Clinical Oncology (1995) 7:179-183 © 1995 The Royal College of Radiologists Clinical

Oncology

Original Article

An Audit of Craniospinal Irradiation for Medulloblastoma in Newcastle 1970-1992

D. Tinkler and H. H. Lucraft Newcastle General Hospital, Newcastle upon Tyne, UK

Abstract. The case notes were reviewed of 55 patients treated with craniospinal irradiation for cerebellar medulloblastoma during the period 1970- 1992. Twenty patients treated by various techniques before 1978 had a survival at both 5 and 10 years of 33%. Thirty-five patients treated from 1978 onwards were irradiated using a standard technique, which is described; their actuarial disease free survival was 59% at 5 years and 47% at 10 years. Our results are similar to those reported from other centres. The recent literature is reviewed.

Irradiation of the whole craniospinal axis (CSA) is necessary for disease control, but the optimum dose of radiation is still disputed. It is likely to be in excess of 25 Gy but less than 35 Gy to the whole CSA, and 50 Gy or greater to the posterior fossa. The role of adjuvant chemotherapy is still not proven. The clini- cal significance of the dose inhomogeneity across the junction between the cranial and spinal fields, and the effect of feathering, are uncertain.

Keywords: Craniospinal irradiation; Medulloblas- toma

INTRODUCTION

An audit of craniospinal irradiation for medullo- blastoma in Newcastle was undertaken to ensure that treatment results are comparable with published results from other centres, and also to review current techniques in the light of treatment results and the published literature.

There has been a dramatic improvement in the survival of patients with medulloblastoma over the past 30 years, with recent reports of 5-year survivals of about 60% or better in most centres [1-5]. This improvement is partly due to better diagnostic imaging techniques and stricter staging of patients before treatment. This leads to the identification of all macroscopic disease at the outset. It can also be attributed to better surgical techniques improving the

Correspondence and offprint requests to: Dr S. D. Tinkler, Northern Centre for Cancer Treatment, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK.

operative mortality and postoperative morbidity. In addition, the technique of craniospinal irradiation (CSI) has been improved with more accurate dosi- metry, beam shaping and matching of junctions.

The field arrangement for CSI usually involves two large opposed lateral cranial fields, with individually shaped blocks to protect the face, and one (or two) long orthogonal posterior spinal fields. This tech- nique includes at least one junction (usually in the mid-cervical region), which is a potential site for dose inhomogeneity. It is vital to avoid both overdosage at the junction due to overlapping fields and under- dosage due to a gap. The former risks a fatal radiation myelopathy and the latter increases the risk of tumour recurrence.

A change of location of the junction in the cervical cord one or more times during the planned course of radiotherapy (feathering) has been adopted in many centres [2,4,6-9]. This procedure acts to 'smear out' any dose inhomogeneity across the junction and provides a further safety margin against critical under- or overdosage. It is often recommended as the optimum treatment technique for CSI [6,8,10].

The CSI technique used in Newcastle does not involve the movement of the junction between the cranial and spinal fields but it is similar to that practised elsewhere in other respects. In this paper, the results of patients treated with CSI for medullo- blastoma in Newcastle over a 22-year period from 1970 to 1992 are presented and the literature is reviewed.

MATERIALS AND METHODS

The case notes of 55 patients treated with CSI for medulloblastoma in Newcastle from 1970 to 1992 were reviewed. Twenty patients presenting before 1978 were treated using non-standard techniques. Their survival as a group was compared with the 35 patients treated from 1978 to 1992 using the standard technique.

The following information was recorded from the case notes: age at diagnosis; sex; stage of disease at diagnosis (estimated retrospectively using the surgi- cal staging system suggested by Chang in 1969 [11];

180 D. Tinkler and H. H. Lucraft

Table 1. Staging, after Chang etal. 1969 (surgical)

T~ 3 cm, limited to classical mid-line in vermis, roof IVth ventricle; less so to hemispheres

3"2 3 cm, invading adjacent structure or partially filling IVth ventricle

T3A Invasion two adjacent structures, completely filling IVth ventricle, with extension to aqueduct of Silvius, foramen of Magendie for foramen of Luschka, causing marked internal hydrocephalus

T3B Arising floor IVth ventricle or brain stem, or filling IVth ventricle.

