|Year : 2017 | Volume
| Issue : 4 | Page : 594-600
Demographic profile, clinicopathological spectrum, and treatment outcomes of primary central nervous system tumors: Retrospective audit from an academic neuro-oncology unit
Tejpal Gupta1, Sridhar Epari2, Aliasgar Moiyadi3, Prakash Shetty3, Jayant Sastri Goda1, Rahul Krishnatry1, Girish Chinnaswamy4, Tushar Vora4, Hari Menon4, Vijay Patil4, Ayushi Sahay2, Nazia Bano5, Rakesh Jalali1
1 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Neuro-surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Neuro-Oncology Disease Management Group, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||30-Jul-2018|
Dr. Tejpal Gupta
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Primary tumors of the central nervous system are relatively uncommon, comprising only 1%–2% of all neoplasms. However, they constitute the second most common type of malignancy in children (after leukemia) and the leading cause of cancer-related morbidity and mortality in children and young adults worldwide. Globally, there is substantial variability with nearly five-fold difference in incidence between various parts of the world. Brain tumors are quite heterogeneous with regard to histology, biological behavior, and prognosis mandating multidisciplinary therapeutic decision-making. This retrospective audit of all consecutive patients registered in a single calendar year (2013) in the neuro-oncology disease management group at Tata Memorial Centre is reflective of the ground reality and fair representation of outcomes in routine neuro-oncologic practice.
Keywords: Audit, brain tumors, epidemiology, neuro-oncology, outcomes
|How to cite this article:|
Gupta T, Epari S, Moiyadi A, Shetty P, Goda JS, Krishnatry R, Chinnaswamy G, Vora T, Menon H, Patil V, Sahay A, Bano N, Jalali R. Demographic profile, clinicopathological spectrum, and treatment outcomes of primary central nervous system tumors: Retrospective audit from an academic neuro-oncology unit. Indian J Cancer 2017;54:594-600
|How to cite this URL:|
Gupta T, Epari S, Moiyadi A, Shetty P, Goda JS, Krishnatry R, Chinnaswamy G, Vora T, Menon H, Patil V, Sahay A, Bano N, Jalali R. Demographic profile, clinicopathological spectrum, and treatment outcomes of primary central nervous system tumors: Retrospective audit from an academic neuro-oncology unit. Indian J Cancer [serial online] 2017 [cited 2019 Aug 18];54:594-600. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/594/237906
| » Background|| |
Primary tumors of the central nervous system (CNS) are relatively uncommon, comprising only 1%–2% of all neoplasms,, However, brain tumors constitute the second most common type of malignancy in children (after leukemia), and are the leading cause of cancer-related morbidity and mortality in children and young adults worldwide., Overall, age-adjusted annual incidence of malignant brain tumors is 5.57/100,000 population; however, globally, there is a substantial variability in its incidence with nearly five-fold difference between regions with the highest rates (Europe and Canada) and lowest rates in Southeast Asia including India., Not only in terms of incidence and demographics, brain tumors are quite heterogeneous with regard to histology (typing and grading), biological behavior (benign, intermediate, and aggressive), and resultant clinical outcomes (excellent, fair, and poor prognosis).
Neuro-oncology disease management group (DMG) at Tata Memorial Centre, Mumbai, has always had a long tradition of multidisciplinary approach toward the management of these tumors. Even before neurosurgery facilities were created within the hospital, liaison and collaboration with other academic and private neurosurgical departments (both within the city and outside) ensured a steady stream of patients for evidence-based multidisciplinary therapeutic decision-making regarding adjuvant therapy following index surgery. The establishment of “state-of-the-art” neurosurgical oncology backed by advanced, dedicated neuropathology, and molecular diagnostics has further consolidated the leadership position of the group within the country and truncate. This has resulted in consistent and progressive increase in the workload reflected in over three-fold increase in the number of annual registrations (case files and second opinion cards) over the last decade within the neuro-oncology DMG [Figure 1].
|Figure 1: Bar chart showing year-wise (2004–2013) annual registration of patients with central nervous system tumors in the neuro-oncology disease management group at Tata Memorial Centre|
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This is a retrospective audit of demographic profile (age and gender distribution), clinicopathological spectrum (major histological tumor types), treatments (neurosurgery and adjuvant therapy), and clinical outcomes (treatment-related morbidity/mortality and survival) for all consecutive patients registered in the year 2013 within the neuro-oncology DMG at Tata Memorial Centre, Mumbai.
