Modern chemoradiation and chemotherapy protocols for locally advanced rectal cancer: The current and future standards of care
Introduction
The treatment paradigm of locally advanced rectal cancer (cT3 or cT4 and cN0 or cN+ disease) has changed significantly in the last two decades. Prior to the introduction of radiotherapy, chemoradiotherapy, and total mesorectal excision (TME), the local recurrence rate for LARC was up to 40%, resulting in an overall poor prognosis despite curative intent surgery.1 Several randomized trials showed that preoperative radiotherapy followed by surgery had better local control compared to surgery alone. A meta-analysis of fourteen randomized controlled trials showed that preoperative radiotherapy significantly reduced the 5-year overall mortality rate (OR 0.84; 95% CI, 0.72–0.98; p = 0.03) and local recurrence rate (OR 0.49; 95% CI, 0.38–0.62; p < 0.001).2 Earlier trials had also shown a benefit of postoperative 5-fluorouracil (5-FU) chemotherapy with radiotherapy in improving survival and reducing local recurrence rates as compared to surgery or surgery with postoperative radiotherapy.3, 4 This set the stage for trials to be conducted over the subsequent 15–20 years which sought to answer the following four essential questions: (1) At what point in the treatment course should the chemotherapy and radiation therapy be given? (2) Is chemotherapy actually needed in rectal cancer? (3) Should it be given with radiation therapy, separate from it, or both? (4) Which chemotherapy agents should be used? In this article we will answer these questions based on the existing data and then move to the questions that will occupy clinical trialists in the coming decades.
Section snippets
Sequencing of chemoradiotherapy (Table 1)
In order to improve the outcomes of LARC, preoperative chemoradiotherapy (CRT) approaches were tried in large randomized controlled trials in mid-1990s. The preoperative approach could potentially have several advantages including surgical downstaging, sphincter preservation, superior overall tolerability, addressing systemic micro-metastatic disease earlier, providing in vivo evidence of response, improving R0 resection rates, and increasing pathological complete response (pCR) rates. The
Preoperative radiotherapy vs. chemoradiotherapy
Both the Dutch and Swedish rectal cancer trials showed a clear advantage to preoperative radiation therapy vs. surgery alone in LARC,10, 11 so it is fair to ask whether chemotherapy adds anything to this advantage. There are two landmark trials comparing preoperative chemoradiotherapy with preoperative radiotherapy only. The EORTC 22921 answered two questions, benefit of preoperative CRT over RT alone and the role of adjuvant chemotherapy in a 2 × 2 factorial design.12 In this trial, LARC
Adjuvant chemotherapy vs. no adjuvant chemotherapy
The above have established the role of preoperative CRT vs. postoperative CRT or vs. preoperative RT alone. The next question is: what is the role of additional chemotherapy. The current standard of care in the United States is to give 4–6 months of adjuvant 5-FU-based chemotherapy (usually FOLFOX), which is mainly an extrapolation from colon cancer trials.16, 17 The theoretical advantage of adjuvant therapy is the reduction in the micro-metastases and thereby distance recurrences which have
The choice of chemotherapy with radiation therapy (Table 2)
Although most of the landmark neoadjuvant CRT trials were done with 5-FU with or without leucovorin, many investigators have tried to substitute oral fluoropyrimindines (capecitabine) or to add other drugs, such as, oxaliplatin, irinotecan, anti-EGFR agents (cetuximab and panitumumab), or bevacizumab, in order to improve the outcomes of neoadjuvant CRT.
Current issues: The appropriate sequencing of chemotherapy with CRT (Table 3)
The current standard of care for LARC in the United States is neoadjuvant CRT with continuous infusion 5-FU or capecitabine followed by total mesorectal excision (TME) and then adjuvant chemotherapy for 4–6 months. However, it is debatable what the optimal sequence of multimodality therapy for LARC is. Moreover, it has been shown that pCR rate after preoperative CRT is an important predictor of better prognosis.41 However, pCR rates remain low despite aggressive preoperative CRT and different
Conclusions
We will now return to the original 4 questions we posed at the beginning of this review:
- (1)
At what point in the treatment course should the chemotherapy and radiation therapy be given? The evidence clearly supports CRT given in a preoperative setting based mainly on the results of the German rectal trial and not directly contradicted by the underpowered NSABP R-03 and Korean trials.
- (2)
Is chemotherapy actually needed in rectal cancer? There is no question that chemotherapy, when either added to
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