Evolving considerations in the design and interpretation of phase I trials investigating gemcitabine based chemoradiotherapy regimens.

I he Phase I trial of gemcitabine dose escalation with concurrent radiation therapy for patients with advanced gastrointestinal cancer, reported by Mohiuddin et al1 in this issue of The Cancer Journal, represents further effort to define an optimal schedule for the concomitant delivery of gemcitabine and radiation in patients with abdominal or pelvic malignancies. The regimen was based on the initial in vitro studies of gemcitabine based radiosensitization, which indicated significant radiosensitization following a 24-hour exposure to a non-cytotoxic concentration of drug in human colon and pancreatic cancer cell lines.2–3 The profile of toxicities observed is consistent with the toxicities seen in other trials of gemcitabine dose escalation with radiation therapy in this patient population. As would be anticipated, gastrointestinal and hematological toxicity increased with increasing doses of gemcitabine, and the maximum tolerated dose (MTD) was found to be lower than the MTD of gemcitabine alone, when used in a similar schedule. These data are meaningful to investigators who may be considering trials of weekly continuous 24-hour infusion of gemcitabine with concurrent radiation therapy, and contribute to the growing body of literature on this general topic. The response rates were impressive, as is often the case in Phase I trials utilizing agents with documented cytotoxic and radiosensitizing activity in combination with radiation therapy With respect to response rates, caution is appropriate, as the trial was not designed to assess response as a primary endpoint. Any conclusions with respect to late toxicity are premature given the median follow-up of 8 months, as the authors suggest. This report also provides an opportunity to comment on the wide variety of issues that must be considered when gemcitabine-based chemoradiotherapy trials are designed and evaluated. Several are obvious: radiation dose, history of prior radiation therapy, anatomic location of the radiation field with respect to normal tissue toxicity, and the use of chemotherapy agents concurrent with gemcitabine and radiation therapy The most relevant issues include the primary goal ascribed to the combined modality regimen and the volume of normal tissue included within the radiation treatment volume. As would be expected, the radiation dose, an uncontrolled variable in this trial, correlated with the observed toxicity. In an ideal trial of gemcitabine dose escalation with concurrent radiation, one would like to maintain radiation dose (along with volume and anatomic location, discussed below) as a uniform variable. This was not possible in this trial considering the heterogeneity of patients entered, which is often the case in Phase I trials. However, it raises the question of an uncontrolled variable which may have influenced the primary conclusion. There are no data provided with respect to radiation dose at each gemcitabine dose level, which limits our ability to assess the impact of radiation dose on toxicity observed. Were all 10 patients treated to ≥ 50 Gy in the higher gemcitabine dose levels, or were they equally distributed in all dose levels? When decisions regarding escalation or MTD are based on one or two patients, these data are relevant. History of prior radiation therapy was also considered, and appropriately influenced the radiation dose prescribed. With only three patients having had a prior history of radiation, it is unlikely that this issue influenced the primary conclusion. The anatomic location of the target (and by extension, specific normal tissue irradiated) is also addressed. The authors have concluded that no significant differences were noted between groups stratified by anatomic site.