How to Achieve a Higher Pathologic Complete Response in Patients With Locally Advanced Rectal Cancer Who Receive Preoperative Chemoradiation Therapy

Suk-Hwan Lee

doi:10.3393/ac.2019.02.17

Articles

Page Path: HOME > Ann Coloproctol > Volume 35(1); 2019 > Article

Review How to Achieve a Higher Pathologic Complete Response in Patients With Locally Advanced Rectal Cancer Who Receive Preoperative Chemoradiation Therapy: Suk-Hwan Lee; Annals of Coloproctology 2019;35(1):3-8.
DOI: https://doi.org/10.3393/ac.2019.02.17
Published online: February 28, 2019

Department of Surgery, Kyung Hee University Hospital at Gangdong, Seoul, Korea

Correspondence to: Suk-Hwan Lee, M.D. Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Korea Tel: +82-2-440-6134, Fax: +82-2-440-6073 E-mail: leeshdr@gmail.com

• Received: January 14, 2019 • Accepted: February 17, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next

4,480 Views
109 Download
3 Web of Science
3 Crossref
2 Scopus

Full Article

Download PDF

Abstract
INTRODUCTION
HOW TO ACHIEVE A HIGHER pCR AFTER PCRT IN LARC
CONCLUSIONS
ARTICLE INFORMATION
REFERENCES

Abstract

The current standard of care for treating patients with locally advanced rectal cancer includes preoperative chemoradiation therapy (PCRT) followed by a total mesorectal excision and postoperative adjuvant chemotherapy. A subset of these patients has achieved a pathologic complete response (pCR) and they have shown improved disease-free and overall survival compared to non-pCR patients. Thus, many efforts have been made to achieve a higher pCR through PCRT. In this review, results from various ongoing and recently completed clinical trials that are being or have been conducted with an aim to improve tumor response by modifying therapy will be discussed.
Keywords: Rectal cancer; Preoperative chemoradiation therapy; Pathologic complete response; Disease-free survival; Overall survival

INTRODUCTION

Colorectal cancer (CRC) is a major health concern in Korea. Nationwide cancer statistics in Korea report that more than 26,000 new cases of CRC were diagnosed in 2015 [1]. The current standard of care for patients with locally advanced rectal cancer (LARC) includes preoperative chemoradiation therapy (PCRT) followed by a total mesorectal excision (TME) and postoperative adjuvant chemotherapy [2]. Although this multimodal treatment strategy has achieved a significant reduction in the local recurrence rate after surgery, it has not achieved an improved survival of patients [3-9]. Interestingly, a subset of patients who achieved pathologic complete response (pCR) after PCRT showed improved disease-free survival (DFS) and overall survival (OS) compared with non-pCR patients [10-13]. Moreover, the subgroup of patients who achieved a clinical complete response (cCR) after PCRT was able to do so with nonoperative management or a deferral of surgery strategy [14].

Furthermore, the treatment of patients with rectal cancer compromises their quality of life profoundly, mainly because of stoma formation. However, even after patients have received sphincter-saving procedures, such as a low anterior or an intersphincteric resection, they suffer from low anterior resection (LAR) syndrome, which occurs in up to 40% of patients after surgery [15].

This review will discuss recent clinical trials or approaches to improve tumor response by using various modifications of treatment. Because organ preservation strategies and watch-and-wait approaches are recent strategies, solid evidence supporting their survival benefits is lacking. Therefore, research on such treatments was not included in this review.

