Introduction

Chemoradiotherapy (CRT) and total mesorectal excision (TME) are the standard treatment approaches for locally advanced rectal cancer (LARC).1,2 Despite improvements in local tumor control and survival, this combination therapy cannot effectively control distant metastasis.3,4 Additionally, TME-associated complications, including long-term bowel, bladder, and sexual dysfunction, considerably impair the quality of life (QoL) of the patients.2,5 Organ-preservation approaches, such as consolidation neoadjuvant therapy and total neoadjuvant therapy (TNT), can improve functional outcomes and long-term QoL of the patients.6–8

The key focus of this article is to present clinical evidence on the positive outcomes of neoadjuvant therapy in patients with LARC. Preoperative neoadjuvant therapy for organ preservation can potentially become the primary treatment option for LARC, providing better functional outcomes and long-term QoL.

The Definition of LARC

LARC is defined as adenocarcinoma identified via endoscopy, with distal margin no more than 15 cm from the anal verge. Additionally, its staging should be consistent with cT3/cT4 N0 or cT (any) cN1/2, as confirmed by endorectal ultrasound or magnetic resonance imaging.9,10

Consolidation Neoadjuvant Therapy of LARC Preoperative Radiotherapy

The following two main preoperative radiotherapy strategies are used for LARC: short-course radiotherapy (SCRT) and long-course radiotherapy (LCRT). The irradiation dose for SCRT is 25 Gy in 5 fractions, which is immediately followed by radical TME surgery. LCRT, as a component of conventional CRT, comprises 45–50 Gy at 1.8–2 Gy/fraction, followed by 5-fluorouracil (FU)-based chemotherapy. Radical TME surgery is then performed within 6–8 weeks.11–14 CRT can improve local rectal cancer control.13–15 SCRT is considered an alternative therapy to CRT for stage II and III rectal cancer but does not contribute to tumor downsizing.16 In contrast, LCRT, when combined with 5-FU-based chemotherapy, effectively reduces tumor size and promotes sphincter preservation. Hence, LCRT is the preferred option for high-risk patients with cN+ and cT4 stage tumors in the lower region, where sphincter preservation is intended.12,16 LCRT, along with 5-FU-based chemotherapy, has become a standard neoadjuvant therapy for LARC.

Simultaneous Integrated Boost Intensity-Modulated Radiation Therapy (SIB-IMRT)

Three-dimensional conformal radiation therapy (3D-CRT) is commonly used in clinical practice. Nevertheless, integrated boost methods using modern inverse-planning techniques, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy, and tomotherapy, have emerged, offering dosimetric advantages compared with 3D-CRT.17–19 Compared with 3D-CRT, IMRT enhances tumor response by increasing local radiation dose and decreases radiation-induced toxicities by preventing the irradiation of healthy tissues.20 IMRT increases the pathological complete response (pCR) rate and survival rate.21,22 Clinical trials on patients with LARC undergoing preoperative CRT with SIB-IMRT have shown favorable prognosis with acceptable toxicity levels.21–23

Brachytherapy

Neoadjuvant CRT, along with conventional external beam radiation therapy (EBRT), has become a standard treatment for LARC.24 Although its efficacy against rectal cancer has improved in the last decade, local tumor control, sphincter preservation, and considerable side effects remain major challenges. The local control rate can be improved by increasing the radiation dose. Endocavitary brachytherapy with EBRT can improve pCR rates in patients with rectal cancer, which can help achieve higher R0 resection rates without severe toxicity.25–27 Compared with external beam irradiation, endocavitary brachytherapy damps rapidly by delivering a high dose to the tumor and protecting the peripheral tissues from significant damage.28 This technique can efficiently increase the dose, resulting in higher reactivity and downstaging with manageable acute toxicities in preoperative chemoradiation for LARC. Thus, this can be a preferable option, particularly for elderly patients who cannot undergo intensive chemoradiation.24,29

Chemotherapy Intensification

The FU-based regimen is considered the standard neoadjuvant CRT and adjuvant chemotherapy for stage II or III rectal cancer.30 This regimen includes multiple infusions of 5-FU/leucovorin and oral daily capecitabine.30,31 Chemotherapy intensification, such as including a second drug, can enhance outcomes and optimize preoperative therapy.32

Oxaliplatin is highly effective against colorectal cancer; however, its clinical significance in neoadjuvant CRT remains controversial.33 Several Phase 3 trials have reported that combining oxaliplatin with 5-FU or capecitabine does not improve local tumor control or provide any survival benefits.34–37 However, the CAO/ARO/AIO-04 study reported contradictory results.38 Additionally, oxaliplatin can lead to serious adverse events, such as acute and late peripheral neuropathy.34

