Neoadjuvant treatment of rectal cancer: where are we now?

Colorectal cancer is the third leading cause of cancer-related mortality in the United States [1]. Of this group of patients, approximately 39 000 cases of rectal cancer were reported in the US in 20151]. Treatment of rectal cancer truly requires combinatorial therapy with surgery, chemotherapy and radiation (RT), which now comprise the cornerstone of treatment for rectal cancer. Advanced rectal and colon cancers are generally treated similarly, with most clinical trials not distinguishing between these two anatomic origins. This is in contrast to early stage and locally advanced disease in which the natural histories are distinct, stemming from the fact that the vascular supply for the rectum drains into the inferior vena cava instead of the portal vein [2]. The difference in vascular drainage results in an increase in pulmonary metastases rather than liver metastases [2]. Historically, recurrence within the pelvis has been more common than distant metastases. It is not surprising that treatment objectives focus on minimizing and/or eliminating both local recurrence and distant metastases. Early in the 1970s and 1980s, the recurrence rates were extremely high, nearing 50%, which led to numerous clinical studies evaluating the role of postoperative RT and adjuvant therapy with 5-fluorouracil (5FU) as the backbone. Consensus guidelines from 1990 have established trimodality therapy with chemotherapy, RT and surgery as the standard of care for locally advanced rectal cancer (stage II/stage III) [2,3]. Significant improvements in local disease control have been achieved ever since with the introduction of total mesorectal excision and neoadjuvant chemoradiotherapy (CRT). More recently, questions have been raised as to whether trimodality therapy in the neoadjuvant setting is truly required to obtain disease control for all patients with locally advanced rectal cancer. Furthermore, while local recurrence rates have been stable at 5–6% [4] with this trimodality strategy in recent clinical trials, distal recurrence rates for locally advanced rectal cancers remain at around 25% [5]. In fact, metastases now represent the main cause of death. It is for these reasons that new studies are evaluating the role of systemic chemotherapy in the neoadjuvant setting to address micrometastatic disease and hence potentially reduce the rate of distant recurrence [2,6–8]. In this brief review, we summarize the current literature for neoadjuvant treatment of rectal cancer. Staging in rectal cancer Management of locally advanced rectal cancer is complex, in part due to the necessity of integrating multi-modality treatment consisting of chemotherapy, RT and surgery, which are often required for curative intent. The timing and sequencing of these modalities are challenging because the location of the rectal tumor, the extent of spread and nodal involvement all determine optimal delivery of these treatments. The objective of neoadjuvant treatment remains optimization of disease-free survival (DFS) and overall survival (OS) while minimizing toxicity from RT and chemotherapy and eliminating local recurrence [2]. Early-stage disease, defined as T1-2N0, is usually treated with surgery alone. Locally advanced disease, defined as stage II/III disease, requires initial clinical staging with pelvic MRI and endoscopic rectal ultrasound (ERUS) evaluation to determine the extent of disease and nodal involvement. Staging provides critical information about the likelihood of achieving a complete resection (R0) as well as the likelihood of sparing the rectal sphincter and thereby maintaining fecal continence [2]. Colonoscopic evaluation is required for all patients to determine the extent of resection that will be required and to explore for synchronous lesions. MRI is a vital tool for presurgical management assessment as it can better delineate encroachment on the mesorectal fascia and thereby help determine the potential for a positive radial margin at the time of surgery [8]. The precision of MRI in this setting was evaluated in the MERCURY trial in which high-resolution MRI accurately predicted whether the surgical resection margins were clear or affected by tumor [9].