Three studies from Memorial Sloan Kettering Cancer Center (MSK) address two pressing questions in rectal and anal cancer care: How can organ preservation be made more durable, and can blood tests help identify patients at high risk of treatment failure? Reported in three oral presentations on September 28 at the 2026 American Society for Radiation Oncology (ASTRO) annual meeting in Boston, the studies examined radiation approaches for rectal cancer and circulating tumor DNA (ctDNA), fragments of tumor DNA in the bloodstream, as a marker of treatment response and recurrence risk.
“Together, these studies build on MSK’s leadership in ctDNA and organ-sparing treatment for GI cancers,” said Paul Romesser, MD, Director of Colorectal and Anal Cancer Radiation Oncology at MSK.
Study 1: Which radiation approach yields more durable organ preservation in rectal cancer?
This study was presented by Revathi Ravella, MD, a resident in radiation oncology at MSK. In the study, researchers evaluated the durability of watch-and-wait after long-course chemoradiation (LCCRT) versus short-course radiation (SCRT) in total neoadjuvant therapy for rectal cancer. Watch-and-wait is an approach that can be used to monitor patients who have achieved clinical complete response to total neoadjuvant therapy for rectal cancer. This approach can enable organ preservation in locally advanced rectal cancer.
During the COVID-era, a shift from long-course chemoradiation to short-course radiotherapy was mandated at MSK. This created a natural experiment for comparing the durability of organ preservation after long-course chemoradiation versus short-course radiation in this treatment setting.
The study included 323 patients with locally advanced rectal cancer who were treated with total neoadjuvant therapy between January 2018 and January 2021 at MSK. Of these, 247 received LCCRT and 76 received SCRT. Patient response to therapy was assessed at about 8 weeks after completing total neoadjuvant therapy. Those with a clinical complete response were offered watch-and-wait. Median follow-up was 72 months (95% CI 70-74) for patients treated with LCCRT, and 65 months (95% CI63-67) for those treated with SCRT.
Key results comparing LCCRT with SCRT:
- Similar initial clinical complete response rates: 44.5% after LCCRT versus 43.4% after SCRT.
- Higher five-year organ preservation after LCCRT among watch-and-wait patients: 83% after LCCRT (95% CI 76–91) versus 63% after SCRT (95% CI 48–82) (p=0.016).
- Lower five-year local regrowth after LCCRT: 22% after LCCRT (95% CI 14–30) versus 40% after SCRT (95% CI 21–55), an absolute difference of 18 percentage points (p=0.028).
- No statistically significant differences in survival among watch-and-wait patients: Five-year disease-free survival was 82% after LCCRT versus 84% after SCRT (p=0.6), and overall survival was 89% after LCCRT versus 94% after SCRT (p=0.5).
Initial clinical complete response rates were similar, but long-course chemoradiation was associated with more durable organ preservation among patients who entered watch-and-wait. At five years, organ preservation was 20 percentage points higher and local regrowth was 18 percentage points lower after LCCRT than after SCRT.
“Both approaches allowed patients to pursue organ preservation, but our findings suggest that long-course chemoradiation offers a greater likelihood of maintaining it over time, which is especially important for patients hoping to avoid major rectal surgery” Dr. Romesser said. “Long-course-based total neoadjuvant therapy remains our preferred approach when organ preservation is the priority.”
Study 2: Using ctDNA with standard endoscopic/MRI monitoring in rectal cancer
The second study, also presented by Dr. Ravella, looked at whether enhanced surveillance using ctDNA monitoring can be used to complement endoscopic/MRI surveillance after neoadjuvant therapy in locally advanced rectal cancer. Selection for watch-and-wait after neoadjuvant therapy relies on endoscopy and MRI, which can miss microscopic residual disease. Researchers looked at whether monitoring with ctDNA could better detect molecular residual disease, predict treatment failure, and predict organ preservation.
The real-world cohort study included patients with locally advanced rectal cancer who were treated at MSK with neoadjuvant therapy followed by surgical excision (n=32) or watch-and-wait (n=25). Testing for ctDNA was done at 12 weeks or less after completing neoadjuvant therapy, within about 3 months of clinical failure, and throughout surveillance for patients without treatment failure. The analysis included 207 blood samples from 57 patients. Median follow-up was 82 months (range 24-255).
Key results:
- Watch-and-wait patients: ctDNA detected clinical failure with 100% sensitivity when sampled within 3 months of the event; persistent ctDNA negativity predicted complete response with 100% specificity.
- Surgical excision patients: ctDNA detected clinical failure with 100% sensitivity;persistent ctDNA negativity predicted complete response with 100% specificity.
“Adding ctDNA to endoscopy and MRI may help us better identify patients likely to achieve durable organ preservation and those at high risk of treatment failure,” Dr. Romesser said. “Our goal is to use that information to design clinical trials of new therapies for the patients who need better treatment options.”
Study 3: Using ctDNA to identify patients with anal cancer at high risk for progression
The third study looked at ctDNA testing after chemoradiation in anal squamous cell carcinoma as an early biomarker for treatment response, and was presented by Elisa Liu, MD, a resident in radiation oncology at MSK. Researchers evaluated whether ctDNA positivity could identify patients at high risk for clinical progression and treatment failure.
The study included patients with anal squamous cell carcinoma who were treated with chemoradiation at MSK or the University of South Florida and Tampa General Hospital. Blood samples for ctDNA monitoring were collected during chemoradiation and after completion of treatment. Patients with positive ctDNA tests received heightened surveillance. The analysis included 1,270 plasma samples from 151 patients. Median follow-up was 23 months (range 3-60).
Key results:
- 15% (n=23) of patients had positive ctDNA after completing curative treatment.
- Progression-free survival at 18 months: 29% with positive ctDNA (95% CI 15-56%) vs 97% with negative ctDNA (95% CI 92-99 %)
- Post treatment ctDNA positivity was associated with an eightfold higher hazard of death (hazard ratio [HR] = 7.98, 95% CI 2.2-29, p = 0.002)
Results suggest that ctDNA positivity after completing curative treatment for anal squamous cell carcinoma identifies patients at high risk for relapse who may be candidates for enhanced surveillance and clinical trials of earlier intervention.
“A positive ctDNA test after chemoradiation identified patients at high risk of recurrence,” said Dr. Romesser, “The next question is whether acting on that signal before recurrence becomes clinically apparent can improve outcomes. These findings directly informed a new MSK clinical trial designed to test that approach.” The trial has received institutional review board approval and is expected to begin enrollment soon. It will enroll patients with anal cancer who have positive ctDNA after chemoradiation but no clinical or radiographic evidence of recurrence.
“Drs. Ravella and Liu are outstanding young physician-scientists whose curiosity, rigor, and commitment to patients are reflected in this work,” said Dr. Romesser. “Investing in their growth through mentorship is essential to developing the next generation of leaders in cancer research and care.”
Results for these studies are pending publication, according to Dr. Romesser.