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    -  Basu A
    -  Roy P
    -  Chowdhury H

 
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ORIGINAL ARTICLE
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Incidence and clinical profile of brain metastasis treated with whole brain radiotherapy in a tertiary hospital in eastern India: A retrospective audit


1 Department of Radiation Oncology, R.G. Kar Medical College & Hospital, Kolkata, West Bengal, India
2 Department of Radiation Oncology, Burdwan Medical College & Hospital, Purba Bardhaman, West Bengal, India
3 Department of Radiation Oncology, Medical College & Hospital, Kolkata, West Bengal, India

Date of Submission23-Oct-2020
Date of Decision21-Dec-2020
Date of Acceptance16-Feb-2021
Date of Web Publication12-Oct-2022

Correspondence Address:
Abhishek Basu,
Department of Radiation Oncology, Burdwan Medical College & Hospital, Purba Bardhaman, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_1211_20

  Abstract 


Introduction: Management of brain metastases (BM) is witnessing marked advancement worldwide and modern technologies with better outcomes are gradually being adopted in developing countries. However, data regarding current practice in this field is lacking from the Indian subcontinent prompting us to plan the current study.
Materials and Methods: A retrospective, single institutional audit was performed on 112 patients with solid tumors metastasizing to the brain treated over the last 4 years at a tertiary care center in eastern India, of which 79 were ultimately evaluable. Demography, patterns of incidence, and overall survival (OS) were determined.
Results: The prevalence of BM was 5.65% among all patients with solid tumors. The median age was 55 years with a slight male preponderance. Lung followed by breast were the most common primary subsites. Multiple BM (54%), left-sided (61%), and frontal lobe lesions (54%) were the more common. Metachronous BM was found in 76% of patients. All patients received whole brain radiation therapy (WBRT). The median OS for the entire cohort was 7 months (95% confidence interval [CI]: 4 - 19 months). The median OS for lung and breast primaries were 6.5 and 8 months and for recursive partitioning analysis (RPA) classes I, II, and III the OS were 11.5, 7, and 3 months, respectively. Median OS did not differ by number of or other sites of metastases.
Conclusions: The outcomes from our series about BM from solid tumors in patients from eastern Indian are in congruence to those available in the literature. Patients with BM are still largely treated with WBRT in resource-limited settings.


Keywords: Brain metastases, brain neoplasms, cancer, cranial irradiations, radiotherapy
Key Message: BM from solid tumours is a major clinical problem. However, there is a paucity of epidemiological data analyzing the incidence, as well as treatment outcomes after standard WBRT, in this subset of patients, especially from Eastern India. Our study was conducted to fill in this gap in available literature..



How to cite this URL:
Sammaddar D, Basu A, Roy P, Chowdhury H. Incidence and clinical profile of brain metastasis treated with whole brain radiotherapy in a tertiary hospital in eastern India: A retrospective audit. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 2]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=358393





  Introduction Top


Brain metastases (BM) are the most common intracranial neoplasms with the worldwide incidence varying between 9% and 50%.[1] The ratio of BM to primary intracranial neoplasm is as high as 10:1 and is ever increasing with the advent of advanced brain imaging technologies.[2],[3] In adults, lung cancer is the most common cause of BM (50%–60%), followed by breast cancer (15%–20%) and melanoma (5%–10%).[4] The clinical presentation of BM is similar to any intracranial mass lesion and includes headache (70%), seizures (30%–60%), cognitive impairment (30%), papilledema (8%), and miscellaneous focal neurological deficits.[5] Contrast-enhanced computed tomography (CECT) scan of the brain is often the initial investigation of choice in suspected cases of BM owing to its easy accessibility and low cost, although contrast-enhanced magnetic resonance imaging (CEMRI) is more sensitive, especially in patients with apparently single BM on a CECT scan or with the limited disease in whom the detection of asymptomatic BM would alter the therapeutic approach.[6],[7],[8]

Whole brain radiotherapy (WBRT) has remained the common choice for the management of BM in the last few decades, although an ever-expanding arsenal of other choices now exists for the management of BM, including surgical resection, modified WBRT, stereotactic radiosurgery (SRS), and targeted systemic therapy with the main aim directed at reducing neurological complications and death.[9],[10],[11] However, even with the advent of newer modalities of management, WBRT remains the only option for most centers due to resource constraints, especially in developing countries like India.[8] There is also a paucity of series on BMs from the Indian subcontinent compared with the rest of the world except the study by Ghosh et al.[12] This study was thus conducted to gather insight into patients with BMs treated with WBRT in eastern India.


