Question

What is the effect of neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy compared to TME surgery only without neoadjuvant therapy in patients with a resectable cT1-3N0-1 rectal carcinoma in the area of morbidity, local follow-up, survival and quality of life?

Recommendation

All patients with a rectal carcinoma should be discussed prior to surgery in a multidisciplinary oncological consultation.

 

For low-risk resectable rectal carcinoma (cT1-3N0, extramural invasion to ≤5 mm, distance to MRF >1 mm), surgery according to the TME principle without neoadjuvant radiotherapy should be considered the standard.

 

For high risk and locally advanced rectal carcinoma (cT3 with a distance to the MRF ≤1 mm or cT4, and/or high chance of 4 or more positive lymph nodes within the mesorectum or positive lymph nodes outside the mesorectum on the basis of MRI), neoadjuvant chemoradiotherapy followed by surgery should be considered the standard.

As chemoradiotherapy, a radiotherapy schedule with a dose of 45-50 Gy (in fractions of 1.8-2 Gy) with oral chemotherapy (capecitabine 825-1.000 mg/m2 twice per day for a duration of 5-7 days per week throughout radiotherapy) should be considered.

 

For intermediate risk resectable rectal carcinoma (cT1-3N1 or cT3N0 with extramural invasion >5 mm, distance to the MRF >1 mm), short-lasting preoperative irradiation (25 Gy in fractions of 5 Gy) prior to TME surgery should be considered.

 

Given the uncertainty of the clinical N-stage, it is recommended to discuss the benefits and disadvantages of neoadjuvant radiotherapy expressly with the patient.

 

Possible postoperative (chemo)radiotherapy after TME surgery without pre-treatment should not be considered.

 

As alternative for chemoradiotherapy at, for example, a high age, or with comorbidity, a short schedule (25 Gy in fractions of 5 Gy) may be considered, with delayed surgery (interval of at least 8 weeks).

 

On the basis of the available data, no clear recommendation can be given in relation to the time interval between the end of chemoradiotherapy and surgery. The usual interval is 8-12 weeks.

 

The distance to the MRF of the primary rectal carcinoma is the leading factor in ascertaining the indication for neoadjuvant therapy and not the distance of a possible pathological node to the MRF.

 

Table 1 Schematic display of the indication for neoadjuvant treatment

Tumour stage (MRI staged)

Neoadjuvant   treatment

cT1-2N0 or cT3N0 ≤5 mm extramural invasion;

distance to the MRF >1 mm

None

cT1-3N1 or cT3N0 >5 mm extramural invasion; distance to the MRF >1 mm

5x5 Gy pre-operative radiotherapy

cT4 of cT3 with distance to the MRF ≤1 mm

and/or

cN2 / extramesorectal pathological nodes (each N)

Chemoradiotherapy

Conclusions

Neoadjuvant radiotherapy

For patients with an operable rectal carcinoma, not staged with MRI:

  • there is evidence of high quality that neoadjuvant radiotherapy (5 x 5 Gy) + TME results in the same survival as TME only, with possible adjuvant radiotherapy, to 10 years after treatment
  • there is evidence of low quality that neoadjuvant radiotherapy (5 x 5 Gy) + TME results in the same survival in patients with tumour stage I, II and III as TME only, with possible adjuvant radiotherapy, to 10 years after treatment
  • there is evidence of moderate quality that neoadjuvant radiotherapy (5 x 5 Gy) + TME results in 5% less local recurrences than TME only, with possible adjuvant radiotherapy, to 5 years after treatment
  • there is evidence of very low quality that neoadjuvant radiotherapy (5 x 5 Gy) + TME in:
    • patients with a stage I tumour results in 0.9 to 1.3% less recurrences
    • patients with a stage II tumour results in 1.9 to 4.5% less recurrences
    • and patients with a stage III tumour results in 8 to 10% less recurrences
  • three to five years after treatment, than TME only with possible adjuvant radiotherapy
  • there is evidence of moderate quality that there is no difference in quality of life between neoadjuvant radiotherapy (5 x 5 Gy) + TME or TME only, with possible adjuvant radiotherapy Neoadjuvant patients are more often incontinent for faeces but this does not influence general quality of life
  • there is evidence of moderate quality that sexual functioning for neoadjuvant patients (5 x 5 Gy + TME) is poorer than for patients who only undergo TME (with possible adjuvant radiotherapy)

