Patients with mismatch repair proficient (pMMR) locally advanced rectal cancer who underwent non-operative management of their disease did not experience an impact in distance relapse-free survival (the time when a patient survives without signs of that cancer; DRFS) when undergoing non-operative management of the disease, recent study results demonstrated.
Of note, mismatch repair proficient refers to a type of rectal cancer where the cells in the tumor have intact mismatch repair genes, which help repair errors in DNA replication.
Findings from the NO-CUT trial were presented at the 2024 European Society of Medical Oncology (ESMO) Congress.
A clinical complete response (disappearance of all signs of cancer from treatment; cCR) was noted in 26% of patients who then proceeded with non-operative management. A total of 90% of patients who had an incomplete response underwent surgery. The DRFS rate was 96.9% in those who had non-operative management and 76.7% in all patients.
The organ preservation (minimizing the removal of healthy tissue while effectively treating the cancer) rate was 85% (39 of 46 patients), and all patients with local regrowth underwent rescue surgery with 42% (3 of 7 patients) having sphincter-sparing treatment. Overall, local regrowth (tumor recurrence in the same area it originated) occurred between four and 18 months.
After total neoadjuvant therapy (first treatment given to shrink a tumor before the main treatment), circulating tumor DNA (small pieces of DNA released into a patient’s blood by tumor cells while they die; ctDNA) was assessed to look for clinical responses and DRFS. Of the 108 evaluable patients, the absence of ctDNA was significantly associated with tumor response. For those who were ctDNA-negative, a cCR was observed in 92%, and an incomplete response occurred in 69%. For those who were ctDNA-positive, the cCR rate was 8%, and the incomplete response rate was 31%.
ctDNA was also assessed regarding DRFS. The two-year DRFS rate for those who were ctDNA-negative was 89.4% and 64% for those who were ctDNA-positive. The three-year DRFS rates were 85.8% versus 64%, respectively.
In the 121 patients who underwent surgery, the two-year progression-free survival (the time during and after treatment when a patient with cancer lives with the disease without worsening; PFS) rate was 68.7%, and at three years, it was 66.2%. It was noted that those who were ctDNA-positive had a significant increase in the risk of progression.
“An optimal selection of candidates to [non-operative management] may take advantage of translational biomarkers,” Dr. Alessio Amatu, a surgeon and oncologist at Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda in Milan, Italy, said during the presentation. “Future trials for the cure of pMMR/microsatellite stable [tumor cells can effectively repair errors in the DNA; MSS] locally advanced rectal cancer will aim at increasing cCR rates by refined patient selection through multi-omics studies (assessments of multiple layers of biological information from a single sample) and improved total neoadjuvant treatment strategies.”
Investigators of this trial enrolled 180 patients with mid/low cT3 (tumor grew beyond the tissue of origin but has not spread to nearby structures) to cT4 (tumor growth beyond the organ/tissue and spread to nearby structures) and/or cN1 (cancer spread to one to three nearby lymph nodes) to cN2 (spread to four or more nearby lymph nodes), cM0 (cancer that has not spread to other parts of the body), pMMR/MSS rectal adenocarcinoma. Those with an ECOG performance status of 0 to 1 (fully active or requiring slight limitations in activity) who were fit for surgery were enrolled in the trial.
The main focus of the study was to assess the percentage of patients alive and distant relapse-free at 30 months. Other areas of interest included cCR rate and organ preservation rate in patients who received non-operative management.
Induction therapy (first treatment for a disease) began during weeks 1 to 12 and included 4 cycles of Xeloda (capecitabine) plus oxaliplatin (a type of chemotherapy), then moved to restaging 1, which included digital rectal examination, MRI and CT. Weeks 13 to 18 included Xeloda plus intensive modulated radiation therapy followed by a treatment-free interval for 11 to 12 weeks. Weeks 29 to 30 included restaging 2, which occurred with a digital rectal examination, MRI, CT, endo-ultrasound with tumor biopsy and liquid biopsy. Patients with a cCR then received non-operative management with intensive follow-up, while those with an incomplete response underwent surgery with standard follow-up.
Between June 2018 and August 2023, 180 patients were enrolled across four high-volume centers. The median follow-up was 27 months, and one patient died due to toxicity (0.5%), nine (5%) to tumor progression and two (1%) to other causes.
The median age was 62 years old, 56% were male, and 73% had an ECOG performance status of 0. The most common tumor location was medium (middle portion of the rectum) in 59%, 74% had stage T3 disease (tumor growth beyond the wall of the rectum and to nearby tissues/organs, but not to distant lymph nodes) and 80% had TNM stage 3 disease.
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