Total neoadjuvant therapy: A new era for patients with locally advanced rectal cancer

When rectal cancer advances to involve nearby lymph nodes but hasn’t spread to other areas of the body, it’s considered to be locally advanced. 

The traditional standard of care has been a three-part regimen consisting of chemoradiation followed by surgery and chemotherapy once again.

“The old approach has been turned on its head based on recent data,” says Josh Smith, M.D., Ph.D., chair of Colon and Rectal Surgery. 

Previously, 30% to 40% of patients wouldn’t receive the final step of chemotherapy, and, therefore, would be less likely to be cured.

“We saw that we needed a better, more effective way to treat patients and to optimize response,” Smith says. 

Frontloading neoadjuvant therapy helps patients receive full treatment course: adjuvant vs. neoadjuvant

When a therapy is given before surgery, it’s called neoadjuvant therapy. When therapy is administered after surgery, it’s known as adjuvant therapy. 

Neoadjuvant chemoradiation before surgery aims to reduce the risk of the cancer returning in the rectum. Adjuvant chemotherapy after chemoradiation and radical surgery helps ensure that any residual microscopic disease is treated, but the three-part regimen is challenging for patients.

“Chemoradiation and then rectal surgery can be a big hurdle for patients,” Smith says.  

In some cases, patients skip adjuvant chemotherapy because they haven’t recovered well enough from surgery, or they have post-surgical complications. Some patients opt out because they don’t feel like they can handle more. 

Several international studies have helped determine a new approach that frontloads all therapy prior to surgery. The approach is known as total neoadjuvant therapy. 

“The studies show that with total neoadjuvant therapy, almost all patients are able to receive their allocated treatment,” Smith says. This means patients have the best opportunity for curative care, but it offers the added benefit of an improved therapeutic response to the primary tumor. “It leads to a higher chance of a complete response,” Smith says. 

Total neoadjuvant therapy allows some patients to skip surgery

Another significant paradigm shift in the treatment of locally advanced rectal cancer came with the organ preservation in rectal adenocarcinoma (OPRA) clinical trial. The multicenter, randomized, Phase II study found that more than half of patients could preserve their rectum and forgo a total mesorectal excision (radical surgery) if they received chemoradiation followed by the chemotherapy regimen FOLFOX (fluorouracil, oxaliplatin and leucovorin). This sequencing is referred to as consolidated chemotherapy. 

The OPRA clinical trial findings opened the door to a watch-and-wait strategy for some patients versus the historical approach of immediately undergoing surgery after completion of standard chemoradiation as neoadjuvant therapy.

New combinations for total neoadjuvant therapy may improve response

Recent clinical trials have changed the standard of care for locally advanced rectal cancer, but Smith feels there’s an opportunity to do more. 

Smith is serving as the primary investigator for the successor study to the OPRA trial. Called the JANUS rectal cancer clinical trial, the Phase II/III study is investigating whether the chemotherapy regimen of FOLFIRI (fluorouracil, irinotecan and leucovorin) in a total neoadjuvant therapy approach can improve complete response compared to standard FOLFOX. The study also uses a watch-and-wait strategy for patients with a complete response.

“I think this could be another game-changing trial, just like OPRA changed the standard of care,” Smith says.

Integrating immunotherapy into total neoadjuvant therapy

Smith and colleagues hope the inclusion of immunotherapy will also improve the response even more. 

Previous research by Smith and his team helps explain why rectal and colon cancers that are mismatch repair deficient have a better response to immunotherapy. Building on that progress, current research aims to improve response in mismatch repair proficient status tumors, which have traditionally been thought of as immunologically “cold.”   

“Our hypothesis is that if we take a total neoadjuvant approach and integrate immunotherapy, it will lead to higher rates of complete response,” Smith says.

Immunotherapy has other benefits, too. “When immunotherapy works well, it can spare patients from radiation and sometimes even standard chemotherapy. If someone has a complete response, they may be able to avoid surgery altogether. That’s a huge benefit for patients,” Smith says.

Patients drive advances in care

Despite being a surgeon, Smith is glad that fewer patients require surgery to treat locally advanced rectal cancer. 

“My job as a scientist and a surgeon is to say, 'How do we best identify patients who can be cured without surgery?’ Our goal is to put the patient’s interests, well-being and desire for a cure first,” Smith says.

He emphasizes that patients are the driving force behind his research, and their perspective is helping drive future clinical trials. “The message to patients is that we’re listening. We want to know what you think and how you want to be treated. And we’re integrating your input into the design of the trials for the future,” Smith says.

At the 2026 Society of Surgical Oncology Annual Meeting, Smith will be moderating a session titled “Patient-Centered Rectal Cancer Care.” Learn more about UT MD Anderson at the 2026 SSO Annual Meeting.

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