Modern chemoradiation and chemotherapy protocols for locally advanced rectal cancer: The current and future standards of care

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Abstract

The introduction of radiotherapy, chemoradiotherapy, and total mesorectal excision has significantly changed the treatment landscape of locally advanced rectal cancer (LARC) in the last two decades. A number of large randomized controlled trials have established preoperative chemoradiotherapy followed by total mesorectal excision as the standard of care treatment. The addition of oxaliplatin, irinotecan, bevacizumab, or anti-EGFR therapies to 5-fluorouracil or capecitabine and radiation therapy has failed to improve outcomes at an acceptable toxicity. With excellent control of local recurrences (5–10%), the focus has shifted to reducing distant metastases and improving pathological complete response. Despite no proven benefit, adjuvant chemotherapy remains the standard of care in the United States based on extrapolation from colon cancer trials. Defining the best chemotherapy combination has remained a challenge. Trials are ongoing to address the best sequence of the most efficacious combination chemotherapy to be given either before or after preoperative chemoradiotherapy. In this review, we have summarized the literature of LARC and addressed the role and sequence of different chemotherapy combinations with respect to surgery and radiotherapy in the multimodality treatment. Lastly, we discuss important questions that need to be addressed for future clinical trials.

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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