Modulation of the Fas signaling pathway by IFN-gamma in therapy of colon cancer: phase I trial and correlative studies of IFN-gamma, 5-fluorouracil, and leucovorin.

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-gamma in colon carcinoma cells is dependent on FUra-induced DNA damage, the Fas death receptor, and independent of p53 and RNA-mediated FUra toxicity, which occurs in normal gastrointestinal tissues. This provides a rationale for enhancing the selective action of FUra/LV by IFN-gamma in the treatment of colorectal carcinoma. Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m2) and LV (200 mg/m2), i.v. bolus daily x 5 days, with escalating doses of IFN-gamma (10-100 micro g/m2) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-gamma on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 micro g/m2 IFN-gamma. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of < or =50 micro g/m2 and > or =75 micro g/m2 IFN-gamma, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 micro M; at 100 micro g/m2 IFN-gamma plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-gamma correlated with a 2-3-fold up-regulation of Fas expression at 24 h in CD15+ cells in peripheral blood samples. Furthermore, clinically relevant IFN-gamma concentrations up-regulated Fas expression and sensitized HT29 colon carcinoma cells in vitro to FUra/LV cytotoxicity. On the basis of the modulation of Fas signaling, FUra/LV combined with IFN-gamma has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.

Description and predictors of direct and indirect costs of pain reported by cancer patients.

The purpose of this study was to describe direct and indirect costs associated with pain in cancer patients and to examine potential predictors of these costs. The study surveyed cancer outpatients about direct costs resulting from pain-related hospitalizations, emergency department visits, physician office visits, and use of analgesic medications and indirect costs related to money spent on pain-related transportation, complementary methods to improve pain management, educational materials, over-the counter medication, domestic support, and childcare. Furthermore, the study examined age, marital status, race, income level, pain severity, pain interference, and presence of breakthrough pain as predictors of direct and indirect costs. Three hundred and seventy-three cancer outpatients were sampled. One hundred and forty-four cancer patients (39%) reported experiencing cancer-related pain and completed the study questionnaires. Seventy-six percent (76%) of the patients had experienced at least one pain-related cost, resulting in an average monthly direct cost of US$ 891/month per patient. Sixty-nine percent (69%) of patients had experienced some type of direct medical cost due to pain, resulting in an average total direct pain-related cost of US$ 825/month per patient. Fifty-seven percent (57%) of patients reported incurring at least one indirect pain-related expense for an average indirect cost of US$ 61/month per patient. Higher pain intensity, greater pain interference, and presence of breakthrough pain predicted higher direct and indirect medical expenses. Younger age and lower income level also predicted higher direct medical expenses.

The Zero Acceptance of Pain (ZAP) Quality Improvement Project: evaluation of pain severity, pain interference, global quality of life, and pain-related costs.

The Zero Acceptance of Pain (ZAP) Quality Improvement Project was a multi-site effort to improve the lives of outpatients with cancer pain by enhancing the clinical practice of pain assessment and management. Independent samples of patients completed self-report measures of severity of pain, pain interference, global quality of life, pain treatment satisfaction, general medical treatment satisfaction, pain attitudes, and pain-related medical costs before and after the implementation of ZAP. Results suggested that ZAP decreased the severity of recent pain, decreased interference of pain on daily functioning, and improved satisfaction with pain treatment and attitudes about addiction to opioid medication. Direct medical costs consisting of pain-related hospitalizations, emergency department visits, and physician office visits were greatly reduced. In summary, the findings of this study support the idea that clinic-based efforts to improve the practice of pain management are effective in improving the lives of cancer patients who are experiencing pain.