126Radiotherapy dose fractionation Third edition
Background
The oligometastatic state can be dened as 1–3 isolated metastatic sites, typically
occurring more than six months after successful treatment of primary disease.
1
In colorectal cancer (in addition to sarcoma and other sites), surgical treatment of
oligometastatic disease (most frequently liver metastases) is associated with prolonged
overall survival.
2
Multiple single-arm studies have shown that stereotactic radiotherapy is
eective and well tolerated in the oligometastatic setting, across multiple histologies and
anatomical sites. Thus, it may be deployed as an alternative to surgery or where surgery is
not possible.
There is no randomised data, and no established consensus for dose fractionation in
radiotherapy for oligometastatic disease. Recommendations have been derived from
systematic reviews of non-randomised studies (prospective and retrospective [Level 3a]),
along with expert consensus from the Comissioning through Evaluation (CtE) Service
Specication (Level 5).
3,4
For all sites, it is recommended that the critical organ dose
constraints agreed by the UK Stereotactive Ablative Radiotherapy (SABR) consortium
should be followed.
5
It is not possible to discuss dose fractionation without discussing treatment technique.
The majority of evidence comes from stereotactic body radiotherapy (SBRT or stereotactic
ablative radiotherapy [SABR]). Developments in radiotherapy technology have allowed
the safe delivery with high-precision of an ablative dose in ve or fewer fractions. Patients
have been treated using dedicated stereotactic systems (such as Cyberknife) and using
conventional gantry-based systems with stereotactic capability. The optimal system for
delivery is unknown, but image guidance, either with implanted ducials and/or soft tissue
tomography, is essential. Dose fractionation recommendations are, however, independent
of the stereotactic platform used.
Oligometastases: bone (including spine) and lymph nodes
In this setting, treatment can expect to achieve a local control around of 80% and
progression-free survival (PFS) of approximately 20% at 2–3 years.
1
Doses delivering a
biologically equivalent dose (BED) at 2 Gray (Gy) per fraction (EQD2) >100 Gy, and those
tumours ≤3 centimetres (cm) have best outcomes. Treatment is, in general, well tolerated
with myelopathy rates for spinal treatments being less than 1% in most series.
6,7
Contouring for spinal treatment should be based on the expert consensus guidelines by
Cox et al (Level 5).
4,8
Recommendations
Initial treatment:
18–24 Gy single dose (Grade C)
30–45 Gy in 3 fractions over 1 week (10–15 Gy per fraction given on alternate days)
(Grade C)
Retreatment
Pelvis: 30 Gy in 5 fractions over 2 weeks, given on alternate days (Grade C)
Spine: 20–30 Gy in 2–5 fractions over 1–2 weeks, given on alternate days (Grade C)
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
20.
Oligometastases
127Radiotherapy dose fractionation Third edition
In this setting, it is vital to take into account the dose previously received by critical organs.
As far as possible, cumulative doses to critical organs should be calculated and, allowing
for recovery, tolerances described in the UK SABR consensus document should not be
exceeded, if necessary modifying prescription doses to the planning target volume (PTV).
5
In the specic case of remaining spinal cord tolerance, the method described by Sahgal is
recommended.
7
Following this, the maximum cumulative dose to the thecal sac (similar to
cord planning organ at risk volume [PRV]), at a minimum of six months after initial irradiation,
should not exceed a BED of 140 Gy (αβ=2 Gy). For other organs, there is no consensus on
recovery of tolerance following radiation and clinical judgment, along with the available
literature, should be used.
9
Oligometastases: lung
Lung oligometastases present a similar clinical problem to early-stage primary lung
cancer, for which stereotactic treatment is a standard of care.
10
Specically for patients with
oligometastases, an EQD2 >100 Gy is associated with approximately 90% local control
at 1–2 years.
10,11
Although Timmerman et al found a signicant increase in toxicity when
treating central lung tumours, other series have found no increase in toxicity when treating
with more than three fractions.
12–15
These current recommendations are consistent with the
CtE Service Specication.
3
Recommendations
48–54 Gy in 3 fractions over 1 week given on alternate days (Grade C)
Peripheral lung oligometastases in contact with chest wall or where three
fraction constraints cannot be met:
55–60 Gy in 5 fractions over 2 weeks given on alternate days (Grade C)
Lung oligometastases in the central lung/mediastinum:
60 Gy in 8 fractions over 1 week given on alternate days (Level 4)
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
128Radiotherapy dose fractionation Third edition
Oligometastases: liver
The use of surgery and radiofrequency ablation to treat liver oligometastases is well
established. For colorectal liver tumours under 6 centimetres (cm) in diameter, local control
above 90% at one year can be achieved with stereotactic doses of at least 48 Gy in three
fractions.
