Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Elapsed radiation therapy treatment time as a predictor of survival in patients with advanced head and neck cancer who receive chemotherapy and radiation therapy.

PURPOSE: To determine whether elapsed radiation therapy treatment time relates to survival in patients with head and neck cancer treated sequentially with chemotherapy and radiation therapy. MATERIALS AND METHODS: From 1981 to 1988, 76 adult patients with bulky stage II-IV head and neck cancer received induction chemotherapy (fluorouracil and cisplatin). Those with a complete or partial response (n = 46) received full-dose definitive radiation therapy (range, 64.0-77.5 Gy; median, 70 Gy). Those with less than a partial response (n = 21) underwent surgery and postoperative radiation therapy (n = 15), palliative radiation therapy (n = 4), or palliative chemotherapy (n = 2). Nine patients refused to undergo radiation therapy after induction chemotherapy. RESULTS: The 5-year overall survival rates were as follows: 32% in all patients, 38% in patients who underwent chemotherapy and radiation therapy, and 27% in patients who underwent chemotherapy, surgery, and radiation therapy. The number of days between radiation therapy treatments was highly predictive of overall survival. In the groups with treatments less than 55 days apart, 56-65 days apart, and more than 66 days apart, the 5-year survival rates were 56%, 46%, and 15%, respectively (P = .02). CONCLUSION: The time between radiation therapy treatments is strongly predictive of survival in patients undergoing sequential chemotherapy and radiation therapy. The use of induction chemotherapy does not negate the need to avoid treatment interruptions during definitive radiation therapy.

Pericardial angiosarcoma after mediastinal irradiation for seminoma. A case report and a review of the literature.

BACKGROUND: Second malignancies are a well recognized complication of radiation therapy. METHODS: We performed a computer search of the literature using the Medline Database for Pericardial Tumors and Post-Irradiation Sarcomas. RESULTS: The case history of a patient who developed a radiation-induced pericardial angiosarcoma is described. We present a detailed review of pericardial sarcomas. CONCLUSIONS: We believe this to be the first report of a radiation-induced pericardial sarcoma. The importance of continued long-term observation for patients who receive mediastinal irradiation is stressed.

Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation.

PURPOSE: To assess the potential downstaging of advanced rectal cancer with combined preoperative chemoradiation. METHODS AND MATERIALS: Thirty-one patients with fixed rectal cancers (stage > or = cT3) were treated with concomitant preoperative chemotherapy and high-dose radiation in an effort to improve resectability. Three (10%) patients had partially fixed low rectal cancers, 24 (77%) patients had fixed tumors, and 4 (13%) had advanced fixation with pelvic sidewall invasion. Radiation was delivered to the whole pelvis using shaped anterior and posterior and lateral fields to 45 Gy followed by a boost to the tumor. Median total radiation dose was 55.8 Gy. Chemotherapy consisted of low dose continuous infusion of 5-FU (200-300 mg/m2/day) for the duration of radiation treatment. All 31 patients underwent surgical resection of tumor 6-8 weeks following treatment. Median follow up is 24 months (range 9-60). RESULTS: Twenty-three (74%) of the tumors were clinically downstaged following preoperative treatment. Of 24 fixed cancers, 11 (46%) became mobile, 6 (25%) became partially fixed, and 7 remained fixed. Of the four tumors with advanced fixation, two (50%) became mobile and two (50%) no longer had tumor extension to the pelvic sidewall. Two of the three initially partially fixed cancers became mobile and one remained partially fixed. Following surgery, the pathologic postradiation T-stages were as follows: T0: 10%, T1: 0%, T2: 32%, T3: 42%, and T4:16%. Seven patients (23%) were also node-positive (T0-2: 2, T3: 4, T4: 1), and two patients (6%) had liver metastases at surgery. Preoperative chemoradiation was well tolerated. There was no significant hematological toxicity. Acute grade 3 gastrointestinal toxicity was seen in six patients requiring a short hospitalization for dehydration and/or abdominal discomfort. No patient developed grade 4 toxicity. Five patients (16%) developed local recurrence of disease (T0-2: 0/13, T3: 1/13, and T4: 4/5). The actuarial 3-year survival is 68%. CONCLUSIONS: Concomitant preoperative chemoradiation using low dose continuous infusional 5-FU for advanced rectal cancer is relatively safe with acceptable morbidity. This approach is associated with considerable clinical and pathologic downstaging of cancer. Tumor resectability is improved with potential for improved local control of disease and survival.

A randomized comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil with triethylenethiophosphoramide and methotrexate, both as sequential and as fixed rotational treatment in patients with advanced ovarian cancer.

