Omission of radiation therapy before rectal cancer surgery

July 19, 2023Linda Wang

Radiation therapy combined with chemotherapy, also known as chemoradiation, is routinely given to patients with rectal cancer whose tumor can be removed by surgery. This treatment can shrink the tumor, making it easier to remove the entire tumor and preventing the disease from recurring.

Now, results from a large NCI-funded clinical trial suggest that radiation therapy before surgery may not be necessary for all patients with this type of rectal cancer, which is called locally advanced because the cancer has spread within the rectum but not to other organs. The trial showed that a new type of combination chemotherapy given before surgery appears to be as effective as chemoradiation therapy in stopping the cancer from progressing.

“This is a game-changer,” said study leader Deborah Schrag, MD, of Memorial Sloan Kettering Cancer Center.

Dr. Schrag continued that patients with certain clinical stages of rectal cancer may be able to safely skip radiation therapy, “and if they don't have radiation therapy, they won't suffer the long-term ill effects of radiation. That's very important for some people. And globally, that's important because in some countries it's very difficult to get radiation therapy.”

In the trial, called PROSPECT, nearly 1,200 patients with locally advanced rectal cancer were randomly assigned to receive either a chemotherapy regimen called FOLFOX or chemoradiation using just one chemotherapy drug before surgery.

After an average of nearly five years of follow-up after surgery, 81 percent of patients in the FOLFOX group were alive without any signs of cancer (known as disease-free survival), compared with 79 percent of those in the chemoradiotherapy group, Dr. Schrag reported at the American Society of Clinical Oncology (ASCO) annual meeting in June. New England Journal of Medicine.

During treatment, patients in the chemoradiotherapy group had fewer side effects than patients in the FOLFOX group. But a year after surgery, patients in the FOLFOX group had fewer side effects than patients in the chemoradiotherapy group. These results were published separately on June 4. Journal of Clinical Oncology.

“What PROSPECT gives us is an alternative,” said Carmen Allegra, M.D., of NCI's Cancer Therapy Evaluation Program, who was not involved in the trial. “Patients now have options other than chemoradiation.”

Younger patients who want to avoid the harmful effects of radiation on fertility may choose FOLFOX, while those who cannot tolerate the side effects of FOLFOX may choose chemoradiation instead, Dr. Allegra said.

Questioning the need for radiation

In 2023, approximately 800,000 people will be diagnosed with rectal cancer worldwide, of which approximately half will be diagnosed with locally advanced tumours.

For over 30 years, neoadjuvant chemoradiation prior to surgery has been the standard of care for patients with locally advanced rectal cancer in the United States. This treatment is highly effective when combined with modern surgical techniques. However, pelvic radiation is associated with numerous short- and long-term side effects, including impaired bladder, bowel, and sexual function, pelvic fractures, and secondary malignancies.

In recent years, multiagent chemotherapy regimens such as FOLFOX have become the standard postoperative (adjuvant) treatment for patients with locally advanced rectal cancer. In addition, screening rates for colorectal cancer have improved, leading to earlier diagnosis. Surgical techniques and methods have also improved to accurately diagnose patients' cancer and ensure they receive the most effective and appropriate treatment.

“Other things have gotten better, but we just [neoadjuvant] “Radiation therapy has advanced,” Dr. Schrag said, “and it's time to take full advantage of those advances.”

So she and her colleagues set out to answer some important questions: Can preoperative chemoradiation be omitted for patients who respond to combination chemotherapy without increasing the risk of recurrence? And how do the two treatment options compare in terms of side effects?

Following promising results from a pilot study of FOLFOX administered before surgery in patients with this stage of disease, Dr. Schrag and her colleagues launched PROSPECT to compare these options head-to-head.

Similar results with chemotherapy alone

In the PROSPECT trial, conducted by the Consortium for Clinical Trials in Oncology, researchers randomly assigned 1,194 patients with locally advanced rectal cancer (stages T2 or T3 with lymph node involvement or T3 without lymph node involvement) to receive either pelvic chemoradiation or six cycles of FOLFOX before surgery. Adjuvant chemotherapy was recommended but not required.

This study was a non-inferiority trial designed to test whether preoperative FOLFOX was as effective as preoperative chemoradiation in patients with tumors not at high risk of metastasis.

After approximately five years, the cancer-specific outcomes for the FOLFOX and chemoradiation groups were very similar: patients in both groups had nearly identical disease-free survival rates, as well as similar five-year overall survival rates and other cancer-related outcomes, including rectal cancer recurrence.

Patients in the FOLFOX group who had severe side effects or whose tumors shrunk by less than 20% were given chemoradiotherapy before surgery. Only 9% of patients in the FOLFOX group received preoperative chemoradiotherapy.

With regard to side effects, there were notable differences between the groups with regard to timing: for example, fewer people in the chemoradiotherapy group reported side effects such as loss of appetite, constipation, fatigue, and neuropathy during treatment than in the FOLFOX group.

However, one year after surgery, the pattern was reversed, with fewer people in the FOLFOX group reporting lingering side effects than those in the chemoradiotherapy group. Participants in both groups reported a similar overall quality of life during and after treatment.

Give people more choices

Commenting on the study at the ASCO meeting, Corrie Marijnen, MD, PhD, of the Netherlands Cancer Institute, said treatment guidelines for locally advanced rectal cancer vary around the world. In Europe, for example, neoadjuvant therapy is typically reserved for patients with tumors considered high risk. As such, the PROSPECT findings are likely applicable to people being treated primarily in North America, she said.

Additionally, she noted, new approaches to treating rectal cancer have emerged since the trial began in 2012.

One approach being evaluated is fully neoadjuvant therapy, which combines chemotherapy and chemoradiation before surgery. In some cases, fully neoadjuvant therapy may allow some patients to avoid surgery altogether.

Other studies are testing immunotherapy specifically in patients with locally advanced rectal cancer who have certain genetic mutations. In a recent study of 12 patients with rectal cancer whose tumors had these mutations, the immune checkpoint inhibitor dostallimab completely shrank their tumors in all patients. Updated data from the trial published earlier this year showed that 30 patients were treated and all of their tumors completely disappeared.

On the other hand, for many patients with locally advanced rectal cancer, avoiding the effects of radiation can be empowering, Dr. Allegra said.

“Before we introduced PROSPECT, [know if it was] “Nobody thought it would be safer to not give radiation,” he says. “Now we know it's safer to not give radiation, if that's what you want. There are a lot of factors that go into that decision, but at least you have the opportunity to make that decision.”