T4 Spread through aqueduct of Silvius to involved IIIrd ventricle or mid-brain, or tumour extending to upper cervical cord

M 1 Microscopic cells in CSF M2 Gross nodular seedings in cerebellar subarachnoid spaces

or IIIrd or lateral ventricles M 3 Gross nodular seedings in spinal subarachnoid space M4 Metastases outside CSA

Table 1); time from surgery to the commencement of the radiotherapy; details of the radiotherapy tech- nique; adjuvant chemotherapy; sites of recurrent disease; and survival.

The standard technique for CSI employs mega- voltage photons produced by a linear accelerator. Patients are immobilized and treated prone. Two large opposed lateral fields are used to treat the whole brain and upper cervical spine, down to the C3/4 level, protecting the face and eyes with individu- ally cast blocks. The spine is treated using a single direct posterior field extending from C4/5 to $2. The inferior field edges of the cranial fields are matched exactly to the superior edge of the spine field at the skin surface in the mid-saggittal plane with no gap.

A custom made tissue compensator is used to correct for the variable depth of the spinal cord beneath the skin. The whole of the infratentorial region is included in the boost volume, extending inferiorly to the C2/3 interface. The dose of radiation given has varied over the period of study and with the age of the patient. The current target absorbed dose given to the craniospinal axis (CSA) is 35 Gy in 21 fractions, at 1.67 Gy per fraction treating daily five times a week. In addition, a further 20 Gy in 12 daily fractions is given to the posterior fossa at the same dose per fraction to a total of 55 Gy. This dose/ fractionation schedule follows that recommended in the current International Society of Pediatric Onco- logists (SIOP III) trial.

STATISTICS [12]

The actuarial disease free survival curves were produced from life tables. The survival for the two time periods under study were compared using the log-rank test. The chi-square test (with 1 degree of freedom) was used to compare the effect of stage at diagnosis and also the effect of the extent of surgical excision on survival. The effect of time from surgery to the start of the radiotherapy on survival was analysed using the Mann-Whitney U test. All con-

fidence limits are quoted at the 95% level. P ~<0.05 was considered to be statistically significant.

RESULTS

The overall actuarial disease free survival for all 55 patients was 48% at 5 years and 37% at 10 years. For the 20 patients treated unconventionally, the actuarial survival was 30% at 5 and 10 years (95% CI 11-51). Patients treated with the standard technique from 1978 onwards had an actuarial disease free survival of 57% at 5 years (95% C138-72) and 47% at 10 years (95% CI 27-64; Fig. 1). This difference was not statistically significant (P=0.091).

Only the 35 patients treated with the standard technique were analysed in detail. The median age at diagnosis was 6 years (range 15 months to 35 years). Nineteen patients (54%) were male and 16 (46%) female.

Using retrospectively the surgical system sug- gested by Chang [11], 15 patients were Stage T1-2, 17 were Stage T3-4, two were stage M + , and one patient could not be staged. Few of these patients were fully staged: only four (11%) had a myelogram, six (17%) had their CSF analysed for cytology, and eight (23%) had a postoperative CT scan. Six of the 15 patients staged as T1 or Ta (40%) died from medulloblastoma and ten of the 19 patients with more advanced stage disease at presentation (53%) also died of their disease. This difference was not statistically signifi- cant (P = 0.54).

Nine patients (26%) were entered into a clinical trial. Four additional patients received adjuvant chemotherapy outside the confines of a clinical trial.

The extent of surgical excision of the primary tumour was assessed retrospectively. Nineteen patients (54%) had 75% or more of their tumour excised, 14 (40%) had a 'subtotal' resection or 'partial' excision. The extent of surgical excision was not documented in the case notes of the remaining two patients. Eight of the 19 patients (42%) who had had more than 75% of their tumour resected died of

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Time (months] Fig. 1. Actuarial disease free survival for medulloblastoma treated with craniospinal irradiation 1970-1992.

Craniospinal Irradiation for Medulloblastoma 181

their disease, compared with eight of the 14 patients (57%) undergoing a partial excision only. This differ- ence was not statistically significant (P=0.51).

The time from surgery to the start of the radiother- apy ranged from 14 to 175 days, with a mean of 37 and a median of 24. In two patients, radiotherapy was delayed by 2 months because of the administration of adjuvant chemotherapy as part of a clinical trial. There was no difference in the time from surgery to the start of the radiotherapy in those patients who died compared with those who survived, with a median of 28.5 days and 22 days respectively (P = 0.53; 95% CI 3.99-25:01).