HOW TO ACHIEVE A HIGHER pCR AFTER PCRT IN LARC

Adding various cytotoxic or molecular target agents with radiation therapy to improve tumor response; less is more

Traditionally, 5-fluorouracil (5-FU) has been used as a radio-sensitizing agent in a neoadjuvant setting for the treatment of patients with rectal cancer. After a new cytotoxic agent, oxaliplatin, showed improved disease control in an adjuvant setting, many trials were conducted to improve the tumor response by adding more cytotoxic agents, or even molecular target agents, during radiation therapy. The results of recent clinical trials are summarized in Table 1. A German trial was the only one that showed statistically significant differences in the pCR rate by adding oxaliplatin to radiation therapy [16]. Other trials, including NSABP R-04, showed an increase in grade 3–4 chemotherapy-related toxicities and a decreased compliance of treatment when oxaliplatin was added [17-26]. Additionally, the NSABP R-04 trial showed that continuous infusion of 5-FU was equivalent to oral capecitabine in terms of pCR rate and downstaging of the tumor [17, 25]. Based on these clinical trials, many other recent trials have adopted oral capecitabine as a radiosensitizer.

Effect of increasing the time interval between completion of PCRT and surgery on the pCR rate

The decision to prolong the time interval from 2 weeks to 6 to 8 weeks to achieve a higher pCR is based on the findings of recent clinical trials [27]. More recently, some investigators have tried to delay surgery beyond the classical 6 to 8 weeks from the time of completion of radiation therapy. Petrelli et al. [28] performed a meta-analysis regarding prolonging the time interval and concluded that the pCR rate increased from 13.7% to 19.5% in the longer interval group (>6–8 weeks). However, OS, DFS, R0 resection rate, sphincter preservation and complication rates were similar between the longer interval (>6–8 weeks) and the shorter interval (<6–8 weeks) groups.

Recent studies have suggested an even longer waiting period of up to 12 weeks or more. A UK 6- vs. 12-week trial reported a pCR rate of 6% in the 6-week group compared with 20% in the 12-week group [29]. Conversely, the French GRECCA-6 study reported no differences in pCR rate between the 7-week and the 11-week groups, but postoperative complications (32% vs. 44.5%) were increased and the quality of TME specimens (90% vs. 78.7%) was poor in the 11-week group [30].

An increased waiting period might achieve pCR even in short-course radiation therapy [31]. However, concerns about tumor-cell repopulation during the prolonged waiting period have been expressed, so currently no consensus as to the length of the waiting period exists. Greater, well-designed randomized studies are needed to confirm the efficacy of an increased waiting period in the treatment of patients with rectal cancer.

Upfront or induction chemotherapy, followed by preoperative radiation therapy and/or adding consolidation chemotherapy during the waiting period, has led to the era of total neoadjuvant chemotherapy

Although PCRT has shown an improvement in local control, it has not shown improved DFS or OS for patients with LARC (Table 2) [3-9]. Upfront chemotherapies, such as induction or consolidation chemotherapy and total neoadjuvant therapy (TNT), have been introduced to improve and achieve survival benefits and are being actively tested in ongoing trials.

Updated National Comprehensive Cancer Network (NCCN) guidelines suggest induction chemotherapy with FOLFOX or CAPEOX followed by PCRT and transabdominal surgery as treatment options for patients with LARC [2]. Even though induction chemotherapy is not yet approved for coverage by Korean insurance, it has been widely applied in the care of patients with LARC. Gao et al. [32] reported the results of a phase-2 trial using neoadjuvant sandwich treatment with CAPEOX administered prior to and concurrently with flowing radiation therapy for patients with LARC. Among 49 eligible patients, 45 patients underwent optimal surgery, and the pCR rate was 42.2%. When the 4 patients with cCR who refused surgery were considered, the pCR rate rose to 46.9%. The French GRECCA-4 trial tested induction chemotherapy with FOLFIRINOX (5-FU, irinotecan and oxaliplatin) chemotherapy in patients with LAR [33]. Of these patients, 15% showed more than 75% tumor shrinkage 2 weeks after induction chemotherapy. The study was terminated early due to the relatively low treatment efficacy of induction chemotherapy; however, when the inclusion criteria of the patients, such as more than mrT3c or mrT4 tumors or a threatened circumferential resection margin less than 1 mm, were examined, induction chemotherapy might have played some role in the management of patients with LARC.