 

General quality of evidence= moderate

 

Neoadjuvant chemoradiotherapy

For patients with a resectable rectal carcinoma:

  • there is evidence of moderate quality that survival after neoadjuvant chemoradiation is the same as survival after adjuvant chemoradiation
  • there is evidence of low quality that 5% less local recurrences occur after neoadjuvant chemoradiation compared to adjuvant chemoradiation

 

General quality of evidence= low

 

Literature summary

Neoadjuvant radiotherapy

Two randomised, controlled studies described the effect of neoadjuvant radiotherapy with 5 x 5 Gy compared to only total mesenteric excision (TME) surgery in patients with a resectable rectal carcinoma: the Dutch TME study and the Medical Research Council (MRC) 07 trial. The Dutch TME study (N=1805) was described in seven relevant articles (Kapiteijn 2001, Marijnen 2002, Marijnen 2005, Peeters 2006, Peeters 2007, Lange 2008 and van Gijn 2011). The MRC 07 trial (N=1350) was described in two relevant articles (Sebag-Montefiore 2009 and Stephens 2010). In this trial, 92% of patients underwent a TME and patients who did not have a tumour-free resection margin received postoperative chemoradiotherapy. Staging with MRI did not take place in either trial.

 

Quality of the evidence

The quality of the evidence concerning survival was high, and concerning disease-free survival was moderate. The value was lowered because patients and outcome assessors were not blinded, in which it was assumed that this would not present a risk of bias for the outcome survival, but would present a risk of bias for other outcomes. As a result, the quality of the outcomes local and distal recurrence, and quality of life were assessed to be moderate. The quality of the outcome recurrence (local and/or distal) was assessed to be low because the value was also lowered due to inaccuracy. The quality of the subgroup analyses started low, because patients were not randomised per tumour stage. In addition, the value was lowered for the subgroup analysis of local recurrence per tumour stage because of a high risk of bias.

 

Desired effects

Effect on survival and disease-free survival (crucial outcome measure)

There was no difference in survival between the treatment groups in both trials. The hazard ratios (HR) for survival were 1.02 (95%CI: 0.83-1.25) after two years (Kapiteijn 2001) and 0.91 after five years (95%CI: 0.73-1.13) (Sebag-Montefiore 2009). The disease-free survival was 7% higher in patients who received neoadjuvant radiotherapy (73.6% versus 66.7%; HR: 0.76, 95%CI: 0.62-0.94) (Sebag-Montefiore 2009). Subgroup analyses did not show a difference in the 10-year survival for patients with stage I (65 versus 72%, p=0.32), stage II (50 versus 55%, p=0.24) or stage III (39 versus 37%, p=0.53) (van Gijn 2011). However, patients with a stage III tumour and a negative resection margin after neoadjuvant radiotherapy did have a better 10-year survival (HR: 0.76; 95%CI: 0.59-0.98). In patients with a stage I or II tumour and a negative resection margin, no difference was seen in the 10-year survival (HR: 1.17; 95%CI: 0.86-1.59 respectively 1.19; 95%CI: 0.91-1.56).

 

Effect on local follow-up (crucial outcome measure)

After five years, there were approximately 5% less local recurrences in the neoadjuvant groups of both trials: 5.6 versus 10.9% (p<0.01); HR: 0.47; 95%CI: 0.33-0.68 (Peeters 2007); respectively 4.7 versus 11.5%; HR 0.39; 95%CI: 0.27-0.58 (Sebag-Montefiore 2009). Subgroup analyses in both trials, in which the effect per TNM stage was evaluated, showed the smallest absolute difference for patients with stage I and the greatest absolute difference for patients with stage III, in which these differences were not always statistically significant.

 

Table 1 Subgroup analyses from the Dutch TME study and the Medical Research Council 07 trial on the difference in local recurrences per TNM stage

 

Risk of local recurrence after 3 years (HR and 95%CI)

(Sebag-Montefiore   2009)

Risk of local recurrence after 5 years (HR and 95%CI)

(Peeters 2007)

Risk of local recurrence after 10 years (HR and 95%CI) (van Gijn 2011)

TNM I

1.9  vs.   2.8% (0.68 (0.16–2,81))

0.4 vs. 1.7 (p=0.09) (na)

<1% vs. 3%   (p=0.03)   (na)

TNM II

1.9  vs. 6.4% (0.29 (0.12–0.67))

