Phase II evaluation of amonafide in advanced sarcoma: a Southwest Oncology Group study.

Soft tissue sarcomas are generally resistant to most chemotherapeutic agents, and individuals with advanced disease have a poor prognosis. We evaluated amonafide, a new drug that has significant activity against several tumor cell lines, to determine its activity against sarcomas. Amonafide was administered to 18 patients with advanced soft tissue sarcoma (16 of whom had received prior chemotherapy) at a dose of 300 mg/m2 over 60 min daily for 5 days. Courses were repeated every 21 days. Toxicity was mild, but no responses were observed. We conclude that amonafide is not an active agent in previously treated, advanced soft tissue sarcomas in the dose and schedule utilized.

Mitoxantrone (dihydroxyanthracenedione) in acute leukemia. An evaluation of two treatment schedules by the Southwest Oncology Group.

Fifty-eight evaluable patients with acute leukemia were treated with Mitoxantrone (DHAD) according to two schedules: 14 mg/M2 as a single I.V. pulse dose administered three-week intervals, and 4 mg/M2/day for five days every three weeks. Six of 58 patients achieved a complete remission. One complete remission and 1 partial remission were observed among 26 patients treated with the single pulse schedule. Five (16%) complete remissions were attained among 32 patients treated on the daily x 5 schedule. Responses were observed only in patients with non-lymphoblastic leukemia. DHAD was very well tolerated with myelosuppression as the major toxicity. Nausea and vomiting were minimal. Subclinical cardiac toxicity occurred in two patients. This was identified by serial reductions in cardiac ejection fractions. DHAD appears to have significant activity in acute non-lymphoblastic leukemia with minimal toxicity.

Phase II evaluation of didemnin B in advanced adenocarcinoma of the kidney. A Southwest Oncology Group study.

The Southwest Oncology Group studied the response rate and toxicity of didemnin B (3.47 mg/m2 i.v. q 28 days) in patients with advanced renal cell carcinoma. There were no responses in 22 response evaluable patients. Toxicity was significant with 10 patients having grade 3 or 4 toxicity. Toxicity seen included nausea and vomiting, exacerbation of coronary artery disease, hyperglycemia, anorexia, diarrhea and hepatitis. Didemnin B was toxic but inactive in patients with renal cell treated at this dose.

A phase II randomized study comparing sequential and combined intraarterial cisplatin and radiation therapy in primary brain tumors. A Southwest Oncology Group study.

The Southwest Oncology Group conducted a trial of intra-arterial cisplatin (150 mg intravenously every 21 days for 2 doses) administered concomitant with or before radiation therapy. Because of technical difficulties cannulating the artery, 27 of 33 eligible patients were able to receive the cisplatin by arterial injection. Five patients died before completion of the study, and 11 patients in each treatment arm were evaluable for response. Three patients (27%) had an objective tumor regression in each treatment arm. Thromboembolic problems complicated 8 of 57 (14%) chemotherapeutic courses. The median survival for the 33 eligible patients was comparable for both groups: 10.8 months in the concomitant treatment arm and 9.6 months with sequential therapy. Problems related to drug administration and toxicity made it impossible to determine the role of intraarterial cisplatin in the initial management of primary high-grade gliomas.

Unbound immunoglobulins are a major source of error in the quantitation of platelet surface-bound immunoglobulin levels.

Analysis of assays for the determination of platelet-associated immunoglobulins (PAIgs) has led to disagreement over the amount of surface-bound Igs in both normal controls and patients with elevated platelet Ig levels. By the use of radiolabeled platelets and platelet counts, it was demonstrated that more than 10(8) platelets are disrupted after each centrifugation during platelet isolation procedures, releasing intraplatelet contents into the fluid phase of resuspended platelets in buffer. It was shown that suspensions of whole washed platelets contain a significant, but generally overlooked, amount of unbound Igs that have been liberated from platelets disrupted during processing. When platelet suspensions are evaluated for Igs with assays that fail to incorporate a final separation of whole platelets from the suspension fluid, unbound Igs as well as those bound to the platelet surface are measured, which yields a logarithmic overestimation of surface-bound Igs. It has been further demonstrated that patients infected with human immunodeficiency virus type 1 can have elevations of PAIgG, PAIgA, and PAIgM in both the thrombocytopenic and nonthrombocytopenic states. These elevations are due to increased internal platelet pools of Igs and not to increased surface-bound Igs.

A weekly cisplatin-based induction regimen for extensive non-small cell lung cancer. A Southwest Oncology Group study.

