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Table of Contents    
ORIGINAL ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 2  |  Page : 467-475

Health-related quality of life after surgery in supratentorial gliomas


Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Science (SGPGIMS), Lucknow, Uttar Pradesh, India

Date of Web Publication13-May-2019

Correspondence Address:
Dr. Kuntal K Das
Department of Neurosurgery, SGPGIMS, Raibareily Road, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.257998

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 » Abstract 


Introduction: With improvements in overall and progression-free survival in gliomas, current focus in neurosurgical oncology has largely shifted to the issue of quality of life (QOL) after treatment. There are not too many prospective studies evaluating QOL in these patients. We prospectively analyzed the health related quality of life (HRQOL) using the short form (SF) 36 questionnaire among patients harbouring a supratentorial glioma who underwent surgery at a tertiary care center in India.
Methods: HRQOL was evaluated prospectively in 103 patients, between May 2016 and November 2017, at Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow. Score improvements were evaluated in terms of the smallest difference that a patient perceived to be clinically beneficial. The responsiveness of scores was assessed as minimum clinically important difference (MCID), effect size (ES) and relative efficiency. Cronbach's alpha co-efficient was used to assess the reliability of the result obtained.
Results: The mean pre-operative score was the highest in the mental health domain (50.21±21.45) and significantly lower in patients with raised intracranial pressure (ICP), pre-operative deficits, a poor Karnofsky performance scale (KPS) score, in large tumors (>4cm) located in an eloquent location and in deep-seated tumors. A significant improvement was noted across all domains except the physical role (P-value 0.20). Overall, the general health domain was most responsive to change with the largest t-value (6.56) and 55.7% patients achieved their target MCID in general health (GH) domain. Among all the factors studied, only a low baseline SF-36 score was significantly associated with a change in QOL after surgery.
Conclusion: Most parameters of HRQOL improved following surgery. Only small-to-moderate improvements occured in the early follow-up period. Large improving trends were noted on a long-term basis, irrespective of the histo-pathological grade. Similar improvements were also noted in patients who subsequently underwent re-surgery despite the development of post-operative complications or new deficits. Also, a low baseline QOL score heralded a poor survival.


Keywords: Glioma, life, post-operative, quality, supratentorial
Key Message: Improving trends in various QOL parameters were noted on a long-term basis irrespective of the histopathological grade of tumor or the number of surgeries performed. Therefore, the HRQOL evaluation in patients harbouring a glioma has considerable importance in guiding treatment decisions, in counselling their family, in post-operative care and in the further management plan.


How to cite this article:
Khatri D, Jaiswal A, Das KK, Pandey S, Bhaisora K, Kumar R. Health-related quality of life after surgery in supratentorial gliomas. Neurol India 2019;67:467-75

How to cite this URL:
Khatri D, Jaiswal A, Das KK, Pandey S, Bhaisora K, Kumar R. Health-related quality of life after surgery in supratentorial gliomas. Neurol India [serial online] 2019 [cited 2019 Sep 19];67:467-75. Available from: http://www.neurologyindia.com/text.asp?2019/67/2/467/257998




Since the last few decades, with the advent of modern neurosurgical techniques and adjuvant therapeutic management protocols, the trends of overall survival (OS) and progression-free survival (PFS) in patients with a glioma have improved.[1],[2],[3] A paradigm shift has been observed in the treatment objectives from “survival” to “functional outcome and quality of life.” Clinicians have started to focus on the “actual benefit” of surgery rather than on the radiological extent of tumor removed. Studies evaluating the health-related quality of life (HRQOL) in different types of brain tumors are on the rise.[4],[5],[6],[7] The patient outcome status is commonly over-assessed by clinicians and a discrepancy exists in the actual outcome status. The health and functional status of a patient are most accurately perceived by the patient himself.[8] Hence, patient-reported outcomes are considered better than objective tools [such as OS, PFS, Karnofsky's Performance Scale (KPS)] for HRQOL studies.[7],[8] However, such questionnaires are often time-consuming. This fact results in an inherent limitation to their frequent use in common practice. At times, the symptomatology and disease progression in glioma patients may itself affect the capacity to accurately judge their health status.

