ORIGINAL PAPER

Treatment outcome and patterns of failure in patientsof pinealoblastoma: review of literature and clinical experiencefrom a regional cancer centre in north India

Ahitagni Biswas1 & Supriya Mallick1& Suvendu Purkait2 & Ajeet Gandhi1 &

Chitra Sarkar2 & Manmohan Singh3& Pramod Kumar Julka1 & Goura Kishor Rath1

Received: 27 February 2015 /Accepted: 15 May 2015 /Published online: 4 June 2015# Springer-Verlag Berlin Heidelberg 2015

AbstractPurpose Pinealoblastoma is a highly malignant embryonaltumour of the pineal region affecting children and youngadults. We herein intend to report the clinical features andtreatment outcome of patients of pinealoblastoma treated atour institute.Methods Clinical data was collected by retrospective chartreview from 2003–2012. Histopathology slides werereviewed, and relevant immunohistochemistry stains weredone. Overall survival (OS) and recurrence-free survival(RFS) were analysed by Kaplan-Meier product-limit method.Univariate and multivariate analyses of prognostic factorswere done by log rank test and Cox proportional hazard re-gression model, respectively.Results Seventeen patients met the study criterion(male:female = 11:6). Median age at presentationwas 14 years(range 4–47 years). Surgical resection was gross total in 6(35.29 %), near-total in 2 (11.76 %), sub-total in 2(11.76 %), and limited to biopsy in 7 (41.18 %) patients. Atpresentation, 4 patients had leptomeningeal dissemination.Radiation therapy was delivered in all patients—craniospinal

irradiation in 15 (88.24 %), whole brain irradiation in 1(5.88 %), and whole ventricular irradiation followed by boostin 1 (5.88 %) patient. Systemic chemotherapy (median 6 cy-cles) was given in 14 (82.35 %) patients. The most commonregimen was a combination of carboplatin and etoposide, usedin 10 (58.82 %) patients. After a median follow-up of30.3 months (mean 32.01 months), death and disease recur-rences were noted in 3 (17.65 %) and 7 (41.18 %) patients.Amongst the patients with recurrent disease, 4 had spinal dropmetastases and 3 had local recurrence along with spinal dropmetastases. Median OS was not reached, and estimated medi-an RFS was noted to be 5.49 years. The actuarial rates of OSand RFS at 2 years were 85.6 and 73.1 %, respectively. Onunivariate analysis, age more than 8 years (P=0.0071) andM0stage (P=0.0483) were significant predictors of improvedRFS. Age retained significance on multivariate analysis ofRFS (P=0.02932).Conclusion Maximal safe resection followed by craniospinalirradiation and systemic chemotherapy with 6 cycles ofcarboplatin-etoposide regimen is a reasonable treatment strat-egy in patients of pinealoblastoma more than 8 years of age ina developing nation. However, the same strategy is less effec-tive in younger children and innovative study designs of in-tensification of post-operative treatment must be explored inthis age group.

Keywords Craniospinal irradiation . Pinealoblastoma .

Pineal parenchymal tumour . Radiotherapy

Introduction

Pineal tumour constitutes less than 1 % of primary tu-mours of the central nervous system, and pineal paren-chymal tumour represents less than 30 % of all pineal

Part of the data was presented as oral abstract in 10th ASNO-5th ISNOConference at Mumbai, India, March 2013. J Cancer Res Ther 2013(March); 9(S1):S8.

* Ahitagni Biswasdr_ahitagni@yahoo.co.in

1 Department of Radiation Oncology, All India Institute of MedicalSciences, New Delhi, India 110029

2 Department of Pathology, All India Institute of Medical Sciences,New Delhi, India

3 Department of Neurosurgery, All India Institute of Medical Sciences,New Delhi, India

Childs Nerv Syst (2015) 31:1291–1304DOI 10.1007/s00381-015-2751-1

neoplasms [1–3]. World Health Organization (WHO)classifies pineal parenchymal tumour into pineocytoma(grade II), pineal parenchymal tumour of intermediatedifferentiation (grade II/III) and pinealoblastoma (gradeIV) [2]. Pinealoblastoma is a highly malignant embryo-nal tumour of the pineal region affecting children andyoung adults [3]. The current study was conducted atour institute to evaluate the clinical features, treatmentprotocol, patterns of failure and survival outcome in 17consecutive patients of pinealoblastoma.

Methods

Medical records were reviewed and clinical data collected onpatients of pinealoblastoma attending the Institute RotaryCancer Hospital, All India Institute of Medical Sciences,New Delhi, in a 9-year period (2003–2012). Histopathologyslides were reviewed, and relevant immunohistochemistrystains were done. The diagnostic work-up in these patientscomprised full blood count, liver and kidney function test,chest X-ray, contrast-enhanced magnetic resonance imaging(MRI) of the entire neuraxis and cerebrospinal fluid (CSF)cytology. These patients underwent maximal safe resectionin the department of neurosurgery. Subsequently, they wereassessed by the neuro-oncologist for adjuvant treatment. Fitpatients were offered craniospinal irradiation—36 Gy/20fractions/4 weeks to entire neuraxis followed by local boost20 Gy/10 fractions/2 weeks usually by three-dimensional con-formal radiotherapy on linear accelerator (2 cranial fields and1–2 spinal fields with 6MVX-rays). In children below 5 yearsof age, immobilization was achieved with the aid of generalanaesthesia if required. Blood counts were repeated twice ev-ery week, and toxicity charting was done weekly using theRadiation Therapy Oncology Group (RTOG) acute radiationmorbidity scoring criterion. One month after the completionof craniospinal irradiation and full recovery of blood counts,systemic chemotherapy was administered every 3 weeks for6 cycles. The most commonly used regimen included injcarboplatin 400 mg/m2 IV D1 and inj etoposide 100 mg/m2

IV D1–D3. Intrathecal methotrexate (10 mg weekly) wasadded in patients with leptomeningeal dissemination. Dosereduction and chemotherapy interruption were done in caseof severe (grade 3/4) toxicity. Thereafter, follow-up was doneevery 3 months for the first 2 years, every 6 months from 3rdto 5th year and annually thereafter. Contrast-enhancedMRI ofthe neuraxis was done 3 months and 1 year after completion oftreatment and then only on suspicion of disease recurrence.Response assessment was done as per modified Mc Donaldcriterion [4]. Overall survival (OS) and recurrence-free surviv-al (RFS) were analysed by Kaplan-Meier product-limit meth-od. Univariate analysis of factors predictive of RFS was doneby log rank test. Cox proportional hazard regression model

was used for multivariate analysis of factors predictive ofRFS. P value less than 0.05 was considered statistically sig-nificant. MedCalc software (version 11.3.0) was used for sta-tistical analysis.

Results

Patient characteristics

Seventeen patients met the study criterion. A male sex predi-lection was noted (male:female = 11:6). Median age at presen-tation was 14 years (range 4–47 years). Presenting featuresincluded headache in 15 (88.24 %), vomiting in 9(52.94 %), visual deterioration in 6 (35.29 %), ataxia in 5(29.41 %) and seizures in 2 (11.76 %) patients. MedianKarnofsky performance scale (KPS) was noted to be 80 (range50–90) (Table 1).