The purpose of this Phase II pilot study was to determine whether a dose-intensive regimen of weekly cisplatin combined with other active non-cross-resistant agents would improve the response rate and survival time of patients with extensive non-small cell lung cancer. Patients received cisplatin (50 mg/m2/wk) on days 1, 8, 15, 22, 36, 43, 50, and 57 combined with mitomycin C (8 mg/m2) on days 1 and 36, vinblastine (3 mg/m2) on days 8 and 43, and 5-fluorouracil (5-FU) (1 g/m2) by continuous infusion over 24 hours on days 15 and 50. Responding patients received consolidation therapy with cisplatin and etoposide (VP-16). Of 82 registered patients, 80 were eligible and 77 were evaluable for response. The overall response rate was 23% with 1 patient achieving a complete response (CR) and 17 patients achieving a partial response (PR). The median survival time was 4.6 months. The toxicity profile was not different from that described for standard-dose regimens. Although this regimen does not offer any benefit over standard-dose cisplatin regimens for patients with extensive non-small lung cancer, the weekly schedule permits a dose-intensive regimen with acceptable toxicity for tumors that may benefit from this approach.

Clinical cancer research in Louisiana.

The Ochsner Medical Institutions of New Orleans and Baton Rouge, the Louisiana State Medical Centers in New Orleans and Shreveport, and the Tulane Medical Center of New Orleans are all actively involved in the conduct of National Cancer Institute approved and sponsored clinical trials. Through the efforts of investigators at these institutions, avant-garde, state-of-the-art cancer clinical trials are being made available to the citizens of the state of Louisiana.

Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer. A Southwest Oncology Group Study.

Small cell lung cancer patients who failed primary systemic therapy or who failed after response were randomly assigned to salvage treatment with etoposide (VP-16) and cisplatin (CDDP) or bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide (BTOC). Good risk patients were those who had tolerated prior chemotherapy well, those who had not had prior radiation therapy, and those who were 65 years of age or younger. Patients with a history of poor tolerance, prior radiation therapy, or those who were older than 65 years of age were classified as poor risk. Forty-five patients were randomized to the BTOC regimen and 58 to the VP-16/CDDP regimen. The overall remission rate was 13% (13 of 103 patients). Good risk patients treated with the BTOC regimen had a remission rate of 27% (three of 11 patients), which was the same rate as patients treated with the VP-16/CDDP regimen (three of 11 patients). Poor risk patients had remission rates of 9% (three of 34 patients) with the BTOC regimen and 9% (four of 47 patients) with the VP-16/CDDP regimen. The median survival time from the start of therapy was 16 weeks for all patients. BTOC good risk patients had a median survival time of 10 weeks, as compared with 14 weeks for poor risk patients. VP-16/CDDP good risk patients had a median survival time of 35 weeks, as compared with 12 weeks for poor risk patients. Although based on small numbers, the advantage in survival time for good risk patients treated with VP-16/CDDP over those treated with BTOC is statistically significant. Prior exposure to VP-16 did not influence the outcome of patients treated with VP-16/CDDP. Both regimens produced moderate toxicity, but were generally well tolerated. It was concluded that VP-16/CDDP may be a useful salvage treatment for good risk patients, despite its limited remission rate. Also, it was found that BTOC has no value for patients in this setting and that neither regimen helps patients who are poor risk.

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group Study (SWOG-8037).

Conservative treatment of esophageal cancer with radiation therapy has afforded few long-term survivors. In order to improve outcome, patients with locoregional disease were treated using a combined modality approach. Patients were treated with chemotherapy consisting of a 96-hour continuous infusion of 5-fluorouracil (5-FU), 1,000 mg/m2/d, days 1 to 4 and days 29 to 32; cisplatin 75 mg/m2, day 1 and 29; and radiation 3,000 rad, days 1 to 19. In the absence of progressive disease, patients underwent esophagectomy. One hundred twenty-eight patients were registered of whom 113 were eligible and 106 were evaluable. Toxicity included gastrointestinal (GI) symptoms, mucositis, and myelosuppression. One hundred two patients completed chemoradiotherapy. Following its completion, 11 patients refused surgery, six were considered poor surgical risks, and 14 had progressive disease. Of the remaining 71 patients, 16 had unresectable disease, 13 had residual disease which was incompletely resected, 24 had disease which could be completely resected, and 18 were without disease on pathologic examination. The overall operability rate was 63% and the overall resectability rate, 49%. Surgical mortality was 11%. Eighty-nine of 113 eligible patients have died, with a median survival of 12 months and a 2-year survival of 28%. The median postsurgical survival for all 71 patients was 14 months and was 32 months for those patients attaining complete remission (CR). Combined modality therapy remains an investigational approach. Attempts should be directed at increasing response rate to initial therapy. A randomized comparison between combined modality treatment and radiation therapy is necessary to definitively determine the usefulness of this more aggressive approach.

