The management of rectal cancer has evolved over the past decades, yielding several major practice changes that have substantially improved outcomes. However, rectal cancer treatment remains challenging and even with improved outcomes can result in life-altering morbidity. To shed light on the current state of rectal cancer therapy, The ASCO Post recently spoke with David P. Ryan, MD, of the Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center (MGH), who has more than 2 decades of clinical experience in this setting.
David P. Ryan, MD
Background
Please tell us a bit about your background and your current position and work.
I am a gastrointestinal cancer specialist and have been treating patients with gastrointestinal cancers for 20 years. The principal focus of my clinical research is the design and implementation of phase I and II trials in gastrointestinal malignancies. Since 1998, I’ve been a member of both the Experimental Therapeutics Program at MGH and the Massachusetts General Hospital Tucker Gosnell Center for Gastrointestinal Malignancies. In 2009, I became Clinical Director of the Division of Hematology/Oncology at Massachusetts General Hospital Cancer Center and, in 2012, I was appointed Chief of the Division of Hematology/Oncology.
Yesterday and Today
In a nutshell, please describe the arc of rectal cancer therapy from the early trials in the 1990s to today.
First, there have been three major improvements in the management of rectal cancer over the past 20 or so years. The surgical techniques have advanced dramatically in that we now do total mesorectal excision instead of blunt dissection of the rectal cancer, as was done in earlier years. This has led to lower rates of local recurrence in patients, both those with early- and locally advanced disease. Moreover, there has been a real subspecialization in the management of this disease along those lines that has further improved outcomes. Second, improved imaging techniques such as magnetic resonance imaging (MRI) give us the ability to much more accurately diagnose people with T3 disease, where the cancer has spread to lymph nodes (ie, node-positive disease), than before these tools were available.
“There have been three major improvements in the management of rectal cancer over the past 20 or so years.”— David P. Ryan, MD
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Further, the expertise in reading MRI results has also improved substantially. Lastly, there has been the movement of chemotherapy and radiation to the preoperative setting as opposed to the postoperative setting, which has also improved the management of patients with rectal cancer. We have gained more knowledge about the morbidities associated with the treatments of this disease, and that knowledge allows us to have better informed decision-making conversations with our patients. It is important to note that all of those advances have also made the management of rectal cancer more complicated for oncologists.
Upper and Lower Rectal Cancers
Please elucidate for the readers the different approaches in the management of upper and lower rectal cancers.
Upper rectal cancers have a much lower risk of local recurrence than do cancers of the lower region. The pelvis is shaped a little bit like a cone coffee filter, and you can imagine that the lower into the filter you go, not only is it more difficult to perform the surgery, but it is also more likely that microscopic metastases can be left behind in the perirectal tissues. From the patient’s standpoint, the side effects of treatment increase the closer the tumor is to the anal sphincter. On top of that, the major complication of lower rectal cancer surgery is being left with sphincter dysfunction or a permanent colostomy, which can lead to a decrease in quality of life, and so this factor also adds to the stress of managing lower rectal cancer as opposed to treating a patient whose tumor is in the upper region of the rectum. Sphincter dysfunction can result in chronic bowel accidents, because it becomes tough to differentiate between gas and stool, making it difficult to control bowel movements.
“I think that total neoadjuvant therapy is going to maintain its foothold as standard of care in this setting.…”— David P. Ryan, MD
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The other complicating factor in this setting is the emergence of the use of preoperative chemotherapy and chemoradiation, which is also referred to as total neoadjuvant therapy. Total neoadjuvant therapy can shrink the tumor dramatically, and approximately 30% will have complete clinical responses. We have recently learned that this may obviate the need for surgery. Now, we have patients with very low rectal cancer who are told that they will probably need a permanent colostomy but choose to receive total neoadjuvant therapy on the chance that they may have a complete clinical response. That also complicates the clinical decision-making process.
Surgery vs Surveillance
One of the more significant challenges in treating this disease is the ability to discern which patients may be able to avoid surgery. What are your thoughts on this?
Twenty years ago, we first began moving radiation treatment up to the presurgery setting, and 10% to 20% of patients would have a complete clinical response (meaning all of the tumor was eradicated prior to surgery). Based upon years of clinical trials, the standard
approach was to proceed to surgery and then offer 4 to 6 months of postoperative adjuvant chemotherapy. However, many of those patients who experienced a complete response would ask if they could avoid an operation, but as oncologists we were taught that surgery was absolutely necessary to prevent a recurrence, and we would strongly advise patients to have surgery.
Every once in a while, a patient would opt out of an operation and enter on a surveillance protocol hoping that, if the cancer did recur, it would be localized, and the tumor could be excised. Lo and behold, several centers in Brazil, Spain, and New York began collecting data on their patients who had gone on active surveillance and discovered that only about 20% of those patients who had a complete clinical response wound up recurring. They then looked at total neoadjuvant therapy to increase the possibility of having a complete clinical response and avoiding surgery.
Now, we have patients with low-lying, high-risk T1 and T2 disease (early-stage disease and no positive nodes) coming to us as specialists and saying their surgical oncologist advised an abdominoperineal resection, but they want to do total neoadjuvant therapy instead. Even when we tell them that chemotherapy might not be associated with improved survival, some patients say they will take the chance for fear of living the remainder of their lives with a colostomy. This presents a difficult situation for us because we still don’t have the data to support that clinical pathway.
Human Papillomavirus (HPV) Infection: Anal vs Rectal Region
HPV infection is related more to cancers of the anal region than the rectum. Would you comment on this?
The adenocarcinomas in the rectal region are not HPV-associated as opposed to squamous cell carcinomas, which are HPV-related, and by convention, are called anal cancers, even if they are several centimeters up in the rectum. The reason is that the anal mucosa has columns that can go up even 6 cm or more into the rectal vault, and a patient can develop a cancer from that mucosa. Squamous cell cancers are all treated as anal cancer with chemoradiation using fluorouracil and mitomycin C as initial therapy. Surgery is done only after it becomes clear that there is not going to be a complete clinical response, and it can take up to 6 months for that to happen.
Immunotherapy
What role does immunotherapy play in this setting?
In the metastatic setting, immunotherapy has produced terrific success for those patients with disease that is microsatellite high. Studies are underway evaluating microsatellite-high patients with immunotherapy in the adjuvant setting. Most rectal cancer tends to be microsatellite-stable, and the current checkpoint inhibitors do not have a role in treating microsatellite-stable disease. Further, I think that total neoadjuvant therapy is going to maintain its foothold as standard of care in this setting, which will make oncologists comfortable in managing their patients with this disease. We’ve come a long way since I began more than 20 years ago. ■
DISCLOSURE: Dr. Ryan owns stock or other ownership interests in Acworth Pharmaceuticals, Inc. and MPM Capital; has received honoraria from Research to Practice and UpToDate; has served as a consultant or advisor to Gritstone Oncology, Maverick Therapeutics, MPM Capital, Oncorus, TCR2, and 28/7 Therapeutics; has received institutional research funding from SU2C; holds patents, royalties, or other intellectual property such as Johns Hopkins University Press and McGraw Hill Chapter Royalties; and has had other relationships with TCR2 Therapeutics.
