory and was designed to learn about their pain and how it was managed. Nearly one‐third of the entire sample experienced ‘worst pain’ of severe intensity. There was little difference between the public and private cancer care centers. The lowest percentage of patients with severe ‘worst pain’ was in the hospice setting, but even in this group about one‐fourth of the patients had peak pain that was severe. Of non‐whites combined, 81% experienced ‘worst pain’ of moderate to severe intensity as compared to 65% of whites (P<0.001). Only 21% of patients reported that they had achieved 100% pain relief. Patients experienced interference in general activity, mood, walking, working, relations with others, sleeping, and enjoyment of life related to their pain. 30.5% of the entire sample had a negative score on the pain management index, a comparison of the most potent analgesic used by a patient relative to their worst pain. Of this group, 58.1% were experiencing severe ‘worst pain’. Unrelieved cancer pain is a significant problem. Government and non‐government leaders, educators, and practitioners must collaborate to address the barriers to effective pain management and to implement improvements in education, health policy, and health care delivery.

Primary liver cancer. An eastern cooperative oncology group trial

One hundred ninety‐two patients with unresectable primary liver cancer studied by members of the Eastern Cooperative Oncology Group (ECOG) were evaluable in a prospectively randomized clinical trial. Patient discriminants such as performance status were carefully evaluated to assess their influence on prognosis and to evaluate the importance of patient status on response and survival. Patients who were totally bedridden or with signs of overt liver failure were not entered on study. The median survival time for all evaluable previously untreated patients was 17 weeks (19 weeks for North American and European, and 10 weeks for South African black patients). Among the South African patients, however, there was a significantly larger proportion with an initially poor performance status. Prognostic variables (performance status, jaundice, and reduced appetite) dominate any differences among the treatments studied. Among North American and European patients on intravenous (IV) 5‐fluorouracil (5‐FU) + Methyl‐CCNU (MeCCNU) + Adriamycin (ADM, doxorubicin), the 19% response rate is offset by 63% with severe toxicity and a median survival time of only 17 weeks, making this treatment unacceptable clinically. The median survival time of North American and European patients treated with IV 5‐FU + MeCCNU was 28 weeks in contrast to a median survival time of 12 weeks with ADM (P ≤ 0.01). EST 2273 was the ECOG study of patients with primary liver cancer. The results of the first part of the trial were published in 1978. This report updates those findings and reports the results of patients entered subsequently on the second part of that study after it was amended in 1979. With more than 300 evaluable patients in EST 2273, this duet of studies is the largest ever conducted in patients with primary liver cancer, and draws a new baseline from which to measure the disease and its response to treatment.

Combination Chemotherapy Compared to Tamoxifen as Initial Therapy for Stage IV Breast Cancer in Elderly Women

In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.