5.3 vs. 7.2 (p=0.33) (na)

5% vs. 8%   (p=0.21) (na)

TNM III

7.4    vs.15.4% (0.46 (0.28–0.76))

10.6 vs. 20.6 (p<0.001) (na)

9% vs. 19% (p<0.0001) (na)

Abbreviations: CI: confidence interval; HR: hazard ratio; na: not available

 

Quality of life (crucial outcome measure)

In both trials, there was no difference in the general quality of life, nor in the subscales (activity, physical symptoms, defaecation, psychological suffering, emptying the bladder) of the quality of life questionnaires to two years after randomisation, except on the activity subscale on which neoadjuvant patients scored worse three months after randomisation. While there is therefore no difference between treatment groups on the defaecation subscale, neoadjuvant patients from both trials scored poorer on the items ‘incontinent for faeces’, also from this subscale. On both trials, men from the neoadjuvant group scored poorer for questionnaires on sexual function (Marijnen 2005; Stephens 2010). Men from the neoadjuvant groups scored poorer for both the questionnaires on ejaculation as for questions on an erection. In the Dutch TME trial, women also scored poorer for the questionnaire on sexual functioning. This outcome was not reported because in the MRC07 trial only a fifth of the women completed the questionnaires on sexual functioning.

 

Undesirable effects

In the Dutch TME trial, postoperative death was the same for both groups 3.5 versus 2.6%, p=0.38). There were 7% more postoperative complications in the neoadjuvant group (48% versus 41%; p=0.008), largely attributed to the difference in perineal wound healing. In the MRC07 trial, a difference was also not seen in postoperative death (2 versus 2%).

 

Neoadjuvant chemoradiotherapy

Three randomised, controlled studies evaluated neoadjuvant chemotherapy versus adjuvant chemotherapy, in patients with resectable rectal carcinoma. The first trial from Germany included 823 patients and randomised them between neoadjuvant treatment (5040 cGy, fractionated to 180 cGy/day + fluorouracil during the 1st and 5th week + four five daily cycles of fluorouracil postoperative (TME)) or the same regimen postoperative, including a 540 cGy boost (Sauer 2004; Sauer 2012). The second trial, from Korea, included 22 patients and randomised between neoadjuvant or adjuvant chemoradiotherapy + TME, consisting of 50 Gy in 25 fractions + concomitant capecitabine (Park 2011). The third, a Turkish trial, included 51 patients and randomised between neoadjuvant chemoradiation (4500-5040 cGy in 25-28 fractions + 5-fluorouracil + leucovorin) or adjuvant chemoradiation (5040 cGy in 30 fractions + 540 cGy boost + 5-fluorouracil + leucovorin) + TME (Kaçar 2008). None of the trials staged patients using MRI.

 

Quality of the evidence

The quality of evidence for survival was moderate. The value was lowered because patients in the neoadjuvant group received the full radiotherapy (92% versus 54%), and chemotherapy (89% versus 50%), and in addition received no chemoradiation less often (<1 % versus 10%) (Sauer 2004) or more often completed their chemoradiation according to protocol (93% versus 74) (Park 2011). For local recurrence, the value was also lowered because this outcome was not determined in a blinded manner, so that the resulting quality of evidence was moderate.

 

Desired effects

Effect on survival (crucial outcome measure)

There was no difference between treatment group in survival after four to five years (HR: 1.04; 95%BI: 0.76-1.43).

 

Effect on local follow-up (crucial outcome measure)

There were 5% less local recurrences in the neoadjuvant patients (meta-analysis of three trials -5% (95%BI: -8 to -2%; I2: 10.5).

 

Quality of life (crucial outcome measure)

None of the trials reported on quality of life.

 

Undesirable effects

There was no difference in relation to postoperative death (0.7 versus 1.3%, p=0.41) in the number of postoperative complications (36 versus 34%) in the German trial (Sauer 2004). In the Korean trial, no treatment-related death was seen (Park 2011). In the German trial, there were less grade 3 and 4 acute toxic effects (27 versus 40%; p=0.001) in the neoadjuvant treatment group and less toxic side effects in the long term (14 versus 24%; p=0.01) (Sauer 2004). In the Korean trial, there was no difference between treatment groups in relation to toxic side effects (Park 2011).