  Materials and Methods Top


A retrospective single institutional audit of patients with BM undergoing treatment at the Department of Radiation Oncology, at a tertiary care hospital in eastern India was conducted with patient records between January 2017 and January 2020. A total of 96 patients presenting with BM from solid tumor primaries were identified. Of them, 17 were excluded from the study (Three cases had poor performance status, four patients refused treatment and others were either lost to follow up or opted for SRS or metastectomy in other institutions). The remaining 79 patients were included in this audit, which recorded the demographic characteristics, primary tumor histopathology, other sites of metastases, time gap between initial diagnosis and detection of BM, number of BM, and outcome after treatment of BM with WBRT. The Progression-Free Survival (PFS) (defined as the time from date of registration to the date of the first detection of BM [only for patients who did not present with BM de novo]) and the overall survival (OS) (defined as the period from the date of registration to the date of death due to any cause) were ascertained. Data were recorded in a standardized case record form and subsequently analyzed using Microsoft Excel (Microsoft Inc., USA) and Statistical Package for the Social Sciences (SPSS) v25 (SPSS Inc., IBM, USA). All continuous data were described by their central tendencies and categorical data by their proportions. Survival was plotted using the Kaplan–Meier survival plots. Institutional ethical clearance was obtained for the study and all International Conference on Harmonization-Good Clinical Practice (ICH-GCP) and Indian Council of Medical Research (ICMR) ethical protocols were complied with.


  Results Top


Demography

The prevalence of BM in all solid tumors in this cohort was found to be 5.65%. On analysis of the final sample size of 79 patients, the median age for all patients was 55 years (range 19–74 years). Twenty-six (32.91%) patients were in the age group of 50–59 years followed by 23 (29.11%) in the age group of 60–69 years. There was a male preponderance in the incidence of BM, with a male to female ratio of 1.39:1 [Table 1].
Table 1: Patient and tumor characteristics of brain metastases in the entire cohort

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Characteristics of the brain metastases

Synchronous BM was found in 19 (24.05%) patients, of which 11 (57.89%) and eight (42.11%) were solitary and multiple metastases, respectively [Table 2]. Of these 19 patients, 12 had lung cancer primaries, followed by five with breast cancer and one patient each with gastrointestinal and genitourinary cancers as primary. The majority of the synchronous metastases were in the frontal lobe (10, 52.63%) followed by the parietal lobe (7, 36.84%). The left cerebral hemisphere was primarily affected (68.42%).
Table 2: Patient data of brain metastases by time of incidence: synchronous and metachronous.

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Sixty (75.95%) patients had metachronous BM. In this group, a majority of 37 (61.67%) patients were diagnosed with BM within 6 months of detection of the primary lesion and most of the remaining patients had developed BM within the subsequent 6 months (15.25%) [Table 2]. Lung was the most common site of primary cancer in 40 (66.67%) patients followed by breast cancer in 11 (18.33%) patients. Frontal (33, 55%) and parietal (19, 31.67%) lobes were the most commonly affected lobes in this subset and predominantly in the left cerebral hemisphere (35, 58.33%).

Overall, 36 (45.56%) and 43 (54.43%) patients had solitary and multiple BM, respectively. The same spatial preponderance of frontal followed by temporal lobe and left cerebral hemisphere was observed in these groups too.

Primary subsite

Lung was found to be the most common site of primary tumor contributing to 52 (65.82%) cases of BM, followed by 16 (20.25%) patients with breast cancer. Further analysis of patients for the site of the primary tumor was thus restricted to these patient subsets [Table 3]. The median age of incidence of BM in the lung primary subset was 57 years with a strong male preponderance (3.3:1). Among the 52 patients with lung carcinoma, 35 (67.30%) had Non Small Cell Lung Carcinoma (NSCLC) (71.40% Adenocarcinoma, 28.57% Squamous cell carcinoma) while 17 (32.69%) had Small Cell Lung Carcinoma (SCLC). A majority of 32 (61.54%) patients had American Joint Committee on Cancer (AJCC) stage group IV disease at presentation followed by 18 (34.62%) patients in stage group III. The brain as the only site of metastasis was found in 29 (55.77%) patients. Among the remaining 23 (44.23%) patients, bone (19.23%), cervical lymph nodes (13.46%), and adrenal gland (11.54%) were the other sites of metastases. Twenty-nine patients had single brain metastasis.
Table 3: Patient data of brain metastases by primary subsite for the two most common primaries: lung and breast cancer.

