Combination of neoadjuvant and adjuvant chemotherapy with FOLFOX compared with adjuvant chemotherapy in management of locally advanced rectal cancers: a randomized trial of a promising therapeutic approach.
Humans
Rectal Neoplasms
/ drug therapy
Female
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Male
Neoadjuvant Therapy
/ methods
Middle Aged
Leucovorin
/ therapeutic use
Fluorouracil
/ therapeutic use
Chemotherapy, Adjuvant
/ methods
Organoplatinum Compounds
/ therapeutic use
Adult
Aged
Neoplasm Staging
Neoplasm Recurrence, Local
/ drug therapy
Treatment Outcome
Disease-Free Survival
Disease-free survival
FOLFOX
Follow-up studies
LARC
Neoadjuvant therapy
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
18 Jul 2024
18 Jul 2024
Historique:
received:
03
03
2024
accepted:
12
07
2024
medline:
19
7
2024
pubmed:
19
7
2024
entrez:
18
7
2024
Statut:
epublish
Résumé
Colorectal cancer (CRC) is a significant malignancy with widespread implications. Despite progress in surgical interventions for rectal cancer, improvements in overall prognosis remain disproportionate. Standard preoperative chemoradiation, while established as the standard treatment for the majority of rectal cancers, exhibits limited effectiveness in enhancing disease-free survival (DFS) and mitigating distant metastases, particularly in cases of locally advanced rectal cancer (LARC). This randomised clinical trial assessed 286 patients with LARC in two paralleled groups. Group A underwent six courses of neoadjuvant MFOLFOX chemotherapy, chemoradiation, surgery, and six adjuvant chemotherapy cycles. Group B received concurrent chemoradiation, surgery, and twelve adjuvant chemotherapy cycles. Patient evaluations were achieved at multiple stages of treatment and follow-up. Group A had significantly lower local recurrence (11.64%) than Group B (21.74%, P = 0.025). The distant metastasis rate in Group A (8.90%) was lower than in Group B (20.29%) but was not significant (p = 0.143). More patients in Group A experienced downstaging (80.82% vs. 60.87%, p < 0.001). Specifically, 72.60% demonstrated downstaging of tumour invasion and 54.79% downstaging of lymph node involvement, compared to 57.25% and 41.30% in Group B (p = 0.009 and p = 0.025, respectively) as well as higher pCR rate (26.03% vs. 15.25%, p = 0.030) and three-year DFS rate (82.19% vs. 71.01%, p = 0.035) in group A compare to group B. This innovative strategy for LARC showed promising results with lower local recurrence and higher rates of downstaging and pCR. Treatment side effects were similar in both groups but less frequent in Group A. Anaemia was the most common haematological side effect (A: 58%, B: 68%), and peripheral sensory neuropathy was the most common non-haematological complication (A: 63%, B: 64%). These findings suggest this regimen could be a valuable therapeutic approach for LARC. This trial was registered on 2023-12-08 within the IRCT.IR database under the number IRCT20210308050628N1.
Sections du résumé
BACKGROUND
BACKGROUND
Colorectal cancer (CRC) is a significant malignancy with widespread implications. Despite progress in surgical interventions for rectal cancer, improvements in overall prognosis remain disproportionate. Standard preoperative chemoradiation, while established as the standard treatment for the majority of rectal cancers, exhibits limited effectiveness in enhancing disease-free survival (DFS) and mitigating distant metastases, particularly in cases of locally advanced rectal cancer (LARC).
METHODS
METHODS
This randomised clinical trial assessed 286 patients with LARC in two paralleled groups. Group A underwent six courses of neoadjuvant MFOLFOX chemotherapy, chemoradiation, surgery, and six adjuvant chemotherapy cycles. Group B received concurrent chemoradiation, surgery, and twelve adjuvant chemotherapy cycles. Patient evaluations were achieved at multiple stages of treatment and follow-up.
