Phase II study of cisplatin and 5-fluorouracil in previously treated metastatic breast cancer: an Eastern Cooperative Oncology Group study (PA 185).

PURPOSE: The present study was conducted to investigate the efficacy and toxicity of a cisplatin and 5-fluorouracil (5-FU) combination in previously treated advanced breast cancer. METHODS: Thirty-six women with recurrent metastatic breast cancer were entered on a phase II study of 5-FU 1000 mg/m2/day given intravenously as a continuous infusion on days 1-3 and cisplatin 30 mg/m2/day given intravenously over 1 h on days 2-4, repeated every 21 days. All subjects had received one previous chemotherapy regimen for metastatic disease and either progressed during treatment or relapsed after responding to previous chemotherapy. Fourteen patients had also received previous adjuvant chemotherapy, 17 patients had previous radiation therapy, and 29 patients had previous hormonal therapy. RESULTS: Among 32 response-evaluable patients, there were 10 partial remissions (31%) and 1 complete remission (3%), with an overall objective response rate of 34%. Median duration of response was 4 months. Median survival was 10.5 months for responders and 9.5 months for the entire group. Toxicity was mild to moderate in most patients. Overall twelve patients experienced grade 3 toxicity (10 hematologic, 1 mucositis, and 2 nausea). There were no grade 4 or 5 toxicities. CONCLUSION: Infusional cisplatin and 5-FU is a well tolerated and active regimen in women with previously treated advanced breast cancer.

Conventional dose melphalan is inactive in metastatic melanoma: results of an Eastern Cooperative Oncology Group Study (E1687).

Despite reports that i.v. melphalan is active in the settings of conditioning regimens utilizing high-dose chemotherapy for autologous bone marrow transplantation and in isolated limb perfusion for the treatment of malignant melanoma, its activity at conventional doses has never been defined in this disease. We conducted a phase II study of conventional-dose i.v. melphalan (30 mg/m2) in 17 patients with metastatic melanoma. All patients were previously untreated with chemotherapy with performance status 0, 1 or 2. Forty-seven cycles were given with a median of two cycles. One patient was not evaluable due to early death. There were no responses in the 16 patients, resulting in a 0% response rate (95% confidence interval = 0-17%). We conclude that conventional-dose melphalan by i.v. administration has no appreciable activity in patients with metastatic malignant melanoma.

Pseudomyxoma peritonei: Sudden cardiac death complicating post operative intraperitoneal treatment with 5-fluorouracil.

BACKGROUND: Pseudomyxoma peritonei, a tumor which spreads chiefly along peritoneal surfaces, has recently been treated by resection followed by intraperitoneal infusion of 5-fluorouracil (5-FU). Reports on the cardiotoxicity of this drug, given intravenously, indicate an incidence of 1.4-2.9%. Although several deaths have been reported following 5-FU therapy by continuous intravenous infusion, none has apparently been reported following bolus intravenous injection. METHOD: Radical resection of an extensive pseudomyxoma peritonei was performed. Following convalescence, intraperitoneal infusion of 5-FU was initiated in a daily dose of 20 mg/kg body weight (1,440 mg), planned for administration in multiple 5-day cycles. RESULTS: After three uneventful daily infusions of 5-FU, the patient suddenly died, apparently of a sudden cardiac event. Autopsy provided no explanation for his death. The coronary arteries were free of disease and no residual tumor was found. A review of the literature reveals no report of a cardiac death from 5-FU following its intraperitoneal administration. CONCLUSIONS: The fatality suggests the potential toxicity of 5- FU when administered intraperitoneally, a factor to be considered in decisions to use this drug intraperitoneally.

Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators.

PURPOSE: We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials. METHODS: We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded. RESULTS: All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions. CONCLUSION: This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.

Alpha interferon, leucovorin, and 5-fluorouracil (ALF) in advanced cancer: results of a dose-finding study and evidence of activity in non-small cell lung cancer.

