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Clinical Trial
. 2022 Aug 10;40(23):2546-2556.
doi: 10.1200/JCO.22.00032. Epub 2022 Apr 28.

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy

Julio Garcia-Aguilar  1 , Sujata Patil  2 , Marc J Gollub  3 , Jin K Kim  1 , Jonathan B Yuval  1 , Hannah M Thompson  1 , Floris S Verheij  1 , Dana M Omer  1 , Meghan Lee  1 , Richard F Dunne  4 , Jorge Marcet  5 , Peter Cataldo  6 , Blase Polite  7 , Daniel O Herzig  8 , David Liska  9 , Samuel Oommen  10 , Charles M Friel  11 , Charles Ternent  12 , Andrew L Coveler  13 , Steven Hunt  14 , Anita Gregory  15 , Madhulika G Varma  16 , Brian L Bello  17 , Joseph C Carmichael  18 , John Krauss  19 , Ana Gleisner  20 , Philip B Paty  1 , Martin R Weiser  1 , Garrett M Nash  1 , Emmanouil Pappou  1 , José G Guillem  21 , Larissa Temple  22 , Iris H Wei  1 , Maria Widmar  1 , Sabrina Lin  2 , Neil H Segal  23 , Andrea Cercek  23 , Rona Yaeger  23 , J Joshua Smith  1 , Karyn A Goodman  24 , Abraham J Wu  25 , Leonard B Saltz  23
Affiliations
Clinical Trial

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy

Julio Garcia-Aguilar et al. J Clin Oncol. .

Abstract

Purpose: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited.

Methods: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival.

Results: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates.

Conclusion: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

Trial registration: ClinicalTrials.gov NCT02008656.

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Conflict of interest statement

Leonard B. Saltz

Consulting or Advisory Role: Genor

Research Funding: Taiho Pharmaceutical

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram illustrating the eligibility, random assignment, outcomes, and follow-up of the trial cohort. Primary and secondary analyses of the 158 INCT-CRT and 166 CRT-CNCT patients followed an intention-to-treat principle. CRT-CNCT, chemoradiotherapy followed by consolidation chemotherapy; INCT-CRT, induction chemotherapy followed by chemoradiotherapy; LE, local excision; NOM, nonoperative management; TME, total mesorectal excision.
FIG 2.
FIG 2.
Kaplan-Meier estimates of (A) DFS, (B) overall survival, (C) local recurrence-free survival, and (D) distant metastasis-free survival in the intention-to-treat population by study group. CRT-CNCT, chemoradiotherapy followed by consolidation chemotherapy; DFS, disease-free survival; INCT-CRT, induction chemotherapy followed by chemoradiotherapy.
FIG 3.
FIG 3.
Kaplan-Meier estimates of (A) time to regrowth in watch-and-wait patients, (B) TME-free survival by intention to treat, and (C) for patients who underwent TME. CRT-CNCT, chemoradiotherapy followed by consolidation chemotherapy; INCT-CRT, induction chemotherapy followed by chemoradiotherapy; NAT, neoadjuvant therapy; TME, total mesorectal excision.
FIG 4.
FIG 4.
Kaplan-Meier estimates of DFS for (A) patients recommended TME after restaging and after tumor regrowth by intention to treat and (B) patients who actually underwent TME. Patients who developed distant metastasis before TME was recommended (three at restaging and six at regrowth) and patients in whom TME was not performed because of disease progression found at surgery (one at restaging and two at regrowth) are not included in the analysis. Six patients in each group have not reached the first follow-up clinical assessment after TME. DFS, disease-free survival; TME, total mesorectal excision.
FIG A1.
FIG A1.
Trial schema. CAPEOX, capecitabine and oxaliplatin; CRT-CNCT, chemoradiotherapy followed by consolidation chemotherapy; DRE, digital rectal exam; FU, fluorouracil; Gy, gray; INCT-CRT, induction chemotherapy followed by chemoradiotherapy; mFOLFOX, modified infusional fluorouracil, leucovorin, and oxaliplatin; MRI, magnetic resonance imaging; WW, watch-and-wait.
FIG A2.
FIG A2.
Kaplan-Meier estimates of (A) DFS and (B) TME-free survival in the initial cohort. CRT-CNCT, chemoradiotherapy followed by consolidation chemotherapy; DFS, disease-free survival; INCT-CRT, induction chemotherapy followed by chemoradiotherapy; TME, total mesorectal excision.
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References

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