Intraprostatic inflammation is positively associated with serum PSA in men with PSA <4 ng ml(-1), normal DRE and negative for prostate cancer.

BACKGROUND: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. METHODS: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml(-1), normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml(-1)). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. RESULTS: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles (P-trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml(-1) (P=0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P-trend ≤0.05). CONCLUSIONS: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.

Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.

PURPOSE: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. PATIENTS AND METHODS: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). RESULTS: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. CONCLUSION: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.

Chemotherapy-induced lactose intolerance in adults.

BACKGROUND: Anorexia and weight loss contribute to the morbidity and mortality from cancer. This study was designed to test the hypothesis that chemotherapy produces lactose intolerance which could have an adverse effect on the nutritional status of patients receiving cytotoxic drugs. METHODS: Twenty-seven patients were evaluated for the development of lactose intolerance during chemotherapy. Lactose breath hydrogen testing (LBHT) was used to assess lactose malabsorption objectively. This test is based on the principle that in patients with lactase deficiency, lactose is not hydrolyzed in the small intestine and ultimately is degraded by colonic bacteria. This results in the production of hydrogen gas, which is excreted by the lungs and can be quantified with a breath hydrogen analyzer. RESULTS: Of the 27 patients studied, 8 (30%) had an abnormal postchemotherapy LBHT results, and for the population as a whole, postchemotherapy LBHT values were significantly greater than prechemotherapy values (P = 0.04). However, only three patients (11%) showed clinical symptoms of lactose intolerance during the post-chemotherapy LBHT. Five patients had asymptomatic elevations in breath hydrogen excretion on prechemotherapy testing. One of these patients had a further increase in hydrogen excretion on Day 8 after chemotherapy, which was accompanied by symptoms of lactose intolerance. Twenty-two patients had normal prechemotherapy LBHT results. Two of these patients had abnormal post-chemotherapy LBHT results, which were associated with symptoms of lactose intolerance. CONCLUSION: Although chemotherapy may interfere with lactose metabolism, the development of symptomatic lactose intolerance is uncommon. Dietary restriction of milk products in patients receiving chemotherapy therefore is not warranted unless clinical symptoms of lactose intolerance are observed.

Protein calorie malnutrition and cancer therapy.

Anorexia and cachexia frequently complicate the late stages of malignancy and may be a prominent feature of early disease. The resulting weight loss often becomes a major focus of concern for the patient and the family and may significantly add to the morbidity and mortality of cancer. Factors which contribute to the wasting syndrome include the effects of the tumour, effects of chemotherapy, abnormalities of carbohydrate, fat and protein metabolism and the cytokine response. Administration of total parenteral nutrition (TPN) is an important method of addressing malnutrition, particularly in patients with nonfunctioning gastrointestinal tracts. A critical review of the TPN cancer literature is provided along with a discussion of new approaches and future directions in the nutritional support of patients with malignant disease, such as anabolic agents, hydrazine sulfate and megestrol.

A phase I/II study of high-dose megestrol acetate in the treatment of metastatic breast cancer.

A dose-response relationship has been suggested for medroxyprogesterone acetate in the treatment of advanced breast cancer. To determine the tolerability and efficacy of increasing doses of megestrol acetate in the treatment of metastatic breast cancer, we conducted a phase I/II study among 57 patients. Three patients each received 480, 800, and 1280 mg/d; 48 patients received 1600 mg/d. Of the 57 patients, 56 patients had had disease progression on prior hormone therapy, chemotherapy, or both. Twenty-seven patients had previously received standard-dose MA (160 mg/d). Among the 37 patients with measurable disease, high-dose megestrol acetate (HDMA) produced 6 (16%) complete responses (CRs) and 6 (16%) partial responses (PRs); 11 patients achieved stable disease (SD). HDMA resulted in improvement or stabilization in 12 of the 20 patients with evaluable, non-measurable disease. There were no responses among the 6 patients with liver metastases. Among the 27 patients who were previously treated with standard-dose MA, including 9 patients with primary treatment failure, HDMA resulted in 1 CR, 3 PRs, and 10 SD. Toxicities, which were mild and reversible, included fluid retention, hypertension, hyperglycemia, and mild congestive heart failure. Two patients had superficial phlebitis. The most profound side effect was weight gain which occurred in 43 patients (75%). This study suggests a dose-response relationship for MA in the treatment of advanced breast cancer. A randomized trial to determine the optimal dose is ongoing.

Phase I/II study of cyclophosphamide, doxorubicin, fluorouracil, and leucovorin for treatment of metastatic adenocarcinoma.

Leucovorin enhances the cytotoxicity of fluorouracil (5-FU) in patients with colorectal cancer and may increase the efficacy of combination chemotherapy regimens containing 5-FU. To determine the maximum tolerated dose of 5-FU with leucovorin for use in combination with cyclophosphamide and doxorubicin, we conducted a phase I/II trial in 20 patients. The doses of leucovorin (200 mg/m2 on days 1-5), cyclophosphamide (500 mg/m2 on day 1), and doxorubicin (40 mg/m2 on day 1) were held constant, while the dose of 5-FU was escalated in cohorts of patients beginning at 150 mg/m2 on days 1-5. Cycles were repeated every 3 weeks. Significant mucositis, diarrhea, and myelosuppression were infrequently observed in patients receiving up to 250 mg/m2 5-FU on days 1-5. In contrast, at a dose of 300 mg/m2 on days 1-5, three of six patients had granulocyte count nadirs of less than 500/microL during the first cycle of therapy, and two of these three had platelet counts of less than 25,000/microL. In addition, two patients treated at this dose had significant mucosal toxic effects, and three had insufficient recovery to permit a second course by day 22. Among 14 patients with assessable breast cancer, there were one complete and nine partial responses (response rate 71%). Leucovorin modulation of 5-FU can be safely incorporated into combination chemotherapy with cyclophosphamide and doxorubicin and provides a highly active regimen for treatment of metastatic breast cancer. Further study will be required to determine whether the addition of leucovorin significantly enhances the activity of this regimen.

Dietary immunomodulation: beneficial effects on oncogenesis and tumor growth.

Our understanding of the interrelationship between nutrition, immunology, oncogenesis, and tumor growth is steadily increasing. Well known are the detrimental effects of malnutrition on host defenses. New work has shown that the addition of omega-3 polyunsaturated fatty acids or the amino acid arginine to the diet may significantly enhance immune function. These dietary manipulations have been shown to inhibit tumorigenesis and cancer spread in animal models, and form the basis for exciting new work in the prevention and treatment of cancer in humans.