Radiology

Contrast-enhanced MRI of the brain usually revealed hetero-geneous contrast-enhancing solid cystic pineal lesions. At pre-sentation, hydrocephalus, contrast enhancement, calcification,tectal plate involvement, cystic component and intraventricu-lar extension were evident in 14 (82.35 %), 12 (70.59 %), 5(29.41 %), 5 (29.41 %), 3 (17.65 %) and 2 (11.76 %)patients respectively. Three (17.65%) patients had spinal dropmetastases on contrast-enhanced MRI of the whole spine (M3disease). One patient had positive CSF cytology but normalMRI spine (M1 disease) (Fig. 1).

Surgery

Surgical resection was gross total in 6 (35.29 %), near-total in2 (11.76%), sub-total in 2 (11.76%) and limited to biopsy in 7(41.18 %) patients. Eleven (64.71 %) patients required theplacement of medium pressure ventriculo-peritoneal(MPVP) shunt for hydrocephalus.

Pathology

Post-operative histopathology showed highly cellular, poorlydifferentiated tumour comprising small round cells with highnucleo-cytoplasmic ratio. The tumour cells were arranged insheets and had brisk mitotic activity. On immunohistochem-istry, synaptophysin and chromogranin were positive in 100and 50 % of the patients, respectively. The MIB-1 labellingindex was high in all cases (median 34 %; range 20–80 %)indicating high proliferative activity of the tumour (Fig. 2).

1292 Childs Nerv Syst (2015) 31:1291–1304

Radiation therapy

Radiation therapy was delivered in all patients—craniospinal irradiation (36 Gy/20 fractions/4 weeks tocraniospinal axis followed by local boost of 20 Gy/10fractions/2 weeks) in 15 (88.24 %), whole brain

irradiation in 1 (5.88 %) and whole ventricular irradia-tion followed by boost in 1 (5.88 %) patient. Concurrentchemotherapy was not used in this cohort. Treatmentinterruption of more than 1 week was noted in 1 patient.Two patients required the aid of general anaesthesia(Fig. 3).

Table 1 Compendium of patient and tumour characteristics, treatment and clinical outcome in 17 consecutive patients of pinealoblastoma

Serialno.

Age(years)

Sex KPS Mstage

Surgery Radiotherapy Chemotherapy No. ofcycles

Recurrence FU duration(months)

Status atlast FU

1 12 F 90 M0 GTE CSI None 0 None 1.9 CR

2 4 M 70 M0 GTE WBRT CBDCA, VP-16 4 Local + lepto-meningeal 8.1 PD (E)

3 26 M 70 M0 Bx CSI BEP 3 None 9.33 CR

4 47 M 60 M0 Bx CSI CBDCA, VP-16 6 None 25.8 CR

5 10 M 70 M0 STE CSI None 0 None 69.27 CR

6 14 F 70 M0 Bx CSI CBDCA, VP-16 3 None 57.37 CR

7 4 F 80 M3 NTE CSI CBDCA, VP-16 6 Lepto-meningeal 67.3 PD

8 7 F 80 M3 GTE CSI CBDCA, VP-16 6 Lepto-meningeal 38.93 PD

9 16 M 90 M0 GTE CSI CBDCA, VP-16 6 None 56.47 CR

10 4 M 90 M3 STE CSI CBDCA, VP-16 6 Local + lepto-meningeal 35.1 PD

11 29 M 80 M0 GTE CSI None 0 None 6.23 CR

12 7 M 90 M0 Bx CSI CBDCA, VP-16 6 Leptomeningeal 29.03 PD (E)

13 18 M 70 M0 NTE CSI VCR, CBDCA, VP-16 6 None 43.73 CR

14 17 F 80 M1 Bx CSI VCR, CBDCA, VP-16 6 Local + leptomeningeal 18.5 PD (E)

15 25 F 50 M0 Bx WVRT VCR, CBDCA, VP-16 6 None 36.3 PR

16 24 M 80 M0 Bx CSI CBDCA, VP-16 3 None 30.3 CR

17 7 M 80 M0 GTE CSI CBDCA, VP-16 3 Lepomeningeal 10.43 PD

KPSKarnofsky performance scale,FU follow-up,Mmale,F female,GTE gross total excision,NTE near total excision, STE subtotal excision,Bx biopsy,CSI craniospinal irradiation, WBRT whole brain RT, WVRT whole ventricular RT, CBDCA carboplatin, VP-16 etoposide, VCR vincristine, BEPbleomycin, etoposide, cisplatin, CR complete response, PR partial response, PD progressive disease, E expired

Fig. 1 a T1weighted plain sagittal MRI brain and b T2weighted coronalMRI brain images showing a 2.8×1.9-cm well-defined mass in pinealregion, isointense and slightly hyperintense to grey matter on T1 and T2weighted images, respectively, in patient no. 7. T1 weighted post-contrastc sagittal and d axial MRI brain images showing a 1.6×1.6-cm well-

defined homogeneously enhancing lesion in pineal region with featuresof obstructive hydrocephalus in patient no. 17. T1 weighted post-contraste sagittal MRI spine, f coronal MRI and g sagittal MRI of brain imagesshowing diffuse leptomeningeal dissemination in patient no. 7 on follow-up

Childs Nerv Syst (2015) 31:1291–1304 1293

Systemic chemotherapy

Systemic chemotherapy was administered in 14(82.35 %) patients. The most common regimen was acombination of carboplatin and etoposide, used in 10(58.82 %) patients. Inj vincristine—1.5 mg/m2 IV D1(top dose of 2 mg) was added to the combination ofcarboplatin-etoposide in another 3 (17.65 %) patients.The median number of cycles of chemotherapy givenwas 6 (range 0–6). Chemotherapy-related severe(grade3/4) haematological toxicity was observed in 3(17.65 %) patients and included anaemia in 2, leucope-nia in 2, neutropenia in 2 and thrombocytopenia in 1patient. The most common sequence of treatment wassurgery followed by radiotherapy and chemotherapy.

Survival analysis

After a median follow-up of 30.3 months (mean32.01 months), death and disease recurrence were notedin 3 (17.65 %) and 7 (41.18 %) patients. The cause ofdeath in all the 3 patients was disease progression. Me-dian OS was not reached and estimated median RFSwas noted to be 5.49 years. The actuarial rate of OSat 2 and 3 years were 85.6 % and 77 %, respectively.The actuarial rate of RFS at 2 and 3 years were 73.1 %and 57.5 %, respectively. On univariate analysis of fac-tors determining RFS, patients with M0 disease hadsignificantly better RFS (median RFS not reached) com-pared with patients with M+ disease (median RFS26.23 months) (P=0.0483). Also, older children (age

>8 years) and adults had significantly improved RFS(median RFS not reached) compared with younger chil-dren (age <8 years) (median RFS 25.17 months) (P=0.0071). The impact of other factors e.g. sex, KPS, ex-tent of resection, and number of cycles of chemotherapyon RFS was non-significant (Table 2). Age retained sig-nificance on multivariate analysis of RFS (P=0.02932;hazard ratio=0.0935) (Figs. 4, 5, 6, 7).