The main ideas of consolidation chemotherapy are in regard to the potential benefits of improved local and systemic control of LARC when chemotherapy is added during the waiting period between completion of PCRT and surgery. A timing trial reported both short- and long-term outcomes [34, 35]. That study divided patients into 4 groups according to the duration of consolidation chemotherapy. Compared with the no-consolidation group (pCR rate of 18%), adding 2-, 4-, and 6-cycles of FOLFOX consolidation chemotherapy resulted in pCR rates of 25%, 30%, and 38%, respectively. With a median follow-up of 59 months, DFS differed significantly between the no-consolidation group and the consolidation groups. Furthermore, the consolidation groups showed a better compliance to chemotherapy compared to the nonconsolidation group. Other studies, done by Polish and Korean groups used short-course radiation therapy for the treatment of patients with LARC and demonstrated an increased pCR rate with consolidation chemotherapy; however, the improved pCR rate was not statistically significant [31, 36].

Currently, the NCCN guidelines recommend 4 months of adjuvant fluoropyrimidine-based chemotherapy for all patients who receive PCRT and undergo surgical resection, regardless of pathologic findings [2]. These recommendations are not based on direct evidence from randomized trials, but are instead supported by extrapolation from the demonstrated survival benefits in colon cancer adjuvant chemotherapy trials. To date, only 4 randomized clinical trials [37-40] and 1 meta-analysis [41] to test the benefits of adjuvant chemotherapy in the treatment of patients with rectal cancer have been published. Many compounding factors have precluded the finding of evidence in those trials. Of these factors, postoperative complications and resultant poor compliances in adjuvant chemotherapy should be considered. Adopting upfront systemic chemotherapy, which is a growing area of active research on treating patients with LARC, may be a way to overcome these limitations in the effective administration of adjuvant chemotherapy. Recent trials to evaluate the effectiveness of TNT are summarized in Table 3 [42-47]. Many potential benefits, such as early control of micrometastases and improved compliance of chemotherapy, can be achieved by delivering all scheduled systemic chemotherapy before surgery. Moreover, TNT that is effectively delivered before surgery may improve tumor response and increase the probability of successful sphincter-preserving surgery.

High-dose chemoradiotherapy

The traditional radiation dose for patients with LARC is 5,040 cGy or 2,500 cGy. A recent trial conducted in Denmark proposed increasing the radiation dose to 70 Gy, and this achieved a cCR in 78.4% of the patients [48]. Brachytherapy is also an alternative treatment option for patients that are medically unfit for surgical approaches [49, 50].

CONCLUSIONS

Despite recent advances in the treatment of patients with LARC, the OS of those patients has not significantly improved. PCRT remains the major treatment strategy to combat LARC, and reports that a subgroup of patients achieved a pCR after PCRT have greatly encouraged clinical and biological research that aims to identify the factors influencing pCR. However, no solid evidence for the benefit of a pCR after PCRT has yet to be reported, and no specific factors influencing pCR have yet to be identified. Many factors need to be considered if the OS of patients with LARC is to be improved. More information is needed in several areas, such as how to predict tumor response after PCRT, maximizing tumor response, determining the best time to assess tumor response, how to identify true cCR, etc.

Treatment paradigms for patients with LARC are slowly shifting from the current, standard trimodal treatment of PCRT followed by surgery and adjuvant chemotherapy to more aggressive perioperative treatments, such as induction or consolidation chemotherapy and total neoadjuvant therapy. This modification of treatment paradigms aims to improve local control, improve survival of patients, increase the frequency of sphincter-saving surgery, and possibly lead to an avoidance of surgery or to organ-preserving treatment for patients with rectal cancer.

ARTICLE INFORMATION

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

Table 1.

