Review on adjuvant chemotherapy for rectal cancer – why do treatment guidelines differ so much?

Figures & data

Table I. International and national guidelines on postoperative adjuvant chemotherapy for rectal cancer.

	ESMO	NCCN	Norway	Sweden	Finland	Denmark	Spain	Dutch	NICE
Year	2013 [22,23]	2012 [2]	2013 [24]	2014 [25]	2009 [26]	2013 [27]	2013 [28]	2014 [29]	2011 [30]
RC High-risk stage II	FU/5FU	5FU/Ox#	No	5FU	5FU-Ox§	5FU(+ Ox)	Yes*	No	Yes
RC stage III	FU/5FU	5FU/Ox	No	5FU(+ Ox)	5FU-Ox	5FU(+ Ox)	Yes*	No	Yes
After preop. CRT**	n.s.	Yes	No	No	n.s.	Yes	No	No	n.s.

ESMO, European Society for Medical Oncology; 5-FU, 5-Flurouracil; NCCN, National Comprehensive Cancer Network, USA; n.s., Not stated; Ox, Oxaliplatin.* If no CRT was given **Does the guideline recommend use of postoperative adjuvant chemotherapy after preoperative (chemo) radiotherapy. # recommended for stage 0, 1 & 2. §Unknown if all stage II or only high-risk stage II.

Figure 1. Study flowchart.

Table II. Included trials. *Studies included patients with both colon and rectal cancer. Only patients with rectal cancer are included here. Either the authors published the separate data or provided them for the Cochrane analysis [55]. **p ≤ 0.05.

Year	Author	n = (Total/RC)	Stage	Regimen	Hazard ratio	OS	Result	DFS	Result
Asian studies
1991	Matsuda [31]	2450/1243*	n.s.	Observation	0.97	5y OS	No diff.		n.s.
				Adj FT	(0.77–1.23)
1995	CCSGJ [32]	1004	n.s.	Observation	0.66	5y OS	60.2%	5y DFS	57%
				Adj 5-FU+ MMC	(0.52–0.84)	**	73.6%	**	73%
				Adj. 5-FU+ MMC+ MMC IP		**	70.7%	**	72%
1996	Ito [33]	173/77*	II-III	Observation	1.33	5y OS	No diff.	5y DFS	63%
				Adj. HCFU	(0.68–2.59)			**	77%
1998	Kodaira [34]	794	II-III	Observation	0.93	5y OS	66.3%	5y DFS	59%
				Adj UFT+ MMC	(0.73–1.19)		70.1%	**	69%
2002	Kato [35]	320/143*	II-III	Observation	0.66	5y OS	66.7%	5y DFS	60%
				Adj UFT	(0.35–1.25)		75.9%	**	76%
2004	Watanbe [36]	1429/669*	II-III	Observation	0.88	5y OS	No diff.	5y DFS	No diff.
				Adj HCFU + 5FU+ MMC	(0.57–1.36)
				Adj HCFU + 5FU+ MMC+ immunotherapy
2011	Hamaguchi [37]	606/274	III	Observation	0.60	5y OS	72.1%	5y RFS	56%
				Adj UFT	(0.38–0.97)	**	85.3%	**	69%
Studies with preoperative chemoradiotherapy (CRT)
2006	EORTC 22921 [38]	1011	II-III	RT - surgery - observation	0.85	5y OS	63.2%	5y DFS	52%
				CRT - surgery - observation	(0.69–1.04)
				RT - surgey - adj 5FU			67.2%		58%
				CRT - surgery - adj 5FU
2010	Cionini [39]	634	II-III	CRT - surgery - observation	No HR	5y OS	69.8%		n.s.
				CRT - surgery - adj 5FU			68.0%
2013	Proctor/Script [40]	470	II-III	RT/CRT* - surgery - observation	0.88	5y OS	75.9%	5y DFS	58%
				RT/CRT* - surgery - adj 5FU or cape	(0.59–1.31)		74.4%		62%
2014	Chronicle [41]	113	I-II-III	CRT - surgery - observation	1.18	3y OS	88%	3y DFS	71%
				CRT - surgery - adj capox	(0.43–3.26)		89%		78%
Studies without preoperative radiotherapy
1981	Grage [42]	233/64*	II-III	Observation	0.41	5y OS	p = 0.05	5y DFS	p = 0.04
				Adj 5FU	(0.20–0.84)	**		**
1985	Hafstrøm [43]	421/137	II-III	Observation	No HR	5y OS	No diff.		n.s.
				Adj oral 5FU
1988	Fisher [44]	574	II-III	Observation	0.79	5y OS	43%	5y DFS	p = 0.006
				Postop RT	(0.61–1.03)	**		**
				Postop RT with adj SFV			53%
1988	Thomas [45]	202/106	II-III	Observation	0.75	OS	36%		n.s.
				Adj FS	(0.49–1.14)		46%
				(Postop RT)
				(Postop CRT - adj FS)
1990	Hafstrøm [46]	334/99*	III	Observation	0.71	5y OS	34%		n.s.
				Adj FCV	(0.43–1.17)		49%
1991	Krook [47]	204	II-III	Postop RT	0.71	OS-gain	29%		n.s.
				Postop CRT - adj FS	(0.55–0.92)	**
1996	Kornek [48]	57	II-III	Observation	0.42	5y OS	54%	5y RFS	46%
				Adj intraabd. mitoxantrone and iv 5FU	(0.17–1.04)		70%		68%
1999	Athanassiou [49]	220	II-III	Postop CRT	No HR	3y OS	73.3%	3y DFS	68%
				Postop 5FU x1 - CRT - 5FU x 3			77%		70%
2003	Cafiero [50]	218	II-III	Postop RT	1.33	5y OS	p = 0.18	5y DFS	p = 0.66
				Postop RT - adj 5FU + FA	(0.90–1.96)
2005	Glimelius [51]	2224/691*	II-III	Observation	0.90	5y OS	No diff.		n.s.
				Adj 5FU with FA, levamisole or both.	(0.74–1.10)
Studies with AND without preop RT
1992	Li [52]	423	n.s.	Observation	No HR	5y OS	28.8%		n.s.
				Preop RT			34.4%
				Adj CT			47.5%
				Preop RT - adj CT		**	52.4%
2001	Taal [53]	1029/299*	II-III	Observation	0.95	5y OS	p = 0.13		n.s.
				Adj 5FU+ lev	(0.66–1.36)
2007	Quasar [54]	3239/948*	I-II-III	Observation	0.77	5y OS	p = 0.05	RR	0.68
				Adj 5FU+ FA	(0.60–0.99)	**		**

