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. 2018 Oct 3;2018(10):CD002102. doi: 10.1002/14651858.CD002102.pub3

van Gijn 2011.

Methods Randomisation method: computer generated and based on permuted blocks of 6 with stratification according to centre and the expected type of surgery. Enrolment period: January 1996 to December 1999
Abdominal imaging: none
Chest imaging: not stated
2‐arm study: arm 1 preoperative radiotherapy  +  TME  (897 allocated to treatment) and arm 2 TME alone (908 allocated to treatment) (ratio 1:1)
Total randomised 1861 with 56 excluded (allocated to treatment: 1805).

  • 0 excluded from survival analysis;

  • 24/897 in RT+S 33/908 in S alone excluded from local recurrence analysis because of macroscopically incomplete resection

  • 206/897 in RT+S 217/908 in S alone excluded from analysis CRM negative because of a positive CRM or signs of distant metastases, or both.
Participants Adenocarcinoma of the rectum without evidence of distant disease
Location: below the level of S1/S2 with an inferior tumour margin located 15 cm or less from the anal verge
Resectability: clinically defined
No upper age limit was given.
64% male and 36% female
TNM stage:

  • 0: RT + TME: 11 (1%); TME alone: 17 (2%)

  • I: RT + TME: 264 (29%); TME alone: 243 (27%)

  • II: RT + TME: 251 (28%); TME alone: 245 (27%)

  • III: RT + TME: 299 (33%); TME alone: 325 (26%)

  • IV: RT + TME: 62 (7%); TME alone: 61 (7%)

  • Unknown: RT + TME: 10 (1%); TME alone: 17 (2%)
Interventions Surgery: AP/anterior resection/HP with TME technique
RT : 25.00 Gy in 5 fr
BED: 38.7 Gy10
RT volume: primary tumour, mesentery with vascular supply, perirectal, presacral, internal iliac nodes up to S1‐2
RT‐S: within 10 days
Multiple fields
Co‐intervention: postoperative radiotherapy was used for participants who had positive margins (< 1 mm) and did not receive preoperative XRT.
Outcomes

  • Primary endpoint: local control

  • Perioperative mortality: S 28/695, RTS 24/719

  • Mets @ lap: S 61/695, RTS 61/719

  • Curative resection: S 827/937, RTS 826/924

  • Overall resection: not available

  • Compliance to radiotherapy: not available

  • Overall survival: yes

  • Cause‐specific survival: no

  • Tox post RT: not given

  • Acute tox post S (reported in detail for Dutch subgroup 1530/1861 participants)

    1. No complication S 428/718, RTS 359/695

    2. Infectious complications:

      1. Wound infection S 45, RTS 43

      2. Abscess S 20, RTS 31

      3. Haematoma S 2, RTS 7

      4. Sepsis S 40, RTS 63

      5. Other S 2, RTS 2

    3. General complications:

      1. Cardiac S 22, RTS 36

      2. Multiorgan failure S 10, RTS 11

      3. Pulmonary S 57, RTS 53

      4. Thromboembolic S 12, RTS 11

      5. Line sepsis S 9, RTS 9

      6. Neurological S 12, RTS 10

      7. Psychological S 10, RTS 28

      8. Renal S 6, RTS 4

      9. Other S 23, RTS 25

    4. Surgical complications:

      1. Perforation S 7, RTS 8

      2. Intestinal necrosis S 7, RTS 6

      3. Fistula S 14, RTS 8

      4. Bleeding S 29, RTS 23

      5. Abdominal dehiscence S 25, RTS 16

      6. Diarrheoa S 2, RTS 11

      7. Ileus S 48, RTS 37

      8. Other S 10, RTS 22

  • Late tox post S: not given

  • Local recurrence: yes 12

  • Quality of life: no
Notes Overall recurrence analyses were done on the basis of the number of eligible participants who had a macroscopically complete local resection without distant metastases at the time of surgery. As specified in the trial protocol, secondary analyses were done on participants with a negative circumferential resection margin (> 1 mm) and no signs of distant tumour spread.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomsation was computer generated. Quote: "Randomisation was computer‐generated and based on permuted blocks of six with stratification according to centre and the expected type of surgery. Randomisation was managed centrally at the data centre of the Department of Surgery of Leiden University Medical Centre, Netherlands. For every stratification group and participating centre, a list was printed by the Department of Medical Statistics. Patients were assigned to a treatment by these lists, which were only available in the central data centre. Local investigators enrolling patients had no knowledge of the next assignment in the sequence."
Allocation concealment (selection bias) Low risk The allocation was adequate and clearly reported. Quote: "Randomisation was computer‐generated and based on permuted blocks of six with stratification according to centre and the expected type of surgery. Randomisation was managed centrally at the data centre of the Department of Surgery of Leiden University Medical Centre, Netherlands. For every stratification group and participating centre, a list was printed by the Department of Medical Statistics. Patients were assigned to a treatment by these lists, which were only available in the central data centre. Local investigators enrolling patients had no knowledge of the next assignment in the sequence."
Blinding of participants and personnel (performance bias) 
 All outcomes High risk Blinding is not possible with the type of intervention.
Blinding the outcome assessor (detection bias; objective outcomes) Outcomes: mortality; local recurrence; distant metastases; curative resection 
 Outcomes: mortality; local recurrence; distant metastases; any recurrence; curative resection Unclear risk Mortality: no information was provided on the blinding of the outcome evaluator.
Recurrence: it was unclear whether the outcome evaluator was blinded. Quote: "Investigators reviewing primary endpoints [i.e. local recurrence] were not aware of the allocated treatment and those analysing data were unmasked"
Metastases: no information was provided on the blinding of the outcome evaluator. Quote: "Distant recurrence analyses were done on all eligible patients who did not have distant metastases at the time of surgery."
Curative resection: no clear information was provided. Quote: "Local recurrence analyses were done on all eligible patients who underwent a macroscopically complete local resection"
Since the outcomes were objective, we considered the study to be at low risk of detection bias for the listed outcomes.
Blinding the outcome assessor (detection bias): subjective outcomes: Postoperative morbidity; sphincter preservation; acute and late toxicities; quality of life 
 Outcomes: Postoperative morbidity; sphyncter preservation Unclear risk No information about the blinding of the outcome assessor regarding postoperative morbidity was provided.
Incomplete outcome data (attrition bias) 
 All outcomes Low risk Local recurrence: due to macroscopically incomplete resection, 24 (2.7%) in the preoperative radiotherapy group and 33 (3.6%) in the surgery‐alone group were excluded from local recurrence analysis. We concluded that the proportion of exclusions was not relevant to introduce bias in the results.
Survival analysis: no exclusions, missing data, or loss to follow‐up. All participants were included in analysis.
Selective reporting (reporting bias) Low risk Clinically relevant outcomes were considered.

AP: abdominal perineal; BED: biological equivalent dose; CRM: circumferential resection margin; CT: computed tomography; CXR: chest X‐ray; fr: fraction; FU: follow‐up; IQR: interquartile range; Mets @ lap: metastatic identified at the time of laparotomy; HP: Hartmann procedure; RT: radiotherapy; RTS: radiotherapy + surgery; RT‐S: time between radiotherapy and surgery; S: surgery; TME: total mesorectal excision; Tox post RT: toxicity postradiotherapy; WHO PS: World Health Organization Performance Status; XRT: Chermoradiation therapy