NCI Study Research Articles

Phase II study of dose-adjusted EPOCH-R in untreated de novo CD20+ diffuse large B-cell lymphoma (DLBCL)-CALGB 50103

6530 Background: DA-EPOCH-R is a rationally designed regimen based on schedule optimization and pharmacodynamic dosing. Studies suggest it overcomes adverse effects of tumor proliferation and bcl-2 in de novo DLBCL and adjusts for differences in patient drug clearance. An NCI study in 83 untreated de novo DLBCL patients shows a PFS and OS of 82% at 32 months median follow-up and no relapses beyond 2 years. PFS is 94% for low (0–2) and 57% for high (3–5) IPI at 3 years. Hence, CALGB undertook a confirmatory phase II study. Methods: Eligibility: untreated de novo CD20+ DLBCL; ≥ 18 years; stage II-IV; ECOG PS 0–2; and adequate organ function unless due to disease. Patients received DA-EPOCH-R + filgrastim for 6–8 cycles, based on response, and no patients received radiation. Endpoints were PFS, OS and toxicity. Study design is a cooperative group prospective phase II. Results: Of 78 patients, 5 were ineligible. Patient characteristics are median age (range) 58 (23–80) years, and IPI of low (0–2) in 60% and high (3–5) in 40% of patients. Treatment was administered in 18 centers and toxicity assessed in 72 patients. The pharmacodynamic endpoint of grade 4 neutropenia occurred in 96% of patients. Febrile neutropenia occurred in 33% of patients. Grade 4 anemia and thrombocytopenia occurred in 11% and 15% of patients, respectively. Gastrointestinal, thrombosis or neurological toxicities were rare at grade 4 (0–3%) and infrequent at grade 3 (0–14%). No patients had cardiac failure and there was one treatment associated death from CNS hemorrhage. Ninety percent of patients completed at least 6 cycles and 20% received 8 cycles. ORR was 100% with 68% CR and 32% PR. With a median (range) follow-up of 11 (2.4–22.8) months, 10 patients progressed (8 in the first year) with similar rates in CR’s (6/49) and PR’s (4/23). At 18 months, PFS is 80% overall, and 93% and 46%, respectively, in low (0–2) and high (3–5) IPI. Survival is 88% at 18 months. Conclusions: DA-EPOCH-R can be administered in a cooperative group with acceptable toxicity. Preliminary survival results are encouraging and consistent with the NCI study. A CALGB randomized phase III study of DA-EPOCH-R versus R-CHOP with microarray tumor analysis will begin early next year. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech Genentech Genentech

Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia: a collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study.

In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46 +/- 0.68 microM and the AUC ranged from 0.18 to 9.5 microM.h (mean 1.5 microM.h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 microM, respectively. The mean (+/- SD) TG clearance was 935 +/- 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.

Quality of life and breast cancer: relationship to psychosocial variables.

The aim of this article is to shed more light on the relationship between quality of life and aspects of the psychosocial experience for women with breast cancer. The literature is briefly reviewed, including highlights of the psychosocial consequences of cancer, an exploration of the relationship of psychosocial variables to cancer, and a brief review of psychosocial interventions for cancer. Further, preliminary findings of an on-going NCI study are introduced. Finally, clinical implications are discussed. The purpose of this article is to provide a context and foundation on which future researchers and clinicians can build. Ultimately, we suggest that the biomedical model of disease, though crucial, does not take into account all of the complex factors involved in cancer. The current literature lends support to the argument that a broader, more integrative framework, which includes psychosocial factors, is needed.

