Key Takeaways in the Treatment of Advanced Colorectal Cancer - Episode 2

Key Takeaway 2: Frontline Neoadjuvant Chemotherapy


Tanios S. Bekaii-Saab, MD: Rectal cancer is a bit separate from colon cancer in terms of how we manage it. I mean, if you want to think about where the rectum lies, the rectum is a fixed structure, it lies in a very tight space, and there are a lot of nerves, blood vessels, and bones. Unlike colon cancer, rectal cancer has a propensity to come back locally following surgery. And so radiation becomes a very important component of how we treat rectal cancer.

Now, studies looking at giving radiation before or after surgery have not shown a difference in survival between the 2. But the difference in terms of giving radiation before surgery versus after surgery was primarily with cutting down on the risk of local recurrence and cutting down on the risk of having the need for an ostomy, which is a quality-of-life issue. For all these purposes, for patients with rectal cancer, we do treat them with radiation and chemotherapy prior to surgery. That’s a standard.

For more and more patients, we’re moving the chemotherapy that we typically give adjuvantly after surgery into the preoperative setting, so chemotherapy followed by chemotherapy and radiation. And we call this the total neoadjuvant therapy, meaning all therapies are administered before surgery. The patient goes to surgery, and then they’re done. That certainly controls locally, improves the outcomes with systemic recurrence, improves survival and local recurrence rates as well as the need for an ostomy.

We continue to struggle with whether we have patients who do not need surgery. We think there’s a group of patients with rectal cancer who respond really well to chemotherapy, radiation, and chemotherapy prior to surgery and may not even need surgery because of their low risk of local and systemic recurrence. The problem today is that we don’t have a clear path about who those patients are. A number of studies actually look at how to best identify those patients. Those are the patients who are essentially in the lowest part of the rectum, so the low-lying rectal tumors. Those are the patients who essentially will end up with an ostomy, which is a quality-of-life issue when they have the rest of their lives to live.

More importantly, some of the studies suggested that—and depending on what study you look at, it’s an average of 10%, maybe you could reach up to 20%—with the right concoction of treatments, patients will have a clinical complete response. In this scenario, a composite of the tumor actually shrivels to nothing, so when you use the endoscopic ultrasound, you don’t see evidence of it. And biopsies confirm pathologic complete response or at least pathologically no evidence of tumor. Because the only way you can confirm pathologic complete response is if you do the surgery.

When a study looked at applying a watch-and-wait strategy, it found that a small percentage of patients, about 10%, never actually had the cancer come back. These numbers were difficult to reproduce across other studies. At this point of time, I frankly don’t think there’s a clear path for us in the clinic to decide who doesn’t and who does get surgery, although again one can argue that it may not be a significant risk for some of these patients who decide they don’t want to have that surgery. Can we just watch and wait, especially for the lower-lying tumor, with a local complete response. That discussion can happen in the clinic, and if the patient understands the risks and the physician understands the literature surrounding that, then I think it’s OK for some of these patients. But for the overwhelming majority of patients, surgery after chemotherapy and chemotherapy and radiation will remain the standard.

The NORDIC group looked at essentially taking our typical 5½ weeks of chemotherapy and radiation and bringing it to 5—what we call 5 times 5—so shortened-course high-dose radiation. The experience, at least from the NORDIC trial, is it historically provides outcomes that are very similar to what we expect with standard chemotherapy and radiation. That has been confirmed in smaller studies, including in the United States. Although there was 1 study that suggested that we may lose local control by applying the 5 times 5 versus the full chemotherapy and radiation. How do we do it today in our clinics? In our institution, all patients are in.

In our institution, all patients who are early stage or who have early-stage rectal cancer will have 5½ weeks of chemotherapy and radiation. The only times we apply the 5 times 5 are if 1) the patient desires or refuses to get the full-blown, but 2) more importantly, for those patients with limited metastatic disease for whom local control remains desirable, because a patient has a single lesion or a couple of lung lesions or liver lesions that are resectable, and then you want to make sure that the patient’s local control is optimized. In that group of patients, we favor the 5 times 5 because the intent is different in this case.

For the stage IV limited-disease patients, for whom local control is desirable, 5 times 5. For the earlier-stage patients, we still apply the 5½ weeks. Keep in mind that for stage IV rectal cancer, 95% plus of the patients will never require radiation. We’re talking about a very small subgroup of patients who may have just very limited disease and can get them into remission, and then local control becomes desirable. That’s very important. I don’t want everyone to think we should give radiation to every patient with rectal cancer as a stage IV rectal cancer. And that’s important to keep in mind—only very select few. This is where you go with the 5 times 5.

Transcript Edited for Clarity