RESULTS
RESULTS
Group A had significantly lower local recurrence (11.64%) than Group B (21.74%, P = 0.025). The distant metastasis rate in Group A (8.90%) was lower than in Group B (20.29%) but was not significant (p = 0.143). More patients in Group A experienced downstaging (80.82% vs. 60.87%, p < 0.001). Specifically, 72.60% demonstrated downstaging of tumour invasion and 54.79% downstaging of lymph node involvement, compared to 57.25% and 41.30% in Group B (p = 0.009 and p = 0.025, respectively) as well as higher pCR rate (26.03% vs. 15.25%, p = 0.030) and three-year DFS rate (82.19% vs. 71.01%, p = 0.035) in group A compare to group B.
CONCLUSION
CONCLUSIONS
This innovative strategy for LARC showed promising results with lower local recurrence and higher rates of downstaging and pCR. Treatment side effects were similar in both groups but less frequent in Group A. Anaemia was the most common haematological side effect (A: 58%, B: 68%), and peripheral sensory neuropathy was the most common non-haematological complication (A: 63%, B: 64%). These findings suggest this regimen could be a valuable therapeutic approach for LARC.
TRIAL REGISTRATION
BACKGROUND
This trial was registered on 2023-12-08 within the IRCT.IR database under the number IRCT20210308050628N1.
Identifiants
pubmed: 39026218
doi: 10.1186/s12885-024-12634-7
pii: 10.1186/s12885-024-12634-7
doi:
Substances chimiques
Leucovorin
Q573I9DVLP
Fluorouracil
U3P01618RT
Organoplatinum Compounds
0
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
863Informations de copyright
© 2024. The Author(s).
Références
Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233–54.
doi: 10.3322/caac.21772
pubmed: 36856579
Franke AJ, Parekh H, Starr JS, Tan SA, Iqbal A, George TJ Jr. Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management. Clin Colorectal Cancer. 2018;17(1):1–12.
doi: 10.1016/j.clcc.2017.06.008
pubmed: 28803718
Hull R, Francies FZ, Oyomno M, Dlamini Z. Colorectal Cancer Genetics, Incidence and Risk Factors: In Search for Targeted Therapies. Cancer Manag Res. 2020;12:9869–82.
doi: 10.2147/CMAR.S251223
pubmed: 33116845
pmcid: 7553623
Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89–103.
pubmed: 31616522
pmcid: 6791134
Huang CM, Huang MY, Ma CJ, Yeh Y, Tsai HL, Huang CW, et al. Neoadjuvant FOLFOX chemotherapy combined with radiotherapy followed by radical resection in patients with locally advanced colon cancer. Radiat Oncol. 2017;12(1):48.
doi: 10.1186/s13014-017-0790-3
pubmed: 28270172
pmcid: 5341372
Hav M, Libbrecht L, Ferdinande L, Geboes K, Pattyn P, Cuvelier CA. Pathologic Assessment of Rectal Carcinoma after Neoadjuvant Radio(chemo)therapy: Prognostic Implications. Biomed Res Int. 2015;2015: 574540.
doi: 10.1155/2015/574540
pubmed: 26509160
pmcid: 4609786
Kapiteijn E, Marijnen CAM, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer. N Engl J Med. 2001;345(9):638–46.
doi: 10.1056/NEJMoa010580
pubmed: 11547717
Zwart WH, Hotca A, Hospers GAP, Goodman KA, Garcia-Aguilar J. The Multimodal Management of Locally Advanced Rectal Cancer: Making Sense of the New Data. Am Soc Clin Oncol Educ Book. 2022;42:264–77.
doi: 10.1200/EDBK_351411
Martin JD, Seano G, Jain RK. Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges. Annu Rev Physiol. 2019;81:505–34.