All patients received 4-8 MV photons to the whole CSA, using a linear accelerator. The dose of radiation given (Table 2) has varied with time, the age of the patient, and the demands of various clinical trials. The dose to the whole CSA ranged from 30 Gy to 35 Gy, and the posterior fossa was boosted to a total dose of 50-55 Gy in 65% of patients. Eleven patients received 40-49 Gy in total to the primary tumour site, a dose considered subop- timal by many [2,3,8,13].

Thirteen patients (37%) were given adjuvant chemotherapy, as detailed in Table 3.

Sixteen patients (46%) treated with the standard technique developed recurrent disease, which was uniformly fatal. The median time from diagnosis to the development of recurrent disease was 14 months (range 3-78). Two patients remained disease free for more than 6 years before developing a recurrence of their medulloblastoma. The other patients all recurred within 3.5 years. The median time from diagnosis of disease recurrence to death was 5 months (range 1-27). The sites of recurrent disease are summarized in Table 4. One patient developed an isolated recurrence of medulloblastoma at the site

Table 2. Radiation dose

Dose (Gy) No. fractions No. patients

Whole CNS 30 18-21 10 31-34 16 8 35 20-26 17

Total dose to posterior fossa 40 20 1 45-49 27-32 10 50-54 29-43 13 55 30-39 9 56-57 34-35 2

Table 3. Chemotherapy given

Type of chemotherapy No. patients

Vincristine, CCNU 6 Vincristine 2 Vincristine, adriamycin, cyclophosphamide 1 Carboplatin, VP16, cyclophosphamide 1 Carboplatin, VP16, cyclophosphamide, vincristine 1 CCNU, procarbazine 1 Vincristine, procarbazine, nitrosurea, methotrex- 1 ate, prednisolone

Table 4. Sites of recurrent disease: total number of patients relapsing = 16 (46%)

Site No. patients No. additional sites of disease recurrence

Posterior fossa 8 4 Sole site 3 Supratentorial 1 Spinal cord

Spinal cord 7 5 Sole site 1 Posterior fossa 1 Posterior fossa

and systemic Supratentorial brain 4 1 Sole site

3 Posterior fossa Systemic metastases 2 1 Sole site (bone + liver) 1 Posterior fossa

and spinal cord

of the junction between the cranial and spinal fields. Four other patients also developed isolated spinal cord relapses, but at sites well away from this junction. There were no cases of radiation myelo- pathy.

DISCUSSION

Disease free survival has improved with our current technique of CSI used from 1978 onwards, compared with patients treated before this time. Although this difference does not reach statistical significance, we feel confident that the benefit in survival for patients treated after 1978 is real, as this trend has been documented previously in the literature and was summarized by Jenkin et al. in 1990 [1]. The statisti- cally non-significant difference between the time periods is likely to be due to the small numbers of patients involved.

The patients reported in this series have a similar age and sex distribution to those documented in the literature [1,2,4,8,14]. We did not find any statisti- cally significant prognostic factors affecting local recurrence or survival, but the number of patients studied was small.

The 5- and 10- year disease free survivals of 57% and 47% respectively of patients treated since 1978 are comparable with those published by many centres [1,2,5,8,13,15-17]. Fifty per cent of patients who recurred relapsed in the posterior fossa; this was the sole site of disease in 25%. These results are similar to other published series [5,8,18], although some authors have reported local recurrence rates of around 75% [2,19]. Forty-four per cent of patients who recurred relapsed in the spine, similar to the 39% reported by Deutsch in 1988 [5] and the 50% reported by Carrie et al. in 1992 [6]. Other authors have reported a much lower incidence of spinal recurrence [8,18,19]. Twenty-five per cent of patients with recurrent disease had supratentorial involve- ment, a result similar to other published series [1,5,19]. The incidence of systemic metastases in most published work is about 5%; 12.5% occurred in our patients.

Thus, the characteristic and treatment results of

182 D. Tinkler and H. H. Lucraft

this series are comparable with the published litera- ture. It is not possible from our series to draw any firm conclusions due to the number of variables present and the small number of patients involved. We can, however, compare our results with other reported series. Review of the published literature also allows us to draw some general conclusions.

