Timothy J. Panella

Phase II Trial of a Single Weekly Intravenous Dose of Ranpirnase in Patients With Unresectable Malignant Mesothelioma

PURPOSE A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible. PATIENTS AND METHODS One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival. RESULTS Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths. CONCLUSION Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.

Anti-human immunodeficiency virus synergism by zidovudine (3'-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells.

The anti-human immunodeficiency virus (HIV) activity and hemopoietic toxicity of zidovudine (AZT) and didanosine (dideoxyinosine;ddI), alone and in combination, were assessed in a variety of cell types. AZT was more potent than ddI as an inhibitor of HIV in vitro. Synergistic inhibition of HIV by the combination of these agents was observed in MT4 cells, peripheral blood lymphocytes, and macrophages. Toxicity assessment in vitro by using progenitor (erythroid and granulocyte-macrophage) colony-forming assays with normal human bone marrow showed ddI to be less toxic than AZT. Addition of inhibitory concentrations of ddI to AZT resulted in additive inhibition of progenitor CFUs. These in vitro findings suggest that combinations of ddI and AZT at appropriately modified doses may provide an enhanced degree of selectivity in anti-HIV chemotherapy.

A phase I/II trial of twice daily irradiation and concurrent chemotherapy for locally advanced squamous cell carcinoma of the head and neck

PURPOSE This study was designed to test the toxicity and efficacy of a regimen of twice daily irradiation and concurrent multiagent chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck. METHODS AND MATERIALS This was a prospective Phase I/II trial. Patients received 125 cGy b.i.d. to 7000 cGy with a 6 hr interfraction interval. Chemotherapy was given during weeks 1 and 6 of irradiation and consisted of a 5 day infusion of 5-fluorouracil at 600 mg/M2/day and 5 daily injections of cisplatin at 12 mg/M2/day. Two additional cycles of chemotherapy were given after the completion of radiotherapy. RESULTS Forty-six patients were evaluable: 28 had technically unresectable disease and 18 had resectable tumors. All had Stage III or IV disease: 84% had T3 or T4 primaries while 53% had > or = N2 neck disease. The primary acute toxicity, confluent mucositis, was seen in 74% of patients. Late side effects occurred in four patients. Median follow-up is 36 months (range 25-44 months). Kaplan-Meier estimates of 2-year disease-free survival and overall survival are 65% and 73%, respectively, while 2-year local regional control and distant disease-free survival are 72% and 88%, respectively. Multivariate analysis revealed that resectability and receiving > 2 cycles of chemotherapy significantly influenced local regional control while age < 60 significantly influenced disease-free survival. CONCLUSION This form of treatment can be delivered safely. The encouraging results have led to the initiation of a Phase III trial comparing this regimen with b.i.d. radiation alone.

Paraneoplastic Hepatopathy Associated With Soft Tissue Sarcoma

Paraneoplastic syndromes associated with mesodermal tumors are relatively uncommon. An unusual case manifested by fever, anemia, thrombocytosis, coagulopathy, and idiopathic cholestatic liver dysfunction in association with soft tissue sarcoma is reported. A paraneoplastic syndrome is postulated in the absence of anatomic obstruction of bile flow, evidence of an infectious etiology, or neoplastic hepatic involvement.

Phase II study of Didemnin B in central nervous system tumors: A Southwest Oncology Group study

Didemnin B 6.3 mg/m2 was administered intravenously to 48 patients with recurrent or progressive central nervous system tumors. One patient of 39 (2.9%, 95% confidence limits 0.1 to 13.5) eligible patients had a confirmed partial response utilizing standard solid tumor criteria which lasted 14 months. Toxicity was significant. Nausea and vomiting and lethargy were the most frequent toxicities, but multiple severe toxicities were seen. Further investigation of Didemnin B at this dose is not warranted in patients with central nervous system malignancies.

Phase II Trial of Pyrazoloacridine in Advanced Non-Small Cell Carcinoma of the Lung: A Kansas Cancer Institute and Thompson Cancer Survival Center Study

AbstractBackground: More active agents areneeded in the treatment of metastaticnon-small cell lung cancer. Pyrazoloacridine (PZA) is a 9-methoxyacridine compound containing a reducible5-nitro substituent. Although themechanism of action of PZA is unknown, theacridine compounds are known to causecytotoxicity by interaction with DNA andRNA. Methods: Eighteen patients withmetastatic non-small cell lung carcinomawere treated with pyrazoloacridine.Pyrazoloacridine was administered as athree-hour infusion at 750 mg/M2 every21 days. Results: There were no objectiveresponses. One patient maintained stabledisease for 20 months. Median survival was4.8 months. The primary toxicity wasgranulocytopenia with 5 patientsexperiencing severe infections. Conclusions: Pyrazoloacridine has nodemonstrable activity in patients withmetastatic non-small cell carcinoma of thelung when given at this dose andschedule.

Absence of phosphatidylinositol (PI)‐linked proteins in a very early human multipotential haematopoietic marrow cell

A very early human haematopoietic progenitor cell population which was negative for the major histocompatibility class II antigen (HLA‐DR) and positive for the CD34 (MY10) antigen was separated into two subsets according to the expression of decay‐accelerating factor (DAF) on the cell surface. Using immunoadherence, cell cycle analysis, and cell culture, we determined that there is a DAF− multipotential cell and a more differentiated DAF+ lineage specific progenitor cell existing in human bone marrow. The DAF+ subset was highly enriched for CFU‐GEMM, while the DAF+ subset contained only BFU‐E and CFU‐GM. The DAF− subset was approximately 0·03% and the DAF+ subset approximately 0·0·08% of the original bone marrow population. MIRL (membrane‐inhibitory of reactive lysis), another Pl‐linked protein, was not expressed on the DAF− population but was expressed on the DAF+ cells. These observations indicate that PI‐linked proteins are absent from the multipotential stem cell but are present on an early lineage specific cell. The absence of expression of PI‐linked proteins can be used to further isolate and characterize a very early multipotential haematopoietic progenitor cell population.

Nasopharyngeal Carcinoma: 1990

Nasopharyngeal carcinoma (NPC) is a malignancy of considerable interest and importance, not only because of its major impact on specific populations, such as Cantonese Chinese and North Africans, but also because of the accumulating information allowing a better understanding of the relative contribution of environmental and genetic factors in this tumor which is believed to have Epstein-Barr virus (EBV) as a necessary etiologic agent. The greater impact of this disease in developing countries, where application of new clinical and laboratory tools is difficult, has undoubtedly delayed progress in controlling NPC, but the development of multidisciplinary studies on an international basis has led to significant improvements in early detection, treatment, and understanding of disease pathogenesis. In this report, we will summarize some of the recent advances that hopefully will lead to the control of this neoplasm.