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    -  Hazarika N
    -  Tiwari P
    -  Munshi A
    -  Patir R
    -  Vaishya S
    -  Ahlawat S
    -  Chaudhoory AR
    -  Goel V

 
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ORIGINAL ARTICLE
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Medulloblastoma outcomes in tertiary care set-up in India using contemporary treatment protocols - A retrospective study


1 Department of Medical and Pediatric Oncology, Fortis Memorial Research Institute, Gurgaon, Haryana, India
2 Department of Radiation Oncology, Fortis Memorial Research Institute, Gurgaon, Haryana, India
3 Department of Neurosurgery, Fortis Memorial Research Institute, Gurgaon, Haryana, India
4 Department of Pathology, Fortis Memorial Research Institute, Gurgaon, Haryana, India
5 Department of Radiation Oncology, Max Super Speciality Hospital, New Delhi, India

Date of Submission05-Dec-2019
Date of Decision20-Jun-2020
Date of Acceptance03-Jun-2020
Date of Web Publication11-May-2021

Correspondence Address:
Nandini Hazarika,
Department of Medical and Pediatric Oncology, Fortis Memorial Research Institute, Gurgaon, Haryan
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_1025_19

  Abstract 


Background: Medulloblastoma is the commonest embryonal brain tumor in children. It has shown improved outcomes with combined modality treatment. We aimed to study patient characteristics and survival outcomes of patients with this disease across two tertiary care centers in India.
Methods: We analyzed data of patients with histological diagnosis of medulloblastoma treated from January 2010 to January 2016. Patient characteristics and follow-up data were retrieved from hospital records. Descriptive statistics were used to describe clinical and pathological characteristics. Overall survival (OS) was calculated from date of diagnosis to death due to any cause. Relapse-free survival (RFS) was calculated from date of diagnosis to occurrence of relapse or death.
Result: Out of 26 patients treated, 24 were children and 2 were adults. Median age was 10 years (range = 0.8–22 years). Twenty (76.9%) patients were male. Fifteen (57.7%) patients were stratified as high-risk (HR), rest 11 (42.3%) were categorized as average risk (AR). Histopathology showed classical variety in majority of patients except for 4 (15%) cases, 3 with desmoplastic and 1 with anaplastic subtype. Median follow-up was 49.7 months (range= 4.2–102.5 months). Overall, eight (30.8%) patients relapsed and six (23%) deaths occurred. Five (33.3%) patients in HR category and 3 (27.3%) patients in AR group showed relapse. Median RFS and OS were not yet reached. Five-year RFS was 69.2% whereas five-year OS was 76.9%.
Conclusion: This study highlighted patient characteristics and treatment outcomes in Indian patients. With adherence to standard treatment, high remission rates and improvement in mortality rates were achieved.


Keywords: Brain tumor, Indian tertiary care set-up, medulloblastoma, retrospective analysisy
Key Message
It is possible to achieve a better outcome with acceptable toxicity even in high-risk medulloblastoma with more intensive treatment and adhering to a standard treatment protocol.



How to cite this URL:
Hazarika N, Tiwari P, Munshi A, Patir R, Vaishya S, Ahlawat S, Chaudhoory AR, Goel V. Medulloblastoma outcomes in tertiary care set-up in India using contemporary treatment protocols - A retrospective study. Indian J Cancer [Epub ahead of print] [cited 2021 Jun 13]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=315798





  Introduction Top


Medulloblastoma is one of the commonest embryonal tumors, more commonly seen in children than adults. As compared to other high-grade brain tumors, medulloblastoma has much better outcome using multimodality treatment comprising surgery, radiotherapy, and chemotherapy. Till recently, risk stratification depended solely on extent of surgery, age, and stage of the disease.[1],[2],[3] Nonetheless, in recent years much work has been done to explore molecular pathways of tumorigenesis leading to molecular subclassification (WNT, SHH, type 3 and type 4). In future, this may help in optimizing treatment plan for the patient, with optimum control rates and least possible toxicities.[4],[5] While considerable research has been done in management of this disease in west, data related to outcomes are sparse from South East Asia.[6],[7],[8] This study aims to present the outcomes of medulloblastoma across two tertiary care centers in India.


  Materials and Methods Top


Patients diagnosed with medulloblastoma, who received treatment during January 2010 to January 2016 were included in this retrospective analysis. Institutional Ethics committee approval was taken to conduct this retrospective study. At the time of presentation, patients were evaluated clinically, and assessed if they require immediate intervention, in case of raised intracranial pressure, neurological deficit, and/or hemodynamic instability. Initial work-up was directed to characterize disease and staging along with organ function assessment.