First, irradiation of the whole CSA is necessary for disease control. Bouffet et al. [14] omitted whole brain irradiation but gave chemotherapy in 16 patients, eight with 'low risk' and eight with 'high risk' disease. The high incidence of supratentorial relapses in this study (9 patients (69%)) necessitated its early closure. It is therefore reasonable to agree with the authors' conclusion that supratentorial irradiation is necessary for long term disease control, and should not be omitted even if chemotherapy is also given.

Secondly, the minimum dose given to the whole CSA for long term disease control is likely to be greater than 25 Gy but less than 35 Gy (the current 'standard') The second SIOP study [20] found that the 'low risk' patients randomized to receive the lower dose of radiation (25 Gy) had a significantly greater risk of relapse compared with those who received the 'standard' 35 Gy to the whole CSA. The 'low risk' patients who received low dose CSI and sandwich chemotherapy fared particularly badly, probably due to the delay in starting the radio- therapy. Two small non-randomized studies looking at low dose radiotherapy to the whole CSA (25 Gy) have been reported [4,21]. Both concluded that this lower dose of radiation did not compromise tumour control rates or survival.

Thirdly, there is conflicting information regarding the optimum dose to the posterior fossa. Some authors have reported better local control rates with >50 Gy compared with <50 Gy [2,3,8]. Other published series have not shown the dose to the posterior fossa to be a prognostic factor [15,17]. Most reported series where the dosage schedule remained constant throughout the period of study used 50-65 Gy. It would seem prudent therefore to recommend a dose of 50 Gy or more to the primary site as routine in all except very young patients.

Fourthly, the role of adjuvant chemotherapy is still not proven. Both the SlOP I trial [16] and the UK CCSG study initially reported a significant benefit at 5 years for patients who received chemotherapy in addition to surgical debulking of the primary tumour and CSA radiotherapy. However, as data from both these trials matured, this benefit was lost overall due to late relapses in the chemotherapy arm. In the SIOP I trial the benefit of chemotherapy persisted for a small subgroup of patients with brain stem involve- ment or incomplete excision. Current evidence does not support the use of adjuvant chemotherapy, except within the confines of a clinical trial such as SIOP III.

The aim of radical radiotherapy techniques is to obtain a homogeneous dose distribution across the whole treated volume. Irradiation of the whole CSA, however, creates special difficulties when trying to achieve this goal. At least one junction between orthogonal cranial and spinal radiation fields is unavoidable, leading to potential dose inhomogen-

eity. A widely used technique for improving the uniformity of dose distribution across the junction is feathering [2,4,6-10]. This has the disadvantage of making an already complicated technique even more so, and therefore more liable to error. It also increases the length of spinal cord at risk of dose inhomogeneity. A similar technique using a station- ary junction has the advantage of being simpler but may have a greater risk of under- or overdosage at the junction.

There are no reported series comparing these two techniques; most centres adopt either one or the other. Our results in terms of survival and disease recurrence using a stationary junction are similar to other published series where feathering is used. One of our patients (2.8%) developed an isolated recur- rence in the region of the junction. However, four other patients (11%) developed isolated spinal recur- rences in regions well away from the junction. Carrie et al. [6] reported the results of a multicentre trial in France; a total of 82 patients were treated by CSI with feathering of the junction between the cranial and spinal fields. Two of their patients (2.4%) devel- oped a relapse only at the site of the mobile junction, an incidence similar to that found in our series. There were no cases of radiation induced cervical myelo- pathy in either series.

C O N C L U S I O N

Audit of survival following CSI for medulloblastoma in Newcastle has shown an improvement with time and results comparable with other centres. This suggests that our current technique is satisfactory, although there was a marked variation in staging and treatment throughout the time period under study. Irradiation of the whole CSA is necessary for disease control. The optimum dose of radiation is still uncer- tain, but is likely to be in excess of 25 Gy and less than 35 Gy to the whole CSA, and 50 Gy or greater to the posterior fossa. The role of adjuvant chemotherapy is still not proven and the results of current clinical trials are awaited. There is little doubt that the junction between the cranial and spinal fields in CSI produces an area of dose inhomogeneity, but the clinical significance of this and the effect of feathering is much less certain. Further progress in this disease can only be made by entry of all patients into randomized clinical trials, leading to uniformity of staging as well as the different treatment modalities.

