Can the Sequencing of Concurrent Capecitabine and Radiation Therapy Improve the Therapeutic Ratio In Rectal Cancer?

For decades, 5-fluorouracil (5-FU)–based chemotherapy regimens have been used as systemic therapy for gastrointestinal (GI) malignancies. Over the years, efforts have been made to optimize the timing and mode of delivery to maximize the therapeutic benefit for a variety of malignancies, including rectal cancer. More recently, a prodrug of 5-FU, capecitabine, has been developed that offers certain therapeutic advantages over its predecessor. Capecitabine can be administered daily to mimic the pharmacokinetics of continuous infusion 5-FU without the complications and inconvenience associated with line access, and it demonstrates a favorable safety profile when compared to continuous infusion 5-FU.

Capecitabine is absorbed unchanged through the mucosa of the GI tract and then enzymatically converted into 5’-deoxy-5-fluorocytidine (5’-DFCR) by hepatic carboxylesterase and subsequently to 5’-deoxy-5-fluorouridine (5’-DFUR) by cytidine deaminase located in hepatic or malignant cells. 5-FU is released by the action of thymidine phosphorylase (TP), an enzyme that is more abundant in tumor cells compared to normal tissue. In fact, capecitabine is more than a 5-FU prodrug, as it is active in some xenograft tumors that are resistant to 5-FU, and it can achieve higher intratumor:plasma ratios of 5-FU drug concentrations in contrast to intravenous 5-FU administration.¹ In patients treated with capecitabine, 5-FU concentrations in tumor tissues have been found to be approximately three times higher than in adjacent normal tissue.^2,3 Thus, this selective activation to 5-FU in cancer cells allows for higher concentration of the active drug in cancer cells with lower systemic toxicity.

To enhance the therapeutic ratio and take advantage of the radiosensitizing properties of 5-FU, many strategies have been employed to increase its concentration in cancer cells relative to normal cells.⁴ In a preclinical study of human tumor xenograft models, it was found that radiation selectively increased the activity of TP in tumor cells but not in normal tissue.⁵ This increase in enzymatic activity translated to an additive benefit over either modality alone. These findings suggest that the addition of radiotherapy helps to selectively increase the tumor concentration of 5-FU, improving the likelihood of capecitabine-mediated radiosensitizing and therefore increasing the therapeutic benefit.

Concomitant chemoradiotherapy is considered a component of standard therapy for patients with rectal cancer. Shortcourse infusion 5-FU (96 hours during the first and last weeks of a 5–6 week course of pelvic radiotherapy) or protracted 5-FU (120 hours during weekdays or a full 7 days per week) is commonly administered. Data support the use of protracted infusional 5-FU during the postoperative setting since this schedule is superior to bolus 5-FU.¹⁰

Other studies have found that the peak plasma concentration of capecitabine and its metabolites is between 1–2 hours after administration and it begins to fall exponentially thereafter, with a plasma half-life of less than 1 hour.^6,7 It would seem, therefore, that proper timing of radiotherapy and capecitabine would be necessary to maximize the treatment effect of the two modalities. The study reported by Bedi et al (see page 44) in this issue of Gastrointestinal Cancer Research examines this question in the neoadjuvant treatment of rectal cancer.⁸

The authors present a retrospective analysis of differences in outcomes observed in 111 preoperative patients with rectal cancer receiving radiation treatments in the morning (closer to the morning administration of capecitabine) and afternoon (several hours after morning capecitabine administration). In that study, no significant differences were observed in the rates of response, acute toxicity, and relapses between the two groups. A similar study by Yu et al evaluated 200 patients treated neoadjuvantly for rectal cancer with capecitabine and radiation therapy.⁹ In this study, 85 patients received capecitabine 1–2 hours before radiotherapy (group A) and 115 did not (group B). They found that patients in group A had a significantly improved pathologic complete response (pCR) rate compared to patients in group B (23.5% vs. 9.6%, P = .01).

Does the timing of radiotherapy with respect to capecitabine administration affect patient outcomes in the treatment of rectal cancer? Preclinical data would suggest that it does. These two retrospective studies, however, conflict regarding that assertion. One notable difference between the two studies that may contribute to these conflicting results is the timing of radiotherapy after the morning dose of capecitabine.

In the study by Yu et al, radiotherapy was delivered within 1–2 hours, when the plasma concentrations of capecitabine are highest. In the study reported herein by Bedi, the range of time between the morning capecitabine dose and radiotherapy was wider. With a plasma half-life of less than 1 hour, levels of capecitabine and its metabolites diminish in an exponential fashion. Given known radiobiologic data, this will almost certainly affect radiosensitization. It is conceivable that even the minor differences in these trial designs led to these conflicting results, suggesting that the added benefit from capecitabine is lost more rapidly than could be detected in the Bedi study. As the authors alluded, however, plasma concentrations of capecitabine metabolites do not necessarily reflect intracellular concentrations, which further confounds the results of these studies. Hence, lacking a clearer knowledge of intratumoral concentrations of 5-FU and other metabolites, optimal timing of capecitabine and radiotherapy remains a question.

Concurrent radiotherapy and systemic therapy will continue to gain importance in the treatment of a variety of malignancies. Many obstacles remain to be overcome in order to maximize the efficacy of treatment. Optimum timing of radiotherapy with chemotherapeutic agents or targeted drugs will often be critical to outcome. This is also likely to be true regarding the timing of various drug combinations, where the potential for drug-to-drug interactions exists. Capecitabine represents an advance in systemic therapy for rectal cancer, and moving forward, studies will focus on optimizing its delivery. Given alone or with other agents, timing of capecitabine delivery will be crucial to maximize outcomes. This current study asks a very important question from a mechanistic standpoint. Further evaluations of capecitabine/radiotherapy designed to optimize favorable subcellular interaction are needed to aid in identifying the answer.