Irinotecan combined with 5-FU is another regimen used in the preoperative CRT of patients with rectal cancer. However, irinotecan is associated with several toxicities, including diarrhea and neutropenia. In terms of adverse events, irinotecan used in neoadjuvant CRT can exacerbate gastrointestinal toxicities, especially diarrhea. The metabolism of irinotecan is influenced by UDP-glucuronosyltransferase (UGT).39 The CinClare Phase III trial reported a significant increase in complete tumor response in Chinese patients with the UGT1A1 genotype when irinotecan was given with capecitabine-based neoadjuvant CRT.40 Moreover, a recent study reported that preoperative CRT with FOLFIRINOX as intensification gained considerable achievements in patients with cT3 or cT4 M0 rectal cancer.41

Biologically Targeted Treatment

Presently, neoadjuvant CRT with 5-FU or capecitabine is considered an optimal treatment approach for the management of LARC.30,42 The clinical efficacies of this standard regimen have garnered increasing attention in the last decade by incorporating biological agents. Because the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) can influence DNA repair, cell proliferation, apoptosis, and angiogenesis, monoclonal antibodies targeting them have been used in neoadjuvant therapy.43 However, for the treatment of LARC, cetuximab, bevacizumab, and panitumumab are not superior alternatives over standard CRT in neoadjuvant treatment.43–47

Immunotherapy

The anti-PD-1 antibody has been approved as a salvage treatment option for solid tumors with metastatic mismatch repair gene deficiency (dMMR) or microsatellite instability (MSI).48 PD-1 blockade is highly effective against dMMR/MSI-H metastatic colorectal cancer. Additionally, preoperative CRT with immunotherapy can significantly improve pCR in patients with LARC.

Total Neoadjuvant Therapy

TNT can be administered as inductive chemotherapy ahead of CRT or consolidation chemotherapy following CRT. However, TNT should be administered exclusively, delivering all planned radiation therapy and chemotherapy in the preoperative setting. The National Comprehensive Cancer Network recognizes TNT as a substitutive treatment for LARC.49 TNT has several advantages, such as improved compliance with planned therapy and slower advancement of tumors. It can allow for the early assessment of chemosensitivity and expose occult micrometastases to chemotherapy at an early stage in the disease progression. Due to improved treatment compliance and reduced toxicities, TNT is linked with a significant increase in distant tumor control and survival in patients with LARC.50 Additionally, TNT can increase the number of candidates for organ preservation.

Summary

Concurrent CRT, along with surgery and adjuvant chemotherapy, can significantly reduce the risk of local recurrence in patients with LARC. Nevertheless, distant metastasis is still considered the major cause of mortality among these patients. Consolidation neoadjuvant therapy and total neoadjuvant therapy are effective preoperative treatments for LARC, particularly for tumors located at lower regions requiring organ preservation. However, neoadjuvant therapy for individual patients warrants further validation.

Data Sharing Statement

Because of no new data created or analyzed in this study, data sharing is not applicable to this article.

Ethics Approval and Consent to Participate

Not applicable, our study is based on open-source public database, and The people’s Hospital of Tongnan District Chongqing City does not require research using publicly available data to be submitted for review to their ethics committee, so there are no ethical issues and other conflicts of interest.

Acknowledgments

We sincerely appreciate the contributions of all workers in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

No funding is supported in this article.

Disclosure

The authors declare no commercial or financial relationships in this research.

References

1. Gollins S, Moran B, Adams R, et al. Association of Coloproctology of Great Britain & Ireland (ACPGBI): guidelines for the management of cancer of the colon, rectum and anus (2017) - multidisciplinary management. Colorectal Dis. 2017;19(Suppl 1):37–66. doi:10.1111/codi.13705

2. Bach SP, Gilbert A, Brock K, et al. Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study. Lancet Gastroenterol Hepatol. 2021;6(2):92–105. doi:10.1016/S2468-1253(20)30333-2

3. Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16(2):200–207. doi:10.1016/S1470-2045(14)71199-4

4. Peeters KC, Marijnen CA, Nagtegaal ID, et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007;246(5):693–701. doi:10.1097/01.sla.0000257358.56863.ce

5. Gilbert A, Ziegler L, Martland M, et al. Systematic review of radiation therapy toxicity reporting in randomized controlled trials of rectal cancer: a comparison of patient-reported outcomes and clinician toxicity reporting. Int J Radiat Oncol Biol Phys. 2015;92(3):555–567. doi:10.1016/j.ijrobp.2015.02.021

6. Joye I, Haustermans K. Which patients with rectal cancer do not need radiotherapy? Semin Radiat Oncol. 2016;26(3):199–204. doi:10.1016/j.semradonc.2016.02.006