The combinations of triethylenethiophosphoramide and methotrexate (TM) and cyclophosphamide, Adriamycin (doxorubicin), and 5-fluorouracil (CAF) were compared, both as sequential and fixed rotational treatments for advanced ovarian cancer, with L-phenylalanine mustard (L-PAM). Treatment with CAF produced a higher response rate (25% complete responses plus 31% partial responses) than treatment with L-PAM (15% complete responses plus 18% partial responses). A fixed rotation of TM and CAF resulted in longer survival (median of 15 months and 75th percentile of 27 months) than sequential treatment with TM initially, followed by CAF upon failure (median of 12 months and 75th percentile of 22 months). The fixed rotation of TM and CAF also increased progression-free survival (median of 12 months and 75th percentile of 24 months) over that achieved by initial treatment with TM (median of 6 months and 75th percentile of 15 months) or L-PAM (median of 9 months and 75th percentile of 21 months). Most patients (96%) on the fixed rotation were treated with both TM and CAF. Fewer patients (62%) on the sequential schedule with TM actually received both combination regimens, and even fewer patients (37%) beginning on CAF ever crossed over to TM. Patient age of 50 years or younger was a favorable prognostic factor for response, survival, and time to first treatment failure (progression-free survival). Disease Stage IIIA or IIIB, surgery including a bilateral salpingo-oophorectomy plus hysterectomy, and treatment within 6 months of initial diagnosis were favorable predictors for both survival and time to first treatment failure. Ambulatory performance status and well-differentiated disease were favorable prognostic factors for survival. Patients with unevaluable disease failed later than those with evaluable disease who, in turn, failed later than patients with measurable disease.

Association of subacute motor neuronopathy with thymoma.

A case of subacute motor neuronopathy in association with thymoma is described. Subacute motor neuronopathy is marked by a painless, progressive, and asymmetric muscle weakness that usually affects the lower extremities. It is a rare paraneoplastic effect of tumors that has been described with both Hodgkin's and non-Hodgkin's lymphoma. This is the first case report of its association with thymoma.

Comparison of melphalan with cyclophosphamide, methotrexate, and 5-fluorouracil in patients with ovarian cancer.

Melphalan (L-PAM) was compared to (C) cyclophosphamide, (M) methotrexate, and (F) 5-fluorouracil (CMF) in 413 patients with advanced ovarian carcinoma. L-PAM was given 3.5 mg/m2 twice daily for 5 days every 5 weeks. CMF doses were: C, 400 mg/m2; M, 15 mg/m2; and F, 400 mg/m2 IV on days 1 and 8 every 28 days. Three hundred seventy-five patients have been analyzed (L-PAM, 190; CMF, 185). One hundred fifty-three patients (41%) had measurable disease, 109 (29%) had evaluable disease, and 113 (30%) had nonmeasurable, nonevaluable disease. Response rates for patients with measurable and evaluable disease combined were similar: L-PAM, 32/130 (24%) (15% complete response); CMF, 47/132 (35%) (18% complete response). Patients with Stage IV measurable disease had a greater response rate to CMF, 22/52 (42%) versus L-PAM, 6/39 (15%). Survival and time to treatment failure were similar for both treatment regimens. Survival was improved in responders. Medians are: complete response, 28.1 months; partial response, 12.3 months; and no response, 6.7 months. Disease stage, performance status and age were identified as important prognostic variables for both survival and time to treatment failure.

Cooperative groups and community hospitals. Measurement of impact in the community hospitals.

The Eastern Cooperative Oncology Group, composed of major cancer treatment centers, has an outreach program which involves community hospitals in ongoing cancer clinical trials. A prevalence survey was carried out in February 1981 among 104 community hospitals and 21 member institutions to determine the characteristics of patients being treated, their staffing, and reasons why patients were not on protocol studies. The survey sampled 25 (50) consecutive patients from community hospitals (member institutions). The purpose of the study was to assess the impact of a community cancer control program. The results of the study demonstrated that 16% of patients surveyed in the affiliated community hospitals were being treated on a research protocol. In addition, a further 35% had their treatment plan influenced by a protocol. Consequently protocols have impacted directly or indirectly on 51% of the patients. The corresponding figures in member institutions were 23% and 38% for a total of 61%. In studying protocol availability, it was found that 66% of all patients were ineligible for any protocol. Of patients eligible for a protocol but not registered on one, 52% were not registered because of physician preference for a specific treatment. The affiliates surveyed were shown to be on average half as large as member institutions in terms of number of beds and staff size. Also, staff/patient ratios are generally smaller in the community hospitals. The median age of patients was considerably lower than SEER incidence data. Also, elderly patients were slightly more prevalent in community hospitals than in member institutions. A clear relationship between disease stage and age in breast cancer patients was noted with the representation of early-stage disease much higher in young women.

A comparative clinical trial of adriamycin and 5-fluorouracil in advanced prostatic cancer: prognostic factors and response.

In patients with metastatic hormone-relapsed adenocarcinoma of the prostate, adriamycin was compared to 5-fluorouracil in a randomized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients. Response to adriamycin was superior as judged by response of measurable disease (25 vs 8%; P less than 0.05) and survival (median 29 vs 24 weeks; Cox analysis, P less than 0.03), but comparable as judged by acid phosphatase response. Ambulatory status and site of metastases influenced rate of response to chemotherapy. Activity level, site of metastases, weight loss, and the symptom of protein aversion were prognostic factors for survival. Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily. Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy.

Comparative trial of two teniposide-based combination chemotherapy regimens for the treatment of advanced malignant lymphomas.