Patterns of failure

Amongst the 7 patients with recurrent disease, 4 had spinaldrop metastases and 3 had local recurrence along with spinaldrop metastases. The median time to disease recurrence was24.57 months (range 5.63–65.83 months). It is important tonote that all of the 6 patients less than 8 years of age experi-enced disease recurrence in contrast to only 1 recurrenceamongst older patients.

Salvage treatment

Salvage therapy was offered to 6 (85.71 %) patients.Multiagent intravenous chemotherapy with a combina-t i o n o f v i n c r i s t i n e , e t o p o s i d e , c a r b op l a t i n /cyclophosphamide and weekly intrathecal methotrexatewas used in 5 patients. Two patients achieved partialresponse and 1 patient had initial complete responsefollowed by subsequent disease progression. Two pa-tients are currently undergoing salvage chemotherapy.One patient with isolated spinal drop metastasisunderwent gross total excision of spinal intradural

Fig. 2 a Photomicrographshowing a highly cellular tumourwith tumour cells arranged indiffuse sheets with foci ofnecrosis (×100). b The tumourcells have high nucleo-cytoplasmic ratio with scant cy-toplasm and indistinct cell bor-ders, vesicular nuclei with indis-tinct nucleoli (×400). c The tu-mour cells are immunopositivefor synaptophysin (cytoplasmicstaining) (×400). d The tumourcells are immunopositive forchromogranin (×400). e MIB-1stain showing high proliferativeactivity of the tumour (×400)

1294 Childs Nerv Syst (2015) 31:1291–1304

metastatic lesion (D4–D6) followed by palliative radia-tion (12 Gy/3 fractions/3 days). He was planned forfurther systemic and intrathecal chemotherapy but

defaulted due to poor general health and died due toprogressive disease 6 months after detection ofrecurrence.

Fig. 3 a, b, c Planning target volume (PTV) encompassing the clinicaltarget volume (CTV—entire craniospinal axis) with an isotropic expan-sion of 5 mm and various organs at risk (OAR) e.g. bilateral eyes, lens,lungs, heart and kidneys outlined on the planning CT images. d Combi-nation of 2 bilateral parallel opposed cranial fields (with half beam block)and a direct spinal field used to treat the entire craniospinal axis, the

cranial fields have been given a collimation twist to match the divergenceof the spinal fields. e Field shaping for the cranial fields with the aid ofmultileaf-collimator (MLC). f 95 % of prescription isodose colour-washshowing good coverage of entire brain and the meningeal sheaths, poste-rior one-third of orbit with simultaneous sparing of bilateral lens

Table 2 Univariate analysis of recurrence-free survival (RFS)

Prognostic factor Median RFS (months) 2-year RFS rate 3-year RFS rate P value Hazard ratio 95 % CI of HR

Age

<8 years (N=6) 25.17 66.7 % 16.7 % 0.0071 0.09859 0.02129 to 0.4567>8 years (N=11) Not reached 90 % 90 %

Sex

Male (N=11) Not reached 80 % 54.9 % 0.7178 1.3132 0.2815 to 6.1264Female (N=6) 65.83 80 % 60 %

KPS

≥80 (N=10) 26.7 76.2 % 38.1 % 0.0746 0.1812 0.04113 to 0.7984<80 (N=7) Not reached 85.7 % 85.7 %

M stage

M0 (N=13) Not reached 90 % 78.7 % 0.0483 0.2177 0.03819 to 1.2412M+ (N=4) 26.23 75 % 25 %

Chemotherapy cycles

>3 (N=10) 26.7 80 % 48 % 0.2152 0.2883 0.06195 to 1.3414≤3 (N=7) Not reached 80 % 80 %

Extent of resection

GTE/NTE (N=8) 45.8 66.7 % 50 % 0.3920 0.5272 0.1171 to 2.3737STE/BX (N=9) Not reached 88.9 % 61 %

KPS Karnofsky performance scale, CI confidence interval, GTE gross total excision, NTE near total excision, STE subtotal excision, Bx biopsy

Childs Nerv Syst (2015) 31:1291–1304 1295

Discussion

Hart et al. described supratentorial primitive neuroectodermaltumour (SPNET) as a poorly differentiated intracranial embry-onal tumour in 1973 [5]. SPNET is an extremely rare centralnervous system tumour and constitutes 2.5 % of all paediatricbrain tumour [5–8]. Although histologically indistinguishablefrom other small round cell tumours of the brain, SPNET ischaracterized by its distinct aggressive clinical behaviour andpoorer outcome [9–11]. There is mounting evidence thatSPNET and medulloblastoma (MB) have different molecularalterations and different responses to treatment [6, 9, 12]. Gainof chromosome 17q is more common in MB, whereas loss ofchromosome 14q is more common in SPNET [12]. Recently,Picard and colleagues reported three distinct molecular sub-groups of the central nervous system PNET distinguished byprimitive neural (group 1), oligoneural (group 2) and mesen-chymal (group 3) lineage with differential expression of celllineage markers—LIN28 and OLIG2 [13].

SPNET is commonly located within the cerebral cortex andpineal region (pinealoblastoma) [14, 15]. These tumours arehistologically heterogeneous with variable amount of glial,neuronal and ependymal differentiation [16]. Pinealoblastomacommonly affects children and young adults, and the medianage at presentation in our study was 14 years. The commonpresenting symptoms include features of raised intracranialtension, Parinaud’s syndrome, ataxia (due to involvement ofthe cerebellum/brainstem) and endocrine abnormalities (dueto hypothalamic involvement or perturbation of melatonin

secretion) [3]. Headache, vomiting, visual disturbance andataxia were the common presenting features in our study co-hort. SPNET shows a high propensity of CSF dissemination(14–20 %) [17, 18]. In the present series, 3 patients had M3and 1 patient had M1 disease at presentation.

The management of SPNET has largely evolved based onthe treatment philosophy for high-risk medulloblastoma [15].Multimodality management comprising surgery, radiationtherapy and systemic chemotherapy is essential for therapeuticsuccess in this rare tumour [17]. Surgery is the cornerstone ofmanagement and offers rapid symptom relief and long-termdisease control [19]. Variable rates of gross total resection(GTR) have been reported in literature ranging from 20–53.33 % (Table 3). Young age at diagnosis, large tumour sizeand extension of tumour to eloquent areas of the brain oftenpreclude GTR. Resection is considered difficult in pineal tu-mour due to deep-seated location, and surgical intervention isoften limited to biopsy. In a study of 35 consecutive patients ofprimary pineal tumours from 7 academic centres of Rare Can-cer Network (RCN), only biopsy was performed in 13(37.14 %) patients [3]. In the available literature, the prognos-tic significance of achievement of GTR is controversial [16,17, 20, 34]. Albright et al. in a series of 27 patients of SPNETtreated on CCG-921 protocol showed that post-operative sur-vival at 4 years was 40 versus 13 % in patients with post-operative residuum of less than and more than 1.5 cm2, re-spectively [21]. There was a trend towards better survival inchildren undergoing GTR (P=0.08) in a series of 36 patientsof SPNET from the Hospital for Sick Children, Toronto re-ported by Dirks et al. [16]. In the present study, GTR could beaccomplished in only 35.29 % of patients.

