QOL Remains a Key Goal of the Use of Radiation in Rectal Cancer

Nina Sanford, MD

Consideration is increasing for the use of a single modality, such as surgery alone or radiotherapy alone, in the treatment of patients with rectal cancer, according to Nina Sanford, MD, who added that the use of radiotherapy in this disease continues to evolve with investigations evaluating brachytherapy, adaptive radiation, intensified triplet chemotherapy, and more.

“Cancer treatments, including radiotherapy, have [adverse] effects [AEs]. Some of them are even serious or irreversible. [Treatments] can also be expensive. [Therefore,] why would a patient be willing to receive radiotherapy? We believe that there are 2 end points that are important to improve in cancer care: survival and quality of life [QOL],” said Sanford, who presented on balancing QOL, local recurrence, and survival with radiotherapy in patients with rectal cancer during the 2024 ACRO Annual Meeting.¹

During the presentation, Sanford discussed how radiation could help improve QOL for patients with rectal cancer; situations when radiation or surgery could be omitted; and ongoing investigations examining novel radiation treatment approaches.

Sanford is an assistant professor and chief of Gastrointestinal Radiation Oncology Service in the Department of Radiation Oncology at the University of Texas (UT) Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas.

Radiotherapy and QOL

Sanford opened by noting that studies have demonstrated that the use of preoperative radiotherapy has reduced local recurrence rates both before the era of total mesorectal excision (TME) and during the TME era.^2,3

However, she also explained the complete excision, which can involve pelvic exenteration if necessary, can severely affect QOL.¹ She explained that definitive radiation can help patients avoid surgery, as patients who achieve a complete response (CR) or near CR after receiving radiotherapy plus chemotherapy can proceed to a watch-and-wait regimen.

Sanford also noted that priorities regarding treatment can vary between patients and clinicians. For example, a survey published in the European Journal of Surgical Oncology in 2020 showed that the highest concerns for patients with locally advanced rectal cancer (n = 94) were colostomy (n = 24), fecal incontinence (n = 20), and urinary dysfunction (n = 20), whereas clinicians (n = 128) were most concerned about cancer recurrence (n = 31), fecal incontinence (n = 21), and sexual dysfunction (n = 15).⁴

“[The survey emphasizes] the importance of asking…the patient in front of you what they value in terms of deciding their treatment guidelines,” Sanford said, adding that balancing toxicity with QOL and recurrence is also crucial.¹

Omission of Radiotherapy

Regarding when to omit radiotherapy, Sanford pointed to several prospective studies that evaluated the omission of radiation for patients with good-prognosis tumors per MRI. In these studies, the rates of patients who proceeded to up-front surgery and had a positive circumferential resection margin were all 5% or lower.

“Based on those studies and others, ASTRO and ESMO have defined groups [of patients in whom it] may be appropriate to go to up-front surgery,” Sanford said.

Sanford next highlighted data from the phase 2/3 PROSPECT trial (NCT01515787), which demonstrated that neoadjuvant treatment with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with selective chemoradiation was noninferior to standard pelvic chemoradiation with fewer AEs in patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery. The 5-year disease-free survival rate was 80.8% (95% CI, 77.9%-83.7%) in the FOLFOX arm (n = 585) compared with 78.6% (95% CI, 75.4%-81.8%) with the standard approach (n = 543; HR, 0.92; 90.2% CI, 0.74-1.14; P = .0051 for noninferiority).⁵

“PROSPECT provides an option in lower-risk, locally advanced rectal cancer, but toxicity tradeoffs really are key,” Sanford said.¹

Omission of Surgery

“We know that total neoadjuvant therapy in rectal cancer increases pathologic CR rates for 2 reasons: a longer interval from radiation to assessment and more systemic therapy,” Sanford said.

Long-term results from the phase 3 OPRA trial (NCT02008656) showed that long-term organ preservation occurred in approximately half of patients treated with total neoadjuvant therapy, and most tumor regrowth occurred in the first 2 years, suggesting that close follow-up during this time is crucial.⁶

Sanford noted that findings allowed long-course chemoradiation, followed by chemotherapy, and response assessment, to become the current preferred regimen for patients in whom a non-operative approach is intended.

