Toxicity comparisons between two chemotherapy regimens as adjuvant or salvage treatment in nonseminomatous testicular cancer.

The Testicular Cancer Intergroup Study was initiated to evaluate the efficacy of adjuvant chemotherapy in Stage II and salvage therapy in Stage I nonseminomatous testicular carcinoma. Chemotherapy regimens of cisplatin, vinblastine, and bleomycin (PVB) or the same drugs plus cyclophosphamide and dactinomycin (VAB) were used at institution or cooperative group preference. A comparison of the toxicities of these two regimens shows that VAB caused significantly more mucosal, dermatologic, and otologic toxicity than PVB, and PVB caused more leucopenia. Both regimens were equally effective in controlling cancer. Either regimen could be used as chemotherapy in testicular cancer, and the decision about which one to use could be based on their differences in toxicity and degree of patient convenience.

Eastern Cooperative Oncology Group: a comparison of adjuvant doxorubicin and observation for patients with localized soft tissue sarcoma.

Forty-seven patients with stage I, II, or III soft tissue sarcoma were entered into a prospective randomized Eastern Cooperative Oncology Group (ECOG) adjuvant protocol. Eligibility included conservative or radical primary treatment for local cure. Patients were then randomized to control or Adriamycin (Adria Laboratories, Columbus, OH). Adriamycin was administered at 70 mg/m2 (slow push, every 3 weeks for seven courses for a maximum of 550 mg/m2). To date, 32 patients, 17 males and 15 females, with an age range of 17 to 75 years (median, 44 years) have been followed sufficiently long to be included in this analysis. Nine patients have died. The median follow-up of the remaining 23 patients is 30 months (range, 2 to 50 months). Survival was not significantly different between Adriamycin or control. However, the disease-free interval was slightly different in favor of observation. This preliminary report does not support the hypothesis that Adriamycin is an effective adjuvant therapy for soft tissue sarcoma. Due to the small numbers, these results must be interpreted in relation to our ability to detect a difference, if in fact one existed. These preliminary data suggest that adjuvant Adriamycin not be used outside the confines of a clinical trial such as the current intergroup adjuvant sarcoma study.

The National Cancer Institute's Cancer Prevention Research Program.

The National Cancer Institute (NCI) develops and supports a broad range of research relevant to screening for preneoplastic events and biological effects of carcinogen exposure. In cancer screening and detection, NCI supports studies on development of new methods for detecting cancer and/or preneoplastic states, systematic testing of new screening methods, and wider application of established methods. Recently, NCI developed clinical trials in chemoprevention and dietary intervention. These studies focus on populations identified by markers of exposure or markers of increased risk, and have as their end point reduction in cancer incidence.

Clinical trials in cancer prevention.

Research in cancer prevention can be divided into laboratory research, epidemiologic research, and clinical trials. When results from laboratory and/or epidemiologic research support the possibility of clinical cancer prevention, these leads should be subjected to study in clinical trials. If clinical trials produce positive results, wide application of these results to the relevant segments of the general population should then be emphasized. Why are clinical trials needed in cancer prevention? There are several considerations: epidemiologic studies may lack specificity, that is, the ability to reach conclusions that apply to only one specific factor; the predictive value of animal models based on laboratory studies is not entirely known; clinical trials quantitate the level of participant acceptance of the intervention; and clinical trials address the issues of risk/benefit ratios. Over the last 3 years, the National Cancer Institute has supported the development of a program of clinical trials in cancer prevention. The aim of these studies includes the reversal of precursor lesions, prevention of progression from a precursor state to overt malignancy, reduction in the incidence of malignancy, reduction in cancer mortality, and reduction in overall mortality. Interventions under study include a diet with less than 20% of calories from fat, and the administration of single agents or combinations of agents, including beta carotene, vitamin A, 13-cis-retinoic acid, vitamins C, E, and B12, and folacin.

A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma.

A randomized evaluation of the effectiveness and toxicity of the combination of doxorubicin and cisplatin and of doxorubicin alone in patients with advanced thyroid carcinoma was carried out. Ninety-two patients were entered and 84 were evaluable. They were stratified according to histological classification, Eastern Cooperative Oncology Group (ECOG) performance status, and metastatic sites. Forty-one patients received doxorubicin as a single agent and seven had partial response (17%). Forty-three patients received the combination, and there were five complete and six partial responses (combined response rate of 26%). This difference for overall response rate is not significant (P greater than 0.1). However, five complete responses were seen in the combination-treatment group, whereas none were observed in the single-agent treatment group; a significant difference was obtained (P = 0.03). Four of these five complete responders survived for more than 2 years, and two patients remained in a complete response after the discontinuation of therapy and are still alive. None of the partial responses exceeded 2 years in duration. The life-threatening toxicities from chemotherapy occurred in five patients treated with the combination of drugs and two treated with doxorubicin alone. However, none of the toxicities were fatal. The study has shown clearly that the quality of response achieved by the combination of drugs is far superior to that achieved by single-agent chemotherapy.

Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer.

During a randomized trial of total parenteral nutrition (TPN) in patients with small cell lung cancer, we evaluated the short- and long-term effects of 4 weeks of TPN on nutritional assessment parameters. All 119 patients who were accrued to the study received the same chemotherapy and radiotherapy protocol which extended over a 1-year period: 57 patients received TPN; and 62 served as controls. At base line, patients with greater than 5% pretreatment weight loss had significantly lower levels of serum albumin, total iron-binding capacity, and creatinine/height index. TPN administration led to a significant increase in mean caloric intake and weight compared with controls (P less than 0.0001). In the short-term study, body fat, as measured by triceps skinfold thickness, was maintained, and there was a small increase in arm muscle circumference. Serum albumin and hematocrit decreased but promptly returned to pretreatment levels when TPN was stopped. There were no long-term differences in any of the nutritional assessment parameters between the two groups.

Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract.

From October 1978 to October 1981, 135 patients with disseminated transitional cell carcinomas of the urinary tract, with either measurable or evaluable disease, were randomized to receive either cis-diamminedichloroplatinum (DDP) or cyclophosphamide (CTX), Adriamycin (ADR) (Adria Laboratories, Columbus, Ohio), and DDP (CAD). DDP was given at a dose of 60 mg/m2, CTX at 400 mg/m2, and ADR at 40 mg/m2 intravenously every three weeks. Patients over the age of 65 and those with prior radiation received 75% of the dose initially. The dose was escalated if only mild toxicity developed. Of the patients on the CAD arm, 34% developed grade 3 or 4 hematologic toxicity, as compared to 3% in patients on the DDP therapy. Of the 93 patients with measurable disease, 48 received DDP. Seventeen percent had a partial or complete remission, as compared to 33% of the 45 patients on the CAD arm (P = .09). The crude median survival of patients on DDP was 6.0 months as compared to 7.3 months in patients receiving CAD (P = .17). We conclude that the CAD combination is more toxic than DDP with, at best, very marginal benefit in survival.

Effect of adjuvant central iv hyperalimentation on the survival and response to treatment of patients with small cell lung cancer: a randomized trial.

The effect of central iv hyperalimentation (IVH) as an adjunct to aggressive antineoplastic therapy for small cell carcinoma of the lung was evaluated in a randomized trial with 119 evaluable patients. IVH was given over a 28-day period with higher caloric and protein intake for patients nutritionally depleted on entry in the study; all patients were escalated in caloric and protein intake to maximize nutritional repletion. Combination chemotherapy and radiation therapy induced a 45.5% complete response rate and an overall response rate of 92.8%. Median survival for patients with limited disease was 18 months; median survival for patients with extensive disease was 11 months. Patients randomized to receive IVH did not have a better response rate (P = 0.97) or survival (P = 0.78) than control patients. IVH did not significantly alter the survival for patients who at baseline had greater than 5% pretreatment weight loss, low caloric intake, decreased serum albumin, or reduced total iron-binding capacity. Significantly more febrile episodes were seen in IVH patients than in control patients (P less than 0.001). Short-term IVH to patients with this malignancy who are capable of enteral alimentation cannot be routinely recommended as adjunctive therapy.

Report on Clinical Nutrition Research Units.

The National Institutes of Health support seven Clinical Nutrition Research Units, which are designed to create or strengthen nutrition research, training, and education through coordinated effort, intellectual stimulation, and use of shared resources. Research at the participating institutions focuses on the role of nutrition in cancer, cardiovascular disease, renal disease, digestive diseases, cystic fibrosis, diabetes, and other illnesses. Contributing substantially to the development of this nutrition research base have been Clinical Nutrition Research Unit-supported pilot studies, core laboratories, and new investigators. In the clinical setting, Clinical Nutrition Research Unit Nutritional Support Services assist in the care of patients receiving total parenteral nutrition and those with anorexia nervosa, burns, cancer, and a spectrum of nutrition-related problems. Participation of Clinical Nutrition Research Unit staff in training activities range from undergraduate, graduate, and postgraduate education courses for medical students and other health professionals to continuing education workshops, lecture series, and information programs for professional and lay audiences.

Treatment of metastatic prostate cancer. An analysis of response criteria in patients with measurable soft tissue disease.

Evaluation of response to systemic therapy in metastatic prostate cancer is often difficult because of the infrequency of nonbony indicator lesions. The authors previously described a set of response criteria for Phase II and III studies which can be applied in patients with only bony disease. They have retrospectively evaluated response to Adriamycin (doxorubicin) and (5-fluorouracil) 5-FU in 38 patients with measurable soft tissue and visceral disease, using their response criteria for acid phosphatase and clinical status and standard definitions of response. No correlation was attempted for bone disease. Agreement between the results obtained with each system was good. Using this system of evaluating response, patients with metastatic prostate cancer with bone-dominant disease are eligible for Phase II and III studies.

