In a multicenter trial, 123 patients with advanced breast cancer who had been treated with tamoxifen and/or chemotherapy were randomized to receive medroxyprogesterone acetate (MPA) orally 300 mg X 3 daily or im 500 mg daily for 4 weeks and 500 mg X 2 weekly thereafter. All case histories were reviewed extramurally by the criteria of the International Union Against Cancer. Five and 11 patients were not eligible and evaluable for response, respectively. Pretreatment characteristics were well balanced in both treated groups. Twenty-five of all 107 (23%) evaluable patients achieved an objective remission, whereas in a further 15% the disease became stable after previous progression. Results in both treatment arms did not differ significantly. The median duration of objective remission was 12 and 14 months for orally and im treated patients, respectively (P greater than 0.10). No statistically significant differences in the survival times of orally and im treated patients were found. Pretreatment characteristics positively correlated with an objective remission during MPA therapy in both groups were age greater than 50 years (P less than 0.02) and no previous chemotherapy (P less than 0.01). Toxicity included an increase in body weight, cushingoid effects, muscle cramps, and tremors in both groups. In four patients on im therapy, local infections developed. Mean serum MPA levels reached values above 100 ng/ml in nine orally and eight im treated patients (P greater than 0.10), and neither differed significantly in the patients responding to or failing therapy. In both MPA arms, plasma cortisol levels were suppressed. The drop in plasma cortisol levels was more pronounced in patients with objective remissions than in patients who failed (P = 0.04). In conclusion, oral and im MPA in the given doses had similar activity. Im administration of MPA should be reserved for patients not able to take oral medication.
Based upon in vitro and in vivo synergistic activity of Type I and Type II interferons (IFNs) in preclinical in vitro and in vivo studies, we initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of combinations of recombinant DNA-produced human IFN-beta ser and IFN-gamma in 27 patients with cancer. Twenty-four patients were treated with a 2-hour infusion of IFN-gamma, followed by a 10-minute iv injection of IFN-beta ser, three times a week. Patients were entered on fixed dose levels of 1 X 10(6), 3 X 10(6), 10 X 10(6), 30 X 10(6), and 100 X 10(6) units of each IFN. In addition, three patients were treated at the highest dose level with a 10-minute iv infusion of IFN-gamma and a 10-minute iv infusion of IFN-beta ser. The maximally tolerated dose when administered by this schedule for greater than or equal to 4 weeks was 30 X 10(6) units of each IFN. Dose-limiting side effects at doses of 100 X 10(6) units of each IFN consisted of fatigue, nausea, vomiting, anorexia, paralytic ileus, and neutropenia. The most common side effects at the three highest dose levels were fever, rigors often requiring parenteral meperidine, and constitutional symptoms. Reversible elevations in SGOT and LDH were also noted. Serum IFN levels were dose related, with peak titers occurring immediately after IFN administration. One patient with a nodular mixed lymphoma had a partial response which has been sustained for over 1 year. We conclude that combinations of IFN-beta ser and IFN-gamma can be safely administered on a chronic basis without enhanced or cumulative toxic effects.
Retinoids, the synthetic and natural analogs of vitamin A, frequently block the phenotypic expression of cancer in vitro; they also inhibit growth and induce differentiation in many animal and human malignant cell types. Only recently has it become possible to propose a unifying mechanism of retinoid action, which involves the protein kinase-C cascade system. This system may mediate retinoids' many diverse actions, including their effects on enzyme synthesis, membrane properties, growth factors, binding proteins, genomic and postgenomic expression, the extracellular matrix, and immunologic responses. Ongoing in vitro studies of retinoid structure-activity relationships, effects on oncogene expression, reversal of drug-resistance, and, especially, the protein kinase-C cascade system should help clarify the precise mechanism of their anticancer action. Many in vitro and in vivo assay systems are available for testing the 2000 + synthetic retinoids. These assays indicate specific drug sensitivities, which may help focus future clinical trials. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, and basal cell carcinoma; however, nondermatologic premalignancies, such as oral leukoplakia, bronchial metaplasia, laryngeal papillomatosis, cervical dysplasia, myelodysplastic syndromes, and the urinary bladder, also respond to retinoid therapy. Significant therapeutic advances are also occurring with this class of drugs in refractory malignancies, including advanced cutaneous squamous and basal cell cancer, mycosis fungoides, and acute promyelocytic leukemia. Newer third-generation retinoids, such as the highly potent retinoidal benzoic acid derivatives, are demonstrating therapeutic indexes far higher than earlier-generation retinoids. Current in vitro testing is also demonstrating that retinoids have synergistic activity in combination with other agents (eg, biologic modifiers, hormones, and DNA synthesis inhibitors) and treatment modalities (eg, irradiation). Notwithstanding the progress already made with retinoids in human cancer, many in vitro questions remain, and clinical work is just beginning.
Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted at all dose levels, whether or not the bone marrow was involved with tumor. Of 39 evaluable patients, 37 had grade 3 or 4 hematologic toxicity. Nonhematologic toxic effects were infrequent and not severe. Two complete responses (Hodgkin's disease, rhabdomyosarcoma), eight partial responses, and 30 failures were seen. There appeared to be a very narrow margin between efficacy and toxicity. Further study of melphalan in pediatric tumors may be warranted in special circumstances: in higher doses (greater than 100 mg/m2) as cytoreduction therapy for specific cancers with marrow rescue, or as part of combination therapy in certain cancers (eg, lymphoma, sarcoma), possibly at doses of 20 to 30 mg/m2 every 4 weeks.
Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Early disease recurrence, rather than excessive toxicity and complications resulting in limitation of therapy is the major factor responsible for this disappointing outcome. The CCG-192P trial was a groupwide pilot study of the Childrens Cancer Study Group for the treatment of ALL in patients at high risk for relapse, which was defined by wbc count greater than 50 X 10(3)/microliters at diagnosis. Because of the recognized poor prognosis, all infants less than 1 year of age were entered in this study regardless of wbc count at diagnosis. Therapy included intensive induction and consolidation followed by a cyclic, sequential maintenance program. The CNS prophylaxis consisted of intrathecal chemotherapy and cranial irradiation, which was deferred until patients were greater than 1 year of age. During the period January 1982 to January 1984, 27 infants ranging in age from 2 days to 11 months who had ALL were entered in this study; 71% had wbc counts greater than 50 X 10(3)/microliters, and 23% presented with CNS leukemia. Complete remission was achieved in 93% of the patients. The median duration of remission is 17 months. With a median follow-up of 43 months, the life-table estimate of event-free survival (EFS) is 36% at 4 years. A recently reported historical control group of infants with ALL who were treated with previous Childrens Cancer Study Group protocols demonstrated a median remission duration of 8 months and an estimated EFS of only 21% at 4 years. Toxicity and therapy-related complications were not observed more frequently in infants than in older patients treated with this protocol. However, EFS of infants was significantly worse than that of patients greater than 1 year of age (P = less than 0.001). All four CNS relapses occurred in patients who had received cranial irradiation. A wbc count less than 50 X 10(3)/microliters at diagnosis demonstrated significance (P = 0.03) as a favorable prognostic indicator in this small patient sample. Although these data are preliminary, they suggest that intensive therapy is reasonably well tolerated by infants and results in prolongation of remission duration and improved EFS.
Fourteen previously untreated patients with metastatic small cell lung carcinoma (SCLC) were treated with carboplatin, 400 mg/m2, given as a 1-hour infusion every 28 days. Eleven patients had a partial response to therapy [response rate, 79% (95% confidence limits, 57%-100%)]. The median duration of response was 8 weeks (range, 4-41) and the median survival was 29 weeks (range, 11-68+). Hematologic toxicity was limited to one patient who developed World Health Organization (WHO) grade IV thrombocytopenia; no patient developed infection due to granulocytopenia. Nonhematologic toxicity was limited to WHO grade I and II nausea and vomiting. This study demonstrates that carboplatin is a highly active drug in SCLC with minimal toxicity. Future studies should evaluate its use in combination with other chemotherapeutic drugs in SCLC.
In 1975, the Southwest Oncology Group initiated an adjuvant study in localized malignant melanoma testing the value of aggressive chemotherapy using carmustine, hydroxyurea, and dacarbazine versus a control arm. Median disease-free survival was 7.1 years for the control arm and 6 years for the treatment arm. Survival was identical for both arms with 65% of the patients alive at 6 years. We conclude that carmustine, hydroxyurea, and dacarbazine chemotherapy is of no value as adjuvant treatment for localized melanoma.
Central vein thrombosis is the major Hickman catheter complication in our patient population. After noting clots attached to the disposable infusion plug of these catheters, we prospectively determined whether the presence of clots indicated a high-risk group for thrombosis. Forty-three patients (41 with solid tumor, two with acute leukemia) were studied. Catheters were flushed daily with heparin (10 units/ml), and urokinase (5000-10,000 units) was injected when blood could not be drawn. Clots within the catheter lumen were detected visually after expressing, onto a 4 X 4-inch gauze pad, the first 5-10 ml of admixed blood and flush solution or iv infusion fluid drawn from the catheter prior to blood drawing. Clots were detected in 153 of 508 specimens (30%). Forty of 43 patients had clots, varying in length from fragments to 5 cm, in at least one specimen. Inpatients and outpatients had a similar percentage of clotted specimens. Eight patients developed clinical (six) or autopsy-proven (two) thrombosis. There was no difference between patients with and without thrombosis in percent of discards positive for clots. This study indicates that clots are frequently present in the lumina of Hickman catheters. It is likely that these clots embolize to the lungs when catheters are flushed. Consequences of embolization are unknown.
A total of 39 women with metastatic breast cancer entered a pilot phase II study of the vindesine-mitoxantrone-mitomycin (VMMc) combination chemotherapy. Most of them had received previous chemotherapy [including doxorubicin (27 patients)] for their primary or metastatic disease. The VMMc drugs were given at usual doses. Hematologic side effects were the most serious, leading mainly to leukopenia (five episodes of infection were successfully treated). A 33% partial response rate was obtained (95% confidence limits, 18%-48%), with a median duration (not yet reached) of greater than 510 days (range, 150-720) for the overall population. The median for pretreated patients was greater than 420 days (range, 150-720) which compares favorably with those previously reported in similar patients treated by mitomycin and vindesine or vinblastine.
An in vitro tetrazolium dye (MTT) reduction technique was modified and evaluated for use in the large-scale screening of anticancer compounds by examining the activity of ten clinically used drugs against 16 different human and murine cell populations. Cell populations included colon and mammary adenocarcinomas, melanomas, leukemias, and freshly isolated normal cells. Cell lines were grown in microtiter plates for 18-20 hours prior to a 72-hour continuous exposure to the drugs. Cultures were initiated at cell densities which maximized both the difference in dye reduction and the number of cell doublings between the beginning and end of the drug exposure period. Drug potency, expressed as the 50% inhibitory concentration (IC50), was comparable whether the effect on cell doublings or dye reduction was determined. There was good agreement between this method and the more labor-intensive, conventional method of counting trypan blue dye-excluding cells in a hemacytometer. Implemented as a large-scale, high-capacity system, our adaptation of the MTT technique is a rapid, sensitive, reproducible first-line screening device for detecting anticancer compounds with cytostatic or cytocidal activity.
