Radiation Therapy (RT) as a Chemosensitizer of Gemcitabine (G) in Patients with Metastatic/Unresectable Tumors of the Gastrointestinal (GI) Tract - a Phase I/II Study Exploring a New Treatment Paradigm

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: October 19, 2005

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Presenter: W. F. Regine, MD
Presenter's Affiliation: University of Maryland, Baltimore, MD
Type of Session: Scientific

Background

  • Gemcitabine is one of the most active chemotherapy drugs for the treatment of metastatic/unresectable pancreatic cancer.
  • In the laboratory, it can be demonstrated that very low doses of radiation (< 1Gy) can be extremely effective against tumor cells, a phenomenon called hyperradiosensitivity.
  • Further laboratory data has shown that low-dose fractionated radiation therapy (<1Gy per fraction) can improve the efficacy of certain chemotherapy drugs, like gemcitabine.
  • Many people have explored the use of chemotherapy as a radiosensitizer, but few have looked into using radiation as a chemosensitizer.
  • Based on laboratory data, a clinical trial was designed using low-dose radiation with gemcitabine in tumors that have shown response to gemcitabine alone.

Materials and Methods

  • This trial is a phase I/II trial where the primary questions to be determined are: how well is the regimen  tolerated, and what is the maximum tolerated dose of the radiation therapy?
  • All patients enrolled on the trial had biopsy-confirmed locally advanced or metastatic tumors of upper GI tract origin, including small bowel, stomach, hepatobiliary, and pancreatic tumors.
  • All patients were deemed unresectable by surgical criteria.
  • Radiation was given as either low-dose upper abdominal radiation (LD-UART), with the lower radiation field border at the top of the iliac crest, or as low dose whole abdominal radiation (LD-WART).
  • LD-WART was given for patients with peritoneal carcinomatosis.
  • Two dose levels of radiation were tested: 60 cGy per fraction or 70 cGy per fraction.
  • Radiation was given twice a day on days 1, 2, 8, and 9.
  • Gemcitabine was given at 1250 mg/m2 over 2 hours on days 1 and 8 of a three week cycle, and a total of 4 three-week cycles were planned.
  • 18 patients have been enrolled to date, and the results of the 10 who received LD-UART are presented.
  • 5 patients had unresectable pancreatic cancer, 4 had metastatic pancreatic cancer, and 1 had metastatic small bowel cancer.
  • Dose-limiting toxicity was defined as grade 4 neutropenia or thrombocytopenia, neutropenic fever, or >/= grade 3 non-hematologic toxicity (except nausea, vomiting, hyperbilirubinemia, or alopecia).

Results

  • At the 60 cGy dose level, 1 patient developed a dose-limiting grade 3 infection and 6 of 6 patients completed the planned 4 cycles of therapy.
  • At the 70 cGy dose level, 2 of 4 patients experienced dose-limiting toxicity, with 1 patient experiencing a grade 3 infection and 1 patient experiencing grade 3 diarrhea.
  • The median survival for all 10 patients is 10 months (range 4-37 months).
  • Based on radiographic definitions, 1 patient had a complete response, 2 had partial responses, 5 had stable disease, and 1 had progressive disease.

Author's Conclusions

  • LD-UART was well-tolerated at the 60 cGy level when combined with gemcitabine.
  • Given the encouraging radiographic responses and median survival of 10 months in this poor-prognosis group of patients, continued phase II evaluation of this regimen is warranted.

Clinical/Scientific Implications

This is a fascinating piece of research that explores a truly novel treatment paradigm. The investigators, based on work performed in the laboratory, moved a new principle into the clinical arena. The idea that low-dose radiation therapy can serve as a chemosensitizer has not been widely tested in clinical medicine. As each of the study patients has such a large volume of disease, it would not be safe to deliver high-dose radiation concurrently with full- strength gemcitabine chemotherapy. Another research group who presented their work at this year's meeting is testing the exact opposite paradigm, using low-dose gemcitabine to act as a radiosensitizer for standard-dose abdominal radiation.

All of the patients in this study, based on their disease presentations, have extremely low chances of achieving lengthy survival outcomes using the current standard of medical care. The finding that 9/10 patients had at least radiographically stable disease is quite remarkable. The authors should be commended for undertaking this interesting and promising research. In the future, phase II and III data utilizing this regimen will help us to determine whether this is actually the most effective treatment strategy for this subgroup of patients with unfavorable prognosis.