Neoadjuvant Treatment Sequencing Warrants Personalized Considerations in Rectal Cancer

Neoadjuvant therapy with chemoradiation followed by chemotherapy remains the standard of care for patients with locally advanced rectal cancer. However, data from emerging treatment strategies may open up the potential for a more individualized approach, according to Melissa A. Lumish, MD.

“The goals of therapy in treating locally advanced rectal cancer are: prevent distant or metastatic recurrence, prevent local regional pelvic recurrence, and, most importantly, limit unnecessary long-term toxicity in patients who may be receiving curative intent therapy,” Lumish, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, said during a presentation at the 40th Annual CFS^®.¹

Historically, treatment with preoperative chemoradiation has been shown to decrease local recurrence rate but has not had a significant impact on overall survival (OS). According to a study published in the New England Journal of Medicine, patients who received total mesorectal excision (TME) with preoperative chemoradiotherapy experienced a lower 10-year rate of local recurrence compared with patients treated with TME alone (5% vs 11%, respectively). However, the 2-year OS rate was nearly identical in both arms at 82.0% and 81.8%, respectively.²

The rationale for neoadjuvant chemotherapy is that adding this component to the treatment regimen can help with the early treatment of micrometastatic disease, leading to an increased response in the primary tumor, and the early detection of nonresponders, Lumish said.

In a retrospective cohort analysis, investigators examined the outcomes for patients with locally advanced rectal cancer who received chemoradiotherapy with planned adjuvant chemotherapy (n = 320) or chemotherapy followed by chemoradiation therapy (n = 308). Findings showed that total neoadjuvant therapy resulted in a higher 12-month complete response rate compared with chemoradiation with planned chemotherapy, 35.7% vs 21.3%, respectively.

Additionally, total neoadjuvant therapy was associated with an increased delivery of chemotherapy compared with chemoradiation with planned chemotherapy. Patients who received a 5- fluorouracil chemotherapy regimen completed a higher percentage of the planned dose (95.9% vs 88.4%, respectively; P = .003) and less patients experienced a dose reduction (25.7% vs 50.5%, respectively; P < .001).³

Despite these findings, Lumish said the ideal treatment sequence of chemotherapy and chemoradiation before surgery remains uncertain with findings from clinical trials supporting different treatment sequences and regimens for this patient population.

“At this point, total neoadjuvant therapy is the new standard for locally advanced rectal cancer,” Lumish said.“[But], what is the optimal sequence of new adjuvant treatment and locally advanced rectal cancer? We know that we should be using chemoradiation and chemotherapy prior to surgery. But the optimal sequence is not known at this point.”

Chemoradiation Followed by Chemotherapy

In the phase 3 RAPIDO trial (NCT01558921), investigators compared the efficacy of short-course radiotherapy followed by chemotherapy and TME with chemoradiotherapy followed by TME and optional postoperative chemotherapy. The primary end point was disease-related treatment failure. Secondary end points included OS, pathological complete response (pCR) rate, and toxicity.⁴

Patients in the preoperative chemotherapy arm (n = 460) received at least 75% of planned chemotherapy at a rate of 84% compared with 58% in the postoperative chemotherapy arm (n = 242). Additionally, patients in the postoperative chemotherapy arm experienced a higher rate of disease-related treatment failure (HR, 0.75; 95% CI, 0.60-0.95; P = .019) and a higher rate of distant metastatic disease (HR, 0.69; 95% CI, 0.54-0.90; P = .0048) compared with those in the preoperative arm. The pCR rate was 28% vs 14%, respectively, and no significant effect on OS was observed.

“We know from RAPIDO that short course radiation therapy followed by chemotherapy before TME is associated with decreased disease-related treatment failure and decreased rates of distant metastatic disease as well as increased pCR rates, but again, with no effect on OS,” Lumish said. “So, this then brings to light the next question, whether chemotherapy should come first in total new adjuvant therapy.”

Chemotherapy Followed by Chemoradiation

The phase 3 PRODIGE 23 trial (NCT01804790) compared the efficacy of administering neoadjuvant chemotherapy before preoperative chemoradiotherapy followed by surgery (n = 231) with that of chemoradiotherapy followed by surgery and adjuvant chemotherapy (n = 230). The primary end point was 3-year disease-free survival (DFS) in the intention-to-treat population.⁵

At a median follow-up of 46.5 months (range, 35.4-61.6), the 3-year DFS rates were 76% (95% CI, 69%-81%) in the neoadjuvant chemotherapy arm and 69% (95% CI, 62%-74%) in the adjuvant chemotherapy arm (HR, 0.69; 95% CI, 0.49-0.97; P = .034). Additionally, the patients in the neoadjuvant chemotherapy arm experienced a benefit in terms of metastasis-free survival compared with those in the adjuvant chemotherapy arm (HR, 0.64; 95% CI, 0.44-0.93; P = .017).

“The next question that comes up is: How can we minimize morbidity while preserving outcomes for locally advanced rectal cancer?” Lumish said. “There are a few ways that we can approach this. The first is omission of radiation.”

