Can Less Treatment for Colorectal Cancer Yield the Same Results? 

Colon and rectal cancer combined are the fourth most commonly diagnosed cancers.  Eighty percent of patients are diagnosed at a stage of disease when treatment is given with curative-intent.  However, treatment can have both short- and long-term side effects that may impact quality of life.  

To address these concerns, investigators at Dana-Farber have led clinical trials that test the possible elimination or reduction of treatment. These trials require careful design, must enroll many patients, and can take a long time — sometimes a decade or more — to complete. But they will have value to patients if they provide evidence that less intense treatment could yield the same anti-cancer benefits but with fewer long-term, life-altering toxicities.  

“You usually think of clinical trials as intensifying therapy to improve outcomes,” says Harvey Mamon, MD, PhD, of the Division of Gastrointestinal Radiation Oncology at Dana-Farber Brigham Cancer Center. “This is the opposite tack. Are there places we could cut back on treatment and have fewer long term side effects without compromising the clinical benefits?” 

Investigating less intense chemotherapy 

For decades, the standard post-treatment regimen for patients with locally advanced colon cancer was six months of chemotherapy to reduce the risk of recurrence. 

About 15 years ago, Dana-Farber’s Jeffrey Meyerhardt, MD, MPH, co-director of the Colon and Rectal Cancer Center at Dana-Farber, and colleagues wanted to understand if a less intense three-month regimen of chemotherapy could provide similar protection from recurrence but with fewer long-term toxicities, such as neuropathy, a form of nerve damage that causes tingling and numbness in the hands and feet and can impair walking and use of the hands. 

The investigation involved 12,835 patients across 6 randomized trials enrolled in the United States, Canada, Europe, and Japan and took 12 years to complete.  

“It takes a long time to run these trials because if a recurrence is going to happen, it might happen years after treatment is complete,” says Meyerhardt. 

Ultimately, the study concluded that patients with better risk stage III colon cancer can safely receive three months of chemotherapy called CAPEOX (capecitabine and oxaliplatin). Patients with more aggressive stage III cancers would benefit from six months of chemotherapy with either CAPEOX or FOLFOX (5-fluorouracil, leucovorin and oxaliplatin). 

“We are trying to find the optimal therapy given how advanced the patient’s cancer is,” says Meyerhardt.  

Reducing the need for radiation therapy 

Investigators have also been looking for ways to safely de-escalate treatment for locally advanced rectal cancer. For decades, these patients have been receiving chemotherapy, radiation, and surgery as standard therapy.  

For the past ten years, Mamon and Meyerhardt have been working to determine if radiation or surgery might be avoided. In 2011, Mamon and others, including Memorial Sloan Kettering’s Deborah Schrag, MD, MPH, who was previously chief of Population Science at Dana-Farber, designed a trial called PROSPECT to investigate whether radiation could be safely omitted without compromising clinical benefit.  

Patients qualified for the trial if they had rectal cancer that had spread, but only locally within the rectum without more than 4 bulky lymph nodes in the area. They were assigned either to receive standard treatment of 6 weeks of chemoradiation therapy with 5FU or capecitabine or 12 weeks of more intensive chemotherapy with FOLFOX. If a patient’s tumor did not shrink by 20% or more with chemotherapy alone, they would be assigned to receive chemoradiation. 

After five years, there was no statistically significant difference between the two treatment arms in terms of clinical benefit. Disease-free survival, the primary endpoint, was similar between the two groups, suggesting that radiation could be avoided without compromising the anti-cancer benefits.  

However, patients taking chemotherapy alone experienced twice as many severe toxic effects.  

“It’s complicated,” says Mamon. “There is a choice, but it’s a choice between different menus of toxicities.” 

For instance, young patients, particularly young women of reproductive age, might choose chemotherapy alone and avoid radiation, which will likely cause infertility. Patients with a hobby or a job that requires manual dexterity might choose chemoradiation because chemotherapy alone might cause neuropathy in the hands and feet.  

“Trial data doesn’t speak to the desires of any individual patient,” says Meyerhardt. “But we can use the data to provide recommendations to individual patients and talk through their preferences.” 

Reducing the need for surgery 

Another trial, called JANUS, is ongoing and is investigating the potential to treat patients with locally advanced rectal cancer with chemotherapy and radiation alone, eliminating the need for surgery. The trial randomly assigns patients to one of two chemoradiation therapy options and will compare outcomes, including the need for surgery after treatment. 

“It’s an evolution,” says Meyerhardt. “In this trial, we’re intensifying the treatment up front to see if there are more patients who can avoid surgery.”  

This trial could benefit patients who are worried about complications of rectal surgery, which may include infections, loss of bowel or bladder control, and infertility or sexual dysfunction. Each case is different and specific features of the cancer, such as the location of the cancer in the body, can affect the likelihood of different complications. 

“When we treat locally advanced rectal cancer, the goal is to have people remain disease free,” says Meyerhardt. “We want to find treatments that don’t compromise that goal but also provide the best long-term quality of life. We still have a lot to learn about how to do this.”