Ralph B. Vance

Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.

PURPOSE Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC. METHODS A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity. RESULTS The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015). CONCLUSION Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Nutrition, cancer, and aging: an annotated review. II. Cancer cachexia and aging.

The interactions of cancer and malnutrition are discussed with the focus on aging. To establish whether the elderly are more likely to develop cancer cachexia and its complications, this review encompasses the pathogenesis of malnutrition in cancer; the age‐related alterations of appetite, gastrointestinal function, energy expenditure, and protein turnover; the diagnosis of malnutrition; and the effectiveness of nutritional support in the elderly. Although metabolic and physiologic changes induced by cancer and age appear synergistic in causing cachexia, more frequent complications of malnutrition have not been observed in the geriatric cancer patients. This may be due to only a small proportion of the elderly with cancer being enrolled in clinical studies or to a reduced cachexia‐inducing ability of tumors in these patients. A limited number of studies indicate nutritional replenishment is obtainable in malnourished elderly by hyperalimentation. As restoration of the lean body mass may be slower in older patients, early institution of nutritional support is recommended in malnourished elderly or elderly at risk for malnutrition during neoplastic treatment.

Nutrition, cancer, and aging: an annotated review. I. Diet, carcinogenesis, and aging.

The interrelationships of diet and carcinogenesis are discussed with the focus on aging. To establish whether the elderly are more susceptible to dietary carcinogens and whether dietary prevention of cancer is a reasonable goal for this population, the mechanisms of chemical carcinogenesis, the age‐related metabolic and physiologic changes, and the current cancer preventive dietary strategies are reviewed. Vulnerability to dietary carcinogens results from a combination of factors that may increase or decrease the occurrence of cancer in the elderly, and it is, therefore, a very individualized feature, unpredictable when based solely on a subjects age. Dietary prevention of cancer may be effective in advanced age, and the dietary guidelines of the National Academy of Sciences should be implemented in this population.

Supraophthalmic carotid infusion for recurrent glioma: rationale, technique, and preliminary results for cisplatin and BCNU.

SummaryThe chemotherapeutic agents 1–3 bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-diamminedichloroplatinum II (cisplatin) have both shown activity against malignant glioma, especially when given by arterial infusion. The combination of these agents given by this method is logical because their individual major toxicities are directed at different organ systems, and because of their differences in restriction by the blood-brain barrier. Both agents are toxic to the eye, and infusion of both agents simultaneously into the internal carotid artery would deliver doses of the drug to the eye which should be associated with an unacceptable level of ocular toxicity. We have developed a technique utilizing a flexible flow-directed catheter with a tip which is manipulated by hydraulic forces for delivery of the drug into the intracranial carotid artery above the origin of the ophthalmic artery, thus sparing the eye from the high concentration of drug during the first pass through the arterial circulation. In 13 patients with recurrent malignant glioma treated by arterial infusion of both agents (cisplatin 150–200 mg, BCNU 300 mg fixed dose), we have had no damage to the ipsilateral eye. Preliminary results of treatment appear to be good, with definite tumor regression following arterial infusion in 10 of 12 radiographically evaluable cases. Median survival to date is 11 months with 3 patients still surviving. The longest survival is 24 months. The supraophthalmic infusion technique protects the eye and the combination of drugs given by arterial infusion produces a high tumor response rate.

Supraophthalmic carotid infusion with low dose cisplatin and BCNU for malignant glioma

SummaryArterial infusion of select chemotherapeutic agents has been shown to deliver increased drug concentration to brain tumors with reduced systemic toxicity. In this study, nine patients with histologically confirmed malignant glioma received cisplatin 110 mg and BCNU 300 mg fixed dose. All patients had received standard doses of cranial radiation after their initial surgical procedures. In three patients, intraoperative modification of the cerebral circulation was accomplished prior to the actual infusion because the vascular supply of the tumor arose from major arteries other than a single internal carotid artery. Supraophthalmic catheterization technique was employed. No neurological deficits occurred post infusion. The radiographic response rate was 25%. No responses were seen in patients who received less than 69 mg/M2 cisplatin this combination. The longest survival is 11+ months in a patient with anaplastic astrocytoma. Our first thirteen patients received cisplatin 150–200 mg and BCNU 300 mg for each infusion with a response rate of 83% in evaluable patients. Since modest reduction in cisplatin dose dramatically reduced the response rate, future studies should be directed at fine tuning the dose of this drug, or at neutralizing recirculating drug after its high dose first pass through the arterial circulation.

