88Radiotherapy dose fractionation Third edition
Background
Rectal cancer is less common than colon cancer but presents dicult treatment decisions
because, while it is frequently curable, treatment may involve radical surgery including the
need for a colostomy, which can have a profound eect on a survivor’s quality of life.
Equally, recurrent rectal cancers produce distressing symptoms and are dicult to treat
and frequently require re-irradiation for symptom control, exenterative surgery or both.
The aim of radiotherapy in rectal cancers is to allow radical treatment to take place for more
advanced cancers or to reduce the risk of relapse for early stage cancers (neoadjuvant
therapy). In recurrent or incurable disease, radiotherapy can reduce the disease burden and
help control symptoms.
Neoadjuvant therapy
Operable tumours
Preoperative radiotherapy is preferred to postoperative treatment as the preoperative
technique is more eective and less toxic (Level 1a).
1–3
For operable rectal cancers, as dened by preoperative pelvic magnetic resonance (MR)
scan and staging chest, and abdomen and pelvis computed tomography (CT) scans,
preoperative short-course rectal radiotherapy (SCRT) has been evaluated in several
prospective randomised controlled trials (RCTs). The Dutch total mesorectal excision (TME)
versus SCRT (25 Gray [Gy] in ve fractions) + TME trial demonstrated a reduction in local
recurrence rate, though with a longer median follow-up of 6.1 years the benet appears
to decrease (10.9% versus 5.6%; 49% relative reduction in risk).
4,5
The overall survival was
same in both groups (Level 1b).
3
The MRC-07 trial demonstrated the advantage of SCRT
(25 Gy in ve fractions) for operable rectal cancer over selective postoperative (chemo-)
radiation, in terms of reducing the relative risk of local recurrence after a median follow-up
of four years by 61% (HR 0.39, CI 0.27
–0.58). This translates to an absolute reduction in risk
of local relapse of 6.2% at three years. There is also an absolute improvement in disease
free survival of 6% at three years with no eect on overall survival (Level 1b).
3,6
SCRT, however, increases long-term toxicity, with poorer functional outcomes especially in
terms of continence (Level 1b).
3,7
The benet seems to be mainly for cancers in the mid-
rectum and ‘intermediate-risk’ cancers as dened in the National Institute of Health and
Care Excellence (NICE) guidance (Level 1b).
3,8
Recommendation
Short course preoperative radiotherapy:
25 Gy in 5 daily fractions (Grade A)
Followed by denitive surgery within a week
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
12.
Rectal cancer
89Radiotherapy dose fractionation Third edition
Inoperable tumours
For inoperable cancers, cancers which involve or threaten the circumferential margin
or for cancers deemed to be at high risk of relapse (NICE guidance), down-staging
treatment is recommended.
8
If not otherwise contraindicated, concurrent chemotherapy is
recommended to improve response rates.
Doses of >30 Gy improve the response rate and long-course chemo-radiotherapy (LCCRT)
has been shown to improve response rate and the likelihood of a R0 resection compared to
long-course radiotherapy alone (Level 1a), though the sphincter preservation rate and long-
term outcomes appear to be similar.
1,3,9,10
A dose of 45–50.4 Gy in 1.8 Gy per fraction with
concurrent chemotherapy is commonly used in the UK, though there is little good quality
RCT research underpinning this.
Fluorouracil (5-FU)-based chemotherapy has been used in all major trials since the 1980s
and more recently, capecitabine has been shown to have similar ecacy in several phase
2 studies (Level 2b); it has replaced infusional 5-FU as the drug of choice for LCCRT to
the rectum.
3,11,12
The UK ARISTOTLE trial (EUDRACT No. 2008-005782-59) is currently
investigating the eect of the addition of intravenous (IV) irinotecan to capecitabine on local
control rates in advanced rectal cancers.
13
Some authors have reported a ‘boost’ of 5.4 Gy in
three fractions to the gross tumour volume plus margin following 45 Gy in 25 fractions to a
larger volume.
12
The ecacy and toxicity of this remains unknown (Level 2b).
3
Retrospective series from Sweden and the UK, looking at patients with locally advanced
unresectable rectal cancer who are unt for standard LCCRT, treated with 25 Gy in ve
fractions, have reported signicant tumour regression, with 60–80% of patients going on to
have delayed surgery (Level 2c).