Considerations

A cost-utility analysis has been performed, this might be of benefit to the guideline development group: van den Brink M, van den Hout WB, Stiggelbout AM, Kranenbarg EK, Marijnen CAM, van de Velde CJH, Kievit J. Cost- utility analysis of preoperative radiotherapy in patients with rectal cancer undergoing total mesorectal excision: a study of the Dutch colorectal cancer group. Journal of Clinical Oncology 2004;22(2):244–253.

Authorization date and validity

Last review : 16-04-2014

Last authorization : 16-04-2014

The validity of this guideline and its associated modules is five years. For various reasons, it may be necessary to edit modules sooner than intended. The National Working Group on Gastrointestinal Cancers therefore annually assesses the content of the guideline and its associated modules. By 2016 it is decided whether a new multidisciplinary working group should be installed to revise the entire guideline.

Initiative and authorization

Initiative : Nederlandse Vereniging voor Radiotherapie en Oncologie

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Maag-Darm-Leverartsen
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Klinische Geriatrie
  • Nederlandse Vereniging voor Nucleaire geneeskunde
  • Nederlandse Vereniging voor Pathologie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie
  • Vereniging Klinische Genetica Nederland

General details

All members were mandated by a scientific, professional or patient association. In the composition of the working group we tried to take national distribution, input from participants from both academic and general hospitals and representatives of various disciplines into account. Patients are also represented by delegation into the working group, as well as a focus group meeting.

Scope and target group

Goal

This guideline and its associated modules are - as much as possible - based on scientific research and / or consensus. It is a document with recommendations to support the daily practice of health care professionals involved in patients with (possible) colon cancer, rectal cancer or colorectal liver or lung metastases. It provides recommendations for diagnosis, treatment, follow-up and organization of care. The guideline and its associated modules are thus seeking to improve the quality of care, to increase transparency of choice for treatment and reduce diversity.

 

Target population

Each year colorectal cancer is identified in approximately 13,000 new patients. Rectal carcinoma occurs in about 1 in 3 patients of this. In the Netherlands, the colorectal cancer in both men and women rank third place in incidence of oncological diseases. The expected number of patients diagnosed with colorectal cancer are increased in 2020 to about 17,000, reflecting a slight increase in incidence (especially in men), population growth and aging.

Colorectal cancer is slightly more common in men than in women and ninety percent of patients 55 years or older. More information about the Dutch population can be found at the Netherlands Cancer Registry: www.cijfersoverkanker.nl

This guideline is applicable to all adult patients with (suspected) a primary colorectal carcinoma and patients with metastatic disease. Particular attention is given to the elderly. A separate guideline is available for adult patients with an increased risk of hereditary colon cancer.

Target Audience

This guideline and its associated modules are intended for all professionals involved in the diagnosis, treatment and rehabilitation of patients with (metastatic) colorectal cancer, such as surgeons, general practitioners, consultants, internists, gastroenterologists, (specialist) nurses, clinical geneticists, paramedics, pathologists, radiologists and radiotherapists. The complete guideline is used to develop a patient education text from the Dutch patients Consumer Federation (NPCF).

 

Members of the guideline panel

Name

Function

Hospital

Mandated

Mw. prof. dr. C.A.M. Marijnen chair

Radiotherapist

LUMC Leiden

NVRO

Mw. prof. dr. R.G.H. Beets-Tan

Radiologist

MUMC Maastricht

NVVR

Mw. S. de Bruijn

Specialist nurse

Renier de Graaf hospital Delft

V&VN

Mw. dr. A. Cats

Gastroenterologist

NKI-AVL Amsterdam

NVMDL

Prof. dr. E.F.I. Comans

Nuclear doctor

VUMC Amsterdam

NVNG

Dr. A.R. van Erkel

Intervention radiologist

LUMC Leiden

NVVR

Mw. dr. M.A.M. Frasa

Clinical chemist

Groene Hart hospitalGouda

NVKC

Mw. C. Gielen

Specialist nurse

MUMC Maastricht

V&VN

Dr. E.J.R. de Graaf

Surgeon

IJsselland hospital Capelle a/d IJssel

NVVH

Mw. dr. M. Hamaker

Geriatrician

Diakonessenhuis Utrecht

NVKG

Mw. dr. J.E. van Hooft

Gastroenterologist

AMC Amsterdam

NVMDL

Mw. H.J.A.M.. Kunneman

Researcher

LUMC Leiden

n.v.t.

