24Radiotherapy dose fractionation Third edition

Central nervous

system (CNS) tumours

Background

Three important considerations underpin the choice of treatment fractionation in neuro-

oncology. First, the results of treatment vary widely and, second, the brain and spinal cord

are susceptible to late radiation damage which is strongly dependent on radiation dose

per fraction. The Quantitative Analysis of Normal Tissue Eects in the Clinic (QUANTEC)

papers published in 2010 provide details of normal tissue tolerances for brain, brainstem,

optic nerves and chiasm, hearing and spinal cord.

1–9

Patients with a life expectancy of more

than 12–18 months are rarely treated with doses per fraction greater than 2 Gray (Gy). With

increased use of inverse planned intensity-modulated radiotherapy (IMRT), consideration

must be given to appropriate dose constraints to serial structures, balancing tumour control

against risk of toxicity. Finally, our understanding of tumours, in particular the gliomas, has

changed substantially recently, and there is clearly a key role for isocitrate dehydrogenase

(IDH) mutations and chromosomal (1p/19q) codeletions. This is likely to further evolve over

time.

High-grade glioma

Radical treatment

Retrospective analyses and one randomised trial have demonstrated a dose–response

relationship for high-grade glioma up to, but not beyond, 60 Gy in 30 fractions.

10–12

This

has led to the adoption of the dose regimen of 60–65 Gy delivered in 1.8–2.0 Gy fractions

as standard in the therapy of better prognosis patients with high-grade malignant

glioma. Further attempts to improve response through hyperfractionation or accelerated

fractionation have not demonstrated a signicant survival benet.

13,14

The addition of

temozolomide to radiotherapy for newly diagnosed glioblastoma has been shown to

improve overall and progression-free survival.

The rst trial only included patients under

the age of 70. However, a subsequent study included older patients and found similar

benets from the addition of temozolomide.

For World Health Organization (WHO) grade III gliomas with 1p and 19q chromosomal co-

deletion, the addition of procarbazine, lomustine and vincristine (PCV) chemotherapy, either

before or after radiotherapy, has recently been shown to improve overall survival.

17,18

The

addition of temozolomide after radiotherapy has been shown to improve survival in patients

with grade III non-1p 19q co-deleted tumours and nal results of this trial are still awaited.

Recent trials for grade III glioma (anaplastic oligodendroglioma and oligoastrocytoma, and

non-1p19q co-deleted WHO grade III glioma) have all used a radiotherapy dose of 59.4 Gy

in 33 fractions, providing Level 2a evidence for this regimen in WHO grade III glioma.

19–22

Previous dose determination studies in high-grade gliomas used a dose of 60 Gy in 30

fractions for grade III gliomas.

11,20

25Radiotherapy dose fractionation Third edition

Recommendations

For patients of good performance status:

WHO Grade IV glioma (GBM)

60 Gy in 30 daily fractions over 6 weeks (Grade A)

WHO Grade III glioma

59.4 Gy in 33 fractions over 6.5 weeks (Grade A)

60 Gy in 30 fractions over 6 weeks (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.

Palliative treatment

Increasing age is a signicant negative prognostic factor for patients with glioblastoma.

Several trials in older patients have evaluated shorter courses of radiotherapy. One

randomised trial which recruited patients aged ≥60 of Karnofsky Performance Status

(KPS) ≥50 showed similar survival for 40 Gy in 15 fractions over three weeks compared

to 60 Gy in 30 fractions.

In another randomised trial in patients aged ≥60 principally of

WHO performance status 0–2, 34 Gy in ten fractions appeared to have similar survival

rates in patients over 60 and better survival in patients over 70 than 60 Gy in 30 fractions

of radiotherapy alone.

Shorter fractionations are therefore an option in elderly patients

unsuitable for chemo-radiotherapy. The recent results using 40 Gy in 15 fractions in older

patients combined with concurrent and adjuvant temozolomide suggest that this may be

the best option in t, older patients.

For patients with high-grade glioma and poor performance status, when treatment is

indiciated, hypofractionated treatments are used.

24,25

The most commonly adopted regimen

in the UK is 30 Gy in six fractions over two weeks.

Recommendations

Elderly patients with glioblastoma unsuitable for chemo-radiotherapy:

40 Gy in 15 fractions over 3 weeks (Grade A)

34 Gy in 10 fractions over 2 weeks (Grade B)

30 Gy in 6 fractions over 2 weeks (Grade C)

For patients of poor performance status being treated for high-grade glioma:

30 Gy in 6 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.

Low-grade glioma

For low-grade glioma, two prospective randomised dose comparison trials have

demonstrated no dierence in outcome between 45 Gy in 25 fractions and 59.4 Gy in 33

26Radiotherapy dose fractionation Third edition

fractions and between 50.4 Gy in 28 fractions and 64.8 Gy in 36 fractions.