3,14,15
Recommendations
For downstaging LCCRT:
45 Gy in 25 daily fractions with concurrent chemotherapy (Grade A)
Optional boost of 5.4 Gy in 3 (Grade C) fractions to smaller volume
50.4 Gy in 28 daily fractions with concurrent chemotherapy (Grade A)
For patients not t for chemotherapy:
45 Gy in 25 daily fractions (Grade A) with or without boost
50.4 Gy in 28 daily fractions (Grade A)
For elderly patients or those with signicant co-morbidities:
25 Gy in 5 daily fractions (Grade B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
90Radiotherapy dose fractionation Third edition
Brachytherapy
Low-energy contact brachytherapy (Papillion technique) and high-dose rate (HDR)
brachytherapy have both been used, generally in combination with external beam
radiotherapy (EBRT), for the treatment of rectal cancers. The aim of treatment has been
either palliative or as part of neoadjuvant treatment to improve response. In patients unt for
surgery, these techniques can be used to improve local control.
Apart from one RCT (Level 1b), most of the evidence for the Papillion technique comes
from case series and retrospective analyses.
3,16
Similarly, there is only one published RCT
evaluating a neoadjuvant 10 Gy in two fractions HDR brachytherapy boost (endoluminal)
along with 50.4 Gy in 28 fractions of EBRT (Level 1b).
3,17
This trial showed no improvement
in pathological complete response (pCR) or long-term survival despite a better R0
resection rate for T3 tumours treated with HDR brachytherapy boost along with standard
chemoradiotherapy.
17
There is increasing experience in the UK and worldwide of the use
of the Papillon technique, usually in combination with EBRT, for the radical treatment of
patients not suitable for surgery or those who refuse a stoma.
18–22
It is also used for the
palliative treatment of patients with a recurrence or metastases not suitable for surgery.
Contact radiotherapy is also oered to patients with a resected pT1 malignant polyp in
combination with EBRT, though there is no randomised trial evidence comparing this
approach with radical surgery. It may be most appropriate for elderly, frail patients who
cannot undergo radical resection.
Dose recommendations are derived from published trials and current consensus among
UK centres oering brachytherapy.
Recommendations
Postoperative:
pT1 or pT2 with R1 resection if patient refuses further surgery
60 Gy in 2 weekly fractions followed by EBRT (Grade B)
Radical treatment (unt patients or those who refuse surgery):
cT1/cNo (≤3 centimetres [cm]) 110 Gy in 4 fractions over 6 weeks (30 Gy every 2 weeks
x 3 and nal boost 20 Gy) (Grade D)
cT1/cN1 or cT2 cNo/cN1 (≤3cm) low-energy contact brachytherapy should be
followed by EBRT (SCRT or external beam chemoradiotherapy (EBCRT)) (Grade D)
High-risk patients not t for surgery cT1, cT2, cT3a, (>3 cm)
45 Gy in 25 fractions or 50.4 Gy in 28 fractions over 5–5.5 weeks with concurrent
chemotherapy (Grade D)
or 25 Gy in 5 daily fractions in 1 week in patients not t for chemotherapy (Grade D)
followed by:
contact radiotherapy boost 90 Gy in 3 fractions over 4 weeks to responders (regression to
<3 cm) and consider nal boost 20 Gy (total 110 Gy in 4 fractions over 6 weeks) (Grade D)
HDR brachytherapy 12 Gy in 2 fractions (Grade D)
Consider salvage surgery if no response after (EBCRT)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
91Radiotherapy dose fractionation Third edition
Palliative treatment
There are no good-quality trials evaluating dierent dose fractionation schedules for
palliative treatment. An appropriate regime should be chosen after considering the patient’s
likely prognosis, disease burden, symptoms and performance status.
Recommendations
30 Gy in 10 daily fractions (Level D)
20–25 Gy in 5 daily fractions (Level D)
HDR brachytherapy 10 Gy at 1 cm single dose (Level D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Re-irradiation
Following previous SCRT or LCCRT, some patients will experience a local or regional
relapse. Such patients should be discussed in specialist multidisciplinary team meetings
(MDTMs) with the relevant expertise in treating recurrent rectal cancer.
Where possible, recurrences after neoadjuvant radiotherapy should be treated with surgery
or systemic therapy, avoiding further radiation. However, if surgery is not feasible with clear
margins or holds excess risks, re-irradiation should be considered for limited volumes,
including the use of stereotactic body radiotherapy (SABR) techniques. This may yield good
symptomatic relief as a palliative treatment and long-term control is possible.