7. Glynne-Jones R, Anyamene N, Moran B, Harrison M. Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation? Ann Oncol. 2012;23(10):2517–2526. doi:10.1093/annonc/mds010

8. Hong TS, Ryan DP. Total neoadjuvant therapy for locally advanced rectal cancer-the new standard of care? JAMA Oncol. 2018;4(6):e180070. doi:10.1001/jamaoncol.2018.0070

9. 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

10. Appelt AL, Pløen J, Harling H, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015;16(8):919–927. doi:10.1016/S1470-2045(15)00120-5

11. Kairevičė L, Latkauskas T, Tamelis A, et al. Preoperative long-course chemoradiotherapy plus adjuvant chemotherapy versus short-course radiotherapy without adjuvant chemotherapy both with delayed surgery for stage II-III resectable rectal cancer: 5-Year survival data of a randomized controlled trial. Medicina(Kaunas). 2017;53(3):150–158. doi:10.1016/j.medici.2017.05.006

12. Guckenberger M, Saur G, Wehner D, et al. Comparison of preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer. Strahlenther Onkol. 2012;188(7):551–557. doi:10.1007/s00066-012-0131-2

13. Wang X, Zheng B, Lu X, et al. Preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer: meta-analysis with trial sequential analysis of long-term survival data. PLoS One. 2018;13(7):e0200142. doi:10.1371/journal.pone.0200142

14. Huang WS, Kuan FC, Lin MH, Chen MF, Chen WC. Prognostic significance of neoadjuvant rectal scores in preoperative short-course radiotherapy and long-course concurrent chemoradiotherapy for patients with locally advanced rectal cancer. Ann Surg Oncol. 2020;27(11):4309–4318. doi:10.1245/s10434-020-09018-z

15. Margalit O, Mamtani R, Lawrence YR, et al. Locally advanced rectal adenocarcinoma: are preoperative short and long course radiotherapy truly equivalent? Mol Clin Oncol. 2019;10(5):555–559. doi:10.3892/mco.2019.1825

16. Sterzing F, Hoehle F, Ulrich A, Jensen A, Debus J, Muenter M. Clinical results and toxicity for short-course preoperative radiotherapy and total mesorectal excision in rectal cancer patients. J Radiat Res. 2015;56(1):169–176. doi:10.1093/jrr/rru089

17. Hearn N, Atwell D, Cahill K, et al. Neoadjuvant radiotherapy dose escalation in locally advanced rectal cancer: a systematic review and meta-analysis of modern treatment approaches and outcomes. Clin Oncol(R Coll Radiol). 2021;33(1):e1–e14. doi:10.1016/j.clon.2020.06.008

18. Stuyck C, Wegge M, Bulens P, Joye I, Haustermans K. Moderate dose escalation with volumetric modulated arc therapy improves outcome in rectal cancer. Acta Oncol. 2017;56(11):1501–1506. doi:10.1080/0284186x.2017.1350286

19. Zhao J, Hu W, Cai G, et al. Dosimetric comparisons of VMAT, IMRT and 3DCRT for locally advanced rectal cancer with simultaneous integrated boost. Oncotarget. 2016;7(5):6345–6351. doi:10.18632/oncotarget.6401

20. Zhu J, Liu F, Gu W, et al. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a Phase II study. Radiat Oncol. 2014;9:70. doi:10.1186/1748-717X-9-70

21. Li JL, Ji JF, Cai Y, et al. Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: a phase II trial. Radiother Oncol. 2012;102(1):4–9. doi:10.1016/j.radonc.2011.07.030

22. Bae BK, Kang MK, Kim JC, et al. Simultaneous integrated boost intensity-modulated radiotherapy versus 3-dimensional conformal radiotherapy in preoperative concurrent chemoradiotherapy for locally advanced rectal cancer. Radiat Oncol J. 2017;35(3):208–216. doi:10.3857/roj.2017.00353

23. Hernando-Requejo O, López M, Cubillo A, et al. Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation. Strahlenther Onkol. 2014;190(6):515–520. doi:10.1007/s00066-014-0650-0

24. Omidvari S, Zohourinia S, Ansari M, et al. Efficacy and safety of low-dose-rate endorectal brachytherapy as a boost to neoadjuvant chemoradiation in the treatment of locally advanced distal rectal Cancer: a phase-II clinical trial. Ann Coloproctol. 2015;31(4):123–130. doi:10.3393/ac.2015.31.4.123

25. Sun Myint A, Mukhopadhyay T, Ramani VS, et al. Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes? Colorectal Dis. 2010;12(Suppl 2):30–36. doi:10.1111/j.1463-1318.2010.02322.x

26. El-Sayed ME, El-Taher ZH. Prospective phase II study of brachytherapy boost as a component of neo-adjuvant chemotherapy and external beam radiation therapy in locally advanced rectal cancer. J Egypt Natl Canc Inst. 2008;20(1):10–16.