Most studies conducted to assess the quality of life in glioma patients are cross-sectional or retrospective.[9],[10],[11],[12] Large prospective studies assessing the clinicoradiological and surgery-related factors that are responsible for quality of life are lacking. Furthermore, the currently available HRQOL data in gliomas represent the scenario in the western world.[1],[2],[3],[4] Similar HRQOL studies after glioma surgery are still limited in this part of the world.[13],[14],[15],[16] In this study, we present a prospective analysis of the postoperative quality of life in patients with a supratentorial glioma at a tertiary care centre in India.


 » Materials and Methods Top


A prospective evaluation of the HRQOL outcome was done among 103 consecutively operated patients harbouring a supratentorial glioma at our center between May 2016 and November 2017.

All the included patients underwent surgical excision of their tumor depending upon the anatomical location of the tumor, followed by the histopathological examination and immunohistochemistry of the harvested tissue sample, and administration of appropriate postoperative adjuvant therapy. The tumors were graded according to the World Health Organisation (WHO) classification of central nervous system tumors.[17] We aimed for the maximum possible safe resection of the tumor in all patients. Patients who were younger than 18 years of age and whose histopathology report was other than a glioma were excluded from this study. Each patient was closely monitored during the postoperative period for development of any complication such as operative site hematoma, cerebrospinal fluid leak, wound infection, meningitis, new-onset neurological deficits, and requirement of prolonged postoperative ventilation/tracheostomy.

All patients were assessed with a routine preoperative contrast magnetic resonance imaging (MRI) to define the anatomical location and tumor size for an operative planning. Other radiological features such as contrast enhancement, peritumoral edema, and mass effect in the form of midline shift were also evaluated. Postoperatively, each patient underwent computed tomographic (CT) scan of the head to look for an operative site hematoma and to determine the extent of surgical removal.

The level of performance impairment in each patient was evaluated using the KPS score in the preoperative period and at follow-up visits. Patients were then allotted to the “poor KPS” group if the KPS score was <80 and to the “good KPS” group if the KPS score was >80. The functional status was also graded on a scale of 0–4 based upon the Zubrod score/Eastern Cooperative Oncology Group (ECOG) score. A change in the KPS/ECOG score following surgery was classified into three groups (unchanged, improved, and deteriorated).

A licensed version of the short form-36 health survey questionnaire (Optum™ SF-36v2®) in English and Hindi language was used for objectively evaluating the HRQOL in patients. The SF-36 questionnaire is a reliable method of objective outcome assessment of HRQOL. It helps to evaluate the functional health and well-being of a patient using norm-based scoring across eight health domains, namely, physical health, physical role, bodily pain, general health, vitality, social functioning, emotional role, and mental health. The scores thus obtained give an objective assessment of the patient's functional status. All patients were asked to fill survey forms at admission and postoperatively at 1 month, 3 months, 6 months and 1 year of follow-up. For patients who were unfit to answer their survey forms, their primary care-givers were utilized to fill the forms. The percentages of patients with the highest (ceiling) and lowest (floor) possible scores at the baseline were also recorded. Patients with a floor score might not be able to appreciate any health deterioration (floor effect), or those with a ceiling score might not report any further improvement (ceiling effect). These effects were considered significant if >15% of patients achieved such scores.[18]

Changes in the SF-36 scores at the subsequent follow-up visit were evaluated in terms of the mean difference seen, and Student's paired t-tests were used to test for statistical significance of the changes. The effect of various factors (the baseline SF-36 score, postoperative complications, development of new deficits, the WHO grade, primary surgery versus re-surgery, and extent of resection) on the score changes was evaluated using paired-samples t -test with significant P value set at 0.05.

An improvement in the SF-36 scores was also assessed in terms of the clinical benefit obtained by evaluating the minimum clinically important difference (MCID), which is the smallest difference in scores that a patient perceives as being clinically important.[19] Hence, MCID may help in monitoring a meaningful change in QOL after surgery. Based upon the previous QOL studies, we chose 0.5 standard deviation (SD) on a paired-sample t-test as a surrogate for MCID.[12],[20]

Assessment of the responsiveness of a scale establishes its validity for evaluation. A QOL scale should be able to detect the change, whether the patient is undergoing improvement or deterioration, in health over time. In the present study, we utilized the effect size (ES), the relative efficiency (R.eff), and the MCID for assessing responsiveness. The ES is computed by dividing the mean score change (i.e., follow-up minus baseline) by the standard deviation. Cohen's benchmarks were used to categorize the impact of effect size as <0.20 – not significant, 0.20–0.49 – small impact, 0.50–0.79 – moderate impact, and >0.80 – large impact.[21] Relative efficiency was calculated by comparing the t-value in each domain with the highest t-value. Thus, it helped to determine the likelihood of a particular domain to change after surgery. Cronbach's alpha coefficient was used to assess the reliability of the scale used in our study.