doi: 10.1146/annurev-physiol-020518-114700
pubmed: 30742782
pmcid: 6571025
Conde-Muíño R, Cuadros M, Zambudio N, Segura-Jiménez I, Cano C, Palma P. Predictive Biomarkers to Chemoradiation in Locally Advanced Rectal Cancer. Biomed Res Int. 2015;2015: 921435.
doi: 10.1155/2015/921435
pubmed: 26504848
pmcid: 4609421
Patel SA, Ryan DP, Hong TS. Combined Modality Therapy for Rectal Cancer. Cancer J. 2016;22(3):211–7.
doi: 10.1097/PPO.0000000000000193
pubmed: 27341601
Yoon WH, Kim HJ, Kim CH, Joo JK, Kim YJ, Kim HR. Oncologic impact of pathologic response on clinical outcome after preoperative chemoradiotherapy in locally advanced rectal cancer. Ann Surg Treat Res. 2015;88(1):15–20.
doi: 10.4174/astr.2015.88.1.15
pubmed: 25553320
Benson AB, Venook AP, Al-Hawary MM, Azad N, Chen YJ, Ciombor KK, et al. Rectal Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(10):1139–67.
doi: 10.6004/jnccn.2022.0051
pubmed: 36240850
Wu HQ, Li J, Miao JD, Li JW. Is Total Neoadjuvant Treatment Beneficial for Locally Advanced Rectal Cancer? A Meta-Analysis of Randomized Controlled Trials. Oncology. 2024;102(5):399–413. https://doi.org/10.1159/000534815 .
Schulz KF, Altman DG, Moher D, the CG. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8(1):18.
doi: 10.1186/1741-7015-8-18
pubmed: 20334633
pmcid: 2860339
Daniel Enderlein G., Wayne W. Biostatistics — A Foundations for Analysis in the Health Sciences. Wiley & Sons, New York—Chichester—Brisbane—Toronto—Singapore, 6th ed. 1995, 780 S., £58.—, ISBN 0–471–58852‐0 (cloth). Biom J. 2007;37(6):744.
Conroy T, Etienne P-L, Rio E, Evesque L, Mesgouez-Nebout N, Vendrely V, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial. J Clin Oncol. 2023;41(17_suppl):LBA3504-LBA.
doi: 10.1200/JCO.2023.41.17_suppl.LBA3504
Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, et al. 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
pubmed: 33301740
Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023;389(4):322–34.
doi: 10.1056/NEJMoa2303269
pubmed: 37272534
pmcid: 10775881
Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH, et al. Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial. Ann Surg. 2023;278(4):e766–72.
doi: 10.1097/SLA.0000000000005799
pubmed: 36661037
Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022;386(25):2363–76.
doi: 10.1056/NEJMoa2201445
pubmed: 35660797
pmcid: 9492301
Borg C, Mantion G, Boudghène F, Mornex F, Ghiringhelli F, Adenis A, et al. Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized, Noncomparative Phase 2 INOVA Study. Clin Colorectal Cancer. 2019;18(3):200-8.e1.
doi: 10.1016/j.clcc.2019.04.006
pubmed: 31311761
Fernández-Martos C, Pericay C, Losa F, García-Carbonero R, Layos L, Rodríguez-Salas N, et al. Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma: The GEMCAD 1402 Randomized Clinical Trial. JAMA Oncol. 2019;5(11):1566–73.
doi: 10.1001/jamaoncol.2019.2294
pubmed: 31465088
pmcid: 6865228
Leichman CG, McDonough SL, Smalley SR, Billingsley KG, Lenz HJ, Beldner MA, et al. Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713. Clin Colorectal Cancer. 2018;17(1):e121–5.
doi: 10.1016/j.clcc.2017.10.008
pubmed: 29233486
Rullier E, Vendrely V, Asselineau J, Rouanet P, Tuech JJ, Valverde A, et al. Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial. Lancet Gastroenterol Hepatol. 2020;5(5):465–74.
doi: 10.1016/S2468-1253(19)30410-8
pubmed: 32043980