Neoadjuvant Chemoradiation for Rectal Cancer: Is More Better?
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. 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. 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. 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.
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. 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. 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.
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. 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. However, an intergroup study showed no advantage for protracted continuous-infusion 5-FU plus RT over bolus 5-FU/leucovorin (LV) plus RT. Thus, current adjuvant 5-FU–based chemoradiation regimens incorporate either continuous-infusion 5-FU or 5-FU and leucovorin.
Neoadjuvant 5-FU–based chemoradiation regimens have been largely extrapolated from prior adjuvant studies. Protracted 5-FU infusion regimens (300 mg/m2/d on radiation days or 225 mg/m2/d including weekends) have been shown to have significant antitumor activity and are commonly implemented in clinical practice in the United States.[20,21] Neoadjuvant bolus 5-FU and leucovorin plus RT (5-FU/LV 350/20 mg/m2/d mg/m2/d including weekends) have been shown to have significant antitumor activity and are adjuvant studies. Protracted 5-FU infusion regimens (300 mg/m2/d on radiation days or 225 Neoadjuvant 5-FU–based chemoradiation regimens have been largely extrapolated from prior × 5 days on weeks 1 and 5 of RT) was developed at Memorial Sloan-Kettering Cancer Center and was similarly associated with favorable antitumor activity and toxicity profile. Both continuous and bolus 5-FU/LV–based chemoradiation were given concurrently with 45 to 50.4 Gy of radiation. The ongoing National Surgical Adjuvant Breast and Bowel Project (NSABP)-R04 neoadjuvant rectal cancer trial has endorsed 5-FU at 225 mg/m2/d with RT at 50.4 Gy as its standard control arm (Figure 1).
Neoadjuvant 5-FU/LV Plus RT vs RT Alone
5-FU–based chemoradiation compares favorably to RT alone in the neoadjuvant treatment of rectal adenocarcinoma. A large phase III French study, Fdration Francophone de Cancrologie Digestive (FFCD) 9203, randomized patients with stage II/III rectal cancer to receive RT alone (45 Gy in 25 fractions) or 5-FU/LV with RT (FU/LV 350/20 mg/m2/d on days 1 to 5 and 29 to 33 of RT). Patients in both arms subsequently underwent surgery and four cycles of 5-FU/LV. The preoperative chemoradiation arm showed a significant improvement in pathologic complete response (pCR) rate (11.4% vs 3.6%, P < .05) and local relapse rate (8.1 vs 16.5%, P < .05). The 5-year survival in both arms was 67%.
Another large phase III study, European Organisation for Research and Treatment of Cancer (EORTC) 22921, randomized patients with stage II/III rectal cancer to receive neoadjuvant RT alone (45 Gy in 25 fractions) vs RT with bolus 5-FU/LV (350/20 mg/m2/d during the first and fifth weeks of preoperative RT), with a subsequent randomization to postsurgical (3 to 10 weeks after chemoradiation) 5-FU/LV chemotherapy or no postsurgical chemotherapy. The study demonstrated no significant difference in overall survival between the groups that received chemotherapy preoperatively and those who received it postoperatively. The 5-year cumulative incidence rates for local relapse were 8.7%, 9.6%, and 7.6% in the groups receiving chemotherapy preoperatively, postoperatively, or both, respectively, and 17.1% in the group that did not receive chemotherapy (P = .002).The authors concluded that in patients with rectal cancer who receive preoperative radiotherapy, adding 5-FU–based chemotherapy either preoperatively or postoperatively conferred a significant advantage in terms of local control.
Neoadjuvant 5-FU/RT vs Adjuvant 5-FU/RT
The German Rectal Cancer Study Group randomly assigned 823 patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. Radiation therapy was delivered at 50.4 Gy, with an additional 5.4 Gy delivered as a boost in the postoperative arm. 5-FU was given in a 120-hour continuous intravenous infusion at a dose of 1,000 mg/m2/d during the first and fifth weeks of RT. Surgery (TME) was performed 6 weeks after the completion of chemoradiotherapy. At 1 month after surgery, four 5-day monthly cycles of 5-FU (500 mg/m2/d) were given.
The results from this study showed a significantly lower 5-year cumulative incidence of local relapse in favor of the preoperative treatment group (6% vs 13%). The 5-year disease-free (68% vs 65 %) and overall survival rates (76% vs 74%) were similar for preoperative and postoperative therapy and the differences between the groups were not statistically significant. Significant tumor downstaging was seen after preoperative combined-modality treatment, with an 8% pCR rate. Posttrial review showed that sphincter-saving surgeries were more likely to occur in the neoadjuvant chemoradiation group than in the adjuvant group (39% vs 19%, P = .004).
Furthermore, acute and delayed grade 3/4 toxicities were less frequent in the preoperative group (27% vs 40%). Despite the lack of survival advantage, the improvements in local relapse rate and toxicity profiles have clearly established neoadjuvant chemoradiation as the standard adjuvant modality in rectal cancer.
Capecitabine Plus RT
Capecitabine (Xeloda) is an oral, tumor-activated fluoropyrimidine carbamate that delivers 5-FU preferentially to tumor cells via a three-step in vivo enzymatic conversion. The final step is mediated by the enzyme thymidine phosphorylase, which is upregulated in tumor tissue compared with adjacent healthy tissue. This also gives capecitabine a theoretical advantage of differential radiosensitization in the tumor, sparing normal tissues. The equivalence of capecitabine to intravenous 5-FU/LV in the treatment of metastatic colorectal cancer has led to its incorporation in the chemoradiation of rectal cancer.[27-31] The advantages of capecitabine over 5-FU include its ease of administration and its favorable toxicity profile.
Dunst et al evaluated the combination of capecitabine and radiotherapy in a phase I clinical trial. Capecitabine at 825 g/m2 twice daily (including weekends) concurrently with 50.4 Gy was determined as the recommended dose with promising efficacy results. Several phase II clinical trials have evaluated this dose and schedule in patients with stage II/III rectal cancer and have shown pCR rates ranging from 12% to 24% (Table 1).[34-37]
There are no efficacy data available from randomized clinical trials comparing capecitabine/RT with 5-FU/RT in the neoadjuvant setting in locally advanced rectal cancer. However, two well-conducted retrospective studies have evaluated the efficacy of capecitabine/RT with 5-FU/RT in locally advanced rectal cancer with comparable response and overall survival rates.[38,39] Kim et al compared 145 patients who received either 5-FU/LV (5-FU at 400 mg/m2/d with LV at 20 mg/m2/d for 3 days in the first and fifth weeks of RT), to 133 patients receiving capecitabine (825 mg/m2 twice daily for the duration of RT), both with concurrent RT (50.4 Gy in 28 fractions). Comparable downstaging (5-FU/LV: 44.3%, capecitabine: 49.9%; P = .571) and pCR rates (5-FU/LV: 11.3%, capecitabine: 16.1%; P = .758) were noted.
Das et al compared outcomes in 89 patients receiving capecitabine at 1,650 mg/m2/d concurrently with RT (45 Gy) and 87 patients receiving protracted infusional 5-FU (300 mg/m2/d). No significant differences in pCR (21% vs 12%, P = .19) or downstaging (52% vs 62%, P = .20) were seen for capecitabine and 5-FU, respectively. Local relapse, distant control, and overall survival were similar across both arms.
The randomized phase III NSABP-R04 study (Figure 1) is currently comparing capecitabine/RT to 5-FU/RT (with and without concurrent oxaliplatin [Eloxatin]). This will help determine if capecitabine can substitute for 5-FU in the neoadjuvant treatment of rectal cancer.