The patient demographic data as well as clinical and radiological data were recorded at the time of admission and follow-up. Data regarding the operative findings was obtained through hospital records. The follow-up data was obtained at subsequent outpatient department visits. All data was entered prospectively into the patient proforma and subsequently in the Statistical Package for the Social Sciences (SPSS) software version 24 (IBM Corp, Armonk, NY, USA).


 » Results Top


The mean age in our study group was 42.50 ± 15.07 years with an age range from 18 years to 75 years and a gender ratio of 1.94:1 (M:F). Based upon their age, all patients were divided into two groups – young (age <40 years) and old (age >40 years). There were 47 patients (45.6%) in the younger age group and 56 patients (54.4%) in the older age group.

The preoperative functional assessment for all cases was done based upon the KPS score and the ECOG score. Fifty-nine patients (57.3%) had a good (≥80) KPS score, whereas there were 44 patients (42.7%) with a poor (<80) KPS score. Among all 103 patients, 5 patients had a preoperative ECOG score of 0, 54 patients had a score of 1, 26 patients had a score of 2, 17 patients had a score of 3, and 1 patient had a score of 4.

The average duration of the presenting clinical symptoms before surgery was 17.34 months (range, 10 days to 168 months). More than 50% of our cases presented within 3 months after the onset of clinical symptoms. In the present study, seizures were the most common (57 patients, 55.3%) presenting symptom closely followed by the clinical features of raised intracranial pressure such as headache or vomiting (50 patients, 48.5%). Among these, 10 (9.7%) patients had already developed painless progressive deterioration of vision due to raised ICP. Altered sensorium (33 patients, 32%), limb weakness (29 patients, 28.2%), and impairment of higher mental functions such as speech or memory (18 patients, 17.5%) were less frequent modes of presentation. At admission, 70 (68%) patients were found conscious and oriented, whereas 26 (25.2%) patients were disoriented and 7 (6.8%) patients were not able to follow commands. Fundus examination revealed various grades of papilledema in 56 (54.4%) patients. The patient's demographic data and clinical details are summarized in [Table 1]a.


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Tumor localization

Majority (n = 98, 95.1%) of the tumors were superficially located, with only 5 (4.9%) deep-seated tumors involving the thalamus or corpus callosum being present. Fifty-four (52.4%) patients had the tumor located on the right side, whereas 47 (45.6%) patients had a left-sided tumor, and corpus callosum (midline) was seen involved in 2 (1.9%) patients. Frontal lobe was the most frequently (n = 36, 35%) involved, followed closely by insular (n = 24, 23.3%) gliomas. An eloquent area of the brain was found involved in 57 (55.3%) patients. A detailed list regarding the site of involvement is shown in [Table 1]a.

Radiological features

Seventy patients (68%) presented with a large tumor size (more than 4 cm in maximum dimension). Overall, 48 (46.6%) patients showed a midline shift >5 mm due to mass effect, whereas only 22 (21.4%) patients did not have any tumor-related mass effect. Contrast enhancement was seen in 62 (60.2%) patients in various patterns – peripheral, nodular, or homogenous. Forty-one (39.8%) tumors were nonenhancing in nature. Three patients (0.03%) showed multiple lesions within the cerebral hemispheres [Table 1]a.

Operative findings

The tumor excision was done through various approaches depending upon their anatomical location. Intraoperatively, a brain bulge was noticed in 52 (50.5%) patients. A total of 55.3% of the tumors were seen having surface changes, which helped in intraoperative localization. A large majority (72.8%) of the tumors had an ill-defined surgical plane at dissection, whereas only 28 (27.2%) patients had a well-defined tumor. Most of the operated tumors were soft (75.7%) in consistency and moderately (76.7%) vascular in nature. Complete tumor excision was achieved in 52 (50.5%) patients, whereas incomplete excision was done in 51 (49.5%) patients. A detailed list of operative findings is shown in [Table 1]b.