Mechanisms contributing to the anemia associated with a localized solid tumor.

The anemia associated with a localized solid tumor is a chronic hypoproliferative process referred to as the anemia of chronic disease. Several mechanisms responsible for this anemia have been proposed. A defect in iron reutilization was well accepted until challenged by a report in 1977. Evidence also exists to support bone marrow failure as a contributing factor. Using Wistar rats made anemic by implantation of Walker-256 carcinosarcoma cells, both possibilities were investigated. By injecting heat-damaged and nonviable 59Fe-labeled red cells, a mild but definite defect in the reutilization of iron was established. Bone marrow function was studied in a separate group of tumor-bearing rats by measuring erythron iron turnover. No difference was found between normal and tumor-bearing rats, suggesting relative bone marrow failure in the latter group.

Lung cancer following treatment for lymphoma.

Six patients with lung carcinoma from a group of 206 treated for non-Hodgkin's lymphoma and 82 with Hodgkin's disease are described. Review of the literature shows that an increased risk of solid tumors following treatment for lymphoma has not been conclusively demonstrated. However, some series have reported a relative risk two to three times normal. A few investigators have suggested that there is an increased risk of carcinoma of the lung following treatment for lymphoma. The development of this tumor in six of 288 patients with lymphoma suggests that there may indeed be an association. Patients who have been treated for lymphoma should be observed for development of both hematologic and solid neoplasms. In particular, a patient who is a smoker should be investigated thoroughly for lung carcinoma if suspicious symptoms or new chest radiographic findings develop.

Hemoglobin production in human bone marrow cultures is inhibited by lyophilized coagulation factor concentrates.

Transfusion of blood products may be followed by viral hepatitis and aplastic anemia despite improved techniques for prevention. In view of the need for intensive therapy of hemophilia with blood products, the authors investigated the capacity of these concentrates to influence cultures of human bone marrow cells. Factor VIII concentrates contained a heat-stable dialyzable substance(s) that drastically impaired 59Fe incorporation in normal human bone marrow. Factor IX concentrates had less and cryoprecipitate had no such inhibitory activity. These studies may offer information regarding the effects of various blood products on bone marrow function.

Salvage treatment of unfavorable non-Hodgkin's lymphoma with cisplatin, amsacrine, and mitoguazone: a Southwest Oncology Group Pilot Study.

We tested the combination of cisplatin, amsacrine, and mitoguazone as salvage treatment for patients with advanced unfavorable non-Hodgkin's lymphomas. An objective response rate of 43% was noted in 30 evaluable patients, but all responses were partial and the median duration of response was only 2 months. Toxicity included life-threatening and fatal leukopenia and severe gastrointestinal intolerance. We conclude that this combination chemotherapy regimen is not a valuable salvage treatment for patients with non-Hodgkin's lymphoma.

Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck region: a Southwest Oncology Group Study.

One hundred eligible patients with inoperable, locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were randomized to receive im methotrexate (50 patients) or iv cisplatin (50 patients). Methotrexate produced a complete plus partial response rate of 16.0% and cisplatin produced a partial response rate of 8.0%, with median durations of response of 18 and 8 weeks, respectively. The corresponding median survival times were 20 and 18 weeks. Methotrexate responders survived 60 weeks, versus 17 weeks for nonresponders. The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks. Good pretreatment performance status had a significantly positive effect on survival (P = 0.04), but prior therapy did not. Toxicity secondary to either agent occurred with the expected frequency. The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy.

Southwest Oncology Group study of Mitoxantrone for treatment of patients with advanced squamous cell carcinoma of the head and neck.

Twenty-two patients are evaluable for response in a Phase II trial of Mitoxantrone for advanced squamous cell carcinoma of the head and neck. One patient had a partial response, one an improvement and twenty had progressive disease. The major toxicities were leukopenia and thrombocytopenia. There was no significant antitumor activity of Mitoxantrone in this group of patients with head and neck cancer, most of whom were previously treated with radiation and chemotherapy.

Common anemias: a practical guide to diagnosis and management.

A thorough search for the cause of iron deficiency in the elderly is mandatory. With rare exceptions, iron deficiency in the elderly is due to gastrointestinal blood loss, the most serious and a frequent cause of which is gastrointestinal cancer. A peripheral blood film interpretation often provides important diagnostic clues. This diagnostic clue should not be disregarded.