In a phase I trial, 17 patients were treated with 5-fluorouracil (5-FU) 500 mg/m2 and leucovorin (LV) 500 mg/m2 intravenously weekly for 6 weeks followed by 2 weeks' rest and interferon alfa-2b 1, 3, 5, 8, or 10 million units (MU) subcutaneously tiw with no rest period. The most common toxicities were fatigue (12), diarrhea (10), nausea/vomiting (7), and fever (7). The maximum tolerated interferon dose was 8 MU tiw. Fatigue and increased incidence of other toxicities rather than a single dose-limiting toxicity occurred at the next highest interferon level. ECOG grade III/IV toxicity occurred in 5 patients and included transient supraventricular tachycardia and brief seizure episode (1), dyspnea (1), decreased performance status (1), anemia requiring transfusion (1), and deep vein thrombosis (1). No toxic deaths occurred. Two patients with non-small cell lung cancer (NSCLC) had partial responses lasting 5 and 4 months. Two other patients with NSCLC had either minor response or stable disease, and 1 patient with colon cancer had a significant decline in serum CEA. The recommended alpha interferon dose is 8 MU tiw when given with this schedule of 5-FU/LV.

Quality of life dimensions that are most important to cancer patients.

Despite the introduction of quality of life measurements into clinical trials during the past several years, there is uncertainty about how to translate quality of life information from the research setting to meaningful practice decisions. In part, this is due to the fact that physicians do not speak the same language as behavioral scientists and are not as comfortable in exploring social and emotional functioning as they are in inquiring about symptoms and other physical concerns. Until more information is available about which quality of life dimensions are of greatest concern to different patient cohorts and until reliable tools evolve to evaluate individual patient quality of life needs, it is likely that most physicians will rely on the unstructured patient interview to obtain quality of life information. As more is learned about the value patients place on specific quality of life dimensions, it will allow physicians to better address patients' symptoms, physical function, and psychosocial health concerns.

Radiation therapy and 5-fluorouracil modulated by leucovorin for adenocarcinoma of the pancreas. A phase I study.

This Phase I study was designed to build on the Gastrointestinal Tumor Study Group's experience with combined modality therapy in patients with pancreatic cancer. Thirteen patients with adenocarcinoma of the pancreas received weekly 5-fluorouracil by rapid intravenous infusion midway through a 2-h infusion of high dose leucovorin during external beam radiation therapy. Twelve patients received 100% of planned external beam radiation; treatment delays occurred in only three. Four patients received 100% of planned chemotherapy doses. Leukopenia and thrombocytopenia caused reduction of the number of chemotherapy doses given during radiation in six patients; diarrhea, severe nausea and vomiting, and wound abscess caused reduction in three patients. Ten patients were evaluable for response; two had complete responses, one had a partial response, and two had minor responses. In this small series baseline and post-treatment CA 19-9 levels predicted and correlated with response. We conclude that radiation and 5-FU modulated by leucovorin is a tolerable treatment regimen for carcinoma of the pancreas, with preliminary suggestion of activity, that warrants further Phase II testing.

Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study.

BACKGROUND: Studies have shown that response to a given chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer is superior to that in patients previously treated with other regimens. This finding raises the question of whether it is necessary and ethical to study the effects of new anticancer agents in untreated patients. Such studies appear to be the best test for drug development, but there has been no evaluation of whether survival of untreated patients, whose cancer is sensitive to established drugs, is adversely affected in trials of new drugs. PURPOSE: This randomized study of untreated patients with extensive-stage small-cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anticancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. METHODS: Eighty-six patients were randomly assigned to receive, as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) every 3 weeks--or the phase II drug menogaril (200 mg/m2) every 4 weeks. Treatment after induction therapy varied, depending on patient response, but nonresponders and those with disease progression received salvage chemotherapy--etoposide (120 mg/m2 on days 1, 2, and 3) and cisplatin (60 mg/m2 on day 1), repeated every 3 weeks. RESULTS: Of the 43 patients on CAV, 42% responded (eight complete responses and 10 partial responses); 5% of the 43 on menogaril responded (two partial responses) (P = .0001). Twelve (22%) of 54 patients responded to salvage chemotherapy (five complete responses and seven partial responses). Within 3 months from start of treatment, twelve patients died--3 patients in the CAV group and nine patients in the menogaril group (P = .12). The estimated median survival was 37 weeks with menogaril and 45 weeks with CAV (P = .28). At 6 months, survival was 76.7% for the CAV group and 67.4% for the menogaril group. At 12 months, survival rates were 24.4% and 27.9%, respectively. Confidence intervals (95%) for the differences between the proportions surviving in the two groups were -9%-28% at 6 months and -25%-14% at 12 months. Use of CAV resulted in significantly higher occurrence of severe and life-threatening treatment-related complications (P = .002). CONCLUSION: The confidence intervals for the differences in survival are too wide to conclude that evaluation of a new drug in untreated patients with extensive-stage small-cell lung cancer is or is not harmful. The data do suggest, however, that use of this study design may have no adverse effect on survival.