Differential association of cytochrome P450 3A4 genotypes with onsets of breast tumors in African American versus Caucasian patients.

Introduction Malignant breast tumors are often hormone-dependent, and to this end, both estrogen and progesterone receptors are good prognostic markers for evaluation of the outcomes after therapy. In addition, HER-2/neu, whose expression is increasingly being associated with poor prognosis of breast cancer, has predictive potential after immunotherapy. Cytochrome P450 3A4 is highly involved in the metabolism of steroids. Thus, we investigated the impact of CYP 3A4 gene variants in association with clinical outcomes in African American (AFAM) versus Caucasian (CAU) patients with breast cancer diagnosis. Methods Patients who had undergone biopsy procedures for diagnosis or for partial or radical mastectomy were recruited. The CYP 3A4 genotypes (A or G) were detected using polymerase chain reaction amplification and primers designed for a single nucleotide polymorphism. The messenger RNA (mRNA) transcripts were screened by reverse transcription-polymerase chain reaction. Clinical data including tumor staging, pathology grades, and family history were evaluated. Results Frequency of the CYP 3A4-G (mutated variant) was significantly increased in AFAM patients as compared with controls (P < 0.001). No statistically significant difference was observed between the genotypes comparing the benign versus ductal carcinomas in situ (DCIS) or infiltrating ductal carcinomas (IDCAs). In AFAM patients, GG alleles were increased in IDCA with stage III tumors, and in CAU patients, the AA alleles were increased with stage III tumors. The mRNA expression was reduced in patients with IDCA versus DCIS or benign tumors (benign vs IDCA, P < 0.0009; DCIS vs IDCA, P < 0.005), as well in HER-2/neu-positive tumors versus samples negative for receptors (P < 0.0024). Conclusions Genotype association was affected by race. Expression levels of total CYP 3A4 mRNA were inversely correlated with clinical diagnosis. This may suggest mRNA testing as an additional tool that accelerates improvement in the diagnosis of the onsets of breast cancer.

Phase II trial of amonafide in central nervous system tumors: A Southwest Oncology Group Study

Amonafide 300 mg/M2 was administeredintravenously on a daily × 5 schedule to 27eligible patients with recurrent orprogressive central nervous system tumors. There were no objective responses. Themost common toxicities weregastrointestinal, hematologic andneurologic. Further study of amonafide inpatients with central nervous systemmalignancies is not indicated.

Experiences with sodium thiosulfate after intracarotid infusion of cisplatin and BCNU for malignant gliomas

The treatment of malignant gliomas with cisplatin has been shown to be of benefit. In order to reduce the side effects of the drug, we employed the use of sodium thiosulfate in ten patients one hour after cisplatin infusion and continued for 6 h. Side effects from this population of patients were compared with those side effects experienced with 13 patients not receiving thiosulfate. No real difference in number or severity of side effects from cisplatin was observed between the two groups although nephrotoxicity appeared to be reduced in the patients who received thiosulfate.

Phase II evaluation of menogaril (NSC-269148) in non-small cell lung carcinoma - A Southwest Oncology Group study

SummaryForty-five patients with non-small cell lung cancer were treated in a phase II trial with menogaril 200 mg/m2 IV every twenty-eight days by a one-hour infusion. One partial response was noted while twenty-two patients had stable disease (51 %). Progressive disease was noted in the remaining twenty-two patients. There was one fatal complication due to pancytopenia and pneumonia. Otherwise, the drug was reasonably well tolerated. At this dosage and schedule, menogaril has no substantial anti-tumor activity for patients with non-small cell lung cancer.