The world of cancer treatment is a rapidly evolving creature, and rectal cancer is no exception. In particular, locally advanced rectal cancer has a number of valid treatment options. While it’s traditionally a surgical disease, in some cases we now have evidence for watch-and-wait approaches that spare patients the morbidity and toxicity associated with oncologic resections. But even when the goal is to get the patient to a total mesorectal excision (TME), several nuances can influence decision making. Suddenly, talking to a patient about rectal cancer has become as lengthy a discussion as those we have with intermediate-risk prostate cancer patients.

We currently have good evidence to suggest that total neoadjuvant therapy (TNT) should be standard of care for locally advanced rectal cancers. But even within this algorithm of chemotherapy and chemoradiation followed by surgery, questions abound. Which treatment should we start with? Which chemotherapy should be used? What radiation fractionation should we employ? And which concurrent chemotherapy should be paired with radiation? While the 5-year follow-up of the RAPIDO trial demonstrated a statistically significant increase in the locoregional recurrence rate (10% vs 6%) with short course radiation,¹ this must be viewed through a critical lens, given that the two arms did not directly compare short- and long-course radiation. Perhaps it was the addition of neoadjuvant chemotherapy, delaying surgery, that resulted in a detriment to the locoregional control. Thus, short-course radiation is still indicated as a reasonable treatment option per NCCN guidelines. Of course, in this case, we would be sure to counsel our patients about the potential risks of locoregional recurrence should a short course of radiation be the preferred regimen (for example, if surgery is urgent).

In a world where trimodality therapy has been the standard of care for so long, it’s remarkable to think that some of these cancers can be cured with a single systemic agent alone.

Adding to this discussion is whether to begin with chemotherapy or chemoradiation. Typically, we begin with chemoradiation when sphincter preservation is the primary concern (for example, a low rectal tumor with positive or close anal involvement). The goal here is to proceed to low anterior resection (LAR) and leave the patient with a functioning anal sphincter (vs a permanent ostomy following an abdominoperineal resection [APR]). Concurrent chemotherapy can be either with capecitabine or infusional 5-FU. Alternatively, in patients who are node positive, there is greater concern for distant spread and often 12 to 16 weeks of chemotherapy is initiated first (using FOLFOX or CAPEOX).

In select patients with T3N0M0 rectal cancers who have completed TNT and have a complete response, a watch-and-wait approach is not unreasonable. However, this is a controversial area and NCCN recommends experienced multidisciplinary management — yet another ambiguity to consider when treating rectal cancer patients.

Complicating the entire oncologic world (in a good way) is the erupting knowledge about molecular markers. In rectal cancer, microsatellite instability (MSI) is a critical marker. Those with MSI-high tumors theoretically may avoid all the previously discussed treatments; they receive immunotherapy upfront (preferred per NCCN) followed by surveillance if they have a complete response. In a world where trimodality therapy has been the standard of care for so long, it’s remarkable to think that some of these cancers can be cured with a single systemic agent alone.

There are further intricacies with high-risk, early-stage rectal cancers that are beyond the scope of this blog. The point is, the more that research advances and the more we learn how cancers behave, especially at the molecular level, the more nuanced our discussions with patients will be.

It becomes clear that experienced multidisciplinary care and planning is crucial for best outcomes and least toxicity for these patients.

Reference

1. Dijkstra EA, Nilsson PJ, Hospers GAP, et al. Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared with long-course chemoradiotherapy and surgery: a 5-year follow-up of the RAPIDO trial. Ann Surg. 2023;278(4). doi:10.1097/SLA.0000000000005799