Preoperative Treatment of Locally Advanced Rectal Cancer
Paradigm shift in rectal cancer therapy? Some may not need surgery, now some may not need radiotherapy.
PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer
Author(s): Andrea Cercek, M.D., Melissa Lumish, M.D., Jenna Sinopoli, N.P., Jill Weiss, B.A., Jinru Shia, M.D., Michelle Lamendola-Essel, D.H.Sc., Imane H. El Dika, M.D., Neil Segal, M.D., Marina Shcherba, M.D., Ryan Sugarman, M.D., Ph.D., Zsofia Stadler, M.D., Rona Yaeger, M.D., J. Joshua Smith, M.D., Ph.D., Benoit Rousseau, M.D., Ph.D., Guillem Argiles, M.D., Miteshkumar Patel, M.S., Avni Desai, M.D., Leonard B. Saltz, M.D., Maria Widmar, M.D., Krishna Iyer, M.D., Ph.D., Janie Zhang, M.D., Nicole Gianino, M.S., Christopher Crane, M.D., Paul B. Romesser, M.D., Emmanouil P. Pappou, M.D., Ph.D., Philip Paty, M.D., Julio Garcia-Aguilar, M.D., Mithat Gonen, Ph.D., Marc Gollub, M.D., Martin R. Weiser, M.D., Kurt A. Schalper, M.D., Ph.D., and Luis A. Diaz, Jr., M.D.
Source: N Engl J Med 2022; 386:2363-2376 DOI: 10.1056/NEJMoa220144
Very impressive results that may change treatment-paradigm. However, number of patients treated, and duration of follow-up are significant issues here for early adoption.
ABSTRACT
BACKGROUND
Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.
METHODS
We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
RESULTS
A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.
CONCLUSIONS
Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response.
Author Affiliations
From the Division of Solid Tumor Oncology (A.C., M.L., J. Sinopoli, J.W., M.L.-E., I.H.E.D., N.S., M.S., R.S., Z.S., R.Y., B.R., G.A., M.P., A.D., L.B.S., L.A.D.) and the Departments of Pathology (J. Shia), Surgery (J.J.S., M.W., E.P.P., P.P., J.G.-A., M.R.W.), Radiation Oncology (C.C., P.B.R.), Epidemiology and Biostatistics (M. Gonen), and Radiology (M. Gollub), Memorial Sloan Kettering Cancer Center, New York; and the Department of Pathology, Yale University School of Medicine, New Haven, CT (K.I., J.Z., N.G., K.A.S.).Related Articles
Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer: The Phase II NEO Trial (CCTG CO.28) Primary End Point Results
Nice study showing a non-radiation approach to node-negative, earlier stage, low-lying rectal cancer, using FOLFOX/CAPEOX x 3 months followed by local excision for those with downstaging to T0/T1 disease. 79% of patients achieved organ preservation, and 2-year locoregional RFS was 90%. A good option for those who are not good candidates for radiation yet still want to avoid an APR-type surgery.