Histopathology

Upon histopathological examination, we observed that a large majority (n = 50, 48.5%) of patients had WHO grade II tumors. Glioblastomas (WHO grade IV) were the second most common (n = 33, 32%) type of tumors in the present study. Seventeen patients (16.5%) showed grade III tumors with anaplastic features on histopathology. WHO grade I tumors were least commonly found on histopathology with only 3 (2.9%) cases being present [Table 1]b.

Postoperative complications

Twenty-seven patients (26.2%) developed complications in the form of postoperative neurological deficits, in the form of development of a hematoma or infarction, deep vein thrombosis (DVT), wound infection, or meningitis [Table 1]b or required a resurgery or a tracheostomy.

Preoperative SF-36 scores

The preoperative SF-36 scores in our patients had a wide distribution across all eight health domains. The score range was 0 to 100 in all domains except physical role (0–93.75) and general health (0–92). Seventeen patients (16.5%) scored 0 (floor score) in role limitation due to emotional problems, whereas no domain had a significant ceiling score. None of the scales used (KPS, ECOG, SF-36) in the study were affected by the floor/ceiling effect [Table 2]. The mean preoperative SF-36 scores were calculated separately in all health domains at the baseline and serial follow-ups [Table 3]. SF-36 scores were found to be significantly lower in patients who presented with features of raised ICP, as well as in those with preoperative deficits, a poor KPS, and large tumors (>4 cm), tumors in eloquent location, and deep-seated tumors [Table 4].
Table 2: Floor/Ceiling score distribution eight health domains, total SF-36 score, KPS, and ECOG score at baseline

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Table 3: Comparison of mean SF-36 score across various health domains at different intervals

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Table 4: Effect of various factors on baseline SF-36 scores

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Changes in SF-36 scores

For comparative analysis, 6 (5.6%) patients who died before the first follow-up (1 month) were excluded. Among the remaining 97 patients, the mean preoperative score was the highest in the mental health domain (50.21 ± 21.45) and lowest in the physical role (36.73 ± 29.25). At a 1-month follow up visit, there was improvement in the mean SF 36 scores across all eight health domains. The mean change in SF-36 scores across all domains were calculated separately. The calculated mean change ranged from 4.04 (physical role [RP] domain) to 15.06 (bodily pain [BP] domain). The difference in mean scores at the first follow-up was significant across all domains except physical role (P value = 0.20). Moreover, t-values were calculated to assess the score change for each domain using Student's paired t-tests. The t-values ranged from 1.29 (RP domain) to 6.56 (general health [GH] domain). Among all the factors studied, only a low baseline SF-36 score was significantly associated (P value = 0.00) with change in QOL after surgery [Table 5].
Table 5: Effect of various factors on change in SF-36 score

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Responsiveness of scores

The responsiveness of SF-36 scores in each domain was evaluated using MCID, effect size, and relative efficiency. At the first follow-up, MCID values ranged from 10.53 (GH domain) to 16.66 (emotional role [RE] domain). The largest number of patients (n = 54, 55.7%) achieved their target MCID in the GH domain. The social functioning domain showed the least improvement with only 30% of patients reaching their target MCID value [Table 6]. Effect size (ES) is one of the several available indices used to gauge the responsiveness of scales to clinical change. At the first follow-up, ES in various domains ranged from the lowest 0.14 (RP domain) to the highest 0.73 value (GH domain). All domains showed improvement in effect size at serial follow-up visits. One month postoperatively, the GH domain was found to be the most responsive, whereas improvements in bodily pain and mental health were most likely at successive follow-ups [Table 7].
Table 6: Number of patients who achieved the estimated MCID in each health domain

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Table 7: Changes in mean SF-36 score and assessment of score responsiveness across various health domains at serial follow-up

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Follow-up and clinical outcome