When curative resection is to be considered but re-irradiation is required to achieve this,
currently, hyperfractionated chemoradiotherapy should be preferred to limit late toxic
(Grade D).
3
References
92Radiotherapy dose fractionation Third edition
1. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview
of 8,507 patients from randomised trials. Lancet 2001; 358(9290): 1291–1304.
2. Frykholm GJ, Glimelius B, Påhlman L. Preoperative or postoperative irradiation in adenocarcinoma of
the rectum: nal results of a randomised trial and an evaluation of late secondary eects. Dis Colon
Rectum 1993; 36(6): 564–572.
3. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009
(last accessed 30/9/16)
4. Kapiteijn E, Marijnen CA, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal
excision for resectable rectal cancer. N Engl J Med 2001; 345(9): 638–646.
5. Peeters KC, Marijnen CA, Nagtegaal ID et al. The TME trial after a median follow-up of 6 years:
increased local control but no survival benet in irradiated patients with resectable rectal carcinoma.
Ann Surg 2007; 246(5): 693–701.
6. Sebag-Monteore D, Stephens RJ, Steele R. Preoperative radiotherapy versus selective postoperative
chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre,
randomised trial. Lancet 2009; 373(9666): 811–820.
7. Peeters KC, van de Velde CJ, Leer JW et al. Late side eects of short-course preoperative radiotherapy
combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated
patients – a Dutch colorectal cancer group study. J Clin Oncol 2005; 23(25): 6199–6206.
8. National Institutue for Health and Care Excellence. Colorectal cancer: diagnosis and management.
Clinical guideline 131. London: National Institute for Health and Care Excellence, 2011.
9. Braendengen M, Tveit KM, Berglund A et al. Randomised phase II study comparing preoperative
radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 2008; 26(22):
3687–3694.
10. Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation versus radiation alone for
stage II and III resectable rectal cancer. Cochrane Database Syst Rev 2009; 1: CD006041.
11. De Bruin AF, Nuyttens JJ, Ferenschild FT, Planting AS, Verhoef C, de Wilt JH. Preoperative
chemoradiation with capecitabine in locally advanced rectal cancer. Neth J Med 2008; 66(2): 71–76.
12. De Paoli A, Chiara S, Luppi G et al. Capecitabine in combination with preoperative radiation therapy
in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 2006; 17(2):
246–251.
13. http://www.isrctn.com/ISRCTN09351447
14. Radu C, Berund A, Påhlman L, Glimelius B. Short-course preoperative radiotherapy with delayed
surgery in rectal cancer – a retrospective study. Radiother Oncol 2008; 87(3): 343–349.
15. Hateld P, Hingorani M, Radhakrishna G et al. Short-course radiotherapy, with elective delay prior to
surgery, in patients with unresectable rectal cancer who have poor performance status or signicant
co-morbidity. Radiother Oncol 2008; 92(2): 210–214.
16. Ortholan C, Romestaing P, Chapet O, Ferard JP. Correlation in rectal cancer between clinical tumor
response after neoadjuvant radiotherapy and sphincter or organ preservation: 10-year results of the
Lyon R 96-02 randomized trial. Int J Rad Oncol Biol Phys 2012; 83(2): e65–e71.
17. Appelt AL, Vogelius IR, Pløen J et al. Long-term results of a randomized trial in locally advanced rectal
cancer: no benet from adding a brachytherapy boost. Int J Rad Oncol Biol Phys 2014; 90(1): 110–118.
93Radiotherapy dose fractionation Third edition
18. Sischy B, Hinson EJ, Wilkinson DR. Denitive radiation therapy for selected cancers of the rectum. Br J
Surg 1988; 75(9): 901–903.
19. Gerard JP, Romestaing P, Chapet O. Radiotherapy alone in the curative treatment of rectal carcinoma.
Lancet Oncol 2003; 4(3): 158–166.
20. Sun Myint A, Grieve RJ, McDonald AC et al. Combined modality treatment of early rectal cancer: the
UK experience. Clin Oncol (R Coll Radiol) 2007; 19(9): 674–681.
21. Dhadda A, Cast J, Hunter I. Organ preservation using contact radiotherapy for early rectal cancer:
outcomes of patients treated at a single centre in the United Kingdom. Ann Oncol 2014; 25(suppl 2):
ii12.
22. National Institutue for Health and Care Excellence. Low energy contact X-ray brachytherapy (the
Papillon technique) for early stage rectal cancer. London: National Institute for Health and Care
Excellence, 2015.