Baseline investigations were usually done by the neurosurgery team and included a contrast magnetic resonance imaging (MRI) of brain and spine, routine complete hemogram, serum biochemistry, and pre-anesthetic work-up as per the surgical protocol. Staging was done post-surgery, after obtaining histopathological diagnosis. Though we tried doing pre-operative MRI spine for all posterior fossa tumors at our center, it was done postoperatively as a part of radiation treatment planning for few initial patients.

The biopsy submitted for histopathology was processed and paraffin embedded, and sections were cut and stained with hematoxylin and eosin. Reticulin stain was performed if morphology suggested nodular medulloblastoma. Immunohistochemistry (IHC) was performed on all cases and included synaptophysin, chromogranin, neuron-specific enolase, neurofilament protein, glial basic fibrillary protein, vimentin, INI-1, and Ki-67 labelling index. If on morphology, myogenic differentiation was suspected, IHC for desmin and myogenin was performed. In case morphology suggested melanocytic differentiation, IHC for S100 was performed.

A post-operative computerized tomographic (CT) scan brain was done by our neurosurgery team for all the patients 24 hours after surgery. Staging work-up included cerebrospinal fluid examination (CSF) (post 2 weeks of surgery), contrast MRI of brain and screening MRI of spine (if not done at baseline before surgery). These MRI sequences also served as a planning images for CT MRI fusion scan for radiation therapy as well as for staging purpose. Besides staging work-up, hearing assessment and hormonal analysis were also done before starting cranio-spinal irradiation (CSI).

Patients were assigned as average-risk (AR) or high-risk (HR) based on extent of residual disease, age of the patients, and extent of disease.

Patients were treated with surgery, CSI with concurrent chemotherapy followed by adjuvant chemotherapy or high-dose chemotherapy with stem cell rescue. For all the patients, radiation therapy was started within 3–4 weeks of surgery. [Table 1] highlights management strategy post-surgery.
Table 1: Management scheme post-surgery after risk stratification

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CSI doses: For AR patients, we used low-dose CSI (23.4 Gy in 13 fractions) followed by boost to tumor bed (30.6 Gy in 17 fractions). For HR patients, the dose of CSI was 35 Gy in 21 fractions followed by boost (19.8 Gy in 11 fractions). A localized deposit in the spine was given a boost dose of 9 Gy in 5 fractions at completion of CSI. All patients were treated using 6 MV X-rays with volumetric modulated arc therapy (VMAT) using partial or full arcs whenever appropriate.

Statistical analysis

Descriptive statistics were used to describe demographic, clinical characteristics, laboratory, and pathological characteristics. Overall survival (OS) was calculated from the date of diagnosis to death due to any cause. Relapse-free survival (RFS) was calculated from the date of diagnosis to occurrence of either relapse of the disease or death. All analyses were performed using SPSS version 22 statistical software (SPSS Inc., Chicago, Illinois).


  Results Top


Patients characteristics

During the given time period, a total of 26 patients were treated, out of which 24 were children and 2 were adults. Median age was 10 years (range= 0.8–22 years). Out of these 26 cases, 20 (76.9%) were male and 6 (23.1%) were female. [Table 2] highlights patient characteristics.
Table 2: Patients characteristics

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Risk stratification and treatment offered

Fifteen (57.7%) patients were stratified as HR either due to spinal metastasis or residual disease or age. Eleven (42.3%) patients were categorized as AR. Spinal metastases and residual disease post-surgery were present in 8 (30.8%) patients each. One had both spinal metastasis and residual disease. All patients underwent surgery. CSI was given to all patients except one in view of age below 3 years. AR patients received concurrent weekly vincristine during CSI. Four HR patients who did not receive high dose chemotherapy, received concurrent vincristine and carboplatin during CSI. For adjuvant chemotherapy 20 (76.9%) patients were treated with Packer's regimen (12 patients received CCNU (Lomustine) and rest received cyclophosphamide along with vincristine and cisplatin). One (3.9%) patient was treated with baby POG (pediatric oncology group) protocol and 5 (19.2%) patients were given high-dose chemotherapy with stem cell rescue as per St Jude's protocol. All patients completed full treatment. However, some dose modifications were required for cisplatin in patients receiving Packer's regimen in view of ototoxicity. Filgrastim support was required for patients receiving concurrent carboplatin with CSI helping to have no major treatment interruption.