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Among patients with breast primaries, the median age of diagnosis was 45.5 years and all the patients were women. Invasive ductal carcinoma was the most common histology found in 15 (93.75%) patients, while one patient had invasive lobular carcinoma. On immunohistochemistry and intrinsic subtyping, 10 (62.5%) patients had human epidermal growth factor receptor 2 enriched breast cancers (Her2neu positive), four had triple-negative breast cancer (TNBC), and two patients had luminal B type breast cancer. Nine had stage III and seven had stage IV disease at the primary site. Half of the patients had the brain as the only site of metastasis, whereas the rest had bone (12.5%), cervical lymph nodes (12.5%), liver (12.5%), and lung (6.25%) as other sites of metastases. Seven patients had solitary brain metastasis.

In both subsets, the frontal lobe was the most commonly affected followed by the parietal lobe.

Treatment

Despite 45% of the patients having a solitary brain metastasis, surgery could not be offered due to the absence of a dedicated Neurosurgery setup at our hospital. Similarly, stereotactic radiotherapy (SRS or SRT) could not be performed, as the facilities were not available at that time. Therefore, all patients in this audit received WBRT. Overall, 67 (84.81%) patients received WBRT with a 30Gy/10#/2 weeks schedule and 12 (15.19%) patients received a 20Gy/5#/1 week schedule (mainly due to poor performance status). Subsequent systemic therapy was received by 52 patients (91.22%) as part of their primary malignancy management.

Survival statistics

The PFS was 14 months (95% confidence interval [CI]: 5 months–72 months) and the median OS was 7 months (95% CI: 6.007 months–7.993 months). Median OS for the entire cohort was 7 months [Table 4] and was slightly higher for women than men [Figure 1]. Median OS for patients with lung and breast primaries were 6.5 months (95% CI: 5.1 months–7.8 months) and 8 months (95% CI: 6.1 months–9.8 months), respectively (Log-rank P = 0.014) [Figure 2]. On further analysis of patients with lung primaries, median OS was found to be 7, 5, and 4 months for adenocarcinoma, squamous cell carcinoma, and small cell histology, respectively [Figure 3]. Median OS in patients with recursive partitioning analysis (RPA) class I, II, and III were approximately 11.5, 7, and 3.5 months, respectively (Log-rank P = 0.0001) [Figure 4]. The median OS for the number of BM and other sites of metastases was not statistically significant.
Figure 1: Overall Survival by Sex

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Figure 2: Overall Survival by Primary Subsite

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Figure 3: Overall Survival by Histopathology among Lung Primaries

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Figure 4: Overall Survival by RPA Class

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Table 4: Overall survival stratified by patient and tumor characteristics.

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Toxicities

Fatigue was the most prominent acute toxicity seen during WBRT. Other acute effects included radiation-induced cerebral edema, alopecia and dermatitis, nausea and vomiting, and decreased appetite. Most of these were usually responsive to conservative treatment (including corticosteroids). The most common late toxicity was neurocognitive impairment, although no formal quality of life (QoL) or neurocognitive assessment could be done as this was a restrospective study.


  Discussion Top


BM is the most common type of intracranial neoplasm among all patients with cancer,[13] and their incidence is increasing likely due to improved diagnostic and screening aids.[14]

Demography

Victor et al.[15] noted that about 60% of patients with BM are aged between 50 and 70 years, with no gender predisposition. However, Nieder et al.[16] showed that significantly more number of women were affected with BM. In the studies conducted in India, the majority of the patients with BM were in the sixth decade of their life, while the gender preponderance was variable.[17] There was a male preponderance in our series and the median age of 55 years was in congruence with the above-mentioned studies.

Primary site

It is well documented in the literature that in the adult population, lung cancer is the main cause of BM followed by breast cancer and melanoma, while tumors of the gastrointestinal tract and renal cell carcinomas are less common primary sites.[4] We observed the same trend in our series.[18] Similar to the series by Ghosh et al.[8] supratentorial metastases were noted in 86.03% of our patients with a fair number of cerebellar metastasis.