She proceeded to discuss the phase 3 OPERA trial (NCT02505750), which showed that ablative radiation could be a curative approach in rectal cancer. Rather than receiving FOLFOX, patients were treated with only capecitabine and 5-fluorouracil in combination with radiotherapy.⁷

In OPERA, patients had early-stage tumors, with 65% at stage T2, and all were less than 5 cm, Sanford explained.¹ Patients also needed to be good candidates for brachytherapy, and after CR, treatment options included local excision or surveillance.⁷ Additionally, 63% of patients treated with brachytherapy experienced grade 1 or 2 bleeding, and Sanford noted that QOL data were pending.

“As we all know, brachytherapy facilities are limited globally, so there is a logistical issue with offering this treatment, as well. However, brachytherapy is very promising,” Sanford said.¹

Sanford then touched on adaptive radiation, which she said she was most excited about, calling this method the future of radiation in rectal cancer. Adaptive radiation involves a radiation dose that is individualized to treatment intent and tumor biology.

An ongoing phase 1 trial (NCT04677413) at UT Southwestern is evaluating the feasibility of selective non-operative management for patients with locally advanced rectal cancer using dose-escalated, ultra-fractionated, short-course radiation in combination with chemotherapy.⁸

“It’s an adaptive radiation trial where patients get 6 months of FOLFOX in the background, which, as we know, is standard of care,” Sanford said.¹ “[Pulses, or fractions,] of radiation are given 4 weeks apart. Why are they spaced out? The goal is to allow us to safely dose escalate the treatment and the radiation dose to the growth of disease, and also to adapt the response and treatment to tumor change, because these patients are getting chemotherapy the entire time.”

The Need for New End Points for GI Cancer Clinical Trials Using Radiotherapy

Sanford closed her presentation by discussing the importance of end point selection in clinical trials involving radiation. She explained that although overall survival is a gold standard as a clinical trial end point, radiation may not improve survival in the neoadjuvant and adjuvant settings.

However, she said radiation can improve QOL, and clinical studies involving radiation regimens should incorporate novel, patient-centered QOL end points. She added that these studies should focus on enrolling patients most likely to benefit from local therapy.

“Radiation trials, in general, need new end points and refined inclusion criteria,” Sanford concluded.

References

1. Sanford N. Radiotherapy in rectal cancer: balancing quality of life, local recurrence & survival. Presented at: 2024 ACRO Annual Meeting; March 13-16, 2024; Orlando, FL.
2. Swedish Rectal Cancer Trial, Cedermark B, Dahlberg M, et al. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997;336(14):980-987. doi:10.1056/NEJM199704033361402
3. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638-646. doi:10.1056/NEJMoa010580
4. van der Valk MJM, van der Sande ME, Toebes RE, et al. Importance of patient reported and clinical outcomes for patients with locally advanced rectal cancer and their treating physicians. Do clinicians know what patients want? Eur J Surg Oncol. 2020;46(9):1634-1641. doi:10.1016/j.ejso.2020.04.014
5. Schrag D, Shi Q, Weiser MR, et al. PROSPECT: a randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048). J Clin Oncol. 2023;41(suppl 17):LBA2. doi:10.1200/JCO.2023.41.17_suppl.LBA2
6. Verheji FS, Omer DNR, Williams H, et al. Sustained organ preservation in rectal cancer patients treated with total neoadjuvant therapy: long-term results of the OPRA trial. J Clin Oncol. 2023;41(suppl 16):3520. doi:10.1200/JCO.2023.41.16_suppl.3520
7. Gerard JP, Barbet N, Schiappa R, et al. Neoadjuvant chemoradiotherapy with radiation dose escalation with contact x-ray brachytherapy boost or external beam radiotherapy boost for organ preservation in early cT2-cT3 rectal adenocarcinoma (OPERA): a phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023;8(4):356-367. doi:10.1016/S2468-1253(22)00392-2
8. Ultra-fractionated radiotherapy for rectal cancer. ClinicalTrials.gov. Updated January 10, 2024. Accessed March 14, 2024. https://clinicaltrials.gov/study/NCT04677413