26,27

As a result, a

standard dose of 50.4 Gy in 28 fractions of 1.8 Gy is accepted practice in the UK and

internationally. A dose of 54 Gy in 30 fractions over six weeks was used in a randomised

study of the timing of radiotherapy and also in the Radiation Therapy Oncology Group

(RTOG) 9802 randomised trial which showed an overall survival benet for the addition of

adjuvant procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy for

high-risk low-grade glioma (age 18–39 and incompletely resected, or age ≥40 with any

extent of resection).

28,29

This provides Level 2b evidence for this regimen.

Recommendations

50.4 Gy in 28 daily fractions over 5.5 weeks (Grade A)

54 Gy in 30 daily fractions over 6 weeks (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.

Finally, data from molecular pathology are likely to further rene these guidelines.

Meningioma

For benign meningioma (WHO grade I), radiotherapy may be used as radical treatment

or postoperatively after incomplete resection or recurrence. Radiological surveillance is

often an appropriate option for benign meningioma, depending on tumour growth, location

and the risk to the patient from further tumour growth. Randomised clinical trial evidence

is lacking, but generally excellent rates of local control are reported with radiotherapy

doses of 50–54 Gy in 25–30 fractions. Small-volume benign tumours away from critical

structures (for example, optic apparatus) may also be treated with stereotactic radiosurgery

(SRS). Multiple series conrm long-term local control rates in excess of 80% using both

fractionation and SRS. Lower doses have been used in more recent series with similar local

control rates.

Radiotherapy should be considered for recurrent or incompletely resected meningioma

of atypical histology. As for other benign intracranial tumours, fractionation has been

governed by tolerance of local structures and adjacent brain tissue. There is an absence

of prospective randomised clinical trial evidence for the use of adjuvant radiation therapy.

However, multiple institutional series have demonstrated an improvement in local control

and overall survival with adjuvant radiotherapy doses of 50.4–59.4 Gy in 28–33 fractions.

30–33

There is some evidence to suggest that local control is enhanced at doses greater than

52Gy.

30–33

Patients with grade 2 meningiomas are at higher risk of relapse, and standard practice

has historically been to give radiotherapy. The role of adjuvant radiotherapy, balanced

against the neuro-cognitive side-eects, in patients with completely resected meningioma

are being explored in the ROAM study (EORTC 1308). In patients who have incompletely

resected tumours, radiotherapy has been oered at a dose of 60 Gy in 30 fractions.

Attempts at dose escalation using radiosurgery boost and accelerated hyperfractionation

have failed to achieve improved local control.

The EORTC 26021-22021 phase II trial

(NCT00626730) of postoperative radiotherapy for atypical and malignant meningiomas

which treated Simpson stage 1–3 to 60 Gy and Simpson stages 4–5 to 70 Gy closed in 2013

and is in follow-up.

27Radiotherapy dose fractionation Third edition

Special consideration should be given to meningioma of the optic nerve sheath. There is

now evidence from multiple institutional series that radiotherapy should be considered as a

primary treatment option to achieve tumour control and consequentially prevent visual

deterioration and symptomatic proptosis.

35,36

Recommendations

Tumour grade 1:

50.4–54 Gy in 28–30 fractions over 5.5–6 weeks (Grade C)

50–55 Gy in 30–33 fractions over 6–6.5 weeks (Grade C)

Grade 2:

54–60 Gy in 30 fractions over 6 weeks (Grade D)

Grade 3:

60 Gy in 30 fractions over 6 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.

Pituitary tumours

Fractionation has been governed by tolerance of the local structures and prospective

data is lacking. There are consistent reports of high local control when using 45 Gy in 25

fractions for non-functioning pituitary adenomas.

This is commonly accepted as the

standard dose for tumours without adverse features including suprasellar extension.

There is data to suggest that the dose response may increase up to about 50 Gy, however,

higher doses are generally reserved for tumours with adverse features.

Small inoperable

pituitary tumours away from optic apparatus may be suitable for single fraction stereotactic

treatment which oers a similar local control rate.

Although radiological control rates are high, biochemical remission rates for functional

tumours vary considerably using conventional doses of 45–54 Gy (1.8–2 Gy per fraction).

No clear dose response has been dened using fractionated treatment, however, higher

marginal doses are used when using single fraction stereotactic treatment.