Omission of Radiation

In a phase 2 study (NCT00462501), investigators examined the efficacy of omitting radiation therapy from the standard of care for patients with stage II or stage III rectal cancer. Following neoadjuvant chemotherapy, patients moved into TME with postoperative chemotherapy if a response was observed with neoadjuvant chemotherapy or to chemoradiation followed by surgery and postoperative chemotherapy if progression occurred after initial chemotherapy. The primary end point was R0 resection rate.⁶

Findings from the study showed that, at a median follow-up of 18.2 months, the pCR rate was 27% among 30 efficacy-evaluable patients who completed chemotherapy, most of whom (n = 28) did not quit postoperative radiation therapy. Additionally, only 1 death from cancer was reported and the local recurrence rate was 0%.

In light of these findings, another clinical trial, the ongoing phase 3 prospect study (NCT01515787), was initiated by investigators to further explore the effect of removing radiation therapy from the locally advanced rectal cancer treatment paradigm. In this study, patients will be randomly assigned 1:1 to receive either chemoradiation therapy followed by surgery then chemotherapy (standard arm) or neoadjuvant chemotherapy followed by surgery and postoperative chemotherapy if their response rate to neoadjuvant chemotherapy is at least 20% (selective arm). Another branch of the selective arm will add chemoradiation therapy after neoadjuvant chemotherapy if the response rate to neoadjuvant chemotherapy is less than 20%.⁷

“This trial is personalizing the strategy based on each individual case,” Lumish said. “The results of this will be forthcoming.”

Omission of Surgery

The nonoperative management of locally advanced rectal cancer is also being explored by investigators. In the phase 2 OPRA study (NCT02008656), patients with stage II or stage III locally advanced rectal cancer were treated with induction chemotherapy followed by chemoradiotherapy (n = 158) or chemoradiotherapy followed by consolidation chemotherapy and either TME or watch-and-wait based on tumor response (n = 168).⁸

Patients in the consolidation chemotherapy arm experienced longer TME-free survival compared with those who received induction chemotherapy (log-rank P = .016). Additionally, the 3-year TME-free survival rates were 53% (95% CI, 45%-62%) vs 41% (95% CI, 33%-50%), respectively.

“Surgery-free survival was longer in the consolidation chemotherapy group,” Lumish said. “But the main takeaway was that either strategy was appropriate. A watch-and-wait approach is possible and does not impair patient outcomes.”

Omission of Radiation and Surgery

In multiple retrospective studies, investigators found that patients withdeficient mismatch repair (dMMR)-positive disease experienced progression approximately 29% of the time following initial treatment with FOLOX (leucovorin calcium (fol[nic acid], fluorouracil, and oxaliplatin). Comparatively, patients with proficient mismatch repair status did not experience progression.^9,10

These findings informed the rationale for an ongoing phase 2 trial (NCT04165772) that is examining PD-1 blockade with dostarlimab-gxly (Jemperli) in patients with stage II and stage III dMMR rectal cancer. Patients will receive dostarlimab 500 mg intravenously every 3 weeks for 9 cycles. Following imaging and endoscopy, patients with residual disease will receive chemoradiation therapy then surgery if residual disease is still present. Patients who are found to have achieved a complete response (cCR) after imaging will undergo non-operative follow-up every 4 months.¹¹

The primary end points of the trial are the overall response rate of PD-1 blockade with or without chemoradiation and pCR or cCR at 1-year following PD-1 blockade with or without chemoradiation. Safety and tolerability are secondary end points.

Preliminary results from the study showed that that both the ORR and cCR rates were 100% among 14 efficacy-evaluable patients.

“One-hundred percent of [patients] had a cCR to neoadjuvant PD-1 blockade, and none of these patients require chemoradiation, surgery, or chemotherapy,” Lumish said. “The duration of response is still ongoing and will require further follow-up. But these were relatively long responses with a median follow-up of, at this point, approximately 7 months, but none of the patients have had a recurrence at that point.”

References

1. Lumish MA. Total neoadjuvant therapies for rectal cancer: key considerations. Presented at: 40th Annual CFS®: November 9-11, 2021; New York, NY.
2. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638-646. doi:10.1056/NEJMoa010580
3. 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
4. Hospers G, Bahadoer RR, Dijkstra EA, et al. Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: the randomized RAPIDO trial. J Clin Oncol. 2020;38(suppl 15):4006. doi:10.1200/JCO.2020.38.15_suppl.4006
5. Conroy T, Bosset JF, Etienne PL, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702-715. doi:10.1016/S1470-2045(21)00079-6
6. Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014;32(6):513-518. doi:10.1200/JCO.2013.51.7904
7. PROSPECT: chemotherapy alone or chemotherapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery. ClinicalTrials.gov. Updated October 19, 2021. Accessed November 11, 2022. https://clinicaltrials.gov/ct2/show/NCT01515787
8. 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
9. Alex AK, Siqueira S, Coudry R, et al. response to chemotherapy and prognosis in metastatic colorectal cancer with DNA deficient mismatch repair. Clin Colorectal Cancer. 2017;16(3):228-239. doi:10.1016/j.clcc.2016.11.001
10. 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
11. 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