Concomitant radiation therapy and constant infusion FUdR for unresectable hepatic metastases.

Ten patients with unresectable liver metastases from intraabdominal primary malignancies were treated with combined hepatic irradiation and hepatic artery infusion with FUdR using an Infusaid pump. The median survival for the entire group was 10 months. Four (40%) demonstrated an objective response to treatment: Three patients had a decrease in tumor mass on computed tomography (CT) scan, and one patient had a reduction in liver size as measured by palpation. The survival of two of the three patients whose tumor size was observed to be reduced on CT scan was significantly longer than that of the rest of the group (23, 37, and 12 months). Treatment was generally well tolerated with only mild side effects. Morbidity from chemotherapy did not appear to be enhanced by combination with hepatic irradiation. This form of treatment, although it has not demonstrated improved survival compared with other treatments in this setting, may be considered for adjuvant therapy in patients with hepatic metastases.

Magnetic resonance imaging of hepatic adenoma.

A case of hepatic adenoma imaged by magnetic resonance imaging (MRI) as well as with angiography, computed tomography, and radionuclide imaging is presented. Pathological correlation is also presented. Review of the literature of MRI of hepatic adenoma and related tumors is discussed.

A phase II study of carboplatin and CHIP in patients with metastatic colon carcinoma.

Fifty-six patients were treated in each arm of a study comparing CHIP and carboplatin for the therapy of previously untreated metastatic colorectal carcinoma. There were one partial response (2%) with CHIP and two partial responses (4%) with carboplatin. Side effects were significantly more severe with CHIP than with carboplatin. The most common side effect for both drugs was vomiting followed by hematologic side effects. Sixteen percent of the patients receiving CHIP and 9% of those receiving carboplatin had life-threatening side effects. Neither drug offers significant activity in metastatic colorectal carcinoma.

Combination chemotherapy of advanced breast cancer. Comparison of dibromodulcitol, doxorubicin, vincristine, and fluoxymesterone to thiotepa, doxorubicin, vinblastine, and fluoxymesterone: an Eastern Cooperative Oncology Group Study.

Two Adriamycin (doxorubicin)-based chemotherapy regimens were investigated in patients with carcinoma of the breast who had failed prior systemic therapy. The two chemotherapy programs, dibromodulcitol, Adriamycin, vincristine, and Halotestin (fluoxymesterone) (DAVH), and thiotepa, Adriamycin, vinblastine, and Halotestin (TAVH), were chosen for comparison on the basis of reported response rates of 40% to 50% with remission durations of 11 months in patients refractory to other cytotoxic chemotherapy. Cycles of DAVH were repeated every 4 weeks. Cycles of TAVH were repeated every 3 weeks. Of 184 patients evaluable for response, 32% of patients treated with DAVH and 38% of patients treated with TAVH had a complete response (CR) or partial response (PR). An additional 5% of patients had nonmeasurable improvement in osseous disease for an overall rate of response (CR + PR + improvement) of 40%. Patients who had previously received cytotoxic chemotherapy for metastatic disease or had early failure after adjuvant therapy had a lower response rate to DAVH, but not to TAVH than those who did not fail prior chemotherapy. Duration of response and survival were similar with the two treatments. There were seven treatment-related deaths, five among patients receiving DAVH and two among patients receiving TAVH. Patients receiving DAVH had significantly more thrombocytopenia and neurologic toxicity than those receiving TAVH. These treatments appear to be reasonable second-line regimens and are good candidates to be used in initial therapy of metastatic disease or adjuvant therapy studies that explore the use of alternating non-cross-resistant combinations with cyclophosphamide, methotrexate, and 5-fluorouracil.

Role of scintigraphy in establishing optimal perfusion in hepatic arterial infusion pump chemotherapy.

