Neoadjuvant Chemoradiation for Rectal Cancer: Is More Better?

ABSTRACT: Neoadjuvant chemoradiation is now considered the clear preferable adjuvant standard of care in the management of stage II/III rectal cancer. Neoadjuvant fluorouracil (5-FU) plus radiation results in a decrease in local relapse rates and a favorable toxicity profile in comparison with postoperative adjuvant 5‑FU plus radiation therapy. Recent nonrandomized comparative studies have shown that capecitabine (Xeloda) plus radiation result in downstaging and pathologic complete responses equivalent to those of 5-FU plus radiation, making this combination an acceptable alternative neoadjuvant treatment. The addition of oxaliplatin (Eloxatin) or irinotecan (Camptosar) to 5-FU or capecitabine concurrently with radiation therapy appears to result in more favorable pathologic responses in phase I/II trials. These combinations should be investigated further in larger phase III studies before they are endorsed in the routine neoadjuvant treatment of rectal cancer. This article will review the progress of chemoradiation over the past 2 decades, current standards of care, and investigational treatments in the neoadjuvant treatment of rectal cancer.

Neoadjuvant chemoradiation has become the favored adjuvant treatment for stages II and III rectal cancer. Compared to postoperative chemoradiation, this modality of treatment has been shown to be superior in terms of toxicity, local relapse, and sphincter-saving.[1] This article will focus on the evolution of neoadjuvant chemotherapy over the past 2 decades, current acceptable neoadjuvant standards, and current investigational regimens.

Neoadjuvant Radiation for Rectal Cancer

In the Pre–Total Mesorectal Excision Era

While adjuvant radiation therapy (RT) has never been shown to improve overall survival, there is evidence-at least from the pre–total mesorectal excision (TME) era-that neoadjuvant RT improves both local control rates and overall survival.[2-6]

A Swedish rectal cancer trial randomly assigned 1,168 patients with resectable rectal cancer to undergo preoperative irradiation (5 Gy/fraction × 5 days) followed by surgery within 1 week or to undergo surgery only.[6] The preoperative RT arm showed a significant decrease in local relapse (11% vs 27%, P < .001) and improvement in the 5-year survival rate (58% vs 48%, P = .004). A recent update of this study confirmed that the survival benefits seen with neoadjuvant radiation persisted at 13 years.[7] The survival advantage of neoadjuvant radiation therapy in rectal cancer has been confirmed by two independent meta-analyses, both of which included 14 randomized trials and close to 6,000 patients.[8,9]

In contrast, randomized studies and one meta-analysis of adjuvant radiation studies failed to show any improvement in survival in patients receiving postoperative radiation vs surgery only.[3,4,9,10]

A randomized phase III study comparing neoadjuvant RT to adjuvant RT for stage II/III rectal cancer lends further support to a neoadjuvant radiation strategy. In this study, 471 patients were randomized to receive either preoperative short-term radiation (25.5 Gy in 1 week) or prolonged postoperative radiation (60 Gy in 7 to 8 weeks). After a minimum follow-up of 5 years, investigators found a significant decrease in the local relapse rate in favor of the preoperative RT arm (13% vs 22%, P = .02) but no overall survival benefit.[5]

To summarize, the historic data from the pre-TME era supports the use of neoadjuvant radiation in patients with rectal cancer. However, evidence is inadequate to support a survival impact for single-modality adjuvant radiation therapy.

In the Total Mesorectal Excision Era

Total mesorectal resection requires sharp dissection beyond the plane of the mesorectum, thus permitting en bloc removal of intact tumor with its lymphatics and vascular supply. This technique is more likely to result in a negative circumferential margin and is now endorsed as the standard of care for rectal cancer surgery. In contrast with blunt dissection, TME is associated with low local relapse rates of up to 8% in patients with stage II/III rectal cancer.[11-15]

Given the low relapse rates with TME, two large trials have explored the role of preoperative radiotherapy in this setting.[16,17] A Dutch study randomized 1,861 patients with rectal cancer to receive neoadjuvant RT (5 Gy × 5) followed by TME vs TME alone to assess the impact of neoadjuvant RT on recurrence rate and overall survival. The rate of local relapse at 2 years was 2.4% in the radiotherapy-plus-surgery group and 8.2% in the surgery-only group (P < .001). Neoadjuvant RT did not affect the risks of distant relapse or overall survival.[16] A subgroup post hoc analysis of this study suggested that there was no benefit from RT in patients with stage I disease or with proximal T3, N0 tumors.[16] This study highlights the value of neoadjuvant RT in patients with stage II/III rectal cancer-despite the routine integration of TME in surgical management.

The second trial, the Medical Research Council (MRC) CR07, randomized 1,350 patients with clinically resectable rectal cancer to short-course preoperative radiation therapy (5 Gy × 5) and TME vs TME followed by selective postoperative chemoradiation for patients with a positive circumferential margin (45 Gy in 25 fractions plus fluorouracil [5-FU]). Preliminary results presented at the 2006 annual meeting of the American Society of Clinical Oncology showed a significant decrease in local relapse (4.7% vs 11.1%) and an improved 3-year disease-free survival (79.5% vs 74.9%) in favor of the preoperative RT arm.[17]

This study further confirms that preoperative RT is favored over postoperative chemoradiation in patients with high-risk disease. Also of note, unlike the Dutch trial, MRC CR07 patients with proximal lesions had a significant decrease in local relapse when receiving preoperative RT. No data were presented on the impact of preoperative chemoradiation on the T3, N0 proximal tumor subgroup.

Neoadjuvant Chemoradiation for Rectal Cancer

5-FU Plus RT

Interest in the use of neoadjuvant 5-FU plus radiation stemmed from adjuvant chemoradiation studies of rectal cancer. A randomized adjuvant clinical trial confirmed an improvement in local relapse rates with a survival benefit in favor of 5-FU–based RT in comparison with RT alone.[10] A subsequent randomized adjuvant chemoradiation study reported a disease-free and overall survival advantage favoring protracted continuous-infusion 5-FU over bolus 5-FU with RT.[18] However, an intergroup study showed no advantage for protracted continuous-infusion 5-FU plus RT over bolus 5-FU/leucovorin (LV) plus RT.[19] Thus, current adjuvant 5-FU–based chemoradiation regimens incorporate either continuous-infusion 5-FU or 5-FU and leucovorin.

FIGURE 1

Design of NSABP-R04 Trial

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