FA, folinic acid; FCV, 5FU CCNU and vincristine; FLv, 5FU and folinic acid; FS, 5FU semustin; FSV, 5FU semustin, vincristin; HCFU, carmofur; IP, intraportal; Lev, levamisole; n.s., not stated; RFS, recurrence free survival; RR, relative risk of recurrence; UFT, uftoral.

Schmoll H-J, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, et al. ESMO consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:2479–516.

 PubMed Web of Science ®Google Scholar

Glimelius B, Tiret E, Cervantes A, Arnold D. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi81–8.

 Google Scholar

Benson AB, Bekaii-Saab T, Chan E, Chen Y, Choti MA, Cooper HS, et al. Rectal cancer. J Natl Compr Canc Netw 2012;10:1528–64.

 PubMed Web of Science ®Google Scholar

NGICG. Nasjonalt handlingsprogram med retningslinjer for diagnostikk , behandling og oppfølging av kreft i tykktarm og endetarm. Available from: http://ngicg.no/handlingsprogram/nasjonale_handlingsprogrammer/content_1/filelist_ee59ae57-c583-41bb-8e91-ac712e639640/1395777852047/nasjonalt_handlingsprogram_for_tykk_og_endetarmskreft.pdf . Cited on 28th June, 2014.

 Google Scholar

Socialstyrelsen. Swedish Guidelines. 2014. Available from: http://www.socialstyrelsen.se/publikationer2014/2014-4-2/Sidor/default.aspx . Cited on 28th June, 2014.

 Google Scholar

Lepistö A, Osterlund P, Kouri M, Järvinen HJ. [Rectal cancer].Duodecim 2009;125:857–65.

 PubMedGoogle Scholar

DCCG. Adjuverende kemoterapi ved rectumcancer. Available from: http://dccg.dk/retningslinjer/20140418/2014_AdjKemoRectum.pdf Cited on 28th June, 2014.

 Google Scholar

Maurel J, Grávalos Castro C, Rivera Herrero F, Vera R, Gonzáles Flores E Sast. SEOM clinical guidelines for the adjuvant treatment of colorectal cancer2013. Clin Transl Oncol2013;15:991–5.

 PubMed Web of Science ®Google Scholar

Tumoren L werkgroep GI. Dutch Guidelines: Adjuvante Chemotherapie Rectumcarcinoom. Available from: http://www.oncoline.nl/colorectaalcarcinoom . Cited on 28th June, 2014.

 Google Scholar

NICE. British guidelines: Colorectal cancer: The diagnosis and management of colorectal cancer. Available from: http://publications.nice.org.uk/colorectal-cancer-cg131/guidance# management-of-local-disease . Cited on 28th June, 2014.

 Google Scholar

Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012;3:CD004078.

 Google Scholar

Matsuda T, Yasutomi M, Kikuchi K, Kasai Y, Abe O, Kondo T, et al.[Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report): five-year results.Cooperative Study Group of Surgical Adjuvant Chemotherapy for Colorectal Cancer in Japan].Gan To Kagaku Ryoho 1991;18:461–9.

 PubMedGoogle Scholar

Five-year results of a randomized controlled trial of adjuvant chemotherapy for curatively resected colorectal carcinoma. The Colorectal Cancer Chemotherapy Study Group of Japan. Jpn J Clin Oncol 1995;25:91–103.

