
==== Front
Dis Colon Rectum
Dis Colon Rectum
DCR
Diseases of the Colon and Rectum
0012-3706
1530-0358
Lippincott Williams & Wilkins Hagerstown, MD

39016394
DCR-D-24-00026
00004
10.1097/DCR.0000000000003291
3
Commentaries and Educational Content
Viewpoint
Perspective on the PROSPECT: The Conundrum of Managing T3n0-N1 Mid and Upper Rectal Cancer
https://orcid.org/0000-0003-1948-1986
Aref Amr M.D. 1
Abdalla Ahmed M.D. draabdalla@gmail.com
2
Bhullar Jasneet S. M.D. drjsbhullar@gmail.com
3
Knoll Elon M.D. elon.knoll@ascension.org
4
1 Radiation Oncology, Ascension St. John Hospital, Detroit, Michigan
2 Interdisciplinary Oncology, Mitchell Cancer Center, University of South Alabama, Mobile, Alabama
3 Colorectal Surgery, Ascension Providence Hospital, Detroit, Michigan
4 Hematology/Oncology, Ascension Macomb-Oakland Hospital, Detroit, Michigan
Correspondence: Amr Aref, M.D., Radiation Oncology, Van Elslander Cancer Center, 19229 Mack Ave, Grosse Pointe Woods, Detroit, MI 48236. E-mail: amr.aref@ascension.org
17 7 2024
10 2024
67 10 12291231
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PROSPECT study
Rectal cancer
OPEN-ACCESSTRUE
==== Body
pmcThe standard of care for the management of locally advanced rectal cancer is surgical resection. Older studies have revealed a very high local recurrence rate in the range of 25% after traditional proctectomy alone.

The development of the total mesorectal excision (TME) technique by Dr. Heald significantly decreases local recurrence when the entire mesorectal fat, including all lymphatics, is completely and sharply dissected along a well-defined “holy plane.” Prospective randomized trials are required to discern whether radiation therapy is still necessary to improve the locoregional control rate beyond that achievable by TME alone. Van Gijn et al1 reported the long-term results of a seminal Dutch randomized trial enrolling 1861 patients. The trial compared the local recurrence rate after TME alone or a preoperative short course of radiotherapy followed by TME. Radiation therapy decreased the local recurrence rate observed after TME alone by approximately 50% (5% vs 11%). Sebag-Montefiore et al2 reported the results of a similar British study in 1350 patients, in which preoperative radiation therapy decreased the risk of local recurrence by 61% (4% vs 10.7%). Radiation therapy, when indicated, is currently recognized to be better when delivered preoperatively than postoperatively and is usually administered concurrently with 5-fluorouracil–based chemotherapy. Planned postoperative radiation is seldom used in contemporary radiation oncology practice.

The proportional reduction in local recurrence caused by preoperative radiotherapy has not been found to change (one-half to two-thirds) with the use of TME versus conventional proctectomy; however, the absolute decrease in the local recurrence rate was much less after TME. The small absolute benefit in local control observed after preoperative radiotherapy has motivated further research to identify a select patient subgroup in which optimal local control might be achieved with TME alone.

Continued refinement of MRI has enabled tumor assessment and staging with markedly greater accuracy than can be achieved with other imaging modalities. One important advantage of MRI is its ability to determine the exact extension of the tumor beyond the bowel wall; the proximity of the tumor to the mesorectal fascia; the presence or the absence of significant extramural venous invasion; and the number, size, and location of involved lymph nodes. The risk of local recurrence after TME alone can now be determined on the basis of tumor location as well as MRI characteristics. Taylor et al3 reported a local recurrence rate of only 1.7% among 58 patients included in the MERCURY project who were considered to have a low risk of recurrence after preoperative MRI assessment. All tumors were staged as T3a/b with nonthreatened mesorectal fascia. Interestingly, in that study, lymph node status was not considered to alter the risk of recurrence.

Recent National Comprehensive Cancer Network guidelines allow for TME alone without neoadjuvant therapy for “low risk” T3N0 tumors located in the upper rectum. The European Society for Medical Oncology also allows for TME alone for high or middle rectal tumors staged clinically as T3a/b N0 (cN1 for high tumors) because the risk of local recurrence of these tumors after TME performed by a skilled surgeon is very low and may not justify the potential toxicity of neoadjuvant therapy. Moreover, adjuvant therapy can be tailored according to the pathological staging of the resected tumors.

