9Radiotherapy dose fractionation Third edition
1.
Anal cancer
Background
There are approximately 1,000–1,200 registrations of squamous carcinoma of the anus
per year in the UK. Despite its rarity, a succession of phase III trials have been conducted
which have established the standard treatment of this disease; radical treatment with
chemoradiotherapy allowing sphincter preservation.
Radical treatment
Both the United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) anal
cancer trial (45 Gray [Gy] in 20 or 25 fractions with a boost) and an European Organisation
for Research and Treatment of Cancer (EORTC) trial demonstrated improved outcome
for concomitant chemoradiotherapy using mitomycin C and 5-fluorouracil (5-FU) when
compared with radiotherapy alone.
1,2
A statistically significant reduction in locoregional
failure was demonstrated in both trials. A further phase III trial performed by the
Radiotherapy Oncology Group (RTOG) demonstrated improved colostomy-free survival
when mitomycin C was added to 5-FU chemoradiation.
3
Chemoradiotherapy improves
outcome in anal cancer compared to radiotherapy alone (Level 1b).
4
The UKCCCR ACT2 trial compared concomitant mitomycin C and 5-FU with cisplatin and
5-FU when combined with a two-phase radiotherapy technique delivering a total dose of
50.4 Gy in 28 fractions.
5
A second randomisation tested the role of two subsequent cycles
of cisplatin 5-FU chemotherapy against no further treatment. There was no signicant
dierence between concurrent chemotherapy regimens, and no progression-free survival
benet to the addition of adjuvant chemotherapy (Level 1b).
4
The EXTRA trial was a phase II study substituting capecitabine for 5-FU chemotherapy
that reported minimal toxicity and acceptable compliance.
6
Substitution of 5-FU with
capecitabine has been thoroughly investigated in other tumour sites and the two drugs
have been proven to be equally eective (Level 2b).
4
Treatment technique
The phase 2 RTOG 0529 trial treated patients with inverse planned intensity-modulated
radiotherapy (IMRT) and reported reduced toxicity to that seen in the RTOG 9811 trial where
standard conformal radiotherapy techniques were used (Level 2b).
4,7,8
It is recommended that a standard atlas for delineating volumes is used for IMRT or
arc radiotherapy. Expert opinion was sought from a number of UK clinicians to create a
consensus guideline which is based on ACT II volumes but adapted for inverse planning.
9,10
Recommendations
For standard planned two-phase radical chemoradiation for anal cancers:
50.4 Gy in 28 daily fractions (Grade A)
Phase 1: 30.6 Gy in 17 fractions over 3.5 weeks
Phase 2: 19.8 Gy in 11 fractions over 2.2 weeks
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.
4
10Radiotherapy dose fractionation Third edition
Node positive patients
Analyses of both the UKCCR ACT II and RTOG 9811 trial have highlighted that locally
advanced and node-positive tumours have a signicantly reduced disease-free survival and
overall survival.
5,8
As a result, current guidance and recent trials have used a higher dose for
these patients when using IMRT or arc radiotherapy.
However, due to the excellent outcomes in ACT II in node-negative cancers, the
recommended prophylactic nodal dose remains the same and has been calculated to
deliver the same biologically eective dose over 28 fractions with IMRT or arc radiotherapy
which was previously delivered over 17 fractions during standard 2-phase radiotherapy
(Level 5).
4,11
Recommendations
For radical inverse planned IMRT or arc radiotherapy (chemoradiotherapy) of
anal cancers
Dose to primary (early stage):
50.4 Gy in 28 fractions over 5.5 weeks (Grade D)
Dose to primary and involved nodes (advanced stage):
53.2 Gy in 28 fractions over 5.5 weeks (Grade D)
Dose to uninvolved nodes (prophylactic):
40 Gy in 28 fractions over 5.5 weeks (Grade 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.
4
The Personalising Anal Cancer Radiotherapy Dose (PLATO) trial looking at dose escalation
in locally advanced anal cancers and dose de-escalation in early small-node negative
tumours is currently in set up in the UK and will inform dose fractionation for anal cancers in
the future.
12
Palliative treatment
There are no good-quality trials evaluating dierent 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
For palliative treatment of anal cancer (Grade D):
30 Gy in 10 fractions over 2 weeks
20 Gy in 5 fractions over 2 weeks
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.
4
References
11Radiotherapy dose fractionation Third edition
1. The UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the UKCCCR
randomised trial of radiotherapy alone versus radiotherapy, 5-uorouracil and mitomycin. Lancet 1996;
348(9034): 1049–1054.
2. Bartelink H, Roelofsen F, Eschwege F et al. Concomitant radiotherapy and chemotherapy is superior to
radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized
trial of the European Organisation for Research and Treatment of Cancer Radiotherapy and
Gastrointestinal Cooperative Groups. J Clin Oncol 1997; 15(5): 2040–2049.
3. Flam M, John M, Pajak TF et al. Role of mitomycin in combination with fluorouracil and radiation, and
of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal
canal: results of a phase III randomised intergroup study. J Clin Oncol 1996; 14(9): 2527–2539.
4. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009
(last accessed 22/9/16)
5. James RD, Glynne-Jones R, Meadows HM et al. Mitomycin or cisplatin chemoradiation with or
without maintenance chemotherapy for treatment of squamous cell carcinoma of the anus (ACT II): a
randomised phase 3 open-label, 2x2 factorial trial. Lancet Oncolo 2013; 14(6): 516–524.
6. Glynne-Jones R, Meadows H, Wan S et al. EXTRA – a multicenter phase II study of chemoradiation
using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J
Radiat Oncol Biol Phys 2008; 72(1): 119–126.
7. Kachnic LA, Winter K, Myerson RJ et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity
modulated radiation therapy in combination with 5-uorouracil and mitomycin-C for the reduction of
acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013; 86(1): 27–33.
8. Gunderson LL, Winter KA, Ajani JA et al. Long-term update of US GI intergroup RTOG 98-11 phase
III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation
involving uorouracil/mitomycin versus uorouracil/cisplatin. J Clin Oncol 2012; 30(35): 4344–4351.
9. Muirhead R, Adams RA, Gilbert DC et al. Anal cancer: developing an intensity-modulated radiotherapy
solution for ACT2 fractionation. Clin Oncol 2014; 26(11): 720–721.
10. www.analimrtguidance.co.uk (last accessed 22/9/16)
11. Pettit L, Meade S, Sanghera P et al. Can radiobiological parameters derived from squamous
cell carcinoma of the head and neck be used to predict local control in anal cancer treated with
chemoradiation? Br J Radiol 2013; 86(1021): 20120372.
12. www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=36181 (last accessed 13/10/16)