Summary of trials that added cytotoxic or molecular target agents to improve tumor response in radiation therapy for the treatment of patients with locally advanced rectal cancer

Trial	No. of patients	Chemotherapy regimen	PCR	P-value
STAR-01 [18]	705	5-FU PVI vs. 5-FU+oxaliplatin	16% vs. 16%	NS
ACCORD 12 [22, 23]	584	Capecitabine vs. CAPEOX	13.9% vs. 19.2%	0.09
NASBP R-04 [17, 25]	1,608	5-FU vs. 5-FU+oxaliplatin vs. capecitabine vs. CAPEOX	12.1% vs. 11.2%	0.70
CAO/ARO/AIO-04 [26]	1,236	5-FU vs. 5-FU+oxaliplatin	13% vs. 17%	0.04
PETACC-6	1,094	capecitabine vs. CAPEOX	12% vs. 14%	NS
Dellas et al. [19]	70	CAPEOX+bevacizumab	17.4%	-
EXPERT-C [21]	165	CAPEOX vs. CAPEOX+ cetuximab	7% vs. 11%	0.714
FOWARC TRIAL [20]	495	5-FU vs. mFOLFOX vs. no chemotherapy	14% vs. 27.5% vs. 6.6%	0.005

PCR, pathologic complete response; 5-FU, 5-fluorouracil; PVI, protracted venous infusion; NS, not significant; CAPEOX, capecitabine+oxaliplatin; mFOLFOX, modified 5-fluorouracil+oxalipatin.

Table 2.

Preoperative chemoradiation therapy for the treatment of patients with advanced rectal cancer did not show any survival benefit in most clinical trials

Trial	No. of patients	Study regimen	5-Year OS	P-value
Krook et al. [3]	204	Postop RT vs. Postop CCRT	49% vs. 58%	NS
Swedish rectal cancer trial [4]	908	Surgery alone vs. Preop SCRT	55% vs. 63%	0.008
Dutch trial [40]	1,861	TME alone vs. Preop SCRT	63% vs. 64%	NS
LYON R96-02 [5]	88	Preop RT vs. Preop RT+XBR	67% vs. 67%	NS
CAO/ARO/AIO [16]	823	Postop LCRT vs. Preop LCRT	74% vs. 76%	NS
FFCD 9203 [7]	762	Preop LCRT vs. Preop LCRT	67% vs. 67%	NS
MRC CR07 [9]	1,350	Preop SCRT vs. Postop LCRT	70% vs. 68%	NS

OS, overall survival; Postop, postoperative; Preop, preoperative; RT, radiotherapy; CCRT, chemoradiotherapy; NS, not significant; SCRT, short-course radiotherapy; TME, total mesorectal excision; XBR, external beam radiation; LCRT, long-course radiotherapy.

Table 3.

Total neoadjuvant therapy (TNT) for the treatment of patients with locally advanced rectal cancer

Trial	No. of patients	Study regimen	PCR
GCR-3 [43]	108	Preop CAPEOX+CAPEOX CRT vs.CAPEOX CRT+adjuvant CAPEOX	14% vs. 13%
CONTRE [47]	39	FOLFOX+Cap CRT	33%
Marechal et al. [45]	57	FOLFOX+5-FU CRT vs. 5-FU CRT	32% vs. 34%
Schou et al. [46]	85	CAPEOX+Cap CRT	23%
AVACROSS [44]	47	Bev+XELOX followed by Bev+Cap CRT	36%
EXPERT [42]	105	CAPEOX+Cap CRT+Cap	20%

PCR, pathologic complete response; Preop, preoperative; CAPEOX, capecitabine+oxaliplatin; CRT, chemoradiotherapy; FOLFOX, 5-fluorouracil+leucovorin+oxaliplatin; Cap, capecitabine; 5-FU, 5-fluorouracil; Bev, bevacizumab; XELOX, capecitabine+oxaliplatin.