| » Materials and Methods|| |
All patients registering within the neuro-oncology DMG are entered into a prospectively maintained database that captures the information regarding the patient, disease, and treatment characteristics. A schematic patient-care pathway typically followed within the DMG is depicted in [Figure 2]. Over 75% of patients undergo initial surgery outside and are referred for confirmation of diagnosis and need for further adjuvant therapy. Approximately 25% of patients present preoperatively and undergo initial surgical resection within the institute. Their neurosurgical morbidity and mortality data are captured in detail in a neurosurgical database. Over 90% of the patients are reviewed and advised by a consultant within 1 day of primary registration, and a tentative management plan is formulated. All patients are also timely reviewed by the DMG support staff including an occupational therapist, neuro-oncology nurse, brain tumor foundation of India volunteer, data manager, DMG coordinator, and institutional medical social worker as desired. Following histopathological review and molecular markers, as appropriate, the final management plan regarding further adjuvant therapy is devised after discussion in a multidisciplinary joint clinic. Eligible patients are also actively screened and counseled for participation into active ongoing research studies including interventional clinical trials. The neuro-oncology database is periodically updated by the data managers and coordinators to ensure completeness. Data for the year 2013 were categorized and analyzed in terms of volume indicators, process indicators, and outcome indicators. Given the significant variability in prognosis, survival outcomes were analyzed separately for major histological types and/or risk-categories with June 30, 2017 as the cutoff date for all time-to-event analysis.
|Figure 2: Typical patient-care pathway followed by the neuro-oncology disease management group at Tata Memorial Centre|
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| » Results|| |
2013 also witnessed an increase in the number of new registrations in the neuro-oncology DMG at the institute. A total of 1539 new registrations were recorded, of which there were 1286 new case file registrations and 253 opinion cards [Figure 1]. All analysis was restricted to only new case file registrations of 2013 (n = 1286). In keeping with the institutional mandate of catering predominantly to the socioeconomically backward classes, 69% of the patients belonged to the general category while 31% patients belonged to the private category at initial registration. The age-wise distribution of patients was categorized as follows: children (<18 years of age): 21%; adolescent and young adults (18–39 years of age): 31%; older adults (40–59 years of age): 35%; and elderly patients (≥60 years): 13%. Fifty-two percent of the patients were from the state of Maharashtra (27% from in and around Mumbai), while the remaining 48% of patients were referred from all parts of the country (largely from eastern and central India). A pie-chart of the typical histopathological spectrum of tumors with respective proportions is depicted in [Figure 3]. It may be pertinent to note here that, being a tertiary-level cancer care center, malignant, and higher-grade tumors are much more likely to be referred for therapy compared to benign tumors (meningiomas and pituitary adenomas) or low-grade gliomas (other diffuse astrocytomas). In keeping with international registry data, and previously published Indian data,, malignant gliomas including glioblastoma accounted for over 50% of primary brain tumors in adults while embryonal tumors including medulloblastoma and circumscribed low-grade gliomas were the common histologic entities seen in children.
|Figure 3: Histopathological spectrum of primary central nervous system tumors registered at Tata Memorial Centre|
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A total of 305 neurosurgical procedures were performed in the institute in 2013 encompassing the entire spectrum of open craniotomies, posterior fossa craniectomies, craniofacial resections, skull-base procedures, spinal surgeries, stereotactic biopsies, and shunt insertions [Table 1]. Apart from having the operating microscope and conventional neuronavigation system as standard tools, increasing number of procedures were performed using neurosurgical adjuncts such as three-dimensional (3D) navigable ultrasound (n = 26), minimally invasive endoscopic procedures (n = 20), electrophysiologic mapping/monitoring during awake surgery (n = 15), and 5-aminolevulinic acid-induced fluorescence-guided resections (n = 11), which have considerably enhanced the therapeutic armamentarium.
|Table 1: Spectrum of neurosurgical procedures performed at Tata Memorial Centre in 2013|
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Radiation Oncology Services form an important pillar of the DMG and continue to provide comprehensive neuro-oncology care including clinical evaluation and diagnostic workup at initial presentation, therapeutic decision-making for adjuvant therapy, imaging-surveillance during periodic follow-up after completion of treatment, and salvage therapy options at recurrence/progression. Supportive, rehabilitative, and palliative care, as appropriate, are also made available to all patients throughout their disease trajectory. Radiation Oncology Services within the neuro-oncology DMG have been at the forefront of utilizing modern technology for treatment planning and delivering high-precision conformal techniques such as 3D conformal radiotherapy, stereotactic radiosurgery/radiotherapy, and image-guided intensity-modulated radiation therapy. During 2013, a total of 390 patients were treated with external beam radiotherapy within the institute [Table 2]. Given the increasing number of patients needing fractionated radiotherapy and the limited number of slots available on the treatment machines in the institute, over 350 patients were either referred back to cancer centers at or near their native place or some other center within the city for timely institution of radiotherapy. Notwithstanding, members from the DMG closely liaised and coordinated with the outside treating radiation oncologist through a formal referral letter (including detailed radiotherapy and/or chemotherapy prescription protocol) to ensure appropriate adjuvant therapy as planned. A large majority of these patients subsequently came back to Tata Memorial Centre following radiotherapy (with or without concurrent chemotherapy) for further adjuvant chemotherapy (if required) or for periodic follow-up as per the prevalent protocol.
