Phase I dose escalation study of gemcitabine plus irinotecan in advanced solid tumors.

AIM: To determine the maximally tolerated dose (MTD), recommended phase II dose (RPTD) and toxicity profile of gemcitabine plus irinotecan combination. PATIENTS AND METHODS: Thirty-nine evaluable patients with advanced solid tumors were treated with gemcitabine (Gem) and irinotecan (Iri) on days 1, 8 and 15 of a 28-day cycle. Dose levels included Gem/Iri 700/50, 900/50, 900/75, 500/50 mg/m(2) respectively. Dose-limiting toxicity (DLT) was assessed during cycle one; toxicity evaluation was closely monitored throughout the course of treatment. Treatment continued until disease progression or unacceptable toxicity. RESULTS: DLTs primarily consisted of grade > or = 3 thrombocytopenia lasting > or = 4 days often accompanied by grade > or = 3 neutropenia. Other grade > or = 3 toxicities included vomiting, diarrhea, fatigue and elevated alkaline phosphatase. Three patients had a partial response. Stable disease as best response was seen in 16 patients, ranging from 2-18 months. CONCLUSION: The MTD/RPTD is gemcitabine 500 mg/m(2) plus irinotecan 50 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Given the toxicity profile and negative results of phase III studies, no further testing of this treatment combination is recommended.

Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer.

BACKGROUND: Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. METHODS: Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods. RESULTS: The estimated overall survival (median +/- SE) in the entire group of patients undergoing resection was 23 +/- 4.2 months, with an estimated 3-year survival of 37% +/- 6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation. CONCLUSIONS: Histological response to neoadjuvant CRT--as measured by residual tumor load--may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.