REFERENCES

1. Jung KW, Won YJ, Kong HJ, Lee ES; Community of Population-Based Regional Cancer Registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015. Cancer Res Treat 2018;50:303–16.Article PubMed PMC PDF
2. National Comprehensive Cancer Network. Rectal cancer (version 3. 2018) 2018 [Internet]. Fort Wathington (PA), National Comprehensive Cancer Network; c2018 [updated 2018 Aug 7; cited 2018 Dec 28]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
3. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–15.Article PubMed
4. Swedish Rectal Cancer Trial, Cedermark B, Dahlberg M, Glimelius B, Påhlman L, Rutqvist LE, et al. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980–7.Article PubMed
5. Gerard JP, Chapet O, Nemoz C, Hartweig J, Romestaing P, Coquard R, et al. Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96-02 randomized trial. J Clin Oncol 2004;22:2404–9.Article PubMed
6. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40.Article PubMed
7. Gerard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24:4620–5.Article PubMed
8. Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, 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;246:693–701.Article PubMed
9. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009;373:811–20.Article PubMed PMC
10. Dinaux AM, Amri R, Bordeianou LG, Hong TS, Wo JY, Blaszkowsky LS, et al. The impact of pathologic complete response in patients with neoadjuvantly treated locally advanced rectal cancer-a large single-center experience. J Gastrointest Surg 2017;21:1153–8.Article PubMed PDF
11. Lorimer PD, Motz BM, Kirks RC, Boselli DM, Walsh KK, Prabhu RS, et al. Pathologic complete response rates after neoadjuvant treatment in rectal cancer: an analysis of the National Cancer Database. Ann Surg Oncol 2017;24:2095–103.Article PubMed PDF
12. Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DA. A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum 2003;46:298–304.Article PubMed
13. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010;11:835–44.Article PubMed PMC
14. van der Valk MJM, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets GL, Figueiredo NL, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 2018;391:2537–45.Article PubMed
15. Emmertsen KJ, Laurberg S; Rectal Cancer Function Study Group. Impact of bowel dysfunction on quality of life after sphincter-preserving resection for rectal cancer. Br J Surg 2013;100:1377–87.Article PubMed
16. Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2015;16:979–89.Article PubMed
17. Allegra CJ, Yothers G, O’Connell MJ, Beart RW, Wozniak TF, Pitot HC, 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:pii: djv248. https://doi.org/10.1093/jnci/djv248Article PDF
18. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, 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;29:2773–80.Article PubMed
19. Dellas K, Höhler T, Reese T, Würschmidt F, Engel E, Rödel C, et al. Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer. Radiat Oncol 2013;8:90. Article PubMed PMC PDF
20. Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, et al. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol 2016;34:3300–7.Article PubMed PMC
21. Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, 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;30:1620–7.Article PubMed
22. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne PL, et al. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin Oncol 2012;30:4558–65.Article PubMed
23. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010;28:1638–44.Article PubMed
24. Gormly KL, Coscia C, Wells T, Tebbutt N, Harvey JA, Wilson K, et al. MRI rectal cancer in Australia and New Zealand: an audit from the PETACC-6 trial. J Med Imaging Radiat Oncol 2016;60:607–15.Article PubMed
25. O’Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol 2014;32:1927–34.Article PubMed PMC
26. Rodel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, 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;13:679–87.Article PubMed
27. Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, Partensky C, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999;17:2396. Article PubMed
28. Petrelli F, Sgroi G, Sarti E, Barni S. Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies. Ann Surg 2016;263:458–64.Article PubMed
29. Evans J, Bhoday J, Sizer B, Tekkis P, Swift R, Perez R, et al. Results of a prospective randomised control 6 vs 12 trial: is greater tumour downstaging observed on post treatment MRI if surgery is delayed to 12-weeks versus 6-weeks after completion of neoadjuvant chemoradiotherapy? Ann Oncol 2016;27(Suppl_6): 4520. Article PDF
30. Lefevre JH, Mineur L, Kotti S, Rullier E, Rouanet P, de Chaisemartin C, et al. Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6). J Clin Oncol 2016;34:3773–80.Article PubMed
31. Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol 2016;27:834–42.Article PubMed
32. Gao YH, Lin JZ, An X, Luo JL, Cai MY, Cai PQ, et al. Neoadjuvant sandwich treatment with oxaliplatin and capecitabine administered prior to, concurrently with, and following radiation therapy in locally advanced rectal cancer: a prospective phase 2 trial. Int J Radiat Oncol Biol Phys 2014;90:1153–60.Article PubMed
33. Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, et al. Tailored treatment strategy for locally advanced rectal carcinoma based on the tumor response to induction chemotherapy: preliminary results of the French phase II multicenter GRECCAR4 trial. Dis Colon Rectum 2017;60:653–63.Article PubMed
34. Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 2015;16:957–66.Article PubMed PMC
35. Marco MR, Zhou L, Patil S, Marcet JE, Varma MG, Oommen S, et al. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: final results of a multicenter phase II trial. Dis Colon Rectum 2018;61:1146–55.Article PubMed PMC
36. Kim SY, Joo J, Kim TW, Hong YS, Kim JE, Hwang IG, et al. A randomized phase 2 trial of consolidation chemotherapy after preoperative chemoradiation therapy versus chemoradiation therapy alone for locally advanced rectal cancer: KCSG CO 14-03. Int J Radiat Oncol Biol Phys 2018;101:889–99.Article PubMed
37. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23.Article PubMed
38. Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 2014;25:1356–62.Article PubMed PDF
39. Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, et al. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT). Radiother Oncol 2014;113:223–9.Article PubMed PMC
40. Breugom AJ, van Gijn W, Muller EW, Berglund A, van den Broek CB, Fokstuen T, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol 2015;26:696–701.Article PubMed PDF
41. Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, Cionini L, 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;16:200–7.Article PubMed
42. Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol 2010;11:241–8.Article PubMed
43. Fernandez-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol 2010;28:859–65.Article PubMed
44. Nogue M, Salud A, Vicente P, Arriví A, Roca JM, Losa F, et al. Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS study. Oncologist 2011;16:614–20.Article PubMed PMC
45. Marechal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol 2012;23:1525–30.Article PubMed PDF
46. Schou JV, Larsen FO, Rasch L, Linnemann D, Langhoff J, Høgdall E, et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol 2012;23:2627–33.Article PubMed PDF
47. Perez K, Safran H, Sikov W, Vrees M, Klipfel A, Shah N, et al. Complete neoadjuvant treatment for rectal cancer: the Brown University Oncology Group CONTRE Study. Am J Clin Oncol 2017;40:283–7.Article PubMed
48. Appelt AL, Pløen J, Harling H, Jensen FS, Jensen LH, Jørgensen JC, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol 2015;16:919–27.Article PubMed
49. Buckley H, Wilson C, Ajithkumar T. High-dose-rate brachytherapy in the management of operable rectal cancer: a systematic review. Int J Radiat Oncol Biol Phys 2017;99:111–27.Article PubMed
50. Vuong T, Devic S. High-dose-rate pre-operative endorectal brachytherapy for patients with rectal cancer. J Contemp Brachytherapy 2015;7:183–8.Article PubMed PMC

