- Intensive pre-surgery radiation and chemotherapy are becoming a new standard for treatment for advanced rectal cancer.
- Immunotherapy and cell therapies are in early stages of testing, but researchers believe they have promise for rectal cancer treatment.
The rectum is a six-inch-long portion of the large intestine, which is about five feet in length, but it is the starting point of about one-third of the 145,000 cases of colorectal cancer diagnosed in the United States each year. About 5% of people will develop rectal cancer at some point, and about 11% will be under age 50.
What are the symptoms of rectal cancer?
Nearly all rectal cancer develops from polyps, initially benign growths on the rectal wall. They can be detected and removed by a colonoscopy, reducing the risk of getting rectal cancer, which is why doctors emphasize the importance of undergoing screening colonoscopies, usually beginning at age 45.
Aside from scheduled screening with colonoscopies, rectal cancer can be detected if patients consult their doctors about certain suspicious symptoms, like rectal bleeding or changes in bowel habits.
“Your pattern of bowel habits shouldn’t change much over the course of your life,” says Benjamin Schlechter, MD, a physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber Brigham Cancer Center.
How is rectal cancer treated?
There are special considerations in treating rectal cancer, depending in part on exactly where in the rectum the tumor is located and its pathological stage, and the patient’s age and other medical conditions.
Pathologists classify rectal cancer in four stages:
- In stage I, the tumor has grown below the lining and possibly into the rectal wall.
- Stage II tumors have grown into the rectal wall and may extend into tissues around the rectum.
- In stage III, the tumor has invaded the lymph nodes adjacent to the rectum and some tissues outside the rectal wall.
- Stage IV tumors have spread to distant organs such as the liver or the lungs.
The standard of care for locally advanced rectal cancer (usually stages II and III) has traditionally been neoadjuvant chemoradiation (given before surgery) and surgery to remove part of the rectum and surrounding tissues, followed by adjuvant chemotherapy. This often requires a colostomy.
Recent clinical trial results of regimens for locally advanced rectal cancer that increase the amount of chemotherapy and radiation given before surgery — a strategy known as “total neoadjuvant therapy” — are changing practice.
“Delaying surgery as long as possible is important,” says Schlechter. “Delays should not be indefinite however. If there’s still cancer two months after total neoadjuvant therapy, surgery is the only safe option.”
According to National Comprehensive Cancer Network guidelines, total neoadjuvant therapy is the preferred regimen for all patients with locally advanced rectal cancer. The aim is to preserve rectal structures in as many patients as possible, for example to allow for normal evacuation rather than a colostomy — or even, in some patients, to avoid surgery.
“It turns out that if chemotherapy is given before or after surgery, the chances of cure are similar. But total neoadjuvant therapy makes it more likely you can avoid the colostomy bag,” says Schlechter.
Total neoadjuvant therapy is also aimed at reducing the chances that the cancer will recur elsewhere in the body by targeting micro-metastases sooner. Micro-metastases are small groups of cancer cells shed by the tumor that spread through the blood or lymph nodes and may cause another tumor to develop.
Schlechter adds that trials have demonstrated that radiation given as the first step in total neoadjuvant therapy achieves the best results. According to the results of the phase 3 RAPIDO clinical trial released at the 2020 American Society of Clinical Oncology Annual Meeting neo-adjuvant short-course radiation therapy followed by chemotherapy should be considered part of the standard of care for treating locally advanced rectal cancer. This approach is quicker than conventional chemoradiation, but it is not clear if surgery can be avoided with this treatment type. The recently published OPRA study looked at two different TNT approaches and specifically investigated whether surgery could be avoided in some people.
Patients on this study were treated with either chemoradiation first then chemotherapy, or chemotherapy first followed by chemoradiotherapy. Overall survival was identical between the two groups, but those who were treated with chemoradiotherapy followed by four months of chemotherapy were more likely to have complete resolution of their tumor. Patients who had complete resolution of there tumor were then given the option to avoid surgery. Importantly, many of those who had a complete resolution had no recurrent cancer and avoided surgery entirely.
Research on new therapies is expanding
“Rectal cancer treatment and research remains an exciting area — there has been a lot happening,” says Schlechter.
He comments that in the past decade, doctors who treat rectal cancer have been learning the best ways to give long-approved drugs and radiation to improve outcomes. More recently, he says, “we’re beginning to try giving targeted drugs, immunotherapy and cell therapies.”
For example, overexpression of the HER2 gene has been detected in about 5% of colorectal tumors. Such tumors are resistant to some standard chemotherapy treatments, such as those that inhibit EGFR. But these tumors are also susceptible to targeting with drugs like trastuzumab and tucatinib, and early clinical trials with anti-HER2 targeted therapy, including some rectal cancer patients at Dana-Farber, have shown promise.
Immunotherapy, which has become a highly effective treatment in some advanced cancers, is also being tested in rectal cancer.
In one widely publicized but very small study, treatment with dostarlimab, a drug that blocks the PD-1 immune checkpoint in cancer cells achieved a complete response of locally advanced rectal cancer in 12 patients whose tumors were DNA mismatch-repair deficient, meaning that their DNA lacks the ability to repair certain cell mutations. Although it was a dramatic outcome with single-agent immunotherapy, researchers emphasize that only about 5 to 10% of rectal cancers have this genetic makeup, and the follow-up of the 12 patients in the trial has been relatively short.
Another form of immunotherapy, CAR T cells, in which the patient’s immune cells are modified to be more effective at identifying and killing cancer cells is also in clinical trials for rectal cancer. At this point, says Schlecter, “we will have many trials for cellular therapy, but we have a long way to go” before the role of immunotherapy in rectal cancer is established.
About the Medical Reviewer
Dr. Schlechter is a medical oncologist who specializes in gastrointestinal cancers including colorectal cancer, anal cancer, pancreatic cancer, and neuroendocrine cancers, among others. He is a former intern, resident, chief resident and fellow at Beth Israel Deaconess Medical Center as well as a member of the faculty at Harvard Medical School. In the past he was the Director of Inpatient Hematology and Oncology at Beth Israel Deaconess Medical Center as well as the Assistant Program Director of the Internal Medicine Residency Program. His work at Dana-Farber focuses on providing excellent patient care while trying to advance the treatment of gastrointestinal cancer patients.