Search

Background: Recent clinical trials establish a beneficial effect for adjuvant chemotherapy after surgical resection of the primary tumor (1) as single treatment for patients with colonic cancer and (2) combined with radiation therapy for patients with rectal cancer. Because adjuvant chemotherapy is not universally effective and is associated with toxicity and some degree of risk, it would be desirable to supplement standard pathologic staging criteria to define more precisely the subset of patients at high risk for tumor recurrence who would benefit most from adjuvant therapy. Tumor cell DNA content and cell proliferation measured by flow cytometry were identified as important and independent prognostic factors for patients undergoing curative resection of colorectal cancer. Basic laboratory investigations show a series of more specific molecular and genetic abnormalities that might provide better prognostic discrimination. Recent molecular studies suggest that the process of tumorigenesis in colorectal cancer proceeds through a series of genetic alterations that include both dominant and recessive protooncogenes. Characterization of these molecular genetic abnormalities may provide valuable prognostic information for use in patient management., Methods: Allelic loss was studied for chromosomes 5, 17, and 18, and immunohistochemical analysis was done of the p53 protein product in tumors from 91 patients with colorectal cancer., Results: Preliminary analysis of disease-free survival after surgical resection in 60 patients with Dukes' B or C tumors suggests a poorer prognosis associated with allelic loss on chromosome 18q (P = 0.08)., Conclusions: Additional studies involving a much larger population of patients with Dukes' B and C colorectal cancer are needed to define the true prognostic significance of these molecular markers.

We performed a Phase I assessment of recombinant human tumor necrosis factor (rTNF-alpha) in 27 patients with advanced solid neoplasms. Therapy consisted of a 30-minute intravenous (IV) infusion on days 1 through 5, every 2 to 3 weeks. Daily doses ranged from 5 micrograms/m2 to 200 micrograms/m2. Dose-limiting sequelae were hypotension, rigors, and phlebitis. Transient fatigue and fever (median, 38 degrees C) were not clearly dose-related between 5 micrograms/m2/d and 150 micrograms/m2/d. Other reversible complications in three patients included transient leukopenia (leukocyte count, 1.3, 1.2 X 10(3)/microliters in two patients) at a dose of 5 micrograms/m2/d and 150 micrograms/m2/d, respectively; and thrombocytopenia (leukocyte count, 73 X 10(3)/microliters) at 10 micrograms/m2/d. Among 22 patients with initial and subsequent differential counts, the median number of eosinophils at the commencement of therapy was 182 cells/microliters compared with a subsequent median of 462 cells/microliters. We also detected hypertriglyceridemia in all patients. The median baseline increased from 93 mg/dl (range, 56 to 219 mg/dl) to 203 mg/dl (range, 94 to 454 mg/dl). From our experience, a clinically manageable outpatient regimen for Phase II trials consists of rTNF-alpha (150 micrograms/m2) followed by a 1-hour IV infusion of 500 ml of normal saline to abrogate hypotension daily for 5 days every 2 weeks for four cycles, then every 3 weeks thereafter to facilitate recovery from constitutional sequelae.

Indicine N-oxide is the first member of the large class of compounds comprised of pyrrolizidine alkaloids and their N-oxides to be studied in the treatment of cancer in humans. Twenty-two patients with refractory acute leukemia received indicine N-oxide daily for 5 consecutive days in a dose-seeking study. Of eight patients with refractory acute lymphocytic leukemia, one had a complete remission, and one had a partial remission. Of 11 patients with refractory acute nonlymphocytic leukemia, 2 patients had complete remissions. Of three patients with blast crisis of chronic granulocytic leukemia, one patient had a partial remission. Five patients had severe hepatic toxicity, probably due to veno-occlusive disease induced by the drug. Whether hepatotoxicity and antileukemic activity are a result of the same mechanism of action of indicine N-oxide is not known.

Indicine N-oxide, the first pyrrolizidine alkaloid N-oxide to be studied in the treatment of cancer in humans, was administered to ten patients: four children and two adolescents with refractory acute lymphocytic leukemia and four adults with refractory acute nonlymphocytic leukemia (three acute myelocytic, one myelomonocytic). Two patients, a 4-year-old boy with acute lymphocytic leukemia and a 22-year-old man with acute myelocytic leukemia, achieved complete remission lasting 3 and 5+ months, respectively. Another 15-year-old male with acute lymphocytic leukemia had a partial remission for four months. Toxicities included bone marrow suppression, mild anorexia and nausea, and transient elevation of liver enzymes. Jaundice and liver failure, presumably induced by drug, occurred in two patients.

The authors designed a clinical trial to assess the impact of aspirin (ASA) (600 mg four times daily) on the constitutional sequelae of recombinant leukocyte A interferon (IFN-alpha 2A), 20 X 10(6) U/m2 thrice weekly, in 29 patients with advanced renal cell cancer (RCC). Aspirin provided no meaningful amelioration of side effects compared to our prior experience of IFN-alpha 2A alone. Interestingly, the objective response rate of 34% (10/29) was considerably higher than the 15% recently reported from an aggregate of 344 patients participating in 14 prospective clinical trials. In light of small numbers, subtle selection biases, and the well-recognized hazards of retrospective analyses, currently it is unclear if the apparent therapeutic advantage from ASA plus IFN-alpha 2A reflects chance occurrence or therapeutic potentiation from ASA. A randomized trial is planned to determine if ASA may have enhanced the efficacy of IFN-alpha 2A in patients with advanced RCC.

This article reports a Phase I study of combined therapy with N-(phosphonacetyl)-L-aspartate (PALA) and L-alanosine in 26 patients with advanced cancer. Each agent exhibits antitumor effect by enzyme inhibition: PALA blocks pyrimidine biosynthesis by impeding aspartate transcarbamylase and L-alanosine depletes purine nucleotides by interfering with adenylosuccinate synthetase. These agents were selected for clinical investigation in light of synergistic cytotoxicity in vitro against human tumor cell lines and in vivo against P-388 murine leukemia resistant to cytosine arabinoside. Dose-limiting toxicities were stomatitis and diarrhea to a lesser extent. There was no substantial myelosuppression. The authors recommend either of two intravenous regimens for studies of therapeutic activity in selected patients with neoplastic diseases: a one-day treatment repeated of PALA, 5.0 g/m2 and L-alanosine, 3.0 g/m2, repeated every 3 weeks; or a monthly program of PALA, 500 mg/m2/d 1-5 and L-alanosine, 60 mg/m2/d 1-5.

Chlorozotocin was administered by rapid intravenous infusion to 35 patients with advanced cancer on either single-day of five-consecutive-day schedules. Total doses per course ranged from 12.5 to 200 mg/m2. On either administration schedule, dose limiting toxicities were thrombocytopenia and leukopenia at total doses of 150 mg/m2 to 200 mg/m2. Repetitive courses of drug may produce progressive impairment of renal and bone marrow function. Nausea and vomiting were infrequent and mild without definite relationship to dose. Minor reversible nondose related increases in SGOT and in serum creatinine occurred at all doses on both schedules. The plasma half-life of intact N-nitroso groups averaged 9.5 minutes after rapid intravenous administration of doses up to 40 mg/m2 and 12.5 minutes after doses of 150 or 200 mg/m2. No differences between plasma half-lives were seen between identical doses given on the first and fifth days of the five-day schedule. Objective tumor regression was noted in one patient with bronchogenic large cell carcinoma and one patient with metastatic melanoma.