Less Intense Treatment in Locally Advanced Rectal Cancer Leads to Better Outcomes

Although standard treatment for patients with locally advanced rectal cancer is neoadjuvant chemotherapy and radiation therapy, emerging research suggests that selective use of treatments in some patients with a focus on deintensification may lead to better outcomes. In certain patients, surgical omission, radiotherapy omission, and immunotherapy are being explored, Christopher G. Willett, MD, chair, Department of Radiation Oncology at Duke Health, said during a presentation at the 2024 National Comprehensive Cancer Network Annual Conference held April 5 to 7, 2024, in Orlando, Florida.¹

“Patient-directed deintensification involves total neoadjuvant therapy that considers a nonsurgical approach, omission of radiotherapy, or the use of targeted molecular drivers,” said Willett, the Mark W. Dewhirst Distinguished Professor of Radiation Oncology at Duke Health.

OPRA Trial

The phase 2 OPRA Trial (NCT02008656)2 evaluated 360 patients with stage II or III rectal adenocarcinoma at 18 trial centers to determine if a potentially rectum- preserving approach could achieve outcomes similar to standard resection- based treatment.

After eligibility screening, 324 patients were randomly assigned to receive induction chemotherapy followed by chemoradiotherapy (INCT-CRT; n = 158) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT; n = 166). Both cohorts received 4 months of fluorouracil- leucovorin-oxaliplatin or capecitabine- oxaliplatin via infusion and 5000 to 5600 cGy of radiation combined with either continuous-infusion fluorouracil or capecitabine during radiotherapy. The primary end point for both groups was disease-free survival (DFS) and the secondary end point was total mesorectal excision (TME)-free survival.²

At a median follow-up of 3 years, DFS was 76% (95% CI, 69%-84%) for the INCT-CRT group and 76% (95% CI, 69%-83%) for the CRT-CNCT group. Investigators reported that the findings were similar to the 3-year DFS rate (75%) observed historically. At 3 years, TME-free survival was 41% (95% CI, 33%-50%) in the INCT-CRT group and 53% (95% CI, 45%-62%) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival (OS).²

“These findings suggest an opportunity for nonoperative management,” Willett said. “An update to the OPRA trial was published in 2024, and those data showed that clinical outcomes were persistent.”³

In that follow-up trial, the median follow-up was 5.1 years. DFS rates were 71% (95% CI, 64%-79%) in the INCT-CT group and 69% (95% CI, 62%-77%) in the CRTCNCT group (P = .68). Further, TME-free survival was 39% (95% CI, 32%-48%) in the INCT-CRT group and 54% (95% CI, 46%62%) in the CRT-CNCT group (P = .012).³ Of 81 patients who experienced regrowth of their tumor, 94% occurred within 2 years and 99% occurred within 3 years.

Omission of Radiotherapy

Another approach is the selective omission of radiotherapy, Willett said. “This applies to rectal carcinomas that are staged clinically as T3, N0, and limited, or clearance of the circumferential margin on the pretreatment pelvic MRI scans,” Willett said. “And this just emphasizes the question of do we need radiation therapy anymore, given the low rates of local recurrence by itself and combined with distant metastases?” he asked.

Initial results from the phase 3 FOWARC trial (NCT01211210)4 suggested that preoperative chemoradiotherapy and the modified FOLFOX6 (mFOLFOX6; leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) regimen led to a higher pathologic complete response (pCR) than fluorouracil- based treatment.

In the trial, 475 evaluable patients were randomly assigned to receive fluorouracil- radiotherapy (n = 155), mFOLFOX6- radiotherapy (n = 157), or mFOLFOX6 (n = 163). Investigators reported that the pCR rates were 14.0%, 27.5%, and 6.6%, in the fluorouracil-radiotherapy, mFOLFOX6- radiotherapy, and mFOLFOX6 groups, respectively. Similarly, downstaging (ypStage 0 to 1) was achieved by 37.1%, 56.4%, and 35.5% of patients, respectively.⁴

The primary outcome for the trial was DFS. “There was no statistical difference between the arms in terms of [DFS],” Willett said. “And 10-year outcomes presented at the 2023 American Society of Clinical Oncology conference also showed no significant differences in [DFS], OS, or local regional recurrence rates,” Willett continued.⁵

Findings from the PROSPECT trial (NCT01515787) demonstrated that in patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to DFS.⁶

A total of 1194 patients with clinically staged, T2 node–positive, T3 node– negative, or T3 node–positive rectal cancer were randomly assigned to receive FOLFOX (n = 585) and chemoradiotherapy (n = 543).

At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for DFS (HR for disease recurrence or death, 0.92; 90.2% CI, 0.74-1.14; P = .005 for noninferiority). DFS at a follow-up of 5 years was 80.8% in the FOLFOX group (95% CI, 77.9%-83.7%) and 78.6% in the chemoradiotherapy group (95% CI, 75.4%81.8%). Schrag et al, reported that the groups were similar with respect to OS (HR for death, 1.04; 95% CI, 0.74-1.44) and local recurrence (HR, 1.18; 95% CI, 0.44-3.16).⁶

“This suggests that radiation could be omitted in select mid-to-high locally advanced rectal cancers, but this precludes nonoperative management,” Willett said.

Immunotherapy

A third potential opportunity for deintensification is to focus on immunotherapy that targets molecular drivers, Willett said. A preliminary phase 2 study (NCT04165772) that explored PD-1 blockade in patients with mismatch repair-deficient, locally advanced rectal cancer could lead to further molecularly personalized approaches.⁷

In the study by Andrea Cercek and colleagues, the use of single-agent dostarlimab (Jemperli) was given every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma, followed by standard chemotherapy and surgery. However, patients who had a complete response after completing the dostarlimab regimen would proceed without chemoradiotherapy and surgery.

Primary objectives were sustained clinical response after completing treatment or pCR after completing dostarlimab with or without chemoradiation and overall response with or without chemoradiation.

Investigators reported that all 12 patients had a clinical response, with no evidence of tumor on imaging. “These are small numbers, but impressive,” Willett said. “Twelve out of 12 patients had a complete response with durable disease control after a follow- up of 6 to 24 months. Unfortunately, the probability of rectal cancer having microsatellite instability is less than 10%,” Willett added. “It nonetheless lends optimism to molecularly personalized approaches.”

REFERENCES:

1. Willett CG. Updates in the management of locally advanced rectal cancer. Presented at: 2024 National Comprehensive Cancer Network Annual Conference; April 5-7, 2024. Orlando, FL.

2. 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):25462556. doi:10.1200/JCO.22.00032

3. Verheij FS, Omer DM, Williams H, et al. Long-term results of organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy: the randomized phase II OPRA trial. J Clin Oncol. 2024;42(5):500-506. doi:10.1200/JCO.23.01208

4. Deng Y, Chi P, Lan P, et al. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016;34(27):3300-3307. doi:10.1200/JCO.2016.66.6198

5. Zhang J, Chi P, Lan P, et al. Long-term outcome of neoadjuvant mFOLFOX6 with or without radiation versus f luorouracil plus radiation for locally advanced rectal cancer: a multicenter, randomized phase III trial. J Clin Oncol. 2023;41,(suppl 16):3505. doi:10.1200/JCO.2023.41.16_suppl.3505

6. Schrag D, Shi Q, Weiser MR, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med. 2023;389(4):322-334. doi:10.1056/NEJMoa2303269

7. 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/NEJMoa220144