A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer.

OBJECTIVE: We tested the hypothesis that the combination of trimetrexate (TMTX) and capecitabine (CAP) would be active in patients with previously treated metastatic colorectal cancer (CRC). Because the optimum dose of this combination was unknown, we used a phase I/II design. METHODS: In the phase I cohort, patients received 110 mg/m2 TMTX intravenously weekly x6 and CAP starting at 750 mg/m2 orally twice daily from days 2 to 15 and 23 to 36 (one cycle). Cycles were repeated every 8 weeks. The phase II doses were 110 mg/m2 TMTX and 1000 mg/m2 CAP orally twice daily. RESULTS: Thirty-two patients were entered. All patients had prior 5-fluorouracil therapy and 94% had prior exposure to irinotecan. Grade 3/4 toxicities included abdominal pain in 4 patients (12.5%) and vomiting in 3 patients (9.4%). Twenty-seven patients were evaluable for response: one patient each had a complete response and a partial response for an overall response rate of 7.4%. The median time to progression was 3.3 months (95% confidence interval [CI], 1.6-3.7 months) and the median overall survival was 5.9 months (95% CI, 5.2-10.2 months). CONCLUSIONS: The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting.

Lack of influence of cytokeratin-positive mini micrometastases in "Negative Node" patients with colorectal cancer: findings from the national surgical adjuvant breast and bowel projects protocols R-01 and C-01.

PURPOSE: Results of the few extant reports concerning the clinical significance of so-called "occult micrometastases" of lymph nodes of patients with Dukes A and B colorectal cancer have been variable. We examined the presumably negative nodes of a larger cohort of such patients who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trials R-01 and C-01 for the influence of what we preferably designate as nodal mini micrometastases on parameters of survival. METHODS: Mini micrometastases were detected by immunohistochemical staining of the original lymph node sections with anticytokeratin A1/A3 in a total of 241 Dukes A and B patients with rectal and 158 with colonic cancers. Their frequency, as well as that of nuclear and histologic grades, and an estimation of their relationship to relative risks were correlated with overall and recurrence-free survival by univariate and multivariate analyses. RESULTS: Nodal mini micrometastases were detected in 73 of 399 (18.3 percent) patients of this cohort. They failed to exhibit any significant relationship to overall or recurrence-free survival. No association between the assessments of tumor differentiation and mini micrometastases was found. Nuclear and histologic grades also failed to further discriminate overall or recurrence-free survival in patients with A or B stages of colonic or rectal cancers in this cohort. CONCLUSION: The immunohistochemical demonstration of nodal mini micrometastases failed to discriminate high- and low-risk groups of patients with colorectal cancer who were designated as being node-negative after routine pathologic examination.

Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma.

BACKGROUND: The overexpression of glucose transporters, especially of Glut-1, is a common characteristic of human malignancies, including head and neck carcinoma. Recently, the assessment of glucose metabolism in the tumor with [(18)F]-2-fluoro-2 deoxy-D-glucose (FDG) and positron emission tomography (FDG-PET) has been used to identify particularly aggressive tumors. The authors tested the hypothesis that both glucose transport and its metabolism play a key role in the progression of oral squamous cell carcinoma (OSCC). METHODS: Retrospective analysis of Glut-1 expression was performed by immunohistology in 118 patients with OSCC, and a Glut-1 labeling index (LI) was established for each. A separate group of 44 patients with primary OSCC was evaluated prospectively by FDG-PET prior to surgery. To link the expression of Glut-1 with glucose metabolism, both FDG-PET and immunohistology were determined in a subgroup of 31 patients, and the results were correlated with overall survival. RESULTS: The patients who had OSCC with a low LI for Glut-1 survived significantly longer compared with patients who had OSCC with a high LI (138 months vs. 60 months; P = 0.0034). It was found that Glut-1 expression was an independent marker of prognosis in patients with OSCC. In patients who were evaluated by FDG-PET, the standardized uptake value (SUV) below the median split value of 5.6 was predictive of a longer survival (P < 0.027), whereas an SUV > 5.6 was associated with an increased hazard of death. In combination, a high Glut-1 level and a high SUV predicted shorter survival (P < 0.005) for patients with OSCC. Patients who achieved a complete response to preoperative radiation tended to have tumors with low glucose metabolism, as defined by both the Glut-1 LI and the SUV. CONCLUSIONS: Both glucose transport and glucose metabolism determine the glycolytic tumor phenotype, which is a significant negative biomarker of prognosis and overall survival in patients with OSCC.

A parametric model for long-term follow-up data from phase III breast cancer clinical trials.

We propose a parametric version of a univariate gamma frailty model. The proposed model is shown to be flexible enough to model long-term follow-up survival data from breast cancer clinical trials when the treatment effect diminishes as time progresses, a case for which neither the proportional hazards nor proportional odds assumptions are satisfied. The observed information matrix is computed to evaluate the variances of parameter estimates. A simple parametric test statistic to test proportional odds assumption is also constructed. The model is applied to a data set from a phase III clinical trial on breast cancer.

Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690.

BACKGROUND: The clinical antitumor activity of recombinant interferon alpha2b (IFNalpha2b) has been well documented in patients with advanced and high-risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNalpha2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients). METHODS: This study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNalpha2b at a range of concentrations in vitro. RESULTS: Baseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNalpha2b treatment was observed and was associated with IFNalpha2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM-1) were modulated by exposure to IFNalpha2b in a dose dependent manner. Blood natural killer (NK) cell function, T-cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes. CONCLUSIONS: These data demonstrate changes in immunologic parameters associated with IFNalpha2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNalpha2b and T-cell response to specific antigens of melanoma.

Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis.

This report investigates the influence of liver transplantation and concomitant immunosuppression on the course of progression of inflammatory bowel disease (IBD) and discusses statistical methodology appropriate for such settings. The data on 303 patients who underwent liver transplantation for primary sclerosing cholangitis (PSC) were analyzed using person-time analysis and Cox regression, with the duration of IBD as the time variable and transplantation as a segmented time-dependent covariate, to take into account both posttransplant and pretransplant history of IBD. The need for colectomy and appearance of colorectal cancer were taken as outcome measures. The only significant risk factor in the multivariate model for colectomy was transplantation itself, which increased the risk of colectomy due to intractable disease (Wald statistic; P =.001). None of the variables available for analysis were found to influence the risk of colon cancer significantly. Graphs showing the dependence of the instantaneous risk of cancer on the time from onset of IBD and its independence from the latter in the case of colectomy are presented. The use of a unique statistical methodology described for the first time in this setting led us to the somewhat surprising conclusion that transplantation and concomitant use of immunosuppression accelerate the progression of IBD. At the same time, transplantation does not affect the incidence of colorectal cancer. These results confirm the findings of some recent studies and can potentially shed new light on the disease pathogenesis.