|Table 2: External beam radiotherapy techniques in patients with central nervous system tumors at Tata Memorial Centre in 2013|
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Along with the Radiation Oncology services, DMG colleagues from Medical Oncology (both pediatric and adult) were also involved in the planning and delivering of systemic chemotherapy (as concurrent, adjuvant, or salvage treatment) and/or targeted therapy for recurrent/progressive disease in various histological subtypes within the CNS. As expected, malignant diffuse gliomas (glioblastoma, anaplastic glioma, and high-risk low-grade glioma) were the most common primary CNS tumors that were treated with chemotherapy. Temozolomide was the most common chemotherapeutic agent used in clinical practice. In 2013, over 200 patients with malignant diffuse glioma received temozolomide concurrently with fractionated radiotherapy within the institute. Almost similar number of patients who were referred to other centers for radiotherapy also received concurrent temozolomide outside. Over 400 patients further received the four-weekly regimen of temozolomide chemotherapy either in the postconcurrent phase adjuvant setting (n = 340) or salvage setting at recurrence/progression (n = 66). A small number of patients (n = 15) were also treated with lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) either as single agent or in combination with procarbazine and vincristine (PCV regimen) as salvage therapy. Twenty-one patients with recurrent/progressive glioblastoma after failure of multiple salvage therapies received antiangiogenic therapy such as bevacizumab either alone or in combination with irinotecan. High-dose methotrexate-based regimen was offered to suitable patients with primary CNS lymphoma. A total of 68 children with primary CNS tumors were treated with systemic chemotherapy at the institute in 2013, common indications being medulloblastoma and other embryonal CNS tumors (postradiotherapy adjuvant setting), circumscribed low-grade gliomas (to avoid/defer radiotherapy), and intracranial germ cell tumors (before consolidation radiotherapy). The modified combined biodifferentiating and antiangiogenic therapy metronomic regimen using a combination of temozolomide, valproate, etoposide, and 13-cis-retinoic acid was also offered either as maintenance therapy for high-risk disease or as salvage treatment following recurrence/progression in embryonal CNS tumors.
Neuropathology and molecular diagnostics
Accurate histopathological reporting and interpretation as well as risk-stratification play an important role in deciding adjuvant therapy for primary CNS tumors. Recent advances in molecular diagnostics have further enhanced prognostic and predictive ability facilitating therapeutic decision-making. As previously described in the methods section, every single patient registering in the DMG following a neurosurgical procedure at an outside center has to submit formalin-fixed paraffin-embedded tumor-tissue blocks for detailed and accurate institutional neuropathology review and molecular markers as required. Molecular diagnostic techniques that were commonly employed by neuropathology colleagues within the DMG in 2013 included fluorescence in situ hybridization for the detection of 1p/19q deletion status in oligodendrogliomas (n = 176), epidermal growth factor receptor amplification in a subset of glioblastomas (n = 22), and MYC-amplification in subset of medulloblastomas (n = 15); Sanger gene sequencing for isocitrate dehydrogenase (IDH1/2) mutation in diffuse gliomas (n = 75) and BRAFV600E mutation (n = 50) in pleomorphic xanthoastrocytoma, ganglioglioma, and epithelioid glioblastoma; and methylation-specific polymerase chain reaction (MS-PCR) for methyl-guanine methyltransferase gene promoter methylation status in glioblastoma (n = 56). Pursuant to the incorporation of molecular/genetic information in addition to histomorphology for arriving at an integrated diagnosis in the updated World Health Organization 2016 classification of CNS tumors, several additional molecular diagnostic tests have now been validated and introduced in routine clinical practice including histone alterations for diffuse midline glioma and gene expression profiling/microRNA profiling for molecular subgrouping of medulloblastoma.
These were categorized in terms of dropout rates after index registration, waiting times and turn-around-time for clinical and diagnostic services, and compliance to planned therapy. Process indicators were calculated for all end points for a consecutive 2-month period and assumed to be representative for the entire year.
Nearly 2.5% patients did not return to the OPD after the first visit while another 5% did not follow-up further after initial few visits for an overall dropout rate of 7.5% after index registration.