Keeping in mind the natural history of the tumour,craniospinal irradiation (CSI) followed by local boost to tu-mour bed is considered standard [18]. The most commonlyused time dose fractionation schedule is CSI to a dose of36 Gy (range 18–40 Gy) followed by local boost to 54 Gy(range 45–72 Gy) in conventional fractionation (Table 3). Re-duced dose CSI (23.4 Gy) or focal RT alone has been used invery young children (1.5–3 years) in few studies to minimizethe late effects of radiation (Table 3). Paulino et al. in a seriesof 25 patients of SPNET reported 5-year and 10-year progres-sion-free survival (PFS) rates of 47.1 % in patients treatedwith CSI compared to 12.5 and 0 % in patients undergoingwhole brain RT (WBRT) or focal RT(P=0.02) [18]. Failure atuntreated neuraxis site was the most common cause of pro-gression in 6 out of 8 patients receiving WBRT or focal RT[18]. McBride et al. in a retrospective review of 15 patients ofnon-pineal SPNET observed a statistically significant differ-ence in overall survival in patients who received upfront RTversus those who did not (P=0.048) [17]. In our series, com-prehensive craniospinal radiation was used in 15 (88.24 %)patients, whereas whole brain and ventricular radiation wasused in 1 patient each due to poor general condition. It is

Fig. 4 Kaplan-Meier survival curve depicting overall survival

Fig. 5 Kaplan-Meier survival curve depicting recurrence-free survival

1296 Childs Nerv Syst (2015) 31:1291–1304

important to note that the patient who received whole brainradiation in our series had local and leptomeningeal relapseand eventually died of progressive disease. Craniospinal irra-diation should be a part of the multidisciplinary treatment inall fit patients of SPNET more than 6 years of age and shouldbe strongly considered in younger patients between 3 and6 years of age.

Exploiting the differential repair capacity of normal andtumour tissues, hyperfractionated radiotherapy (HFRT) is anattractive option in this rare tumour, which is believed to bemore resistant to conventional radiotherapy and chemothera-py in comparison to medullobastoma [8, 32, 33]. In variousstudies, CSI (31.2–40 Gy) followed by local boost (up to59.7–72 Gy) has been delivered using 1–1.3 Gy per fractionand 2 fractions per day, 6–8 h apart with a view to achievingsuperior tumour control by dose escalation with simultaneousminimization of late morbidities [8, 32, 33] (Table 3). Theclinical outcome in these studies has been quite satisfactorywith overall survival rates at 3 and 5 years in excess of 60 and50 %, respectively (Table 3). However, this approach is quiteresource intensive and in young children, who require the aidof general anaesthesia or conscious sedation for immobiliza-tion, delivery of 2 fractions per day may be quite challengingfrom the nutritional point of view.

Taking a cue from average-risk medulloblastoma,Chintagumpala et al. explored the efficacy of risk-adaptedtreatment in patients of SPNET [6]. In a study of 16 patientsof SPNET (pineal 7, non-pineal 9), 8 average-risk patientsunderwent CSI to a dose of 23.4 Gy and 8 high-risk patientsunderwent CSI to a dose of 36 Gy in M0 disease with post-operative residuum more than 1.5 cm2 or 36–39.6 Gy in M2disease and 39.6 Gy in M3 disease. All patients receivedthree-dimensional conformal boost to the tumour bed to adose of 55.8 Gy and to metastatic sites to a dose of 50.4 Gy.After a gap of 6 weeks, all patients received 4 cycles of non-myeloablative high-dose chemotherapy with cisplatin, vin-cristine and cyclophosphamide followed by autologous stemcell rescue. After a median follow-up of 5.4 years, 12 patientswere alive with 5-year EFS rates of 75 and 60 % and 5-yearOS rates of 88 and 58% in average-risk and high-risk patients,respectively. This small pilot study suggests that risk-adaptedcraniospinal irradiation is feasible in patients with SPNET,provided they receive high-dose chemotherapy in the adjuvantsetting (Table 3).

Adjuvant chemotherapy using multidrug regimen is advo-cated to enhance systemic control in patients of SPNET [24,28, 35]. In the CCG 921 trial by Cohen et al., 55 patients ofSPNET after surgery were randomized to receive craniospinal

Fig. 6 Kaplan-Meier survivalcurve depicting recurrence-freesurvival in patients with M0 ver-sus M+ disease

Fig. 7 Kaplan-Meier survivalcurve depicting recurrence-freesurvival in patients more than8 years of age versus less than8 years of age

Childs Nerv Syst (2015) 31:1291–1304 1297

Tab

le3

Com

pendium

ofrecent

studiesusingmultim

odality

managem

entfor

patientsof

SPNET

Author

No.of

patients

Pineal/non-

pineal

Extento

fresection

Radiationdose

(CSI)

Chemotherapy

Survivaloutcom

ePatternsof

failure

Observation

Trialsexploringcombinedmodality

treatm

ent:radiotherapy

(CSI)andconventionalchemotherapy

Cohen

etal.(1995)

(CCG921study)

[20]

4417/27

GTE-13(30

%)

NTE-12

STE-11

Partialexcision-3

biopsy-5

36Gy(boostup

to54

Gy)

(inchildren≥3

years)

23.4

Gy(boostup

to45

Gy

inchildren1.5–3years)

Standard

arm:C

CNU+VCR+

prednisone

q6weeks

×8(after

RT)

Experim

entalarm

:8in1chem

owith

VCR,H

U,B

CNU,procarbazine,

CDDP,AraC,prednisone,CTX

(2cycles

preRTand8cycles

afterRT)

3-yearPFS

-45%

3-yearOS-57

%-

OnMVA,pineallocation(P=0.011)andM0

disease(P=0.007)

significantpredictors

ofimproved

PFS

Nosignificantd

ifferencebetweenarmsA

andBwith

respecttoPF

Sbutarm

Bassociated

with

higherhaem

atological

andnon-haem

atologicaltoxicity

Albrightetal.