Serum folate and vitamin B12 levels in patients with small cell lung cancer.

Serum folate and vitamin B12 levels were evaluated in 80 patients with small cell lung cancer at diagnosis and during therapy over a 30-week period. Approximately one half of the patients were randomized to receive hyperalimentation. Folate and vitamin B12 intake was adequate without parenteral nutrition in these cancer patients. Serum folate and Vitamin B12 levels did not correlate with disease extent. At the initiation of therapy, serum folate declined with increasing weight loss. During therapy, the intake of folate was adequate to maintain a normal serum folate despite marked weight loss.

A comparative clinical trial of adriamycin and 5-fluorouracil in advanced prostatic cancer: prognostic factors and response.

In patients with metastatic hormone-relapsed adenocarcinoma of the prostate, adriamycin was compared to 5-fluorouracil in a randomized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients. Response to adriamycin was superior as judged by response of measurable disease (25 vs 8%; P less than 0.05) and survival (median 29 vs 24 weeks; Cox analysis, P less than 0.03), but comparable as judged by acid phosphatase response. Ambulatory status and site of metastases influenced rate of response to chemotherapy. Activity level, site of metastases, weight loss, and the symptom of protein aversion were prognostic factors for survival. Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily. Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy.

Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group Trial.

Patients with advanced breast carcinoma and no prior chemotherapy were prospectively evaluated to assess the induction capabilities of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), Adriamycin and vincristine (AV), and CMF plus prednisone (CMFP). The crossover responsiveness from CMF or CMFP to AV and of AV to CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF and 86 on CMFP induction. One hundred and twelve patients were evaluated on crossover. Induction response rates were similar with 56% on AV, 57% on CMF and 63% on CMFP. Crossover response rates ranged from 32% to 41%. CMFP and AV were superior to CMF in terms of response duration (P = 0.05), and CMFP was superior to either in terms of time to treatment failure (P = 0.04), and survival (P = 0.03). Treatment failures occurred in only the on-study organ sites of disease in 73% of the patients and did not appear to be related to the response achieved. CMF was associated with more thrombocytopenia than either AV or CMFP (P = 0.03). AV was associated with fewer infections than CMFP (P = 0.02), less diarrhea than CMFP (P = 0.04), more emesis than CMF (P = 0.02), and more neurologic toxicity than either CMF or CMFP (P less than 0.0001). There was also more emesis with CMF than with CMFP (P = 0.006). CMFP was associated with greater delivery of CMF than was the CMF regimen despite a similar day 1 leukocyte distribution. These results strongly suggest that CMF(P) and AV are clinically noncross-resistant regimens, that AV and CMF are essentially equivalently active induction regimens, and that CMFP is superior to CMF and AV.

Cyclic adenosine 3':5'-monophosphate-dependent protein phosphorylation and the control of leukemia L1210 cell growth.

Synergistic increases in the survival of mice bearing an L1210 leukemia tumor have been demonstrated previously after treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea together with theophylline over those treated with either agent alone. These results imply that manipulation of cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels in L1210 cells may result in alteration of sensitivity to chemotherapy and alterations in tumor growth. In the present study, we have shown that in vivo treatment of L1210 cells with theophylline results in changes in intracellular cyclic AMP-dependent protein kinase activity levels as well as in an apparent redistribution of both the nuclear and cytoplasmic isozymes. Biochemical events in the tumor cells immediately after administration of theophylline in vivo or a cyclic AMP analog (8-parachlorophenylthio cyclic adenosine 3':5'-monophosphate in vitro were independent of the presence of 1,3-bis(2-chloroethyl)-1-nitrosourea. The changes apparently involve signal transduction via the adenylate cyclase system and manifest as: (a) increased sensitivity of cyclic AMP-dependent protein kinase to activation by cyclic AMP after treatment of L1210 cells with theophylline; (b) decrease in endogenous nuclear protein phosphorylation sites; and (c) protein kinase isozyme redistribution between nuclear and extranuclear compartments, i.e., a relative increase of the type I isozyme activity in the nuclear and of the type II isozyme activity in the 900 x g supernatant fractions after treatment of the mice with theophylline. The relative activity increases are accompanied by a relative decrease of type II activity from the nucleus and type I isozyme activity from the 900 x g extranuclear supernatant fraction. These events appear temporally related to changes in nuclear RNA metabolism as evidenced by altered kinetics of RNA precursor uptake and incorporation into tumor cell RNA after treatment. These results imply that the cyclic AMP-dependent phosphorylative modification of intracellular proteins may play a regulatory role in tumor cell growth and in theophylline-mediated tumor regression.