One hundred and twenty-three patients with advanced measureable malignant lymphomas resistant to conventional chemotherapy were entered in a prospectively randomized trial of two teniposide (VM-26)-based combination chemotherapy regimens: V-PLAT (VM-26, cisplatin, and prednisone) and V-HEX (VM-26, hexamethylmelamine, and prednisone). Ninety-seven eligible and evaluable patients received protocol therapy. Sixteen percent of the patients had Hodgkin's disease, and 84% had non-Hodgkin's lymphoma. All patients were ambulatory (Eastern Cooperative Oncology Group Performance status 0, 1, or 2), 70% had stage IV disease, 59% had "B" symptoms, and all had failed either two or three previous chemotherapy regimens. Toxicity was mainly hematologic and significantly greater with V-PLAT. Objective tumor responses were seen in nine of 45 patients (20%) treated with V-PLAT (duration, 4-35 + weeks) and in four of 51 patients (8%) treated with V-HEX (duration, 10-65 + weeks). Among the 12 patients with histologically confirmed histiocytic lymphoma treated with V-PLAT, five (42%) experienced objective tumor responses, including two complete responses. Overall median survival was approximately 6 months, with no difference between treatment regimens. Limited antitumor activity of these combination regimens in patients with advanced malignant lymphomas has been demonstrated. However, the objective response rates were not higher than we have previously seen with either VM-26 (22%) or hexamethylmelamine (27%) given in maximum tolerable doses as single agents.

Carcinoid tumors of the uterine cervix: response to combination chemotherapy and radiotherapy.

Two cases of advanced (Stage III) carcinoid. tumors of the cervix are presented. Initial treatment in both cases consisted of combination chemotherapy (CCNU, cyclophosphamide and methotrexate) administered in the same regimen used in the treatment of small cell carcinoma of the lung. Initial response in the first case was remarkable, but toxic side effects delayed further treatment. Local tumor progression followed resulting in bilateral complete ureteric obstruction. Radiation therapy was discontinued before an effective dose could be delivered, and the patient expired in uremic coma. In the second case, initial response to chemotherapy was not as effective, but radiation therapy seemed to produce local control of the disease. Review of the English literature produced 21 additional cases of carcinoid tumors of the cervix: eight Stage I, seven Stage II, four Stage III, and one Stage IV. No firm conclusions with regard to therapy could be drawn from such small numbers.

Phase II trial of tamoxifen in metastatic carcinoma of the prostate.

Fifty-one patients with advanced metastatic carcinoma of the prostate were treated with the antiestrogen tamoxifen. Thirty-eight of these patients were refractory to prior hormonal manipulation with estrogens and/or orchiectomy, and five (13%) achieved an objective response (partial regression or stable disease using the National Prostate Cancer Project criteria). Median survival of the responders was significantly longer than that of the nonresponders (P less than 0.05). An additional 13 patients who had not previously received hormonal manipulation were treated with tamoxifen; one partial response and three disease stabilizations were noted. Response was separately evaluated for 15 patients with objectively measurable lesions using standard Phase II response criteria. Only 1/15 (7%) partial response and 3/15 (20%) disease stabilizations were documented. Subjective benefit in terms of significant pain relief was noted in 17/50 (34%) of patients. Toxicity was mild, but two possible "tumor flares" were noted. These results do not support the continued investigation of tamoxifen in advanced carcinoma of the prostate.

Rib destruction: a neglected finding in malignant mesothelioma.

Malignant mesothelioma is extensively described in the radiological literature, but the incidence and importance of rib destruction has not been emphasised. In this communication, four patients with extensive mesothelioma and contiguous rib destruction are described. They represent 12% of the collected series of 36 patients. The differential diagnosis of a pleural mass with rib destruction is discussed.

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer.

Eighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders.

Trials of single-agent and combination chemotherapy for advanced cancer of the pancreas.

In a study of 127 patients with advanced measurable pancreatic cancer, objective response rates of 2% (melphalan), 10% (5-FU and methyl-CCNU), and 7% (5-FU, methyl-CCNU, and streptozocin) were achieved. No responses occurred in the 28 patients treated with VP-16-213 who had already received prior chemotherapy. Toxicity was greater for the two- and three-drug combinations than for melphalan. There was no difference in survival following use of the three treatment regimens. Further studies are needed to develop effective chemotherapy for patients with cancer of the pancreas.

Tamoxifen in refractory metastatic carcinoma of the prostate.

Thirty-one patients with advanced metastatic carcinoma of the prostate were treated with the antiestrogen tamoxifen. Of these patients, 29 were refractory to prior hormonal manipulation with estrogens and/or orchiectomy and five achieved an objective response (partial regression of stable disease using National Prostatic Cancer Project criteria). Median survival of the responders was significantly longer than that of the nonresponders (P < 0.05). Two additional patients who had not previously received hormonal therapy both responded, for an overall response rate of 23% (seven of 31 patients). Toxicity was minimal and no tumor flares were reported. These preliminary results support the further clinical trial of tamoxifen in advanced cancer of the prostate.