Steven Nurkin, MD, MS

Multidisciplinary cancer care has made major strides in recent years, and its impact has been seen in the field of rectal cancers. Particularly in the neoadjuvant setting, researchers have reevaluated the use of therapies to reduce disease recurrence and improve quality of life for patients, leading to significant updates to the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer, according to a presentation at the NCCN 2023 Annual Conference.¹

Studies have increasingly supported the use of total neoadjuvant therapy (TNT), moving chemotherapy use ahead of surgical resection of rectal tumors. Changes in the timing, order, and drug types used to treat patients with stage II and III cancers have demonstrated better long-term outcomes and, crucially, enabled a “watch and wait” approach so some patients can delay or avoid surgical resection, Steven Nurkin, MD, MS, said during the presentation.

“We do see that now more and more. Offering watch and wait and deferral of surgery can be safe, but it has to be done in a safe way with experts following these patients,” Nurkin said. Nurkin is chief of colorectal surgery and associate professor of oncology in the Department of Surgical Oncology at Roswell Park Comprehensive Cancer Center in Buffalo, NY, and a member of the NCCN Colon/Rectal/Anal Cancers Panel.

Studies going back over a decade have shown that response to initial chemoradiation can predict later outcomes and influence the approach to surgery. In 2004, it was demonstrated that patients with a clinical complete response (cCR) could defer surgery with a watch-and-wait approach.advanced rectal cancer. More recently, a large, international, retrospective watch-and-wait registry showed this could be beneficial to some patients, and quality-of-life studies from Memorial Sloan Kettering Cancer Center indicated a watch-and-wait approach was superior to sphincter-sparing total mesorectal excision (TME).^3,4

“Even speaking as a surgeon, there are consequences to radical surgery…to TME, including permanent stomas, hospital mortality, bowel obstructions, sexual dysfunction, urinary incontinence, [and] low anterior resection syndrome, and we…have to weigh the risks vs benefits of what we do for our patients,” Nurkin said.¹ “On the proctectomy side…many of our patients want to avoid, especially, a permanent colostomy.”

However, trying to avoid surgery is not always the best approach. Nurkin noted that overtreatment with neoadjuvant therapy can also impact patients’ quality of life. Pelvic radiation and platinum-based chemotherapy have significant adverse events, and the watch-and-wait approach can harm some patients with rapid disease recurrence.

Exploring TNT

TNT includes long-course chemoradiotherapy (CRT), TME, and adjuvant chemotherapy. TNT may use induction chemotherapy, then CRT, and then TME. In a retrospective study comparing the 2 approaches, TNT induction had a complete response rate of 35.7% vs 21.3% for CRT with planned adjuvant therapy.⁵

Another TNT approach is CRT followed by consolidation chemotherapy before TME, such as in the TIMING trial (NCT00335816), which showed higher rates of pathological CR with this approach.⁶

The OPRA trial (NCT02008656) investigated the induction vs consolidation TNT approaches in patients with distal rectal cancer. If patients had a cCR, physicians would watch and wait; otherwise, they received TME. There was no difference in disease-free survival, overall survival, distant metastases, or local recurrence. The consolidation TNT approach showed a 53% organ preservation rate vs 41% with induction TNT. Local regrowth was lower in the consolidation arm (27%) vs in the induction arm (40%).⁷

The OPRA trial led to a tumor response stratification that classified patients with a CR, near CR, and incomplete response based on combined outcomes of endoscopy, MRI, and digital rectal examination.⁸ This schema improves the selection of patients who may be able to avoid TME, although Nurkin noted the need to be cautious with many patients such as those with near CR who would be put at risk by watch and wait.

Following patients after TNT with these assessment modalities is vital. “Most of the data suggest that if patients recur, they recur within those first 2 years. The interval between these modalities start to broaden as the years go on,” said Nurkin.¹

TNT With Short-Course Radiation

The RAPIDO trial (NCT01558921) investigated long-course TNT vs short-course radiotherapy followed by 6 cycles of chemotherapy. At 3 years, the TNT arm had a disease-related treatment failure rate of 23.7% vs 30.4% for CRT.⁹ At 5 years, the experimental arm maintained this benefit at 28% vs 34% for standard therapy, and the rate of distant metastases was similarly reduced.¹⁰ However, the 5-year update also showed that for some patients with high-risk tumors, the locoregional recurrence rate was increased, at 10.2% vs 6.1%, respectively (HR, 1.61; 1.04%-2.50%; P=.03).¹⁰

A prospective database study of patients who received watch-and-wait outcomes after short-course radiation showed high rates of cCR and 1-year TME-free survival of 47%.¹¹ Nurkin said this shows that some patients with low-risk tumors could receive short-course radiotherapy and potentially avoid TME.

The ongoing Germany-based ACO-AROAIO-18.1 trial (NCT04246684) is comparing the RAPIDO and OPRA approaches to consolidation TNT head-to-head. Investigators reported that it has exceeded its enrollment goal of 702 patients. Nurkin said this trial will show whether short-course radiotherapy can play a role for certain patients who may also be able to avoid TME.

