Neoadjuvant Therapy Holds Promise for Patients With Locally Advanced Rectal Cancer

Mariam F. Eskander, MD, MPH

Research published in 2022 has advanced our understanding of the effect of neoadjuvant therapy on organ preservation for patients with locally advanced rectal cancer. Prospective data support total neoadjuvant therapy and watch-and-wait approaches, with single-institution data on neoadjuvant immunotherapy for select patients with stage II or stage III rectal cancer.

Historically, the standard of care for locally advanced rectal cancer has been neoadjuvant chemoradiation and total mesorectal excision (TME), followed by adjuvant chemotherapy. Total neoadjuvant protocols, in which all chemotherapy is delivered up front (induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy), allow more patients to complete systemic therapy and treat potential micrometastatic disease earlier.¹ According to National Comprehensive Cancer Network guidelines, total neoadjuvant therapy is the preferred regimen for all patients with locally advanced rectal cancer.² Up to a quarter of patients will have a complete pathological response after total neoadjuvant therapy, raising the question of whether some can avoid morbid, life-altering operations.^3,4

Proof Is in the Numbers

Data from the Organ Preservation in Rectal Adenocarcinoma (OPRA) trial (NCT02008656) were published in the Journal of Clinical Oncology in August 2022.⁵ This prospective, randomized trial was designed as 2 stand-alone phase 2 studies, the results of which were compared with historical data.

Oncologic outcomes were assessed for patients with stage II or stage III rectal adenocarcinoma treated with total neoadjuvant therapy and selective watch-and-wait protocols vs TME based on tumor response. The primary end point was disease-free survival (DFS) and the secondary end point was TME-free survival. These data were compared with historical controls who received the standard neoadjuvant chemoradiation and TME. A total of 324 patients from 18 US institutions were randomly assigned to induction chemotherapy followed by chemoradiation (INCT-CRT; n = 158) or CRT followed by consolidation chemotherapy (CRT-CNCT; n = 166). Chemotherapy consisted of 4 months of 5-fluorouracil (5-FU) plus leucovorin and oxaliplatin or capecitabine and oxaliplatin; chemoradiation was 5000 to 5600 cGy combined with 5-FU or capecitabine.

Approximately three-quarters of the patients in each arm (71% in the INCT-CRT arm and 76% in the CRT-CNCT arm) had a complete clinical response or near-complete response and were offered watch-and-wait. At a median follow-up of 3 years, 40% of patients in the INCT-CRT arm and 27% in the CRT-CNCT arm developed tumor regrowth, and all were recommended for TME. Three-year DFS rates were comparable between the groups: 76% (95% CI, 69%-84%) in the INCT-CRT group and 76% (95% CI, 69%-83%) in the CRT-CNCT group, consistent with a 75% historic 3-year DFS rate. The 3-year TME-free survival rate, however, was superior for the CRT-CNCT group (53%; 95% CI, 45%-62%) compared with 41% (95% CI, 33%-50%) for the INCT-CRT group.

These data show that a large proportion of patients are eligible for watch-and-wait and approximately half can achieve rectal preservation at 3 years without a reduction in survival. CRT-CNCT emerges as the preferred regimen for achieving organ preservation, although the sequence of chemoradiation and chemotherapy did not change DFS. Most tumor regrowth events occurred within the 2 years of completion of neoadjuvant therapy. Importantly, patients who underwent TME after tumor regrowth had similar outcomes compared with those who underwent TME after initial restaging, suggesting that delaying surgery until tumor regrowth is not detrimental.

However, mismatch repair–deficient (dMMR) rectal cancers can be resistant to standard systemic therapy, with high rates of progression reported after neoadjuvant chemotherapy for locally advanced disease.⁶ A prospective phase 2 study (NCT04165772), data from which were published in the New England Journal of Medicine in June 2022, evaluated a single-agent anti–PD-1 monoclonal antibody in the neoadjuvant setting for this population.⁷ In this single-institution study, 16 patients with dMMR stage II or stage III rectal adenocarcinoma received single-agent dostarlimab-gxly (Jemperli) every 3 weeks for 6 months (Figure).⁷ This was to be followed by standard chemoradiation and TME for patients who did not have a complete clinical response.

Figure. Phase 2 Trial Design for Dostarlimab in dMMR Rectal Cancer⁷

One primary end point was clinical complete response at 12 months after completion of dostarlimab therapy for patients who did not undergo surgery and pathological complete response for those who did. The only end point reported thus far is overall response to dostarlimab in the neoadjuvant setting.

The results were remarkable: Neoadjuvant immunotherapy elicited a clinical complete response in tumors for all 12 patients who had at least 6 months of follow-up, with no cases of tumor regrowth reported at 6 to 25 months. Most patients showed no viable tumor on biopsy at 6 weeks. There were no adverse events of grade 3 or higher.

This study suggests that anti–PD-1 blockade is more effective for locally advanced rectal tumors than it has been for metastatic colorectal cancer. This could obviate the need for chemoradiation, chemotherapy, and surgery in the 5% to 10% of patients with rectal cancer with dMMR tumors. The durability and reproducibility of this data remain to be seen.

The Role of Surveillance

Both studies highlight that close surveillance is paramount for patients with a complete clinical response who do not undergo surgical management. The methods for assessment of clinical complete response in the rectum include endoscopy, digital rectal examination, and imaging. In OPRA, patients were restaged within 8 weeks (± 4 weeks) of completing total neoadjuvant therapy and reassessed with digital rectal exam and flexible sigmoidoscopy every 4 months for the first 2 years and every 6 months for the next 3 years. Rectal MRI was performed every 6 months for the first 2 years and annually for the next 3 years. CT scans of the chest/ abdomen/pelvis to assess for metastasis were performed at least once per year.

In the immunotherapy trial, patients underwent endoscopy with biopsy; digital rectal exam, MRI of the rectum; ¹⁸F-fluorodeoxyglucose positron emission tomography; and CT of the chest, abdomen, and pelvis every 4 months after completion of treatment. These new neoadjuvant paradigms can transform the way we treat locally advanced rectal cancer, making organ preservation and the resulting benefits in quality of life a reality for more patients for longer periods. Ongoing studies will help us hone patient selection and understand the long-term implications of these choices.

Mariam F. Eskander, MD, MPH, is a surgical oncologist in the Gastrointestinal Oncology Program at Rutgers Cancer Institute of New Jersey and an assistant professor in the Department of Surgery, Division of Surgical Oncology, and Section of Gastrointestinal Oncology at Rutgers Robert Wood Johnson Medical School.

References

Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071. doi:10.1001/jamaoncol.2018.0071

NCCN. Clinical Practice Guidelines in Oncology. Rectal cancer, version 1.2022. Accessed August 11, 2022. https://www.nccn.org/ professionals/physician_gls/pdf/rectal.pdf

Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11(9):835-844. doi:10.1016/S1470-2045(10)70172-8

Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711-717; discussion 717-718. doi:10.1097/01.sla.0000141194.27992.32

Garcia-Aguilar J, Patil S, Gollub MJ, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(23):2546-2556. doi:10.1200/ JCO.22.00032

Cercek A, Dos Santos Fernandes G, Roxburgh CS, et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res. 2020;26(13):3271-3279. doi:10.1158/1078-0432.CCR-19-3728

Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445