Rectal Cancer Patients with IBD Do Not Respond as Well to Neoadjuvant Therapy

Neoadjuvant therapy is less effective in rectal cancer patients with inflammatory bowel disease (IBD) than in patients with sporadic rectal cancer, but it is still beneficial. That is the major finding of the largest study to date that compared outcomes in the two groups; it was presented at the Digestive Disease Week 2025 Annual Meeting.

In recent years, total neoadjuvant therapy (TNT) has become the standard of care for locally advanced rectal cancer (LARC) because it is associated with better outcomes. TNT is an intensified neoadjuvant therapy that always combines radiotherapy and chemotherapy. Historically, IBD, a risk factor for rectal cancer, was a relative contraindication to radiotherapy (RT) because it can cause increased toxicity such as exacerbated diarrhea and rectal bleeding. But as neoadjuvant therapy showed compelling results in sporadic LARC patients, including pathologic complete response, it became the standard of care for all LARC patients.

“We lacked data on how well neoadjuvant therapy works in IBD patients when compared to sporadic patients. We wanted to determine whether IBD patients experience similar benefits from neoadjuvant therapy despite the potential for increased toxicity, ” says David Liska, MD, study co-author and chair of the Department of Colorectal Surgery at Cleveland Clinic.

Cohort characteristics

Study participants -- 92 IBD-LARC patients and 92 matched sporadic LARC patients -- were selected from the Clinic’s institutional registry. All received some form of neoadjuvant treatment: neoadjuvant chemoradiotherapy (CRT), short-course radiotherapy (scRT) or total neoadjuvant therapy (TNT). The primary outcome evaluated was pathological treatment response; other outcomes included recurrence-free survival (RFS) and overall survival (OS).

No differences were found between the two groups in nodal involvement (=0.66) or clinical stage at diagnosis (p=0.75); most tumors were stage III. A baseline ECOG performance of ≥1 was more common in the IBD-LARC group (53.7% vs. 34.1%).

Cancer biology and outcomes differ in the two groups

Poorly differentiated adenocarcinoma was more frequent in the IBD-LARC group (32.7% vs. 7.4%). Surgical treatment was inherently different with total proctocolectomy more common in the IBD-LARC group while low anterior resection was more common in the sporadic LARC group.

Pathologic complete response (TRG 0) was significantly less common following any neoadjuvant treatment in the IBD group (6.8% vs.22.6%; p = 0.02). However, only 10% of patients had a poor response to neoadjuvant therapy (AJCC TRG 3).

After a median follow-up of 37 months in the IBD group and 47 months in the sporadic group, the recurrence rates were higher in the IBD group than the sporadic group (37% vs. 22.8%) and they tended to have decreased 5-year RFS (HR=0.58, 95% CI 0.33–1.02, p=0.06). Five-year OS was not significantly different (HR=0.73, 95% CI 0.45–1.17, p=0.19.)

Although IBD patients did not respond as well as sporadic patients, “it is encouraging that we were able to successfully treat these patients with neoadjuvant therapy. Most were able to complete the treatment with most patients having at least a partial response to therapy. It’s a big step forward to have a large data set that shows the outcomes of IBD patients treated with neoadjuvant therapy,” says Dr. Liska.

Tumor biology a possible factor

The tumor biology of IBD-LARC may account for the less robust treatment response. When IBD is present, cancer develops through different molecular pathways when compared to sporadic colorectal cancer. This may explain why the cancer is more commonly poorly differentiated and less responsive to treatment. “It is possible that IBD tumors are inherently more resistant to therapy,” says Dr. Liska.

New neoadjuvant treatments needed

These results suggest the need for novel more effective personalized neoadjuvant therapies for IBD patients. “If we could find neoadjuvant therapies that would improve responses, we would likely have improved outcomes with less recurrences and better survival,” says Dr. Liska.

In the meantime, this significant new data will help in counseling patients and setting expectations about treatment response. “The take-home message is that IBD patients can be treated with total neoadjuvant therapy, like sporadic cancers, where outcomes are better. We will continue to provide personalized multidisciplinary care that combines neoadjuvant therapy and surgery to optimize outcomes and maximize quality of life,” says Dr. Liska.