Adjuvant chemotherapy in curatively resected rectal cancer: How valid are the data?

Table 1 Sample size and significance of the 21 studies included in the Cochrane meta-analysis

Ref.	ntot	nc	ni (type of intervention)	Weight (%)	Outcome
Grage et al[13] 1981	64	31	33 (adj. CTx)	1.4	S
Fisher 1988 (NSABP)	574	191	190 (adj. RT)	6.8	NS
			193(adj. CTx+RT)
Thomas 1988 (GTSG)	106	58	48 (adj. CTx)	3.5	NS
Hafström 1990	99	56	43 (adj. CTx)	2.6	NS
Krook et al[11] 1991 (NCCTG)	204	100 (adj. RT)	104 (adj. CTx + RT)	6.8	S
Matsuda 1991 (SGACCS)	1243	598	645 (adj. CTx)	7.8	NS
CCCSGJ[10] 1995	1004	335	323 (adj. CTx)	7.6	S
			346 (intra-art CTx + adj. CTx )
Kornek 1996	57	29	28 (adj. CTx)	0.9	NS
Ito 1996 (TSGHCFU)	77	40	37 (adj. CTx)	1.6	NS
Yasutomi 1997 (JFMTC7-2)	713	356	357 (adj. CTx)	6.9	NS
Kodaira 1998 (JFMTC 7-1)	794	398	396 (adj. CTx)	7.4	NS
Taal 2001 (NACCP)	299	150	149 (adj. CTx)	4.4	NS
Kato 2002 (TACSG)	143	72	71 (adj. CTx)	1.7	NS
Cafiero 2003	218	108	110 (adj. CTx+RT)	4.0	NS
Watanabe 2004 (JFMTC15-2)	391	122	269 (adj. CTx)	3.3	NS
Glimelius 2005 (NGTATG)	691	352	339 (adj. CTX)	9.2	NS
Bosset et al[16] 2006 (EORTC)	1011	252 (neoadj. RT)	253 (neoadj. RT + adj. CTx)	8.9	NS
		253 (neoadj. CTx + RT)	253 (neoadj. CTx and RT + adj. CTx)
Sakamoto 2007 (JFMTC 15-1)	447	229	218 (adj. CTx)	5.2	NS
Quasar[12] 2007	948	474	474 (adj. CTx)	7.0	S
Koda 2009	54	29	25 (adj. CTx)	0.3	NS
Hamaguchi et al[14] 2011	274	135	139 (adj. CTx)	2.9	S
Total	94111	43681	50431	100.22	5S vs 16NS

¹Following the description of the studies at pages 6-9 as well as the tables from page 24 to 37 of the original meta-analysis we obtain this total number of included patients which is different from the 9785 reported in the meta-analysis. Consequently, also the total number of patients that receive surgery alone and surgery plus chemotherapy is different;

²The sum of the assigned weight should be 100%. n_tot: Number of patients with rectal cancer included in the study; n_c: Number of patients included in the control group (surgery only); n_i: Number of patients included in the intervention group (operation and adj. chemotherapy or other interventions); Outcome: Results of the study (S: Study result significant for better OS in the intervention group vs control group; NS: Not significant). CTx: Chemotherapy; RT: Radiotherapy.

Table 2 Summary of the three analyzed studies

	CCCSGJ[10] 1995	Krook et al[11] 1991	Quasar[12] 2007
Included patients	335 vs 323 vs 346 [3 trial arms for rectal carcinoma (IV, V, VI)]	104 vs 100	474 vs 474
Inclusion criteria	(1) Rectal carcinomas intraoperatively assessed as T3 or T4 and/or N1, N2, or N3 (before resection); (2) age ≤ 75 and no serious problems; (3) no cancer therapy in the past; (4) no other primary carcinomas; (5) satisfying laboratory tests at the beginning of treatment; and (6) consent to participation	(1) Potentially curative resection of histologically confirmed rectal adenocarcinoma; (2) T3 or T4; N1 or N2; (3) primary rectal carcinoma if extension of the carcinoma within 12 cm from of anal verge or inferior edge extended the sacral promontory; (4) anterior resection: entering in the study no later than 56 d postoperative; Abdominal perineal resection: 70 d; (5) met laboratory value requirements; (6) no prior radiation to the pelvis or CTx; and (7) no other malignancies within the last 5 years apart from superficial skin cancer and CIS of the cervix	(1) Presumably complete resection of colon or rectal cancer; no evident distant metastases; (2) no contraindications to CTx; (3) no prior CTx apart from one-week portal-vein infusion of fluorouracil after surgery; and (4) written consent before randomisation
Intervention group	(1) Trial arm IV: Intraoperative + postoperative mitomycin C iv; postoperative 5-FU po; and (2) Trial arm V: Postoperative mytomycin C iv + 5-FU po	Postoperative CTx with fluorouracil and semustine + radiation	CTx with fluorouracil and folinic acid after apparently curative (until October 1997 levamisole or placebo was added)
Control group	Trial arm VI: Surgery alone	Postoperative radiation alone	Surgery alone
Outcome (intervention vs Control): HR (95%CI)	HR (IV + V compared to VI) shown in the Cochrane meta-analysis: 0.66 [0.52-0.84]	HR shown in the Cochrane meta-analysis: 0.71 (0.55-0.92)	HR shown in the Cochrane meta-analysis: 0.77 (0.60-0.99)
Weight assigned in the Cochrane review (%)	7.6	6.8	7.0

5-FU: 5-fluorouracil; HR: Hazard Ratio; CI: Confidence interval; CIS: Carcinoma in situ; CTx: Chemotherapy.

Table 3 Assessment of validity of the analyzed studies according to the CONSORT checklist

Section/topic	Item number	CCCSGJ[10] 1995	Krook et al[11] 1991	Quasar[12] 2007
Title and abstract	1a	Yes	No	Yes
	1b	No	Yes	Yes
Introduction
Background and objectives	2a	Yes	Yes	Yes
	2b	Yes	Yes	Yes
Methods
Trial design	3a	No	Yes	Yes
	3b	NA	NA	NA
Participants	4a	Yes	Yes	Yes
	4b	No	No	No
Interventions	5	Yes	Yes	Yes
Outcomes	6a	No	No	Yes
	6b	NA	NA	NA
Sample size	7a	No	No	Yes
	7b	NA	NA	No
Randomisation	8a	Yes	No	Yes
	8b	No	No	Yes
	9	No	No	Yes
	10	No	No	Yes
Blinding	11a	NA	NA	NA
	11b	No	No	No
Statistical methods	12a	Yes	Yes	Yes
	12b	No	Yes	Yes
Results
Participant flow	13a	Yes	No	Yes
	13b	Yes	Yes	Yes
Recruitment	14a	Yes	Yes	Yes
	14b	NA	NA	NA
Baseline data	15	Yes	Yes	Yes
Numbers analysed	16	Yes	Yes	Yes
Outcomes and estimaton	17a	No	Yes	Yes
	17b	No	No	Yes
Ancillary analysis	18	Yes	Yes	Yes
Harms	19	Yes	Yes	Yes
Discussion
Limitations	20	Yes	Yes	No
Generalisability	21	No	No	No
Interpretation	22	Yes	Yes	Yes
Other information
Registration	23	No	No	Yes
Protocol	24	No	No	No
Funding	25	No	No	Yes

NA: Not applicable.