Arguments for the Long-Term Use of Combined Androgen Blockade

From what is known about the testicular and adrenal origins of testosterone, and the testosterone dependency of prostate cancer, treatment with combined androgen blockade (CAB) by castration plus an antiandrogen was expected to be beneficial to patients. A number of early studies verified this hypothesis, but the findings needed to be confirmed in large, randomized, prospective studies. Modest but significant benefits of CAB were seen when treatment with leuprorelin plus flutamide was compared with leuprorelin alone. Of note was the increased benefit from CAB seen in patients with minimal metastatic prostate cancer, a finding that needed to be confirmed. A study comparing orchidectomy plus nilutamide with orchidectomy alone showed significant benefits of CAB in terms of time to progression and overall survival. However, a recent major NCI study revealed no benefits for CAB with respect to survival, even for patients with minimal metastatic disease. Results from other clinical studies have been conflicting, perhaps because of the method of castration or differences in antiandrogen used. Before the question of whether CAB significantly benefits patients can be fully answered, a clearer understanding of the interactions between antiandrogens, luteinizing hormone-releasing hormone agonists and receptors, and of the response of prostate cancer to these, is needed.

NCI Study to Assess Clinical Alert Impact

NCI Study to Assess Clinical Alert Impact

Non-Hodgkin's lymphomas. Application of the International Classification of Diseases for Oncology (ICD-O) to the Working Formulation.

International Classification of Diseases for Oncology (ICD-O) code numbers for the non-Hodgkin's lymphomas (NHL) are assigned to the new Working Formulation (WF). This will facilitate the coding of NHL cases by registrars and pathologists by providing a ready means of translation of terms utilized in most of the existing classification schemes. Additional code numbers and synonyms are suggested to accommodate all of the terms in the six major classification systems currently in use and to permit the coding of immunologic cell type when appropriate tests have been performed. To demonstrate how the assignment of these code numbers can be useful, over 8000 incidence cases from the Surveillance, Epidemiology and End Results (SEER) Program (1977-1980) were coded according to the WF groups and the data analyzed. The prognostic significance of the three major groups in the WF is confirmed for each group in the SEER data and comparisons are discussed with the NCI study.

Genotoxicity studies on Di-(2-ethylhexyl) phthalate and adipate and toxicity studies on Di-(2-ethylhexyl) phthalate in the rat and marmoset

These studies have provided evidence that DEHP and DEHA do not bind covalently to DNA and do not therefore possess the characteristics of a genotoxic agent (Lutz, 1982). This suggests that the tumours induced in the rodent liver may result from some non-genotoxic mechanism and supports the view that the weakly positive dominant lethal test seen on administration of DEHP by the ip (but not the oral) route (Singh et al. 1974) is unlikely to have resulted from a direct effect on the genome of the sperm cells. Although the mechanism responsible for the induction of tumours by high doses of DEHP in rodents is not clear, it would appear both from these studies and from work on hypolipidaemic agents, that peroxisomal proliferation and the induction of enzymes associated with this organelle are in some way implicated (Cohen & Grasso, 1981). Other studies have shown that changes of this type are produced by doses of hypolipidaemic agents that induce liver cancer in rodents (Cohen & Grasso, 1981) and our investigations have indicated that they were also prominent at dose levels of DEHP similar to those that induced liver cancer in the NCI study (National Toxicology Program, 1982). No cancer induction would be expected to occur in the absence of these changes. In our dose-response study in rats it was shown that at the lowest dose (50 mg/kg body weight/day, approximately equivalent to a dietary level of 1000 ppm) several effects seen with higher doses were not apparent and others differed only slightly from normal control values. This is particularly relevant to assessments of the risk posed by DEHP and DEHA present as contaminants in foods, since human exposure via the food chain has been estimated by Shiota, Chou & Nishimura (1980) as 30 micrograms/kg body weight/day, several orders of magnitude less than the lowest exposure level used in these experiments. In addition, our studies indicate that none of the changes found in the rat were observed in the marmoset, suggesting that rodents and primates differ fundamentally in their hepatic and testicular response to DEHP. Previous studies by other authors (reviewed by Cohen & Grasso, 1981) indicated that morphological changes in the endoplasmic reticulum and the proliferation of peroxisomes are not features of the response of monkeys and man to high doses of hypolipidaemic agents.(ABSTRACT TRUNCATED AT 400 WORDS)