Toward Curing Rectal Cancer without Surgery

By Julio Garcia-Aguilar, MD, PhD  |  Friday, February 7, 2014

Over the past two decades there has been significant progress in rectal cancer treatment. Advances in surgical technique, instrumentation, chemotherapy, radiation therapy, perioperative care, and imaging have improved survival for patients with this disease.

While we have achieved a great deal, much remains to be done. Patients with locally advanced rectal cancer typically undergo a combination treatment regimen consisting of preoperative chemotherapy and radiation, followed by surgery to remove all or part of the rectum, and postoperative chemotherapy. The purpose of preoperative chemoradiation treatment is to “downsize” or shrink the tumor, making it easier to remove.

Chemotherapy is delivered postoperatively to eliminate circulating tumor cells, reducing the risk of recurrence and metastasis. Sometimes the decision is made to give this chemotherapy first, before radiation, but the overall strategy is the same. This triple-combination treatment—radiation, chemotherapy, and surgery—has increased the number of patients cured of rectal cancer.

Shortcomings

But success comes at a cost. The surgery, total mesorectal excision, is a formidable operation resulting in both short-term complications and long-term impairment of quality of life. Although it is rare, some patients with tumors close to the anal verge must undergo an operation resulting in a permanent colostomy. Even patients who are candidates for sphincter-preserving surgery must live with a temporary ileostomy until completion of all chemotherapy.

After treatment for rectal cancer, many patients develop urinary, sexual, and bowel dysfunction. Furthermore — unlike patients with colon cancer — few patients with rectal cancer ever complete postoperative systemic chemotherapy, because surgery-related complications make it impossible for them to tolerate it. This is very important, as many rectal cancer patients are denied the benefits of adjuvant chemotherapy and are thus more likely to succumb to distant metastatic disease.

Selective Nonoperative Management (NOM)

Memorial Sloan Kettering is launching a study to investigate alternative approaches to rectal cancer treatment, including deferral of surgery. Many rectal tumors respond to chemotherapy and radiation therapy by shrinking dramatically, and — as radiation oncologist Karyn Goodman points out — at least one in five tumors completely disappears. Patients whose tumors disappear completely, meaning that no cancer cells are detected on microscopic examination of the surgical specimen, are said to have a pathological complete response.

It is widely acknowledged that patients whose tumors respond to chemotherapy and radiation are more likely to be cured than those whose tumors do not. This raises concerns about the additional value of removing the rectum in individuals whose tumors appear to be completely eradicated after chemoradiation. One of the most common yet fascinating questions posed is whether some of these patients would benefit just as much, or more, from selective nonoperative management (NOM).

Selective NOM of rectal cancer patients who respond to chemotherapy and radiation therapy has received increasing attention in recent years, and now tops the list of research topics for disease management teams worldwide. Several anecdotal retrospective case series from Brazil, the Netherlands, and our own institution have proven that a nonoperative approach, including close surveillance after neoadjuvant chemoradiation, is reasonable for carefully selected patients with a clinical complete response.

While in some cases tumors that appear to have regressed completely will reemerge, these patients appear to be treatable with surgery at that time. The literature indicates that they are at no greater oncologic risk than patients undergoing total mesorectal excision immediately after chemoradiation. While promising, the results are controversial because of variability in patient selection criteria, definitions of response, and different follow-up agendas.

Experience to Date

We have long recognized the opportunity presented by tumors that respond to chemotherapy and radiation therapy, and have directed our efforts toward increasing the rate of response. In 2006, the Timing of Rectal Cancer Response to Chemoradiation Consortium designed a series of sequential phase II trials on the use of additional cycles of chemotherapy after chemoradiation, with longer intervals between chemoradiation and surgery.

At Memorial Sloan Kettering we found that delivering systemic chemotherapy after chemoradiation and delaying surgery yielded an increase in the rate of pathologic complete response, with no additional complications. Dr. Leonard Saltz, Chief of our Gastrointestinal Oncology Service, has used a different approach that has also yielded good results: delivering systemic chemotherapy first, followed by chemoradiation and then surgery. With these efforts, we have increased the proportion of patients who may potentially benefit from nonoperative management.

The New Trial

With the launching of our new trial, “A phase II randomized trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management,” we will investigate whether delivery of all neoadjuvant therapy before surgery, and selective NOM in patients with a clinical complete response, will improve survival and preserve quality of life.

Delivering the systemic chemotherapy and the chemoradiation therapy before surgery could have several potential advantages for the patient. First, it will treat circulating tumor cells, which we believe are responsible for metastatic disease, earlier in the process. Second, it will increase the proportion of patients who complete the full dose of systemic chemotherapy. Third, it will improve the probability of local tumor eradication, thus improving the patient’s chance for sphincter preservation and selective NOM.

Finally, delivering all chemotherapy before surgery will reduce the amount of time required for patients to carry a diverting loop ileostomy. While we believe that delivering systemic chemotherapy before surgery will be beneficial to patients, we are not sure which sequence will be better: delivering systemic chemotherapy before or after chemoradiation.

This will be the first prospective, multi-institutional, NCI-funded study examining the feasibility of upfront systemic treatment for patients with locally advanced distal rectal cancer, and offering selective NOM to those who achieve an excellent response. We aim to enroll approximately 222 patients over a four-year period, at 16 participating institutions in the United States and Canada. About 80 patients will be recruited at Memorial Sloan Kettering. This exciting new trial began on January 1, 2014, and is now open for accrual

 

 

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