(1995)

(CCG

921study)

[21]

270/27

GTE-10(37

%)

NTE-8

STE-7

biopsy-2

36Gy(boostup

to54

Gy)

(inchildren≥3

years,

N=18)

23.4

Gy(boostup

to45

Gy

inchildren1.5–3years,

N=9)

Standardarm:C

CNU+VCR+

prednisone

q6weeks

×8(afterR

T)

Experim

entalarm

:8in1chem

owith

VCR,H

U,B

CNU,procarbazine,

CDDP,AraC,P

rednisone,CTX

(2cycles

preRTand8cycles

afterRT)

5-yearPFS

-31%

5-yearOS-34

%–

PFSsignificantly

improved

inpatients

with

M0disease(P=0.003)

andage

>3years(P=0.05)

Post-opsurvivalat4years40

versus

13%

inpatientswith

post-opresiduum

<1.5

versus

>1.5cm

2(P=0.19)

Jakackietal.(1995)

(CCG921study)

[22]

25 (8-infants)

(17-older

children)

25/0

GTE-5(20%)

NTE-5

STE-6

PE-4

biopsy-5

36Gyifage>3years

(boostup

to54Gy)

(n=15)

23.4

Gyifage=1.5–3

years(n=2)

Standardarm:C

CNU+VCR+

Prednisone

q6weeks

×8(afterR

T)

Experim

entalarm

:8in1chem

owith

VCR,H

U,B

CNU,procarbazine,

CDDP,AraC,prednisone,CTX

(2cycles

preRTand8cycles

afterRT)

allinfants(N

=8)

received

8in

1chem

owithoutR

T

3-yearPFS

-61%

3-yearOS-73

%Local-8

(32%)

Leptomeningeal-3

(12%)

Local+leptom

eningeal-3

(12%)

Amongstp

atients>18

monthswho

received

CSIandchem

o,thosewith

pinealoblastom

afaredsignificantly

betterthan

non-pinealSP

NE

T(P=0.026)

‘8in

1chem

o’withoutR

Tineffectivefor

infantswith

PBResidualenhancementfollowingRTnot

predictiveof

treatm

entfailure

Dirks

etal.(1996)

[16]

3610/26

GTE-7(19.44

%)

STE-24

biopsy-5

25–35Gy(boostup

to45–

54Gy)

(adjuvantR

Tin

26patients;

CSI-19

andWBRTin7)

– (Adjuvantchemoin

13)

3-yearOS-34

%5yearOS-18

%Local-54%

Leptomeningealcomponent

-46%

Statisticallysignificantw

orse

survivalin

youngchildren<3years(P=0.006)

Trend

towards

bettersurvivalin

children

treatedsince1984

(P=0.11)and

childrenundergoing

GTE(P=0.08)

Amongstthe

survivors,allreceivedCSI

and4received

chem

o

Reddy

etal.(2000)

[15]

2213/9

GTE/NTE-10

(45.45

%)

PE-9

biopsy-3

34–40Gy(Boostup

to46.8–60Gy)

CDDP+

VCR+CCNUq6

weeks

×8

(post-radiation)

WeeklyVCRconcurrent

with

RT

5-yearPFS

-37%

5-yearOS-53

%–

Improved

PFS

inpatientswith

M0versus

M1disease(P=0.04)

Trend

towards

improved

PFS

inpatients

undergoing

complete/near-com

plete

resectionversus

partialresection/

biopsy

(P=0.22)

Nodifference

inoutcom

e(PFS

)inpatients

with

pinealversus

non-pinealtumours

Paulino(2004)

[18]

257/18

GTE-5(20%)

STE-10

biopsy-10

36Gy(boostup

to54

Gy)

CSI→

boost-17

WBRT→

boost-2

focalR

T→

6

8in1chem

owith

VCR,H

U,B

CNU,

procarbazine,C

DDP,AraC,

prednisone,C

TX(m

ostcom

mon

regimen)

Chemoin

16pts(64%)

5-yearPFS

-36%

10-yearPF

S-27

%prim

arysitecontrol

rate-62%

atboth

5and10

years

Local-7

(28%)

Non-primarysitein

brain-

10(40%)

Spinal(leptomeningeal)-9

(28%)

Significantly

improved

PFSin

patients

with

M0disease(10-yearPF

S-30

%)

versus

M+disease(10-yearPF

S-0%)

(P=0.01)andpatientsreceivingCSI

(10-yearPF

S-47.1

%)versus

those

receivingWBRT/focalRT(10-year

PFS-0%)(P=0.02)

Failureatnon-treatedneuraxissitemost

common

siteof

progressioninpatients

receivingWBRT/focalRT(6/8)

1298 Childs Nerv Syst (2015) 31:1291–1304

Tab

le3

(contin

ued)

Author

No.of

patients

Pineal/non-

pineal

Extento

fresection

Radiationdose

(CSI)

Chemotherapy

Survivaloutcom

ePatternsof

failure

Observation

Pizeretal.(2006)

(SIO

P-UKCCSG

PNET3study)[23]

6814/54

GTE-28(45.16

%)

incompleteexcision-25

biopsy-8

unknow

n-1

(surgicald

etails

availablein

62patients)

35Gy

(boostup

to55

Gy)

VCR,V

P-16,C

BDCAalternating

with

VCR,V

P-16,C

TXX4(pre-

radiation)

5-yearEFS

-47%

5-yearOS-51.5

%Local-18(26.47

%)

Local+leptom

eningeal-5

(7.35%)

Distant

leptom

eningeal-6

(10.3%)

Unspecified-1

Death-32

Addition

ofpre-radiationchem

odidnot

improveOSandEFS

5-yearOS71.4

%in

PBand40.7

%in

non-pinealSP

NET

McB

ride

etal.

(2008)

[17]

150/15

GTE-8(53.33

%)

incompleteexcision-7

23.4–36Gy

(boostup

to50.4–72Gy)

(optionof

focalR

Tatthe

discretionof

thetreating

oncologist)

(RTin

10/15patients—

up-

frontin5andas

salvage

treatmentin5)

CDDP,VP-16,CTX,V

CR(m

ost

common

regimen)

high-dosechem

o→

ASCRin

2

–Local-5

(33.33

%)

Local+leptom

eningeal-2

(13.33

%)

OSsignificantly

improved

inpatients

undergoing

upfrontR

T(P=0.048)

Trend

towards

improved

OSin

patients

undergoing

GTE(P=0.10)

Localrecurrence—dominantp

attern

offailure

Trialsexploringdeferral/omission

ofradiotherapy

(CSI)

Duffneretal.(1993)

(POGstudy)

[24]

36-

GTE-8

(27%)

incompleteexcision-

22(surgicald

etails

availablein

30patients)

35.2

Gy(boostup

to54

Gy)

(inM+/residual

orprogressivedisease

afterchem

o)24

Gy(boostup

to50

Gy)

inpatientswith

noresiduum

afterchem

o

CTX+VCRx2alternatingwith

CDDP+VP-16

X1tilld

isease

progressionor2years(inpatients

<2years)or1year(inpatients2–

3years)

2-yearPFS

-19%

2-yearOS-21

%–

Intheentirecohort(N

=198),

completeresectionassociated

with

significantly

improved

PFS(relative

risk-0.33,95

%CI0.2–0.54)

Patientswith

embryonaltum

our(PNET)

onhistopathology

hadsignificantly

worse

PFS

(relativerisk-2.2,95%

CI-

1.4–3.4)

With

theuseof

post-operativechem

o,RT

couldbe

deferred

for1–2yearsespe-

cially

inpatientswho

hadcomplete

resectionof

tumouror

completere-

sponse

tochem

o

Geyeretal.(1994)

(CCG921study)

[25]

198/11

GTE-6(31.58

%)

NTE-5

STE-3

PE-2

biopsy-3

– (FocalRTafter2

cyclesof8

in1chem

oor

CSI

1yearafterdiagnosisat

completionof

chem

oallowed

inprotocol)

8in1chem

owith

VCR,H

U,B

CNU,

procarbazine,,,CDDP,AraC,

prednisone,C

TX

3-yearPF

S-0%

(PB)

55%

(non-pineal

SPNET)