27. Falk AT, Claren A, Benezery K, et al. Interstitial high-dose rate brachytherapy as boost for anal canal cancer. Radiat Oncol. 2014;9:240. doi:10.1186/s13014-014-0240-4

28. Tunio MA, Rafi M, Hashmi A, et al. High-dose-rate intraluminal brachytherapy during preoperative chemoradiation for locally advanced rectal cancers. World J Gastroenterol. 2010;16(35):4436–4442. doi:10.3748/wjg.v16.i35.4436

29. Lestrade L, De Bari B, Montbarbon X, Pommier P, Carrie C. Radiochemotherapy and brachytherapy could be the standard treatment for anal canal cancer in elderly patients? A retrospective single-centre analysis. Med Oncol. 2013;30(1):402. doi:10.1007/s12032-012-0402-x

30. Fu XL, Fang Z, Shu LH, et al. Meta-analysis of oxaliplatin-based versus fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced rectal cancer. Oncotarget. 2017;8(21):34340–34351. doi:10.18632/oncotarget.16127

31. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368. doi:10.1002/14651858.CD008368.pub2

32. Appelt AL, Vogelius IR, Pløen J, et al. Long-term results of a randomized trial in locally advanced rectal cancer: no benefit from adding a brachytherapy boost. Int J Radiat Oncol Biol Phys. 2014;90(1):110–118. doi:10.1016/j.ijrobp.2014.05.023

33. Roselló S, Papaccio F, Roda D, Tarazona N, Cervantes A. The role of chemotherapy in localized and locally advanced rectal cancer: a systematic revision. Cancer Treat Rev. 2018;63:156–171. doi:10.1016/j.ctrv.2018.01.001

34. Chang H, Tao YL, Jiang W, et al. Optimize the dose of oxaliplatin for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by radical surgery and adjuvant chemotherapy. BMC Cancer. 2020;20(1):498. doi:10.1186/s12885-020-06988-x

35. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29(20):2773–2780. doi:10.1200/JCO.2010.34.4911

36. Gérard JP, Azria D, Gourgou-Bourgade S, et al. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin Oncol. 2012;30(36):4558–4565. doi:10.1200/JCO.2012.42.8771

37. Allegra CJ, Yothers G, O’Connell MJ, et al. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015;107(11):djv248. doi:10.1093/jnci/djv248

38. Rödel C, Liersch T, Becker H, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13(7):679–687. doi:10.1016/S1470-2045(12)70187-0

39. Kimura K, Yamano T, Igeta M, et al. UGT1A1 polymorphisms in rectal cancer associated with the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan. Cancer Sci. 2018;109(12):3934–3942. doi:10.1111/cas.13807

40. Zhu J, Liu A, Sun X, et al. Multicenter, randomized, phase III trial of neoadjuvant chemoradiation with capecitabine and irinotecan guided by UGT1A1 status in patients with locally advanced rectal cancer. J Clin Oncol. 2020;38(36):4231–4239. doi:10.1200/JCO.20.01932

41. Conroy T, Bosset JF, Etienne PL, et al. 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

42. Slampa P. [Neoadjuvant chemoradiotherapy of rectal carcinoma with bevacizumab]. Klin Onkol. 2011;24(5):338–342.

43. Benevento I, De Felice F, Musio D, Tombolini V. The addition of target therapy to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a review. Chemotherapy. 2017;62(5):314–322. doi:10.1159/000476056

44. Kang M, Long J, Li G, et al. A new staging system for nasopharyngeal carcinoma based on intensity-modulated radiation therapy: results of a prospective multicentric clinical study. Oncotarget. 2016;7(12):15252–15261. doi:10.18632/oncotarget.7553

45. Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012;30(14):1620–1627. doi:10.1200/JCO.2011.39.6036

46. Gollins S, West N, Sebag-Montefiore D, et al. Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations. Br J Cancer. 2017;117(9):1286–1294. doi:10.1038/bjc.2017.294

47. Helbling D, Bodoky G, Gautschi O, et al. Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07. Ann Oncol. 2013;24(3):718–725. doi:10.1093/annonc/mds519

48. Zhang J, Cai J, Deng Y, Wang H. Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab. Oncoimmunology. 2019;8(12):e1663108. doi:10.1080/2162402X.2019.1663108

49. Benson AB, Venook AP, Al-Hawary MM, et al. Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(10):1139–1167. doi:10.6004/jnccn.2022.0051

50. Ludmir EB, Palta M, Willett CG, Czito BG. Total neoadjuvant therapy for rectal cancer: an emerging option. Cancer. 2017;123(9):1497–1506. doi:10.1002/cncr.30600