Georgios Karagkounis, M.D.
Surgery
For the first time, an immunotherapy drug has generated a 100% remission rate for a specific form of rectal cancer.
This promising study of 12 patients, which was led by Memorial Sloan Kettering Cancer Center (MSKCC), made headlines around the world and piqued the interest of cancer patients and casual observers alike. (In fact, in my nearly 20 years in medicine, this was the first publication that triggered an excited call from my mother!)
The clinical trial’s outcomes were unprecedented: The PD-1 blockade drug dostarlimab, a type of immunotherapy, proved it could induce remission as a standalone treatment for the 5-10% of patients whose rectal tumors are classified as mismatch repair (MMR) deficient – meaning that their DNA lacks the ability to repair certain cell mutations.
While more extensive research will be needed to determine whether dostarlimab represents a long-term cure, the early data are as timely as they are impressive.
Colorectal cancer is the third most common cancer diagnosis in the U.S., excluding skin cancer. And younger patients are being diagnosed with colorectal cancers at an alarming rate. (Colon cancer begins in the colon, while rectal cancer begins in the rectum – colorectal cancer is an umbrella term referring to both types of cancer.)
Despite a decrease of rectal cancer in older patients, current trends predict that by 2030, cases will increase 124.2% in patients 20-34 and 46% in patients 35-49. In Dallas, approximately 30-40% of our patients at Harold C. Simmons Comprehensive Cancer Center already are younger than 50.
While modern surgical techniques to remove part of the colon often preserves quality of life and bowel function, rectal cancer surgery often results in significant bowel function changes, sometimes requiring a permanent colostomy bag to collect and dispose of fecal matter.
Particularly in young patients, providing effective, nonsurgical treatment options can significantly increase quality of life – potentially for 50 years or longer after having rectal cancer. The recent trial is the latest in a series of groundbreaking studies that are moving us closer to eliminating rectal tumors.
A decade of improving rectal cancer care
Ten years ago, rectal cancer treatment started with radiation and/or chemotherapy to shrink the tumor and eliminate errant cancer cells. Then, a patient would have surgery to remove the rectum and potentially the anus to eliminate the cancer and reduce the risk of recurrence, typically followed by additional chemotherapy.
With this approach, approximately 20% of patients had no remaining cancer in the tissue removed during surgery. That means radiation and chemo eliminated the cancer for 1 in 5 patients who still had lifestyle-altering rectal cancer surgery, raising questions about the need for surgery in these patients. However, whether it was safe to avoid surgery for select patients with rectal cancer remained unclear.
Seeing that some patients with rectal cancer did not have any tumor left after the initial treatment (radiation and/or chemotherapy), a handful of cancer centers (initially outside the U.S.) began giving patients the choice to defer surgery and proceed with surveillance if their tumor became undetectable. In these cases, surgery would still be recommended if the tumor reappeared in later. This is called non-operative management, or “Watch and Wait.”
Building a support system
A group of cancer patients, ages 18-39, has forged a deep connection through the Young Adult Support Program at Simmons Cancer Center. They get together every couple of weeks, socialize, and share thoughts and experiences in a place where “people get it.” Most of all, it reminds them they are not alone.
MSKCC led the first U.S. clinical trial to study “Watch and Wait” and determine the efficacy of different approaches to deliver chemotherapy and radiation in rectal cancer – Organ Preservation in Rectal Adenocarcinoma (OPRA) – in 2015. OPRA, which recently reported its outcomes, showed that surgery was not necessary in nearly half the patients who were initially treated with chemotherapy and radiation, and that an estimated three out of four patients were in remission three years after their treatment started. These data helped alleviate concerns over the safety of Watch and Wait and increase its adoption in the U.S.
The rectal cancer trial that made headlines in June 2022 uses dostarlimab, an immunotherapy drug, as the first treatment (before radiation or chemotherapy) in a specific subset of rectal cancer called mismatch repair (MMR) deficient rectal cancer, which accounts for approximately 5-10% of rectal cancers. Study participants had stage 2 or 3 (“locally advanced,” though not spread beyond the rectum and the surrounding lymph nodes) MMR deficient rectal cancer.