–Non

pinealSP

NETandM0disease

significantpredictorsof

improved

PFS

Delayed

orreducedvolumeRTwas

tobe

administeredin

allp

atientsbutinfact

omitted

inmostcases

Intheentirecohort(N

=82),only

3outo

f19

event-free

survivors2yearsfrom

diagnosisreceived

RT

Mason

etal.(1998)

[26]

143/11

GTE-7

(50%)

STE-5

PE-2

– (RTonly

forPD

orresidual

diseaseattim

eof

ABMR)

Inductionchem

owith

VCR,C

DDP,

CTX,V

P-16

q3weeks

×5

Consolidationchem

owith

CBDCA,

VP-16,thiotepafollowed

byABMRin

10/14patients;

7/14

<3yearsof

age

2-yearEFS

-43%

2-yearOS-64

%–

Responserateto

inductionchem

o67

%In

theentirecohortof

malignant

brain

tumour(N

=62),response

rateand

survivalbetterin

MB,P

NETand

ependymom

aIn

theentirecohort,R

Tonly

in19/62pa-

tients

Toxicdeath-8%

Marec-Berardetal.

(2002)

(BB

SFO

Pstudy)

[27]

254/17

(4-m

edullo-

epithelioma)

GTE-9

(36%)

STE-9

PE-3

biopsy-2

None-2

Not

defined

CBDCA,P

rocarbazine(course1);

CDDP,VP-16(course2);C

TX,V

CR

(course3)-alternatingregimens

for18

months

5-yearOS-14

%2-yearOS-30

%2-yearRFS

-4%

Local-15(60%)

Local+leptom

eningeal-7

(28%)

Local+infratentorial-1

(4%)

Local+

distant(peritoneum

)-1

(4%)

Trend

towards

improved

EFS

inpatients

undergoing

completeresection

Patientswith

hemispherictumourshad

improved

OScomparedto

thosewith

deep

tumours

Childs Nerv Syst (2015) 31:1291–1304 1299

Tab

le3

(contin

ued)

Author

No.of

patients

Pineal/non-

pineal

Extento

fresection

Radiationdose

(CSI)

Chemotherapy

Survivaloutcome

Patternsof

failure

Observation

Geyeretal.(2005)

(CCG9921

study)

[28]

4610/36

GTE/NTE-28

(60.87

%)

incompleteexcision-18

18–30.6Gy(depending

onageanddiseasestatus;

only

inM+/recurrent

disease)(boostup

to54

Gy)

(focalRT50.4–54Gyin

M0diseasewith

residuum

afterinduction

chem

o)

Inductionchem

owith

VCR,C

DDP,

CTX,V

P-16(regim

enA)/VCR,

CBDCA,Ifosfam

ide,VP-16

(regim

enB)×5→

maintenance

chem

owith

VCR,C

BDCA,

CTX,V

P-16×8

5-yearOS-31

%5-yearEFS

-17%

Local-23(50%)

Distant-5(10.87

%)

Local+distant-8(17.39

%)

Death-2

Mostsurvivors(50%

ofthosealiveat

5years)didnotreceive

RT

Intheentirecohortof

malignant

brain

tumour(N

=299),R

Rto

induction

chem

o42

%Nosignificantd

ifferencein

between2

armsin

term

sof

RR/E

FS

1.8tim

eshigherrateoftreatm

entfailurein

SPNETcomparedwith

MB

Tim

mermannetal.

(2006)

(HIT

SKK87

andHIT

SKK92

trials

[29]

292/27

GTE-6

(20.69

%)

incompleteexcision-

23

35.2

Gy(boostup

to55.2

Gy)

(RTonly

in14/29patients:

preventiveRTin

10pa-

tientsandsalvageRTin

4patients)

HITSK

K87

(N=13):

Low

risk

(R0/M0):M

aintenance

chem

otillage

of3yearsor

PDHighrisk

(R+/M

+):

Inductionchem

o(C1-VCR,

Procarbazine,M

TXandLV

rescue;C

2-procarbazine,M

TX

andLV

rescue,ifosfam

ide,VP-

16,C

DDP,AraC

HIT

SKK92

(N=16):

MTX(intravenous

and

intraventricular),VCR,C

TX,

CBDCA,VP-16

3-yearPF

S-14.9%

3-yearOS-17.2

%Local-13(44.83

%)

Distant-3

(10.34

%)

Local+distant-8(27.59

%)

Improved

PFSandOSin

patients

receivingRT

Evenifintensivechem

oisgiven,om

ission

ofRTjeopardizessurvival

Delay

ofRTshould

belim

itedto

amaxim

umof

6months

Fangusaroetal.

(2008)

(HeadStartI

andIIstudy)

[14]

4313/30

GTE-21(48.84

%)

incompleteexcision-

22

23.4

Gy(boostup

to55.8

Gy)

(RTreceived

inonly

16pts—

14in

salvage

setting

and2as

partof

prim

aryT/t)

Intensifiedinductionchem

owith

VCR,C

DDP,CTX,VP-16(and

MTXin

M+ds)x5

→high-dose

myeloablativechem

ox1followed

byASC

R

5-yearEFS

-39%

5-yearOS-49

%Local-17(39.53

%)

Local+distant-6(13.95

%)

Distant-2

(4.65%)

Non-pinealS

PNETfaredsignificantly

betterthan

PB12

outo

f20

long

term

survivors(60%)

didnotreceive

RT

Toxicdeath-4.7%

Friedrichetal.

(2013)

(HIT

2000

trial)[30]

178/8

(1-Ependym

oblastoma)

GTE-7

(41.18

%)

incompleteexcision-

10

24Gy(boostup

to54.6

Gy)

(indiffusespinalmets,the

entirespinalaxis

received

36Gy)

(11/17

patientsreceived

CSI;3

aspartof

prim

ary

T/t,

8in

salvagesetting)

M0disease:adjuvantchem

owith

VCR,C

TX,M

TX,C

BDCA,V

P-16

×5cycles

(8months)(SKK

regimen)

M+disease:inductionchem

owith

CBDCA+VP-16(2-

3months)→

tandem

high-dose

chem

o(H

DCT)(containingin-

traventricularMTX)

5-yearEFS

-24%

5-yearOS-40

%Local-9

(52.94

%)

Distant-2

(11.76

%)

Local+distant-2(11.76

%)

Shortintensive

inductionchem

ofollowed

bytandem

HDCTsuperior

toprolongedandless

intensiveinduction

chem

oinCNSPN

ET/PB(Relapse

3/6

versus

10/11;

5-yearEFS

50versus

9%;5

-yearOS67

versus

27%)

Nosignificantd

ifferencein

survival

betweenpatientsof

PBandnon-pineal

SPNET

Trialsexploringhigh-dosechem

otherapy

followed

byASC

Randradiotherapy

(CSI)

Gururanganetal.