Waiting times and turn-around-time
The mean and median waiting time including the interquartile range for various clinical and diagnostic services is summarized in [Table 3]. While this may seem acceptable for any government hospital, it is certainly not desirable. There is a definite need to reduce the waiting times by augmenting infrastructure and human resources to be at par with the international standards.
|Table 3: Representative typical waiting times for therapeutic and diagnostic services in neuro-oncology at Tata Memorial Centre|
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Compliance to planned therapy
Within rapidly increasing annual registrations, limited availability of neurosurgical theaters and radiotherapy slots, and patient/caregiver preference or convenience, a sizeable proportion of patients are referred out for definitive treatment (surgery and/or adjuvant therapy) after therapeutic decision-making following index registration. The overall compliance to planned therapy was 82% for neurosurgery and 89% for adjuvant therapy in 2013. It is pertinent to note here that compliance was substantially higher for patients treated within the institute compared to patients who were referred out for therapy. Once again, augmentation of infrastructure and human resources would allow more patients to be treated within the institute, thereby further improving the overall compliance to planned therapy.
Short-term clinical outcomes for neurosurgery were categorized and analyzed in terms of perioperative (30-day) morbidity/mortality for all neurosurgical procedures as well as quantification of the extent of resection for intraaxial tumors using glioma as the prototypical tumor. Morbidity of radio (chemo) therapy was analyzed as clinically significant Grade III or worse toxicity encountered during or within 3 months of completion of adjuvant therapy. Overall survival was the end point of interest for reporting long-term outcomes.
Perioperative (30-day) morbidity and mortality for all neurosurgical procedures for 2013 is summarized in [Table 4], which is at par and comparable with accepted international standards., Gross total resection was achieved in see below. [Table 5] summarizes the rates of clinically significant Grade III or worse acute toxicity of adjuvant/salvage radio (chemo) therapy that confirms the acceptably low rates of significant toxicity with temozolomide-based chemoradiotherapy in routine clinical practice.
|Table 4: Perioperative (30-day) neurosurgical morbidity and mortality at Tata Memorial Centre in 2013|
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|Table 5: Clinically significant rates of acute toxicity of radiotherapy/chemotherapy in patients with central nervous system tumors at Tata Memorial Centre in 2013|
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Kaplan–Meier curves of overall survival for patients with glioblastoma and medulloblastoma (most common malignant brain tumors in adults and children, respectively) are depicted in [Figure 4]. One hundred and eleven of a total of 249 patients diagnosed with glioblastoma and its variants had died by the time of this analysis resulting in a median survival of 13.8 months. A sizeable proportion (nearly 25%) was lost to follow-up and not contactable even telephonically, leading to censored observations and consequently inflated 2-year and 3-year survival outcomes. In contrast, complete follow-up data were available for all patients with medulloblastoma. Nine of 59 patients with medulloblastoma had succumbed to the disease by the time of this analysis resulting in 5-year overall survival of 76%. Given the relatively short follow-up duration and anticipated low event rate, 5-year survival rates for benign brain tumors have not been presented for the year 2013. Benchmark overall survival data (median survival and 5-year survival as appropriate) for major histological types of brain tumors treated within the DMG over the years is summarized in [Table 6].,,,,,,,,,,,,,,,,,,,,,,
|Figure 4: Kaplan–Meier overall survival curves of patients with common malignant brain tumors such as glioblastoma (a) in adults and medulloblastoma (b) in children|
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|Table 6: Published benchmark survival outcomes for major histological types of primary brain tumors treated at Tata Memorial Centre|
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| » Discussion|| |
Over the years, there has been a progressive and consistent increase in the workload of the neuro-oncology DMG at Tata Memorial Centre, Mumbai. The neuro-oncology DMG strongly believes in and promotes evidence-based therapeutic decision-making using a multi-disciplinary approach and has gained leadership position nationally and recognition globally. In parallel, it has been at the forefront of testing and adopting newer advances in all aspects of neuro-oncology (neuroimaging, neurosurgery, molecular diagnostics, radiotherapy technology, and novel/molecularly targeted therapy). However, despite the impressive numbers and clinical outcomes comparable with international standards, several caveats and limitations remain. First and foremost, the biases inherent to any retrospective analyses cannot be completely ruled out. Second, the histologic spectrum and distribution of patients may not be truly reflective of a primary neurosurgical oncology facility, as a majority (75%) of patients were referred to the DMG after undergoing index surgery outside. Over 40% of all patients requiring radiotherapy were referred out either due to the unacceptably long waiting times and/or patient and caregiver convenience. There is a definite need to augment infrastructure and human resources to successfully reduce waiting-times and accommodate more number of patients within the institute. Finally, there were high attrition rates in malignant gliomas as a substantial number of patients did not follow-up as scheduled after treatment.
| » Conclusion|| |
Primary CNS neoplasms constitute a rare and heterogeneous group of tumors, with diverse histopathologic spectrum and widely varying clinical outcomes. With the caveats and limitations of any retrospective analysis, this clinical audit of consecutive patients registered in the neuro-oncology DMG in a single calendar year at Tata Memorial Centre is reflective of the ground reality and can be considered as a reasonably fair representation of outcomes in neuro-oncologic practice.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]