Rectal Cancer Treatment Enters an Era of Personalized Medicine

Noam VanderWalde, MD, MS

The constantly-evolving rectal cancer paradigm has entered an era of personalized treatment, according to Noam VanderWalde, MD, MS, who added that with the growing number of options available, a multidisciplinary team is needed to inform care decisions for each individual patient with the disease.

“The key point is that we’ve entered an era of personalization when it comes to the treatment of patients with rectal cancer; there’s no longer just 1 standard of care,” said VanderWalde. “Choosing which standard is right for each individual patient is often a difficult decision that needs to be made by a multidisciplinary team, which should be comprised of radiation oncologists, surgeons, medical oncologists, and importantly, the patient. We always try to incorporate patient preference into our treatment decisions.”

In an interview with OncLive during an Institutional Perspectives in Cancer webinar on Gastrointestinal Cancers, VanderWalde, an associate professor of radiation oncology at West Cancer Center and Research Institute, highlighted the importance of treatment personalization in rectal cancer, in addition to a few key studies.

OncLive: Could you speak to how rectal cancer treatment has shifted in recent years?

VanderWalde: Even just 3 to 5 years ago, no matter what type of locally advanced rectal cancer a patient had, everyone received preoperative chemoradiation. In the United States, patients were often given long-course chemoradiation and in Europe, they might receive short-course treatment. Then they would go straight to surgery followed by adjuvant chemotherapy, as needed. Now, we have entered the era of personalization there are different standards of care.

Interestingly, the results from both the RAPIDO and OPRA trials bring up patient preference into our standard of cares now. It’s also important to mention that [plans] can change over the course of a patient’s treatment, depending on how they’re responding to either chemotherapy or radiation.

Could you expand on how radiation therapy is being utilized based on stage of disease?

In patients with earlier-stage disease, for example, those with node-negative disease, the use of preoperative radiation therapy is dependent on the location of the tumor. As such, in a patient who has high [grade] rectal cancer, such as T2 or T3, we may try to avoid radiation. Results from multiple studies have shown that patients with high T3 disease have a very low risk of local regional recurrence. In addition, the patients with T2 disease don't need radiation.

That being said, if patients have a low-lying rectal cancer that may require abdominoperineal resection (APR), if they didn't get any downstaging, we may choose to use radiation even though they have “lower-stage” cancers. [We would want to get them to] nonoperative management or to go from an APR to a low anterior resection.

You mentioned the RAPIDO trial. What did this research examine and what should be taken away from it?

RAPIDO is a Dutch study that is not really examining short-course versus long-course radiation; it’s more so examining a total neoadjuvant (TNT) approach versus traditional neoadjuvant chemoradiation, followed by surgery, followed by adjuvant chemotherapy. This was a large randomized study, where 1 of the arms was short-course radiation therapy, followed by 6 cycles of FOLFOX and then followed by a total mesorectal excision (TME). The other arm received traditional chemoradiation therapy, then TME, and then adjuvant chemotherapy. Results from that study showed a benefit in disease-free survival (DFS) and distant metastasis-free survival (DMFS) with the TNT approach.

From a radiation oncologist perspective, this was interesting because that study was specifically for patients with locally advanced disease who had high-risk features, such as those with T4 disease or those with positive lateral nodes. Traditionally, we would not give short-course radiation to these patients. However, in the study, the pathological complete response (pCR) rate in patients who received short-course radiation therapy followed by chemotherapy was very high; it was approximately 28%.

Again, in that study, chemotherapy was given in between the completion of short-course radiation and surgery and I believe there was about 16 to 18 weeks between them.

This makes us much more comfortable, at least in the TNT setting, with using short-course radiation therapy and then delaying between the end of short-course radiation and surgery, as this may improve pCRrates compared with the older short-course studies where the pCR rates were lower.

What was the significance of the OPRA trial?

Another very important trial for oncologists and surgeons is OPRA, which examined nonoperative management. The trial had 2 arms, although the purpose of the trial was not to compare the arms; it was to compare a nonoperative approach to the historical control of patients to go to surgery. In 1 arm, patients received chemoradiation therapy first, followed by consolidative chemotherapy. Patients who had a clinical complete response were then followed and not taken to surgery. The other arm started with induction chemotherapy, followed by long-course chemoradiation.The results were excellent; the DFS and DMFS were very good compared with the historical controls and were not different between the 2 arms.

Although the goal of the study was not to compare the 2 groups, there did appear to be a slightly better TME-free survival rate in the patients who received chemoradiation first, followed by consolidated chemotherapy. In speaking with some of the authors of that study, it is very possible that the reason for that is simply the timing between the end of chemoradiation therapy and the assessment on whether patients needed surgery. We know that if we assess the patients too soon after chemoradiation, we may not see the complete response that they may get from the therapy. If you look at the actual difference, from when those curves split, it seems to be in the beginning; this means that there were more patients who had a clinical complete response who had chemoradiation further away from when they assessed that compared with when the chemoradiation was closer to the assessment.

Again, it's important to look at that difference skeptically because the study was not designed to look for differences between the 2 arms. The key take-home point of the study is that nonoperative management does seem to be a very feasible approach for many patients. We should start thinking about it for our patients. We should also be taking patient preference in terms of whether they want an operation into consideration, as well, when we’re making treatment decisions.

You were also a senior author on a study examining definitive pelvic radiotherapy in patients with newly diagnosed metastatic anal cancer. Could you shed some light on this research?

We conducted a great study assessing a patient population that we often see in the clinic; these are patients with metastatic anal cancer that has already spread, but they are still experiencing significant symptoms from their primary tumor. If you look at the National Comprehensive Cancer Network guidelines, they [suggest] offering local therapy to those patients, but there are not any prospective data to support that. As such, we decided to look at the National Cancer Database, which is a large retrospective database of patients who are treated across national cancer hospitals.

Using different statistical analyses, we found that patients who were treated with high-dose concurrent chemoradiation therapy survived for much longer than those who were not. This meant that treatment of the primary cancer, even in patients who may have metastatic disease, can significantly impact survival. We’re seeing this trend in other cancers, as well. In fact, another study was done in cervical cancer that was published in JAMA Oncology, and another study done in lung cancer showed that by consolidating the primary [tumor], patients may live longer.

I believe we're in an era where local therapy is being shown to potentially improve survival; that doesn't necessarily mean that this is curing patients. Unfortunately, it means that patients with cancer can have significant morbidity and mortality from their primary cancers themselves. If we can manage their primary cancers, we may be able to help them live longer.

What is your take-home message to your colleagues?

The treatment of rectal cancer is a lot more complex than it used to be; there is no longer 1 standard of care. Multiple great options are available for patients with rectal cancer. The final decision on how to treat these patients should be made in a multidisciplinary setting consisting of surgeons, medical oncologists, radiation oncologists and, very importantly, the patients. We must take patient preference into consideration, along with the specifics of each case when making decisions. It’s difficult to make these decisions alone.

To my colleagues who are treating patients with rectal cancer, please present your patient cases in multidisciplinary clinics. Moreover, please consider having your patients seen by others who have a lot of experience in rectal cancer.