Figure & Data

References

Citations

Citations to this article as recorded by

Predictors of Pathologic Response After Total Neoadjuvant Therapy in Patients With Rectal Adenocarcinoma: A National Cancer Database Analysis
David M McDermott, Sarah A Singh, Paul B Renz, Shaakir Hasan, Josh Weir
Cureus.2021;[Epub] CrossRef
Can Pretreatment Blood Biomarkers Predict Pathological Response to Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer?
Marina Morais, Telma Fonseca, Raquel Machado-Neves, Mrinalini Honavar, Ana Rita Coelho, Joanne Lopes, Elisabete Barbosa, Emanuel Guerreiro, Silvestre Carneiro
Future Oncology.2021; 17(35): 4947. CrossRef
Pretreatment Blood Biomarkers Predict Pathologic Responses to Neo-Crt in Patients with Locally Advanced Rectal Cancer
Aijie Li, Kewen He, Dong Guo, Chao Liu, Duoying Wang, Xiangkui Mu, Jinming Yu
Future Oncology.2019; 15(28): 3233. CrossRef

PubReader
ePub Link

Cite this Article

Cite this Article: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

How to Achieve a Higher Pathologic Complete Response in Patients With Locally Advanced Rectal Cancer Who Receive Preoperative Chemoradiation Therapy

Ann Coloproctol. 2019;35(1):3-8. Published online February 28, 2019

DOI: https://doi.org/10.3393/ac.2019.02.17

XML Download

Related articles

Is clinical complete response as accurate as pathological complete response in patients with mid-low locally advanced rectal cancer?