Schrag et al4 recently published the results of the long-awaited PROSPECT trial. This pivotal trial assessed whether the routine use of preoperative chemoradiotherapy followed by TME and adjuvant chemotherapy might be replaced by 6 cycles of induction (5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX]) chemotherapy and preoperative chemoradiotherapy offered to only a select group of patients with tumors exhibiting unfavorable response to induction chemotherapy, defined as less than 20% tumor response. The study enrolled 1194 patients (1128 of whom were eligible for analysis) between 2012 and 2018. Although most patients (84%) were staged by MRI, the exact T3 substaging into T3a–d was not stated. However, many patients might reasonably be assumed to have presented with a clinical stage of less than T3b because one of the exclusion criteria was the separation of the tumor from the mesorectal fascia by <3 mm. The median distance of the tumors from the anus was 8 cm. Approximately 21% to 22% of tumors were located in the upper rectum or higher, and some tumors were located 15 to 25 cm from the anal verge. On the basis of this description of the study cohort, a substantial number of enrolled patients might plausibly be expected to have been treated successfully with TME alone without any preoperative intervention, such as chemotherapy alone or concurrent chemoradiotherapy. This assumption is supported by the very low rate of local recurrence in both study arms (1.6%–1.8%), which was similar to the results obtained for TME alone in an MRI-defined “good group.” The detected noninferiority between study arms was, therefore, not surprising because both preoperative approaches were probably not required for a substantial proportion of patients.

The PROSPECT study provides important information regarding the tumor response to induction FOLFOX chemotherapy. The complete pathological response rate (PCR) was 21.9%, as compared with the slightly higher rate of 24.3% in the chemoradiotherapy group. An important question is whether PCR could be induced equally for the same group of patients by using either induction of FOLFOX or concurrent chemoradiotherapy. Might each modality lead to PCR in different patient populations, with or without some overlap between them? The results from the OPRA trial5 shed some light on this question: approximately 41% to 53% of the enrolled patients sustained TME-free survival, thus implying that the PCR after TNT is actually higher than that achieved by each modality alone.

The PROSPECT study also examined a comprehensive patient-reported quality-of-life assessment6 for 13 adverse effects, including anxiety, loss of appetite, constipation, depression, edema, fatigue, mucositis, nausea, neuropathy, pain, and vomiting. Some common components of low anterior resection syndrome—such as rectal urgency and incontinence, clusters of bowel movements, and ability to control flatus—were not included. At 18 months after surgery, higher rates of fatigue, neuropathy, and sexual dysfunction were observed in the chemoradiotherapy arm; however, the overall health-associated quality-of-life determination did not differ significantly between groups. The study protocol indicated that the radiation therapy field was required to extend superiorly to routinely cover the common iliac lymph node chains, regardless of the primary tumor location or lymph node status. We believe that the resultant irradiation of the bowel and bone marrow in the superior part of the radiation field might have been unnecessary for a large proportion of the treated patients7 and might well have been responsible for some of the long-term radiation toxicity.

From the design of the PROSPECT trial, the addition of the chemoradiotherapy component might be inferred to be most beneficial for tumors lacking favorable response to induction FOLFOX chemotherapy. We propose that the tumor response to induction chemotherapy might serve as a predictor of the ultimate tumor response after completion of total neoadjuvant therapy (TNT). Preliminary results from our group have indicated that complete responders to induction chemotherapy have a very high chance of TME-free survival if an organ preservation approach is pursued.8

Currently, patients with locally advanced rectal cancer who present with T3N0-N1 tumors in the middle and upper rectum have multiple treatment options. Stratifying the treatment intensity according to the presence or absence of known risk factors for recurrence and avoiding overtreatment as much as possible is imperative. Long-term treatment toxicity is not limited to the use of radiation therapy and extends to the use of chemotherapy.9 We should also recognize the lack of convincing evidence that neoadjuvant or adjuvant therapy can affect the overall survival rate.

TME remains the standard of care and can be the only treatment for patients with stage T3a/b N0 without extramural venous invasion. Neoadjuvant therapy (FOLFOX or concurrent chemoradiotherapy) could be offered to other patients. The exact choice of neoadjuvant modality should be individualized according to the patient’s conditions and preferences.

