skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Low-Dose Radiotherapy as a Chemopotentiator of Gemcitabine in Tumors of the Pancreas or Small Bowel: A Phase I Study Exploring a New Treatment Paradigm

Abstract

Purpose: To determine the maximum tolerated dose of upper abdominal low-dose fractionated radiotherapy (<1.0 Gy per fraction) given in combination with, and as a chemopotentiator for, gemcitabine. Methods and Materials: Gemcitabine was given at 1,250 mg/m{sup 2} at 10 mg/m{sup 2}/min on Days 1 and 8 of a 3-week cycle. Low-dose fractionated radiotherapy was tested at two dose levels: 60 cGy per fraction and 70 cGy per fraction. Radiotherapy was given b.i.d. on Days 1, 2, 8, and 9. Four cycles were planned. Results: Twenty-seven patients have been put on study. Ten patients have been entered in Phase I: 6 with metastatic/recurrent pancreatic carcinoma and 4 with unresectable pancreatic/small bowel carcinoma. Two of four patients at Dose Level 2 experienced dose-limiting toxicity. The overall radiographic response was 30%, and median survival was 11 months (range, 4-37 months). Conclusion: Low-dose fractionated radiotherapy to the upper abdomen is well tolerated at 60 cGy per fraction when combined with gemcitabine. Phase II evaluation is ongoing.

Authors:
 [1];  [2];  [3];  [4];  [5];  [3];  [6];  [7];  [8]
  1. Department of Radiation Oncology, University of Maryland, Baltimore, MD (United States). E-mail: wregine@umm.edu
  2. Department of Surgery, University of Maryland, Baltimore, MD (United States)
  3. Department of Radiation Oncology, University of Maryland, Baltimore, MD (United States)
  4. Department of Medicine, University of Maryland, Baltimore, MD (United States)
  5. Division of Hematology-Oncology, University of Kentucky, Lexington, KY (United States)
  6. Department of Radiation Medicine, University of Kentucky, Lexington, KY (United States)
  7. Department of Biostatistics, University of Maryland, Baltimore, MD (United States)
  8. Geisinger-Fox Chase Cancer Center, Wilkes-Barre, PA (United States)
Publication Date:
OSTI Identifier:
20951629
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 68; Journal Issue: 1; Other Information: DOI: 10.1016/j.ijrobp.2006.11.045; PII: S0360-3016(06)03533-4; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ABDOMEN; CARCINOMAS; EVALUATION; METASTASES; PANCREAS; PATIENTS; RADIATION DOSES; RADIOTHERAPY; TOXICITY

Citation Formats

Regine, William F., Hanna, Nader, Garofalo, Michael C., Doyle, Austin, Arnold, Susanne, Kataria, Ritesh, Sims, Jacqueline, Tan Ming, and Mohiuddin, Mohammed. Low-Dose Radiotherapy as a Chemopotentiator of Gemcitabine in Tumors of the Pancreas or Small Bowel: A Phase I Study Exploring a New Treatment Paradigm. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.11.045.
Regine, William F., Hanna, Nader, Garofalo, Michael C., Doyle, Austin, Arnold, Susanne, Kataria, Ritesh, Sims, Jacqueline, Tan Ming, & Mohiuddin, Mohammed. Low-Dose Radiotherapy as a Chemopotentiator of Gemcitabine in Tumors of the Pancreas or Small Bowel: A Phase I Study Exploring a New Treatment Paradigm. United States. doi:10.1016/j.ijrobp.2006.11.045.
Regine, William F., Hanna, Nader, Garofalo, Michael C., Doyle, Austin, Arnold, Susanne, Kataria, Ritesh, Sims, Jacqueline, Tan Ming, and Mohiuddin, Mohammed. Tue . "Low-Dose Radiotherapy as a Chemopotentiator of Gemcitabine in Tumors of the Pancreas or Small Bowel: A Phase I Study Exploring a New Treatment Paradigm". United States. doi:10.1016/j.ijrobp.2006.11.045.
@article{osti_20951629,
title = {Low-Dose Radiotherapy as a Chemopotentiator of Gemcitabine in Tumors of the Pancreas or Small Bowel: A Phase I Study Exploring a New Treatment Paradigm},
author = {Regine, William F. and Hanna, Nader and Garofalo, Michael C. and Doyle, Austin and Arnold, Susanne and Kataria, Ritesh and Sims, Jacqueline and Tan Ming and Mohiuddin, Mohammed},
abstractNote = {Purpose: To determine the maximum tolerated dose of upper abdominal low-dose fractionated radiotherapy (<1.0 Gy per fraction) given in combination with, and as a chemopotentiator for, gemcitabine. Methods and Materials: Gemcitabine was given at 1,250 mg/m{sup 2} at 10 mg/m{sup 2}/min on Days 1 and 8 of a 3-week cycle. Low-dose fractionated radiotherapy was tested at two dose levels: 60 cGy per fraction and 70 cGy per fraction. Radiotherapy was given b.i.d. on Days 1, 2, 8, and 9. Four cycles were planned. Results: Twenty-seven patients have been put on study. Ten patients have been entered in Phase I: 6 with metastatic/recurrent pancreatic carcinoma and 4 with unresectable pancreatic/small bowel carcinoma. Two of four patients at Dose Level 2 experienced dose-limiting toxicity. The overall radiographic response was 30%, and median survival was 11 months (range, 4-37 months). Conclusion: Low-dose fractionated radiotherapy to the upper abdomen is well tolerated at 60 cGy per fraction when combined with gemcitabine. Phase II evaluation is ongoing.},
doi = {10.1016/j.ijrobp.2006.11.045},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 68,
place = {United States},
year = {Tue May 01 00:00:00 EDT 2007},
month = {Tue May 01 00:00:00 EDT 2007}
}
  • Purpose: To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis. Methods and Materials: Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m{sup 2}/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cyclesmore » of gemcitabine at 1000 mg/m{sup 2}/wk and cisplatin 60 mg/m{sup 2}. Results: In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m{sup 2}/wk cohort and 2 of 3 patients in the 125-mg/m{sup 2}/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m{sup 2}/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort. Conclusions: We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m{sup 2}/wk when using 3D planning. The Phase II dose is 150 mg/m{sup 2}/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine.« less
  • Purpose: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. Methods and Materials: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m{sup 2}) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additionalmore » 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. Results: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. Conclusion: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.« less
  • Purpose: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. Methods and Materials: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m{supmore » 2} gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m{sup 2} within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m{sup 2}) and 52.5 Gy RT within 6 weeks. Results: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. Conclusion: Biweekly gemcitabine (40 mg/m{sup 2}) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.« less
  • Purpose: Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. Methods and Materials: Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatmentmore » unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. Results: Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed {>=}Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. Conclusion: The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long-term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas.« less
  • Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m{sup 2} at 10 mg/m{sup 2}/min) plus cisplatin 20 mg/m{sup 2} on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800more » mg/m{sup 2} orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.« less