In the follow-up period, 27 patients (26.2%) died in our study. Their outcome and functional assessment details are listed in [Table 8]. Upon Kaplan-Meier survival analysis, a significant difference in survival distribution was noted between patients with the baseline SF-36 score lower than the median (median SF-36 score 40.87, n = 51), and patients the with SF-36 score higher than the median at baseline (n = 52). Patients with a low SF-36 score had a significantly shorter mean survival (11.85 months) compared to those with a high SF-36 score (15.99 months; log rank test: P value = 0.04) [Figure 1].
Table 8: Details of outcome and functional status assessment in our study

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Figure 1: Kaplan-meier survival analysis of patients stratified by SF-36 scores at baseline. Baseline score was categorized into Low- if score was less than median baseline score High – if score was more than median baseline score

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 » Discussion Top


Outcome measures such as OS or PFS were traditionally used for objective assessment of neoplastic diseases including central nervous system (CNS) tumors. Now, modern tumor outcome studies focus upon the HRQOL, which yields a subjective evaluation of health.

Only a limited number of studies have previously evaluated the effect of surgery on the quality of life using EQ-5D and KPS scores.[2],[22] In comparison, the SF-36 questionnaire is a relatively simple, patient-oriented, generic tool which helps in the multidimensional evaluation of health. In this study, we also utilized the OS, KPS score, and ECOG score as the adjunctive outcome measures.

Preoperative quality of life status

The baseline mean SF-36 scores in our study ranged from the lowest in the RP domain (36.53 ± 29.38) to the highest in the mental health (MH) domain (50.25 ± 21.52). These scores are comparable with previously reported scores by others.[4] Patients with a larger tumor size usually present early with features of raised ICP features. Our study showed that factors such as a large tumor size and raised ICP are associated with poor QOL baseline scores (P value = 0.00). Surprisingly, we did not find a significant difference (P value = 0.13) in the baseline SF-36 scores based upon the duration of presenting complaints. A deep-seated tumor and a location in the eloquent area were also found to be important determinants of a poor quality of life at presentation. Quite understandably, eloquent region tumors tend to present with neurological deficits and a poor KPS, which are independent predictors of a poor baseline functional status. However, the tumor laterality did not lead to a significant difference in QOL, as has been reported by Drewes et al.[11]

The “response shift effect” is an important phenomenon to be considered in HRQOL studies. Several authors have proposed that it is an adaptive psychological response to cope with the diseased state; patients tend to recalibrate their perception of health and satisfaction. Thus, they may not assess their quality of life with the same criteria for a long time after surgery. Hence, there may not be any difference in the “perceived” quality of life between patients who undergo primary surgery and those with a recurrence of tumor.[9],[10] Similarly, we observed no significant difference (P = 0.87) in the SF-36 scores between patients who underwent primary surgery (n = 91) versus re-operation (n = 6).

A prospective study from India previously found a significant association of old age with poor QOL.[23] In our study, age and gender did not have a significant impact on the baseline QOL scores.

A significant number of patients (n = 17, 16.5%) had the lowest possible/floor score at baseline in the emotional role domain. However, instead of deterioration, there was a steady trend towards improvement in the emotional role scores during serial follow-up visits. No floor effect was noted in other domains. There was no ceiling effect observed across all health domains.

Changes in quality of life with time

The “optimal timing” of follow-up for an accurate evaluation of HRQOL has been a matter of debate. Too early follow-up may be erroneous because quality of life is affected in the postoperative period because of pain and psychological factors. Late follow-up tends to lose patients due to low OS in the high-grade glioma group. Hence, multiple serial assessments have been considered best to follow patients optimally.[2] In the present study, we performed four comparative serial evaluations up to 1 year after surgery.

The bodily pain domain showed the highest observed improvements in mean scores (15.60). Statistically significant change in mean scores was observed in all health domains except the physical role (P = 0.201). However, assessment of P values is not sufficient in quality of life research, as it just states the probability that a change exists between the two groups. Measuring the magnitude of that change, its clinical implication, and responsiveness to treatment is rather important.[24] Concurrently, patients experienced moderate improvements in bodily pain, general health, vitality, and mental health. Only small improvements were noted in physical functioning, social functioning, and emotional role. Although the score improved in the PR domain, the magnitude of that change was not clinically significant (Cohen's d = 0.14). These findings may be attributable to recuperation following surgery. Over a long-term basis, the patient became functionally more active, and the mean changes in the PR domain also achieved statistical significance.