The organ preservation strategy is gaining acceptance by many centers, but we still recommend that it be offered through enrollment in institutional review board–approved trials, if possible. The potential inherent risk and the need for patients to commit to years of close follow-up must be explained to all patients before this approach is followed. Although the incidence of major low anterior resection syndrome is more common after surgery for low rectal cancer, this syndrome affects a substantial portion of patients with tumors in the middle and upper rectum,10 and this patient population might still benefit from avoiding TME. One selection criterion for organ preservation used in several ongoing trials is the location of the lesion within 12 cm from the anus.11 Trials using brachytherapy limit this distance to 10 cm. We recognize that measurement of the distance of the lowest end of the tumor from the anus can vary across assessments by digital examination, endoscopy, and MRI. Unfortunately, rigid endoscopy, the most accurate method to measure this distance, is not frequently used. The findings from the PROSPECT trial illustrate this aspect. The median distance of tumors from the anus was 8 cm, yet approximately 50% of the tumors were palpable by digital examination. On the basis of our daily practice, we do not believe that these 2 findings can be reconciled because many tumors located above 6 to 7 cm cannot be palpated, and the median distance of 8 cm is likely to overestimate the real distance from the anal verge.

TNT is currently recognized as a standard of care to facilitate organ preservation approaches. The OPRA trial results indicate that patients have better TME-free survival when FOLFOX chemotherapy is delivered after completion of the chemoradiotherapy phase compared with the induction sequence when systemic chemotherapy is administered before radiation. The reason for the difference in results between study arms is unclear. One potential benefit of delivering systemic chemotherapy in an induction sequence is investigating the possibility of tailoring subsequent neoadjuvant therapy intensity according to the response of the tumor to chemotherapy. We do not believe, at least at the present time, that clinical research investigating the induction sequence should be abandoned.

Although watchful waiting is the most commonly used organ preservation approach, we suggest that local excision after a favorable response to neoadjuvant therapy may be more suitable for a select group of patients.12

Clearly, more research is needed to continue to refine treatment approaches. The evolving fields of tumor molecular studies and circulating tumor DNA may also prove highly valuable in personalizing the care offered to patients. The results of the PROSPECT trial substantially, but not unexpectedly, advance knowledge regarding managing locally advanced rectal cancer and generate thought-provoking questions.

Funding/Support: None reported.

Financial Disclosure: None reported.
==== Refs
REFERENCES

1. van Gijn W Marijnen CAM Nagtegaal ID ; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12 :575–582.21596621
2. Sebag-Montefiore D Stephens RJ Steele R . Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009;373 :811–820.19269519
3. Taylor FGM Quirke P Heald RJ ; Magnetic Resonance Imaging in Rectal Cancer European Equivalence Study Study Group. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol. 2014;32 :34–43.24276776
4. Schrag D Shi Q Weiser MR . Preoperative treatment of locally advanced rectal cancer. N Engl J Med. 2023;389 :322–334.37272534
5. Garcia-Aguilar J Patil S Gollub MJ . Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40 :2546–2556.35483010
6. Basch E Dueck AC Mitchell SA . Patient-reported outcomes during and after treatment of locally advanced rectal cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023;41 :3724–3734.37270691
7. Valentini V Gambacorta MA Barbaro B . International consensus guidelines on Clinical Target Volume delineation in rectal cancer. Radiother Oncol. 2016;120 :195–201.27528121
8. Abdalla A Aref A Alame A . Does response to upfront FOLFOX predict eventual clinical and pathological response after completion of total neoadjuvant therapy for patients diagnosed with rectal cancer? Observations from a Phase II Clinical Trial. Oral Presentation ASCRS 2020. Dis Colon Rectum. 2020;63 :e87–e468.
9. Malik YG Benth JS Hamre HM Faerden AE Ignjatovic D Schultz JK . Chemotherapy reduces long-term quality of life in recurrence-free colon cancer survivors (LaTE study)—a nationwide inverse probability of treatment-weighted registry-based cohort study and survey. Colorectal Dis. 2024;26 :22–33.38036898
10. Croese AD Lonie JM Trollope AF Vangaveti VN Ho Y-H . A meta-analysis of the prevalence of low anterior resection syndrome and systematic review of risk factors. Int J Surg. 2018;56 :234–241.29936195
11. Alliance for Clinical Trials in Oncology. Testing the addition of an anti-cancer drug, irinotecan, to the standard chemotherapy treatment (FOLFOX) after long-course radiation therapy for advanced-stage rectal cancers to improve the rate of complete response and long-term rates of organ preservation (JANUS). Clinicaltrials.gov identifier: NCT05610163. https://clinicaltrials.gov/study/NCT05610163. Accessed January 30, 2024.
12. Aref A Abdalla A Drelichman ER . The role of local excision after neoadjuvant therapy for locally advanced rectal cancer: a different perspective. Clin Colon Rectal Surg. 2022;36 :290–294.37223224