Toxicity profiles were not discussed in this study.

Pathology

Histopathology showed classical variety in majority of the patients except for 4 (15%) cases. Out of these four patients, three had desmoplastic, and one patient had anaplastic subtype.

Relapse and survival

Median follow-up was 49.7 months (range= 4.2–102.5 months). Overall, 8 (30.8%) patients relapsed. Five (33.3%) patients in HR category and 3 (27.3%) patients in AR group showed disease relapse. Three out of five patients who underwent high dose chemotherapy were disease free till the writing of this paper, one progressed on treatment and the other developed hemophagocytic lymphohistiocytosis (HLH) (Epstain Barr virus induced) after 1 month of completion of therapy. Median RFS was not yet reached [Figure 1]. Five-year RFS was 69.2%. Overall, six (23%) deaths occurred. Four deaths occurred in the HR group and two occurred in the AR group. Median OS was not yet reached [Figure 2]. Five-year OS was 76.9%. Five out of six died due to disease progression, one died due to HLH. None of the mortality was due to treatment related sepsis. Mean RFS in AR was 87.2 months whereas in HR it was 71.9 months [Figure 3]a. Mean OS in AR and HR were 95.4 and 78.7 months, respectively [Figure 3]b.
Figure 1: Relapse-free survival of patients

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Figure 2: Overall survival of patients

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Figure 3: (a) Comparison of relapse-free survival between average risk (AR) and high-risk (HR). (b) Comparison of overall survival between AR and HR groups

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  Discussion Top


Treatment of medulloblastoma has evolved rapidly over last few decades. In the pre-1930 era, when surgery was the mainstay of treatment, 5-year progression-free survival rate was only 10–20%.[9] It increased to 50–60% for AR disease with 36 Gy of CSI therapy supplemented with 18 Gy to 20 Gy of radiotherapy to the posterior fossa.[10] With the addition of chemotherapy (cisplatin, lomustine, and vincristine) in the treatment protocol in 1990s, the 5-year progression-free survival rate for AR disease has nearly reached 70–80%.[11],[12] Packer et al. proved the role of chemotherapy in AR medulloblastoma and also showed that CSI dose could be reduced with use of concurrent chemotherapy without any detrimental effect on survival benefit.[13] Packer et al. again showed that there is no difference in survival rate even when lomustine is replaced with cyclophosphamide.[14] Again addition of adjuvant chemotherapy has shown marked survival benefit in the AR group but not much benefit in the HR group.[15] It became apparent that HR group needed a different or a more intensive treatment approach. St Jude's multicentric trial with high dose chemotherapy and stem cell rescue showed 70% OS in the HR group.[16] Subsequent children oncology group (COG) trial with concurrent use of carboplatin during radiation therapy showed promising results in HR group.[17] Our data also suggests that HR group needs more intensive treatment. In our six HR patients who received only CSI and adjuvant chemotherapy, four relapsed, whereas only one patient out of 5 patients who received high-dose chemotherapy had disease progression. None of 4 HR patients who received concurrent carboplatin during CSI relapsed. Another observation was that 27% of AR patients had relapsed in spite of adequate treatment which again highlights the need for understanding the disease biology.

With the recent advent of the four molecular subgroups of medulloblastoma; WNT, SHH, Group 3, and Group 4, there has been a better understanding of the disease biology. These subgroups are distinct in their biology, clinical characteristics, and survival rates.[18],[19],[20] Therefore, molecular classification of medulloblastoma has become a necessity for risk stratification and better understanding of the disease and its management, although this was not incorporated in our present study.

Surgery still plays an important role in the final outcome of these patients. Currently, the goal of surgery is maximal safe resection. Presence of residual disease is known to affect the progression-free survival and even our data showed that 50% of HR patients who had residual disease had a relapse.[21] The other critical issue in medulloblastoma patients is the long term toxicity. Though the survival has improved with combine modality treatment, the long-term toxicity still remains a major concern. Ototoxicity remains a major challenge for these children and require regular monitoring with audiometry and sometimes dose modifications for cisplatin.[22] Other major long-term concerns are endocrinal abnormalities, cognitive dysfunction, and poor scholastic skills.[23] With improvement of the survival rate, need for regular assessment of long-term toxicities and proper intervention is a necessity for a better quality of life for these children.