Recommendation

45 Gy in 25 fractions over 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.

28Radiotherapy dose fractionation Third edition

Craniopharyngioma

Radiation therapy is typically used as an adjunct to surgery after maximal tumour

resection. Doses between 50–60 Gy in 30 fractions have been used. Historical studies of

postoperative radiotherapy showed a dose of 55 Gy to be a threshold dose in terms of local

disease control, though concern over the risk of radiation induced optic neuropathy has

resulted in median doses of 50–52.2 Gy in more recently published series.

40–42

Recommendations

50–55 Gy in 30–33 fractions over 6–6.5 weeks (Grade D)

52.2–54 Gy in 27–28 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.

29Radiotherapy dose fractionation Third edition

1. Kramer S. The hazards of therapeutic irradiation of the central nervous system. Clin Neurosurg

1968,15: 301–318.

2. Marks JE, Baglan RJ, Prassa SC, Blank WF. Cerebral radionecrosis: incidence and risk in relation to

dose, time, fractionation and volume. Int J Radiat Oncol Biol Phys 1981; 7(2): 243–252.

3. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys

1980; 6(9): 1215–1228.

4. Leibel SA, Sheline GE. Tolerance of the brain and spinal cord to conventional radiation. In: Gutin PH,

Leibel SA, Sheline GE (eds). Radiation Injury to the Nervous system. New York: Raven Press, 1991:

239–256.

5. Corn BW, Yousem DM, Scott CB et al. White matter changes are correlated signicantly with radiation

dose. Observations from a randomized dose-escalation trial for malignant glioma (Radiation Therapy

Oncology Group 83-02). Cancer 1994; 74(10): 2828–2835.

6. Emami B, Lyman J, Brown A et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat

Oncol Biol Phys 1991; 21(1): 109–122.

7. Berg G, Blomquist E, Cavallin-Ståhl E. A systematic overview of radiation therapy eects in brain

tumours. Acta Oncologica 2003; 42(5–6): 582–588.

8. Marks LB, Ten Haken RK, Martel MK. Guest editor's introduction to QUANTEC: a users guide. Int J

Radiat Oncol Biol Phys 2010; 76(3 Suppl): S1–S2.

9. Marks LB, Yorke ED, Jackson A et al. Use of normal tissue complication probability models in the clinic.

Int J Radiat Oncol Biol Phys 2010; 76(3 Suppl): S10–9.

10. Walker MD, Strike TA, Sheline GE. An analysis of dose-eect relationship in the radiotherapy of

malignant gliomas. Int J Radiat Oncol Biol Phys 1979; 5(10): 1725–1731.

11. Bleehan NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the

treatment of grades 3 and 4 astrocytoma. Br J Cancer 1991; 64(4): 769–774.

12. Salazar OM, Rubin P, McDonald JV, Feldstein ML. High dose radiation therapy in the treatment of

glioblastoma multiforme: a preliminary report. Int J Radiat Oncol Biol Phys 1976; 1(7–8): 717–727.

13. Werner-Wasik M, Scott CB, Nelson DF et al. Final report of a phase I/II trial of hyperfractionated

and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial

malignant gliomas: Radiation Therapy Oncology Group Study 83-02. Cancer 1996; 77(8): 1535–1543.

14. González DG, Menten J, Bosch DA et al. Accelerated radiotherapy in glioblastoma multiforme: a dose

searching prospective study. Radiother Oncol 1994; 32(2): 98–105.

15. Stupp R, Hegi ME, Mason WP et al. Eects of radiotherapy with concomitant and adjuvant

temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study:

5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10(5): 459–466.

16. Perry JR, Laperriere N, O’Callaghan J et al. Short-course radiation plus temozolomide in elderly patients

with glioblastoma. N Eng J Med 2017; 376(11): 1027–1037.

17. Cairncross G, Wang M, Shaw E et al. Phase III trial of chemoradiotherapy for anaplastic

oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 2013; 31(3): 337–343.

18. van den Bent MJ, Brandes AA, Taphoorn MJ et al. Adjuvant procarbazine, lomustine, and vincristine

chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain

tumor group study 26951. J Clin Oncol 2013; 31(3): 344–350.

References

30Radiotherapy dose fractionation Third edition

19. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009

(last accessed 26/9/16)

20. Mulvenna P, Nankivell M, Barton R et al. Dexamethasone and supportive care with or without

whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases

unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority,

randomised trial. Lancet 2016; 388(10055): 2004–2014.

21. Roa W, Brasher PM, Bauman G et al. Abbreviated course of radiation therapy in older patients with

glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004; 22(9): 1583–1588.

22. van den Bent MJ, Baumert B, Erridge SC et al. Interim results from the CATNON trial (EORTC study

26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted

anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 2017; 390(10103):

1645–1653.