Related reading: No colostomy bag after colorectal cancer surgery? Avoid it with this advanced procedure
Eliminating rectal tumors at a microscopic level
MMR deficient tumors lack one of four genes that are involved in the repair of DNA. As cells divide through the course of our lives, small errors occur that are corrected by specific enzymes – one group of which is called mismatch repair proteins. MMR deficient tumor cells do not have one of these enzymes due to inheritance or random genetic mutation. It is understood that the lack of these enzymes leads to the accumulation of DNA errors that gradually make these tumor cells different from the “normal” cells of the body and allow the immune system to identify them as abnormal and attack them.
Many cancer cells, however, have a protein on the surface called PD-L1, which connects to the immune system’s T-cells and “tricks them” into “shutting off” the immune response, allowing the cancer to keep spreading.
In the last 10 years, immunotherapy drugs have been developed to target these proteins to “boost” the immune system’s response. Dostarlimab, used in the recent study, blocks the PD-1 on the T-cell from bonding with the PD-L1 on the cancer cell, preventing the cancer from “hiding” and unleashing the immune system on the tumor.
MSKCC researchers reported that dostarlimab alone eliminated all 12 participants’ tumors and induced remission – and none of them needed the radiation and/or chemo that was planned as the next step in treatment, and none have needed surgery.
This outcome was unexpected and astounding. While more research is needed, it is possible that dostarlimab may be an effective, nonoperative treatment option for the 5-10% of patients who have MMR deficient rectal cancer. More time and research are needed – and UT Southwestern is leading the charge for other innovative, nonoperative rectal cancer treatments.
Research under way for novel rectal cancer treatments
UT Southwestern clinical researcher Todd Aguilera, M.D., Ph.D., is enrolling patients in a clinical study of an antiCD40 antagonist immunotherapy for stage 2 and 3 rectal cancers. Patients with MMR deficient tumors, such as those in the recent study, and MMR proficient tumors (which account for the other 90-95% of rectal cancer cases), are eligible for the trial, called INNATE (Immunotherapy During Neoadjuvant Therapy for Rectal Cancer). Learn about eligibility criteria here.
Radiation oncologist Nina Sanford, M.D., is also enrolling patients in a Phase I Trial of Dose-Escalated Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR), for Locally Advanced Rectal Cancer. PULSAR has proven highly effective for several types of cancer that are either inoperable or result in life-altering surgeries, such as lung cancer. The study will assess whether we can increase the dose of radiation given to patients with rectal cancer without worse toxicity, by increasing the amount of time between doses. Learn about eligibility for the PULSAR trial.
Simmons Cancer Center recently underwent a rigorous review process and achieved a three-year accreditation from the National Accreditation Program for Rectal Cancer (NAPRC). And as an academic medical center, UT Southwestern uses the latest research to plan our patients’ care. Our multidisciplinary cancer teams balance aggressive approaches with scientific evidence to provide safe, personalized treatment.
So, when exciting findings are published, our experts immediately start discussing whether and how to start incorporating novel therapies into our patients’ care. The Simmons Cancer Center is the only NCI-designated comprehensive cancer center in North Texas, and as such we consider it our responsibility to develop guidelines to help patients understand who is eligible for these novel therapies, the extent to which novel treatments might help, and any associated risks associated with them.
While the short-term results of the current trial are phenomenal, patients must understand that we do not yet have data for long-term outcomes – we cannot be certain that the patients will not need radiation, chemo, or surgery in the future. Dostarlimab is not yet FDA-approved for non-metastatic rectal cancer. Currently, the drug can be offered on a case-by-case basis and depending on insurance approval.
Immunotherapy can be an effective treatment option for patients who are eligible. Patients who want to try immunotherapy should do so in a center equipped to handle rare but serious complications, such as having an extreme immune response.
Ten years ago, non-operative management of rectal cancer seemed like a pipe dream. Today, it is a reality for many patients. Studies such as these are moving us closer to a future in which most, if not all, patients with rectal cancer could have a nonsurgical curative treatment option.
To talk with a colorectal cancer expert, call 214-645-8300 or request an appointment online.