(2003)

[31]

1212/0

GTE-5(41.67

%)

incompleteexcision-7

36Gy(boostup

to59.4

Gy)

(noRTin

2pts<

2years)

Inductionchem

o(pre-radiatio

n):

Reg

A:C

TXq4

weeks

×4(N=9)

Reg

B:C

DDP+VCR+CTX+VP-

16q4

weeks

×4–6(N=2)

Reg

C:C

BDCA+CTX+VP-16

q4weeks

×4→

OralV

P-16

×4

(N=1)

HDchem

o(post-radiation)

with

CTX+MEL(N

=11)or

BU+

MEL(N

=1)→

ASC

R

4-yearPF

S-69%

4-yearOS-71

%Local-1

(8.33%)

Leptomeningeal-1

(8.33%)

Local+leptom

eningeal-

1(8.33

%)

2infantsdidnotreceive

RT

Notoxicdeathwith

high-dosechem

o→

-ASC

RHigh-dose

chem

omay

beconsidered

inpatientsof

PBwho

areinfantsor

have

metastatic

disease

1300 Childs Nerv Syst (2015) 31:1291–1304

Tab

le3

(contin

ued)

Author

No.of

patients

Pineal/non-

pineal

Extento

fresection

Radiationdose

(CSI)

Chemotherapy

Survivaloutcome

Patternsof

failure

Observation

Trialsexploringalteredfractionationradiotherapy

(CSI)andconventio

nal/high-dose

chem

otherapy

Massiminoetal.

(2006)

[8]

153/12

GTE-6

(40%)

PE-6

biopsy-3

31.2

Gyifage<10

years

39Gyifage>10

years

(n=6)

(HARThyperfractionated

accelerated

radiotherapy-1.3

Gy/#;

2#/day,6

hapart)

(boostup

to59.7–60Gyat

1.5Gy/#;

2#/day,6

hapart)

High-dose

chem

owith

MTX,

CBDCA,V

P-16

andCTX(pre-

radiation)

Maintenance

with

VCR/CCNUor

high-dosethiotepa

followed

byASCR(post-radiation)

3-yearEFS

-34%

3-yearPF

S-54%

3-yearOS-61

%

Local-4

(26.67

%)

Distant-1

(6.67%)

Local+distant-1(6.67%)

Death-5

Inpatients,with

post-operativeresiduum

(N=9),responserateafterchem

oand

HART44

and71

%,respectively

Allenetal.(2009)

(CCG9931

study)

[32]

368/28

R>1.5cm

2 -15

R<1.5cm

2 -18

40Gy(boostup

to60

Gyto

tumourbedand50

Gy

tospinalmets)

(HFR

T:h

yperfractionated

radiotherapy-1

Gy/#,

2#/day,6–8

hapart)

CDDP,CTX,VP-16,VCR(regim

enA)alternatingwith

CBDCA,VP-

16(regim

enB)q4weeks

x5

(Pre-radiation)

5-yearPF

S-46%

(in

SPN

ET)and

75%

(inPB

)5-yearOS-48

%(in

SPN

ET)and

86%

(inPB

)

–In

theentirecohort,(N=124),no

significantd

ifferencein

survivalwith

respecttotumoursite,post-operative

residuum

,Mstage,andresponse

tochem

otherapy

Overall85/124

patients(69%)could

completetheplannedadjuvant

treat-

mentinamedianof

6.1months

Gerberetal.(2014)

(GPO

HP-H

IT2000-A

B4trial)

[33]

2611/15

GTE-6

(23.08

%)

PE-16

36Gy(boostup

to68

Gyto

tumourbedand72

Gy

toresiduum

)(H

FRT:h

yperfractionated

radiotherapy-1

Gy/#,

2#/day,6–8

hapart)

Concurrentw

eeklyVCR

AdjuvantCDDP,VCR,C

CNUx8

(post-radiation)

5-yearPF

S-58%

5-yearOS-58

%Local-5

(19.23

%)

Distant-4

(15.38

%)

Local+distant-2(7.69%)

Death-11(9dueto

PD,2

toxicdeathduring

2nd

linechem

o

5-yearPF

SandOS–both53

%inSP

NET

versus

64%

inPB

Dom

inantp

attern

ofrelapsewas

distant

failureinPB

(N=4)

andlocalfailurein

SPNET(N

=5)

Trialsexploringrisk-adapted

radiotherapy

(CSI)andhigh-dosechem

otherapy

Chintagum

pala

etal.(2009)[6]

167/9

GTE-6

(37.5%)

NTE-1

STE-2

biopsy-7

23.4

Gyifaverage-risk

dis-

ease

(N=8)

36–39.6Gyifhigh-risk

disease(M1-

3,R>1.5cm

2(N

=8)

(boostup

to55.8Gy)

High-dose

chem

owith

CDDP,VCR,

CTXx4

followed

byASC

R(post-radiation)

5-yearEFS

-75and

60%

inaverage-

risk

andhigh-risk

patients,respec-

tively

5-yearOS-88

and

58%

inaverage-

risk

andhigh-risk

patients,respec-

tively

Local-1

(6.25%)

CSF

-1(6.25%)

Distant-1

(6.25%)

Local+distant-1(6.25%)

5-yearEFS

-54and78

%;5

-yearOS-67

and78

%in

pinealandnon-pinealtu-

mours,respectively

Presentstudy

Currentstudy

(2015)

1717/0

GTE-6(35.29

%)

NTE-2

STE-2

biopsy-7

36Gy(boostup

to56

Gy)

(wholeventricularand

wholebrainRTin

1patient

each)

CBDCAandVP-16

x6(m

ostly

post-radiation)

3-yearOS-77

%3-yearRFS

-57.5%

Local+leptom

eningeal-3

(17.65

%)

Leptomeningeal-4

(23.53

%)

Significantly

improved

RFS

inpatients

with

M0diseaseversus

M+disease

(P=0.0483)andage>8yearsversus

<8years(P=0.0071)