  Conclusion Top


This study is an attempt to highlight the characteristics of patients in Indian scenario and feasibility of intensive treatment for patients with high-risk disease. With better understanding of molecular pathways in recent times, treatment may be optimized and directed towards the involved pathways with lesser toxicities and better outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neuroectodermal tumours in adults and children. J Clin Neurosci 2012;19:1541-4.  Back to cited text no. 1
    
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Muzumdar D, Ventureyra EC. Treatment of posterior fossa tumors in children. Expert Rev Neurother 2010;10:525-46.  Back to cited text no. 2
    
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Packer RJ, Rood BR, MacDonald TJ. Medulloblastoma: Present concepts of stratification into risk groups. Pediatr Neurosurg 2003;39:60-7.  Back to cited text no. 3
    
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Sarkar C, Deb P, Sharma MC. Medulloblastomas: New directions in risk stratification. Neurol India. 2006;54:16-23.  Back to cited text no. 4
    
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Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol 2012;123:465-72.  Back to cited text no. 5
    
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Gaur S, Kumar SS, Balasubramaniam P. An analysis of medulloblastoma: 10 years experience of a referral institution in South India. Indian J Cancer 2015;52:575-8.  Back to cited text no. 6
[PUBMED]  [Full text]  
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Jain A, Sharma MC, Suri V, Kale SS, Mahapatra AK, Tatke M, et al. Spectrum of pediatric brain tumor in India: A multi-institutional study. Neurol India 2011;59:208-11.  Back to cited text no. 7
[PUBMED]  [Full text]  
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Mazumdar D, Deshpande A, Kumar R, Sharma A, Goel N, Dange N, et al. Medulloblastoma in childhood- King Edward Memorial Hospital surgical experience and review: Comparative analysis of case series of 365 patients. J Pediatr Neurosci 2011;6:578-85.  Back to cited text no. 8
    
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Rutka JT, Hoffman HJ. Medulloblastoma: A historical perspective and overview. J Neurooncol 1996;29:1-7.  Back to cited text no. 9
    
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Patterson R, Farr RF. Cerebellar medulloblastoma: Treatment by irradiation of the whole central nervous system. Acta Radiol 1953;39:323-36.  Back to cited text no. 10
    
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Evans AE, Jenkin RD, Sposto R, Ortega JA, Wilson CB, Wara W, et al. The treatment of Medulloblastoma: Result of a prospective randomised trial of radiation therapy with or without CCNU, Vincristine and prednisolone. J Neurosurg 1990;72:573-82.  Back to cited text no. 11
    
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Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, et al. Outcome of children with medulloblastoma treated with radiation and cisplatin, CCNU and Vincristine chemotherapy. J Neurosurg 1994;81:690-8.  Back to cited text no. 12
    
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Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, et al. Treatment of children with medulloblastoma with reduced dose cranio spinal irradiation therapy and adjuvant chemotherapy: A Children's cancer Group Study. J Clin Oncol 1999;17:2127-36.  Back to cited text no. 13
    
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Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average risk medulloblastoma. J Clin Oncol 2006;24:4202-8.  Back to cited text no. 14
    
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Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, et al. Outcome of patients with metastatic medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 2005;41:727-34.  Back to cited text no. 15
    
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Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, et al. Risk adapted craniospinal radiotherapy followed by high dose chemotherapy and stem cell rescue in children with newly diagnosed Medulloblastoma (St Jude MBL 96): Long term results from a prospective multicentric trial. Lancet Oncol 2006;7:813-20.  Back to cited text no. 16
    
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Jakacki RI, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, et al. Outcome of children with metastatic Medulloblastoma treated with carboplatin during craniospinal radiotherapy: A Childran's Oncology Group Phase I/II Study. J Clin Oncol 2012;30:2648-53.  Back to cited text no. 17
    
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Kijima N, Kanemura Y. Molecular classification of Medulloblastoma. Neurol Med Chir (Tokyo) 2016;56:687-97.  Back to cited text no. 18
    
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Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, et al. Prognostic value of Medulloblastoma extent of resection after accounting for molecular subgroup. Lancet Oncol 2016;17:484-95.  Back to cited text no. 21
    
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Paulino AC, Lobo M, Teh BS, Okcu MF, South M, Butler EB, et al. Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with Medulloblastoma. Int J Radiol Oncol Biol Phys 2010;78:1445-50.  Back to cited text no. 22
    
23.
Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LW. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet 2004;5:399-408.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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