References

1. Jenkin D, Goddard K, Armstrong D, et al. Posterior fossa medulloblastoma in childhood: Treatment results and a pro- posal for a new staging system: Int J Radiat Oncol Biol Phys 1990;19:265-74.

2. Hughes EN, Shillito J, Sallan SE, et al. Medulloblastoma at the Joint Centre for Radiation Therapy between 1968 and 1984: The influence of radiation dose on the patterns of failure and survival. Cancer 1988;61:1992-8.

3. Berry MP, Jenkin RDJ, Keen CW, et al. Radiation treatment for medulloblastoma: A 21-year review. J Neurosurg 1981;55:43-51.

4. Halberg FE, Wara WM, Fippin LF, et al. Low dose cranio-

Craniospinal Irradiation for Medulloblastoma

spinal radiation therapy for medulloblastoma. Int J Radiat Oncol Biol Phys 1991;20:651-4.

5. Deutsch M. Medulloblastoma: Staging and treatment out- come. Int J Radiat Oncol Biol Phys 1988;14:1103-7.

6. Carrie C, Alapetite C, Mere P, et al. Quality control of radiotherapeutic treatment of medulloblastoma in a multi- centre study: The contribution of radiotherapy technique to tumour relapse. Radiother Oncol 1992;24:7%81.

7. Holupka EJ, Humm JL, Tarbell NJ, et al. The effect of set-up error on the dose across the junction of matching cranial- spinal fields in the treatment of medulloblastoma. Int J Radiat Oncol Biol Phys 1993;27:345-52.

8. Silverman CL, Simpson JR. Cerebellar meduUoblastoma: The importance of posterior fossa dose to survival and patterns of failure. Int J Radiat Oncol Phys 1982;8:1869-76.

9. Landberg TG, Lindgreen ML, Cavallin-Stahl EK, et al. Improvements in the radiotherapy of medulloblastoma. Cancer 1980;45:670-8.

10. Tatcher M, Gliksman AS. Field matching considerations in craniospinal irradiation. Int J Radiat Oneol Biol Phys 1989;17:865-9.

11. Chang CH, Housepian EM, Herbet JR. An operative staging system and a megavoltage radiotherapeutic technique for cerebellar medulloblastoma. Radiology 1969;93:1351-9.

12. Armitage P, Berry G. Statistical methods in medical research. Oxford: Blaekwell, 1987.

13. Bloom HJG. MeduUoblastoma,in children: Increasing survi- val rates and further prospects. Int J Radiat Oncol Biol Phys 1982;8:2023-7.

14. Bouffet E, Bernard JL, Frappaz D, et al. M4 protocol for

183

cerebellar medulloblastoma: Supratentorial radiotherapy may not be avoided. Int J Radiat Oncol Biol Phys 1992;24:79-85.

15. Kopelson G, Linggood RM, Kleinman GM. Medullo- blastoma: The identification of prognostic subgroups and implications for multimodality treatment. Cancer 1983; 51:312-9.

16. Tait DM, Thornton H, Bloom HJG, et al. Adjuvant chemo- therapy for medulloblastoma: The first multi-centre con- trolled trial of the International Society of Pediatric Oncology (SIOP I). Eur J Cancer 1990;26:464-9.

17. Allen JC, Bloom J, Ertel I, et al. Brain tumours in children: Current cooperative and institutional chemotherapy trials in newly diagnosed and recurrent disease. Semin Oncol 1986;13:110-22.

18. Castro-Vita H, Salazar OM, Cova M, et al. Cerebellar medulloblastoma: Spread and failure patterns following irradiation [abstract]. Int J Radiat Oncol Biol Phys 1978;4 Suppl:211-2.

19. Maor MH, Fields RS, Hogstrom KR, et al. Improving the therapeutic ratio of craniospinal irradiation in medullo- blastoma. Int J Radiat Oncol Biol Phys 1985 ;11:687-97.

20. Gnekow AK, Bailey C, Michaelis J, et al. SIOP/GPO medul- loblastoma trial med '84: Annual status report [abstract]. Proceedings of the International Society of Pediatric Oncologists SIOP XXII 1990 meeting. Med Pediatr Oncol 1990;18:426.

21. Brand WN, Schneider PA, Tokas RP. Long term results of a pilot study of low dose craniospinal irradiation for cerebellar medulloblastoma. Int J Radiat Oncol Biol Phys 1987;13: 1641-5.

Received for publication August 1994 Accepted following revision December 1994