 PubMed Web of Science ®Google Scholar

Ito K, Yamaguchi A, Miura K, Kato T, Baba S, Matsumoto S, et al. Oral adjuvant chemotherapy with carmofur (HCFU) for colorectal cancer: Five-year follow-up. Tokai HCFU Study Group – third study on colorectal cancer. J Surg Oncol 1996;63:107–11.

 PubMed Web of Science ®Google Scholar

Kodaira S. Postoperative adjuvant chemotherapy with mitomycin C and UFT for rectal cancer. Oncology (Williston Park) 1997;11:40–3.

 PubMedGoogle Scholar

Kato T, Ohashi Y, Nakazato H, Koike A, Saji S, Suzuki H, et al. Efficacy of oral UFT as adjuvant chemotherapy to curative resection of colorectal cancer: Multicenter prospective randomized trial. Langenbecks Arch Surg 2002;386:575–81.

 PubMed Web of Science ®Google Scholar

Watanabe M, Nishida O, Kunii Y, Kodaira S, Takahashi T, Tominaga T, et al. Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-flu. Int J Clin Oncol 2004;9:98–106.

 PubMedGoogle Scholar

Hamaguchi T, Shirao K, Moriya Y, Yoshida S, Kodaira S, Ohashi Y. Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC). Cancer Chemother Pharmacol 2011;67:587–96.

 PubMed Web of Science ®Google Scholar

Bosset J-F, 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.

 PubMed Web of Science ®Google Scholar

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.

 Google Scholar

Breugom AJ, van Gijn W, Mueller 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) randomised phase III trial.Ann Oncol 2014 Dec 5. pii: mdu560. [Epub ahead of print].

 Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Grage TB, Moss SE. Adjuvant chemotherapy in cancer of the colon and rectum: Demonstration of effectiveness of prolonged 5-FU chemotherapy in a prospectively controlled, randomized trial. Surg Clin North Am 1981;61:1321–9.

 PubMed Web of Science ®Google Scholar

Hafström L, Domellof L, Rudenstam C-M. A randomized trial of oral 5-fluorouracil versus placebo as adjuvant therapy in colorectal cancer Dukes’ B and C: Results after 5 years observation time. Br J Surg 1985;72:138–41.

 PubMed Web of Science ®Google Scholar

Fisher B, Wolmark N, Rockette H, Redmond C, Deutsch M, Wickerham DL, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Natl Cancer Inst 1988;80:21–9.

 PubMed Web of Science ®Google Scholar

Thomas PR, Lindblad AS. Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: A review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol 1988;13:245–52.

 PubMed Web of Science ®Google Scholar

Hafström L, Domellöf L, Rudenstam CM, Norryd C, Bergman L, Nilsson T, et al. Adjuvant chemotherapy with 5-fluorouracil, vincristine and CCNU for patients with Dukes’ C colorectal cancer. The Swedish Gastrointestinal Tumour Adjuvant Therapy Group. Br J Surg 1990;77:1345–8.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Kornek G, Depisch D, Salem G, Karalt M, Rohrbacher M, Scheithauer W. Combined locoregional and systemic adjuvant chemotherapy of stage II and III rectal carcinoma. Onkologie 1996;19:147–51.

 Web of Science ®Google Scholar

Athanassiou E, Dafni U, Liaros A, Briassoulis E, Samantas E, Kosmidis P, et al. Postoperative radiation (RT) and concomitant bolus fluorouracil (FU) with or without additional chemotherapy (CT) as adjuvant treatment in patients with high risk rectal cancer. A randomized phase III study conducted by the Hellenic Cooperative Oncology G. Eur J Cancer 1999;35:S69–70. (Abstxr)

 Web of Science ®Google Scholar

Cafiero F, Gipponi M, Lionetto R. Randomised clinical trial of adjuvant postoperative RT vs. sequential postoperative RT plus 5-FU and levamisole in patients with stage II-III resectable rectal cancer: A final report. J Surg Oncol 2003;83: 140–6.

 PubMed Web of Science ®Google Scholar

Glimelius B, Dahl O, Cedermark B, Jakobsen A, Bentzen SM, Starkhammar H, et al. Adjuvant chemotherapy in colorectal cancer: A joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Acta Oncol 2005;44:904–12.

 PubMed Web of Science ®Google Scholar

Li RL. [Combination of surgery, radiotherapy and chemotherapy for rectal cancer – a 423 cases report]. Zhonghua Zhong Liu Za Zhi 1992;14:213–5.

 PubMedGoogle Scholar

Taal BG, van Tinteren H, Zoetmulder F. Adjuvant 5FU plus levamisole in colonic or rectal cancer: Improved survival in stage II and III. Br J Cancer 2001;85:1437–43.

 PubMed Web of Science ®Google Scholar

Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 2007;370:2020–9.

 PubMed Web of Science ®Google Scholar