We evaluated MCID and responsiveness of each health domain in this study. The introduction of MCID in quality of life research is highly valuable. MCID is the smallest change in QOL scores which the patient perceives as being clinically beneficial, and hence, it may guide a change in the patient management.[12] In the present study, MCID values ranged from 10.53 to 16.66 across the eight health domains [Table 4]. With the smallest MCID (10.53), GH domain showed the highest (n = 54, 55.7%) chances of improvement in the early follow-up period. Only 30 patients (30.9%) were able to achieve clinically perceptible improvements in social functioning. Concurrently, the effect size was found to be the highest (0.73) in the general heath domain. Therefore, general health was found to have the largest improvement and the most responsive domain (R.eff. =1) after surgical intervention. On the long-term basis, patients tended to be satisfied with their new level of health after surgery and adjuvant therapy despite some physical limitations. Therefore, mental health improvements are most significant (t-value = 7.95) and most responsive (R.eff = 1) to treatment. Similar trends were also observed by Bosma et al.[4]

Among all the factors studied, low baseline SF-36 scores correlated significantly with improvements after surgery. Moreover, low SF-36 scores portend a poor prognosis in terms of survival. Few authors have found that the QOL scores do not predict survival.[4],[25] We corroborated our findings with similar studies by Mainio et al., and Sehlen et al.[26],[27] A brief comparative summary with previous Indian QOL studies is presented in [Table 9]. However, compared to the previously published Indian studies, in this study, we have prospectively evaluated the QOL scores in the pre- as well as postoperative period at different time points up to 1 year after surgery. Therefore, our study has been able to demonstrate a pattern in the QOL scores obtained in these patients following surgery unlike the previous studies. We have also determined the influence of various clinicoradiological and operative factors affecting the baseline parameters as well as dynamic changes in these parameters following glioma surgery.
Table 9: A brief comparison with previous QOL studies from India

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Data collection remains a daunting task in QOL studies. We have utilized both English as well as Hindi version of the SF-36 form to overcome language barriers. When patients are unable to fill the questionnaire correctly due to their neurological deficits, assistance from their primary caregivers are taken as “proxy measurement.” Such measures have been reported to be reasonable methods for the procurement of data in similar studies.[28],[29],[30],[31],[32]

Limitations

Apart from the factors studied, there are a few other factors that affect the HRQOL either directly or indirectly. Our study did not take into account factors such as the patient's financial status, educational level, details of the primary caregiver of the patient, dose-related details of adjuvant therapy, and the effect of other medications like steroids and antiepileptics. Each of these factors have been previously reported to affect the HRQOL in glioma patients.[2]

The extent of surgical resection is a proven independent variable affecting the HRQOL directly.[5],[6] Volumetric analysis of the tumor could yield better assessment of a residual or recurrent lesion. External validity of our study will vary depending upon the patient management protocols adopted at other centres because neurosurgeons differ widely in their opinion regarding operative goals in glioma surgery.

Implications for the future

Even though the SF-36 tool is a generic HRQOL questionnaire, it is easy to use, responsive to health status changes, and evaluates health in multiple dimensions. Till date, no ideal disease-specific tools have been developed to evaluate the effect of surgery on the QOL in glioma patients. Therefore, comparative studies using the SF-36 questionnaire with other HRQOL instruments could be of interest.


 » Conclusion Top


Historically, outcome assessments in glioma surgery have largely focused on the oncological outcome with very less attention paid to the quality of life-related issues. This study has shown that improvements in the HRQOL after surgery for intracranial gliomas is generally modest in the early postoperative period. However, the parameters tend to improve significantly as the duration of follow-up increases, which was observed irrespective of the histopathological grade of the lesion. Of particular note is the fact that similar improvements were also noted in patients who subsequently underwent re-surgery despite development of postoperative complications or new onset neurological deficits. Our study also showed that a low baseline QOL score heralded a poorer outcome in terms of survival. Thus, the current study conclusively proves the advantages of resective surgery in improving QOL in glioma patients apart from its well established benefits in attaining PFS and OS. On the basis of our results, we recommend the routine assessment of QOL in all patients harbouring an intracranial glioma as well as in combining these parameters with the conventional oncological outcome parameters for deriving a holistic outcome score for each patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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