Mw. dr. M.E. van Leerdam

Gastroenterologist

NKI-AVL Amsterdam

NVMDL

Dr. H. Martijn

Radiotherapist

Catharina-hospital Eindhoven

NVRO

Mw. dr. A.M. Mendez

Romero

Radiotherapist

EMC Cancer Insititute Rotterdam

NVRO

Mw. prof. dr. I.D. Nagtegaal

Pathologist

UMCN St Radboud Nijmegen

NVVP

Dr. L.A. Noorduyn

Pathologist

Lab. Voor Pathologie Dordrecht e.o.

NVVP

Mw. A. Ormeling

Patient

Stomavereniging

NFK

Drs. T.A.M. van Os

Klinisch Geneticus

AMC Amsterdam

VKGN

Dr. F.T.M. Peters

Gastroenterologist

UMCG Groningen

NVMDL

Mw. J. Pon

Patient

NFK/SPKS

NFK

Mw. dr. J.E.A. Portielje

Medical oncologist

Haga hospital Den Haag

Gerionne

Prof. dr. C.J.A. Punt

Medical oncologist

AMC Amsterdam

NIV

Mw. dr. H. Rütten

Radiotherapist

UMCN Radboud Nijmegen

NVRO

Prof. dr. H.J.T. Rutten

Surgeon

Catharina-hospitalEindhoven

NVVH

Prof. dr. J. Stoker

Radiologist

AMC Amsterdam

NVVR

Dr. P.J. Tanis

Surgeon

AMC Amsterdam

NVVH

Dr. J.H. von der Thüsen

Pathologist

MC Haaglanden Den Haag

NVVP

Prof. dr. H.M.W. Verheul

Medical oncologist

VUMC Amsterdam

NIV

Prof. dr. C. Verhoef

Surgeon

EMC Cancer Insititute Rotterdam

NVVH

Dr. Tj. Wiersma

General practitioner

NHG

NHG

 

 

Name

Function

Location

Mw. drs. A.Y. Steutel

process manager

Utrecht

Drs. T. van Vegchel

process manager

Amsterdam

Mw. S. Janssen-van Dijk

secretary

Rotterdam

M.P.  van den Berg

Researcher

Bilthoven

P.F. van Gils

Researcher

Bilthoven

Mw. J. Robays

Methodologist

Brussels

Mw. drs. Y Smit

Methodologist

Germany

Mw. A. Suijkerbuijk

Researcher

Bilthoven

Mw. dr. L. Veerbeek

Methodologist

Groningen

Mw. dr. L. Verheye

Methodologist

Brussels

Mw. dr. G.A. de Wit

Researcher

Bilthoven

 

Patient involvement

Two patient experts have been part of the guideline development group. One on behalf of the Dutch Ostomy Association and on behalf of SPKS/NFK. Based on a focus group meeting experiences of patients regarding care were collected. The guideline also has been used to develop a patient education text for the Dutch patients Consumer Federation (NPCF).

Method of development

Evidence based

Implementation

Promoting the use of recommendations begins with a broad (digital) distribution of the guideline, using direct mailing and an article published in the Dutch Journal of Oncology. In other journals or training sessions, for example, the guideline is brought to the attention. An implementation plan for this guideline contains the key recommendations and an overview of barriers and facilitators for implementation.

Methods and proces

The working group met in July 2012 for the first time. Based on an initial list of problems by working group members a survey among professionals involved in patients with colorectal carcinoma was held. Through this survey, sixty professionals supplied and prioritized possible subjects for revision. Also, a focus group meeting was held, collection patients' experiences. The eleven most relevant questions were answered, and translated into English. Also, alle recommendations were translated into English.

 

Each clinical question was andwered by a subgroup within the development group. External methodologists provided the literature search, review, critical assessment, evidence tables and a draft literature review. Workgroup members suggested other considerations and recommendations.

Responsibility

The Comprehensive Cancer Organisation the Netherlands (IKNL) promotes that people with cancer and their families have access to a consistent and qualitatively adequate care as close to home as possible. IKNL was established to improve treatment, care and clinical research in oncology. It also has a role in setting up and supporting networks for palliative care. IKNL supports multidisciplinary guideline development for oncology and palliative care and facilitates the maintenance, management, implementation and evaluation of these guidelines.

AGREE was used to check the methodological quality of the guideline.

Search strategy

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