16
This analysis included patients who were heavily pre-treated with systemic
therapy. Further reviews have indicated this dose is eective in other tumour types, with
grade 3–4 toxicity of 1–10% (Level 3a).
4,17,18
Recommendations
45–50 Gy in 3 fractions over 1 week, given on alternate days (Grade C)
For larger PTV volumes or where dose constraints cannot be met with a three-
fraction approach:
50–60 Gy in 5 fractions over 2 weeks (Grade C)
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
Oligometastases: adrenal
Due to a rich sinusoidal blood supply, adrenal metastases are frequently observed
in patients with melanoma, breast, lung, kidney and gastrointestinal tumours. Based
on observations of enhanced survival in patients undergoing adrenalectomy for
oligometastatic disease, stereotactic radiotherapy has also been been used. Local control
rates vary from 55% to 90% with doses ranging from 16 Gy in four fractions to 50 Gy in ten
fractions (Level 4).
4,19,20
Recommendation
30–36 Gy in 3 fractions over 1 week (Grade C)
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
129Radiotherapy dose fractionation Third edition
1. Tree AC, Khoo VS, Eeles RA et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol
2013; 14(1): e28–e37.
2. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011; 8(6): 378–382.
3. www.england.nhs.uk/commissioning/spec-services/npc-crg/comm-eval
(last accessed 13/10/16)
4. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009
(last accessed 30/9/16)
5. www.sabr.org.uk/consortium (last accessed 13/10/16)
6. Bhattacharya IS, Hoskin PJ. Stereotactic body radiotherapy for spinal and bone metastases. Clin Oncol
(R Coll Radiol) 2015; 27(5): 298–306.
7. Sahgal A, Atenafu EG, Chao S et al. Vertebral compression fracture after spine stereotactic body
radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability
neoplastic score. J Clin Oncol 2013; 31(27): 3426–3431.
8. Cox BW, Spratt DE, Lovelock M et al. International Spine Radiosurgery Consortium consensus
guidelines for target volume denition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys
2012; 83(5): e597–e605.
9. Mantel F, Flentje M, Guckenberger M. Stereotactic body radiation therapy in the re-irradiation situation
– a review. Radiat Oncol 2013; 8: 7.
10. Solda F, Lodge M, Ashley S, Whitington A, Goldstraw P, Brada M. Stereotactic radiotherapy (SABR) for
the treatment of primary non-small cell lung cancer; systematic review and comparison with a surgical
cohort. Radiother Oncol 2013; 109(1): 1–7.
11. Siva S, MacManus M, Ball D. Stereotactic radiotherapy for pulmonary oligometastases: a systematic
review. J Thorac Oncol 2010; 5(7): 1091–1099.
12. Timmerman R, McGarry R, Yiannoutsos C et al. Excessive toxicity when treating central tumors in a
phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J
Clin Oncol 2006; 24(30): 4833–4839.
13. Mangona VS, Aneese AM, Marina O et al. Toxicity after central versus peripheral lung stereotactic
body radiation therapy: a propensity score matched-pair analysis. Int J Radiat Oncol Biol Phys.2014;
91(1): 124–132.
14. Nuyttens JJ, van der Voort van Zyp NC, Praag J et al. Outcome of four-dimensional stereotactic
radiotherapy for centrally located lung tumors. Radiother Oncol 2012; 102(3): 383–387.
15. Chang JY, Balter PA, Dong L et al. Stereotactic body radiation therapy in centrally and superiorly
located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;
72(4): 967–971.
16. Chang DT, Swaminath A, Kozak M et al. Stereotactic body radiotherapy for colorectal liver metastases:
a pooled analysis. Cancer 2011; 117(17): 4060–4069.
17. Aitken KL, Hawkins MA. Stereotactic body radiotherapy for liver metastases. Clin Oncol (R Coll Radiol)
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18. Høyer M, Swaminath A, Bydder S et al. Radiotherapy for liver metastases: a review of evidence. Int J
Radiat Oncol Biol Phys 2012; 82(3): 1047–1057.
References
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19. Chawla S, Chen Y, Katz AW et al. Stereotactic body radiotherapy for treatment of adrenal metastases.
Int J Radiat Oncol Biol Phys 2009; 75(1): 71–75.
20. Casamassima F, Livi L, Masciullo S et al. Stereotactic radiotherapy for adrenal gland metastases:
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