How to Achieve a Higher Pathologic Complete Response in Patients With Locally Advanced Rectal Cancer Who Receive Preoperative Chemoradiation Therapy

Trial	No. of patients	Chemotherapy regimen	PCR	P-value
STAR-01 [18]	705	5-FU PVI vs. 5-FU+oxaliplatin	16% vs. 16%	NS
ACCORD 12 [22, 23]	584	Capecitabine vs. CAPEOX	13.9% vs. 19.2%	0.09
NASBP R-04 [17, 25]	1,608	5-FU vs. 5-FU+oxaliplatin vs. capecitabine vs. CAPEOX	12.1% vs. 11.2%	0.70
CAO/ARO/AIO-04 [26]	1,236	5-FU vs. 5-FU+oxaliplatin	13% vs. 17%	0.04
PETACC-6	1,094	capecitabine vs. CAPEOX	12% vs. 14%	NS
Dellas et al. [19]	70	CAPEOX+bevacizumab	17.4%	-
EXPERT-C [21]	165	CAPEOX vs. CAPEOX+ cetuximab	7% vs. 11%	0.714
FOWARC TRIAL [20]	495	5-FU vs. mFOLFOX vs. no chemotherapy	14% vs. 27.5% vs. 6.6%	0.005

Trial	No. of patients	Study regimen	5-Year OS	P-value
Krook et al. [3]	204	Postop RT vs. Postop CCRT	49% vs. 58%	NS
Swedish rectal cancer trial [4]	908	Surgery alone vs. Preop SCRT	55% vs. 63%	0.008
Dutch trial [40]	1,861	TME alone vs. Preop SCRT	63% vs. 64%	NS
LYON R96-02 [5]	88	Preop RT vs. Preop RT+XBR	67% vs. 67%	NS
CAO/ARO/AIO [16]	823	Postop LCRT vs. Preop LCRT	74% vs. 76%	NS
FFCD 9203 [7]	762	Preop LCRT vs. Preop LCRT	67% vs. 67%	NS
MRC CR07 [9]	1,350	Preop SCRT vs. Postop LCRT	70% vs. 68%	NS

Trial	No. of patients	Study regimen	PCR
GCR-3 [43]	108	Preop CAPEOX+CAPEOX CRT vs.CAPEOX CRT+adjuvant CAPEOX	14% vs. 13%
CONTRE [47]	39	FOLFOX+Cap CRT	33%
Marechal et al. [45]	57	FOLFOX+5-FU CRT vs. 5-FU CRT	32% vs. 34%
Schou et al. [46]	85	CAPEOX+Cap CRT	23%
AVACROSS [44]	47	Bev+XELOX followed by Bev+Cap CRT	36%
EXPERT [42]	105	CAPEOX+Cap CRT+Cap	20%

Table 1. Summary of trials that added cytotoxic or molecular target agents to improve tumor response in radiation therapy for the treatment of patients with locally advanced rectal cancer

PCR, pathologic complete response; 5-FU, 5-fluorouracil; PVI, protracted venous infusion; NS, not significant; CAPEOX, capecitabine+oxaliplatin; mFOLFOX, modified 5-fluorouracil+oxalipatin.

Table 2. Preoperative chemoradiation therapy for the treatment of patients with advanced rectal cancer did not show any survival benefit in most clinical trials

Table 3. Total neoadjuvant therapy (TNT) for the treatment of patients with locally advanced rectal cancer