Improving Chemotherapy Regimens

The FFCD 1102 trial (NCT01674309) investigated the addition of irinotecan to standard FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) chemotherapy in patients with metastatic rectal cancer. Because responses were noted in the primary tumor as well as metastases, researchers investigated this combination in the neoadjuvant setting.¹² The PRODIGE 23 trial (NCT01804790) compared standard long-course CRT followed by TME vs FOLFIRINOX (leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin), CRT, TME, plus or minus additional adjuvant therapy. FOLFIRINOX was found to improve disease-free survival, metastasis-free survival, and pathological CR rate.¹³

The JANUS trial (NCT05610163), which began enrollment in November 2022, is comparing long-course CRT followed by consolidation chemotherapy with or without irinotecan followed by restaging and TME vs watch and wait, with a primary end point of cCR.

A trial of immunotherapy with dostarlimab-gxly (Jemperli) in patients with locally advanced mismatch repair–deficient or microsatellite instability–high rectal cancer had unprecedented results with a 100% CR rate in the first 12 patients evaluated.¹⁴ Although patients were expected to go on to CRT and surgery, no patients have required additional therapy at this point. This led to an update in the NCCN guidelines for rectal cancer: Mismatch repair–deficient/microsatellite instability–high tumors have their own pathway, and immune checkpoint inhibitor therapy is preferred vs TNT for locally advanced tumors.¹⁵

Research Targets on the Horizon

Additional questions remain on how neoadjuvant therapy can be optimized. A key question is whether some patients can avoid radiation therapy. The PROSPECT trial (NCT01515787) is randomly assigning more than 1000 patients to standard CRT or to a selective arm in which patients are assessed for response after receiving 6 cycles of FOLFOX and only receive CRT before surgery if response is less than 20%.

New tools to assess patients are under investigation, including endoscopic biopsies, local excision, 18F-fludeoxyglucose–positron emission tomography scans, circulating tumor DNA, and computational biology. These techniques are crucial to identifying which patients will require additional treatment based on initial response, Nurkin said.

Nurkin said that the most important needs in this setting are better survival outcomes and improved quality-of-life outcomes with reduced toxicity.

“In conclusion, total neoadjuvant therapy is a promising modality to optimize response for [patients with locally advanced rectal cancer]. It does seem as though consolidation [chemotherapy] after chemoradiation is associated with the highest rates of organ preservation,” Nurkin said,1 noting that these trials improved response rates, which correspond strongly to outcomes.

The JANUS trial and immunotherapy trials offer new approaches to better outcomes, and some of these trials show advantages to the watch-and-wait approach, which carries risk of recurrence and is best done on protocol.

REFERENCES

1. Nurkin, S. Neoadjuvant treatment approaches for stage II-III rectal cancer. Presented at: National Comprehensive Cancer Network 2023 Annual Conference; Orlando, FL; March 30-April 2, 2023.

2. 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):711-718. doi:10.1097/01.sla.0000141194.27992.32

3. van der Valk MJM, Hilling DE, Bastiaannet E, et al; IWWD Consortium. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391(10139):2537-2545. doi:10.1016/S0140-6736(18)31078-X

4. Quezada-Diaz FF, Smith JJ, Jimenez-Rodriguez RM, et al. Patient-reported bowel function in patients with rectal cancer managed by a watch-and-wait strategy after neoadjuvant therapy: a case-control study. Dis Colon Rectum. 2020;63(7):897-902. doi:10.1097/DCR.0000000000001646

5. 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

6. Garcia-Aguilar J, Chow OS, Smith DD, et al; Timing of Rectal Cancer Response to Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015;16(8):957-966. doi:10.1016/S1470-2045(15)00004-2

7. 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

8. Smith JJ, Chow OS, Gollub MJ, et al; Rectal Cancer Consortium. Organ preservation in rectal adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer. 2015;15:767. doi:10.1186/s12885-015-1632-z

9. Bahadoer RR, Dijkstra EA, van Etten B, et al; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):29-42. doi:10.1016/S1470-2045(20)30555-6

10. Dijkstra EA, Nilsson PJ, Hospers GAP, et al; collaborative investigators. Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared to long-course chemoradiotherapy and surgery - a five-year follow-up of the RAPIDO Trial. Published online January 20, 2023. Ann Surg. doi:10.1097/SLA.0000000000005799

11. Chin RI, Roy A, Pedersen KS, et al. Clinical complete response in patients with rectal adenocarcinoma treated with short-course radiation therapy and nonoperative management. Int J Radiat Oncol Biol Phys. 2022;112(3):715-725. doi:10.1016/j.ijrobp.2021.10.004

12. Bachet JB, Lucidarme O, Levache CB, et al; FFCD 1102 investigators. FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases: results of the FFCD 1102 phase II trial. Eur J Cancer. 2018;104:108-116. doi:10.1016/j.ejca.2018.09.00

13. Conroy T, Bosset JF, Etienne PL, et al; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. 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

14. 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

15. NCCN. Clinical practice guidelines in oncology. Rectal cancers, version 1.2023. Accessed April 5, 2023. https://bit.ly/2IvzwBF