23. Malmström A, Grønberg BH, Marosi C et al. Temozolomide versus standard 6-week radiotherapy

versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic

randomised, phase 3 trial. Lancet Oncol 2012; 13(9): 916–926.

24. McAleese JJ, Stenning SP, Ashley S et al. Hypofractionated radiotherapy for poor prognosis malignant

glioma: matched pair survival analysis with MRC controls. Radiother Oncol 2003; 67(2): 177–182.

25. Thomas R, James N, Guerrero D, Ashley S, Gregor A, Brada M. Hypofractionated radiotherapy as

palliative treatment in poor prognosis patients with high grade glioma. Radiother Oncol 1994; 33(2):

113–116.

26. Karim AB, Maat B, Hatlevoll R et al. A randomized trial on dose-response in radiation therapy of low-

grade cerebral glioma: European Organisation for Research and Treatment of Cancer (EORTC) Study

22845. Int J Radiat Oncol Biol Phys 1996; 36(3): 549–556.

27. Karim AB, Afra D, Cornu P et al. Randomized trial on the ecacy of radiotherapy for cerebral low-grade

glioma in the adult: European Organisation for Research and Treatment of Cancer Study 22845 with

the Medical Research Council study BR04: an interim analysis. Int J Radiat Oncol Biol Phys 2002; 52(2):

316–324.

28. van den Bent MJ, Afra D, de Witte O et al. Long-term ecacy of early versus delayed radiotherapy for

low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet

2005; 366(9490): 985–990.

29. Shaw E, Arusell R, Scheithauer B et al. Prospective randomised trial of low- versus high-dose radiation

therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer

Treatment Group/Radiation Therapy Oncology Group/astern Cooperative Oncology Group Study. J

Clin Oncol 2002; 20(9): 2267–2276.

30. Adeberg S, Hartmann C, Welzel T et al. Long-term outcome after radiotherapy in patients with atypical

and malignant meningiomas – clinical results in 85 patients treated in a single institution leading to

optimized guidelines for early radiation therapy. Int J Radiat Oncol Biol Phys 2012; 83(3): 859–864.

31. Aghi MK, Carter BS, Cosgrove GR et al. Long-term recurrence rates of atypical meningiomas after

gross total resection with or without postoperative adjuvant radiation. Neurosurgery 2009; 64(1):

56–60; discussion 60.

32. Goldsmith BJ, Wara WM, Wilson CB, Larson DA. Postoperative irradiation for subtotally resected

meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;

80(2): 195–201.

31Radiotherapy dose fractionation Third edition

33. Milosevic MF, Frost PJ, Laperriere NJ, Wong CS, Simpson WJ. Radiotherapy for atypical or malignant

intracranial meningioma. Int J Radiat Oncol Biol Phys 1996; 34(4): 817–822.

34. https://clinicaltrials.gov/ct2/show/NCT00626730 (last accessed 13/10/16)

35. Brower JV, Amdur RJ, Kirwan J, Mendenhall WM, Friedman W. Radiation therapy for optic nerve sheath

meningioma. Pract Radiat Oncol 2013; 3(3): 223–288.

36. Roser F, Nakamura M, Martini-Thomas R, Samii M, Tatagiba M. The role of surgery in meningiomas

involving the optic nerve sheath. Clin Neurol Neurosurg 2006; 108(5): 470–406.

37. Erridge SC, Conkey DS, Stockton D et al. Radiotherapy for pituitary adenomas: long-term ecacy and

toxicity. Radiother Oncol 2009; 93(3): 597–601.

38. Grigsby PW, Simpson JR, Emami BN, Fineberg BB, Schwartz HG. Prognostic factors and results of

surgery and postoperative irradiation in the management of pituitary adenomas. Int J Radiat Oncol Biol

Phys 1989; 16(6): 1411–1417.

39. Sheehan JP, Starke RM, Mathieu D et al. Gamma Knife radiosurgery for the management of

nonfunctioning pituitary adenomas: a multicenter study. J Neurosurg 2013; 119(2): 446–456.

40. Varlotto JM, Flickinger JC, Kondsiolk D et al. External beam irradiation of craniopharyngiomas: long-

term analysis of tumor control and morbidity. Int J Radiat Oncol Biol Phys 2002; 54(2): 492–499.

41. Masson-Cote L, Masucci GL, Atenafu EG et al. Long-term outcomes for adult craniopharyngioma

following radiation therapy. Acta Oncol 2013; 52(1): 153–158.

42. Harrabi SB, Adeberg S, Welzel T et al. Long term results after fractionated stereotactic radiotherapy

(FSRT) in patients with craniopharyngioma: maximal tumor control with minimal side eects. Radiat

Oncol 2014; 9: 203.

References