Since 1982, physicians at the Medical College of Ohio, Toledo, have performed 41 hepatic intraarterial chemotherapy infusion pump implantations for palliative treatment of metastatic liver disease from various primary tumors of the gastrointestinal tract. Radionuclide hepatic arterial pump imaging has proven to be a very reliable, cost-effective, and uncomplicated method of evaluating liver perfusion as it relates to pump function, catheter integrity, and positioning. Confirmation of satisfactory hepatic perfusion is the key to acceptable treatment by this modality. In combination with periodic computed tomography (CT) scanning and CEA determinations, scintigraphy plays a major role in establishing effective therapy and aids in determining causal factors behind treatment failures.

Phase II trial of spirogermanium and vindesine in malignant glioma.

Fifty-four adults with recurrent malignant glioma were treated on an Eastern Cooperative Oncology Group (ECOG) trial. All had previous radiation therapy, and 70% had previous chemotherapy. They were assigned to either vindesine 3 mg/m2 weekly or spirogermanium 80 mg/m2 three times weekly with escalation to 120 mg/m2. The response was 4% to vindesine, and 8% to spirogermanium. The duration of response was 53 days for a patient who had clinical improvement only, but greater than 151 days and greater than 1066 days for two patients who had achieved a greater than 50% reduction in tumor size by computed tomography (CT). The toxicities were hematologic for vindesine and neurologic for spirogermanium. Neither agent seems to have sufficient efficacy to warrant further trials in previously treated glioma patients.

Alterations in left ventricular diastolic function with doxorubicin therapy.

To determine whether impaired diastolic function may be an early sign of doxorubicin cardiotoxicity, a retrospective study was performed in 12 patients who had undergone serial radionuclide angiography and were found to have a left ventricular ejection fraction of 55% or more before doxorubicin (Adriamycin) treatment and during follow-up. Average rapid filling velocity and slow filling velocity were both significantly reduced after doxorubicin treatment. Rapid filling velocity decreased from 5.17 +/- 1.52 to 4.18 +/- 0.96 units/s (p less than 0.01), and slow filling velocity decreased from 2.20 +/- 1.32 to 1.42 +/- 0.62 units/s (p less than 0.05). There were no significant changes in filling volume ratio, total diastolic time or diastolic time ratio. Because a change in left ventricular diastolic function can occur before ejection fraction falls to subnormal levels, diastolic function as well as systolic function should be examined for the early detection of doxorubicin cardiotoxicity. The clinical implications of our observations can only be established by a longer-term prospective analysis of left ventricular function in patients receiving doxorubicin therapy.

125I interstitial implant, precision high-dose external beam therapy, and 5-FU for unresectable adenocarcinoma of pancreas and extrahepatic biliary tree.

Twelve patients with adenocarcinoma of the pancreas and two patients with carcinoma of the extrahepatic biliary tree received combined therapy with 125I implant, precision high-dose (PHD) photon external beam therapy, and systemic 5-fluorouracil (5-FU). The 125I implant delivered 120 to 210 Gy (median 140 Gy). PHD external beam therapy was given with high-energy photons (10, 15 or 45 meVp) and was initiated 4 to 6 weeks postimplant. A dose of 48.6 to 63 Gy was delivered over 5.5 to 7 weeks in 1.8 Gy increments. Six patients received 5-FU, 500 mg/m2 via weekly intravenous bolus injection. No patient was lost to follow-up (range, 3.5-57 months). Acute postoperative morbidity included pancreatic fistula in two patients and gastrointestinal tract bleeding, pulmonary embolism, and cholangitis in one patient each. No patient died of radiation complications. Median survival of the patients with pancrease cancer was 15 months. One patient is alive at 41 months with hepatic metastasis. Satisfactory palliation was observed in patients with pancreas cancer treated with 125I interstitial implant followed by PHD external beam photon therapy and 5-FU. Patient survival did not seem superior to that of patients treated with PHD external beam therapy +/- chemotherapy, a less morbid procedure. Two cases of bile duct cancer treated in similar fashion are presented.

A phase II study of bisantrene in advanced refractory breast cancer. An Eastern Cooperative Oncology Group pilot study.

Thirty patients with advanced refractory breast cancer received bisantrene 260 mg/m2 intravenously every 3 weeks. Reversible myelosuppression was the most commonly observed side effect. Four patients (13.3%) achieved objective partial response (90% confidence intervals 3-24%), while two patients (6.6%) had disease improvement with a PR + IMP rate of 19.9%. Seven additional patients (23.3%) had stabilization of disease. This drug has antitumor activity against breast cancer and warrants further study, particularly if problems with drug delivery are overcome.