Estim

ated

medianRFS

-5.49years

CSI

craniospinalirradiation,WBRTwholebrainRT,GTE

grosstotalexcision,NTE

neartotalexcision,ST

Esubtotalexcision,P

Epartialexcision,GyGray,MVA

multiv

ariateanalysis,P

FSprogressionfree

survival,OSoverallsurvival,EFSevent-free

survival,RFSrecurrence-freesurvival,PBpinealoblastom

a,SP

NETsupratentorial

prim

itive

neuroectodermal

tumour,PNETprim

itive

neuroectodermal

tumour,RTradiotherapy,R

Rresponse

rate,P

Dprogressivedisease,#fractio

n,Rresiduum

,CSF

cerebrospinalfluid,

Ara

Ccytosine

arabinoside,BCNUcarm

ustin

e,BUbusulfan,C

BDCAcarboplatin

,CCNUlomustin

e,CDDPcisplatin

,CTXcyclophosphamide,HUhydroxyurea,LV

leucovorin,M

ELmelphalan,M

TXmethotrexate,VCRvincristine,HDCThigh-dosechem

otherapy,A

SCRautologous

stem

cellrescue,A

BMRautologous

bone

marrowrescue

Childs Nerv Syst (2015) 31:1291–1304 1301

radiotherapy followed by 8 cycles of lomustine, vincristineand prednisone (standard treatment) or 2 cycles of 8-in-1 che-motherapy followed by CSI and then eight additional cyclesof 8-in-1[20]. There was no significant difference in overallsurvival in the 2 arms, and there was substantial toxicity in themore intensive 8-in-1 chemotherapy arm. In a retrospectiveanalysis of 36 patients of SPNET treated over 25 years, Dirkset al. demonstrated a trend towards better prognosis in chil-dren receiving systemic chemotherapy [16]. In the SIOP/UKCCSG PNET 3 trial by Pizer et al., 68 patients of SPNET(pineal 23 % and non-pineal 77 %) received post-operativeradiation to a dose of 55 Gy/33 fractions at 1.67 Gy/fraction/day (CSI 35 Gy → boost 20 Gy) [23, 36]. Pre-irradiationchemotherapy (4 cycles—alternating vincristine, etoposide,carboplatin and vincristine, etoposide, cyclophosphamide)was administered in 44 patients. The overall 5-year event-freesurvival (EFS) and OS rates for the entire cohort were noted tobe 51.8 and 51.5 %, respectively. The addition of pre-irradiation chemotherapy did not favourably affect survivaloutcome in this study. In another study of 22 patients, Reddyet al. used 8 cycles of 6 weekly regimen of cisplatin, vincris-tine and lomustine after maximal safe resection and CSI withsatisfactory results (5-year OS 53 %) [15]. In our series, sys-temic chemotherapy was administered in 14 (82.35 %) pa-tients with the most common regimen being 6 cycles of com-bination of carboplatin and etoposide.

Due to concern about long-term neurocognitive and neuro-endocrine sequel associated with CSI especially in young chil-dren (age <3–6 years), attempts have been made to eliminate,delay or limit the use of RT (CSI) with the use of prolonged[24, 25, 27] or intensive [29] or high-dose [14, 26, 30] che-motherapy with autologous bone marrow/stem cell rescue(Table 3). Though CSI was avoided or deferred in a subsetor majority of patients undergoing prolonged conventionalchemotherapy, the clinical outcome was unsatisfactory with2-year OS rates ranging from 20 to 30 % [24, 25, 27](Table 3). In the German HIT-SKK87 and HIT-SKK92 trialinvolving 29 children with SPNET (pineal 2, non-pineal 27),less than 3 years old, use of methotrexate-based intensivechemotherapy led to dismal 3-year rates of overall survivaland progression free survival (PFS) of 17.2 and 14.9 %, re-spectively [29]. In this trial, overall, 14 patients received RTwhile 15 did not. This perhaps reflects the fact that even ifintensive chemotherapy is given, omission of RT jeopardizessurvival and delay of RT should be limited to a maximum of6 months in patients of SPNET. On the contrary, use of post-operative high-dose chemotherapy followed by autologousbone marrow/stem cell rescue in patients of SPNET in HeadStart I and II and HIT 2000 trials lead to fairly impressiveresults with 5-year OS ranging from 40 to 50 % [14, 30].Majority of the long-term survivors did not receive RT as partof primary treatment (Table 3). However, needless to say thathigh-dose chemotherapy is resource intensive has a

formidable toxicity profile (myelosuppression, infection,bleeding, mucositis etc.) and can lead to treatment relatedmortality in 5–10 % of patients [14, 26].

To sum up, in spite of improvement in treatment modalitiesof SPNET, reported clinical outcome is inferior to that ofmedulloblastoma. The OS rates at 3 and 5 years range from17.2 to 73 % and 14 to 88 %, respectively, in different studies(Table 3). The PFS/EFS rates at 3 and 5 years range from 0 to61 % and 17 to 75 %, respectively, in available literature(Table 3). Tumour recurrence may be local (6.25–60 %),leptomeningeal (4.65–28 %) or a combination of both(6.25–28 %) (Table 3). Occasionally, there may be distantfailure also. Though local recurrence is the dominant patternof failure in most studies [8, 17, 23, 27, 28], Gerber et al. intheir study of 26 patients demonstrated that distant failure wasmore common in patients with pinealoblastoma, whereas localfailure was more common in patients with non-pineal SPNET[33]. In our series 4 (23.53 %) patients had spinal drop metas-tases and 3 (17.65 %) had local recurrence along with spinaldrop metastases. The various prognostic factors determiningimproved clinical outcome in patients with SPNET includeage (more than 3 years versus less than 3 years) [16, 21], Mstage (M0 versus M+ disease) [15, 18, 20, 21, 25], extent ofresection (complete versus incomplete resection) [15–17, 21,24, 27] and use of radiation therapy (CSI) [17, 18, 29](Table 3). The impact of tumour location (pineal versus non-pineal) on clinical outcome is unclear with some studiesreporting no significant difference [15, 30, 32], while someshow superior outcome in patients of pinealoblastoma [20, 22,23, 33] and others the contrary [6, 14, 25, 27]. In our study,age more than 8 years and M0 stage were significant predic-tors of improved RFS on univariate analysis. It is notable thatall of the 6 younger children (<8 years) experienced diseaserecurrence suggesting the lack of efficacy of conventionalradiotherapy and chemotherapy after maximal safe resectionin this age group. Though most single institute or cooperativetrials have clubbed patients of both pineal and non-pinealSPNET, we have included only patients of pinealoblastomain our study. At the present juncture, aggressive multimodalitytreatment consisting of maximal safe surgery, craniospinal ir-radiation and adjuvant systemic chemotherapy should bestrongly considered in suitable patients of pinealoblastomawith an aim to achieve an OS rate of 60–70 % at 3 yearsand 50–60 % at 5 years. With the use of this multimodalityapproach, the actuarial rates of OS and RFS at 3 years in ourseries are 77 and 57.5 %, respectively. In spite of a few limi-tations of our study owing to its retrospective nature, relativelyshort follow-up and treatment heterogeneity, overall compli-ance with the multimodality treatment approach was noted tobe good and clinical outcome and patterns of failure in patientsin this study are in concordance with published results inmedical literature. Moreover, the effectiveness of this com-bined modality approach in an unselected patient population

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in the real world scenario can be considered as a strength ofour study. Longer follow-up will no doubt lead to unfolding oflate recurrence and long-term effects of treatment. More atten-tion needs to be focused on improving treatment effectivenessby innovative study designs like altered fractionation, radio-therapy dose escalation, use of concurrent chemotherapyalong with radiotherapy, intensification of adjuvant chemo-therapy and use of high-dose chemotherapy with autologousstem cell rescue especially in younger children. Attemptshould be made to minimize treatment morbidity simulta-neously by use of novel techniques like intensity modulatedradiation with helical tomotherapy and proton beam therapy.Keeping inmind the scarcity of health resources in developingnations, the cost-benefit ratio of any such future approachneeds critical appraisal.

Conclusion

Maximal safe resection followed by craniospinal irradiationand systemic chemotherapy with carboplatin-etoposide regi-men is a reasonable treatment strategy in patients ofpinealoblastoma more than 8 years of age in a developingnation. However, the same strategy is less effective in youngerchildren and innovative study designs of intensification ofpost-operative treatment must be explored in this age group.More attention needs to be focused on neurocognitive andneuroendocrine ramifications of treatment and quality oflife issues in the future.

Conflict of interest The authors declare that they have no competinginterests.

Source of funding Nil

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