Lung as the primary site

Lung cancer is the leading cause of BM globally, with up to 65% of patients developing BM at some point during their disease period.[4] Among the various histopathological subtypes of lung cancer, SCLC is much more prone to metastasize to the brain than NSCLC (more in adeno and large cell histologies), although the overall incidence of SCLC is only around 20% of all lung cancers.[19] The majority of BM were found in patients with NSCLC primaries in our series, possibly due to the higher numbers compared with SCLC.

The incidence of BM increases steadily with the stage.[20] In our series, 61.54% of patients with BM from primary lung cancer had stage IV disease. A preponderance of solitary BM was noted in our cohort congruent with other series.[21],[22] Majority of patients belonged to RPA class II as in other series.[23] The median survival for BM with lung cancer primaries ranges from 2.7–9.7 months, which is similar to the OS of 6.5 months noted in this study.[24],[25] Patients with adenocarcinoma had the highest OS, followed by squamous and small cell histology like in other studies.[21],[22],[23],[24]

Breast as the primary site

Multiple large population-based studies have unequivocally found Her2neu-enriched breast cancers to have the highest incidence of BM.[25] However, TNBCs seem to have the worst outcome with median survival of approximately 3 months.[26],[27] In our series too, this was evident with Her2neu amplified subgroup being the predominant subtype and TNBC showing the worst survival data. According to RPA class I, II, and III, the median survival of breast cancer patients were 15, 11, and 3 months, respectively, whereas the median OS was 12, 23, 10, and 6 months (P < 0.001) in patients with luminal A, luminal B, Her2neu, and TNBC cancers, respectively.[24],[27] Unfortunately, we could not perform such a subset analysis owing to the small patient numbers. The median OS in patients with BM, with breast primary irrespective of immunohistochemistry, and treated with WBRT was found to be 8 months in our study.[24],[27]

Other characteristics of the brain metastases

Saito et al. and Saha et al. documented solitary BM in 38.1% and 22.2% patients, respectively, which is consistent with the present study, but contrary to the findings of Stark et al. where single BM was more common.[17],[28],[29] Patients with metachronous BM had a shorter median time from the diagnosis of the primary to detection of BM of 5.8 months in comparison with other studies.[20] Similar to our study, irrespective of subsite and primary site, the majority of patients belonged to RPA class II.[4],[12],[20]

Management of brain metastases

With the development of therapies that improve extracranial disease control and increase the long-term survival of patients with metastatic cancer, effective treatment of BM with minimal toxicities is becoming important. The possible effect of WBRT on cognitive function has generated some debate leading to wider acceptance of newer radiation therapy techniques for BM, including hippocampal avoidance WBRT (HA-WBRT) and SRS.[30],[31] However, majority of physicians in India do not practice SRS due to a lack of facilities as demonstrated in the study by Manir et al.[32] Therefore the historical options for palliation in the form of WBRT remain an important modality of treatment in resource-limited settings, including ours, as also in patients with multiple BM.[12],[29]

Studies have shown an improvement in symptoms in 64%–83% of patients after treatment with WBRT alone,[33],[34] and have also demonstrated an increase in median OS from 1 month with no treatment to 3–7 months following WBRT. There is a debate regarding the ideal fractionation schedule for WBRT; however, 30Gy in 10 fractions over 2 weeks was found to be effective in palliation and, therefore, the most common fractionation schedule used.[15],[24],[35] This schedule was used in the majority of patients in our study with 20Gy in 5 fractions reserved for patients with poor performance status. Unfortunately, metastasectomy could not be performed in solitary BMs due to the unavailability of an experienced Neurosurgery facility at our Institution at that time. Acute and late toxicity profile following WBRT was comparable with existing literature.[33]

Survival analysis

OS of patients with BM varies widely depending on gender, age, performance status (PS), number and location of the lesions, primary tumor site, presence of extracranial disease, RPA class, scope of surgery, radiation doses-fractionation, technique, and additional systemic therapy[29] The median OS has been shown to range between 3–12 months, which is in congruence with our findings, and therefore, representative of other published series.[24],[25],[29],[36] We also analyzed survival according to sex, and the median OS was numerically better for women than men (7.5 versus 7 months) in this cohort.

Study limitations

Our study had the inherent drawbacks of being a single institutional retrospective audit (with a small sample size) covering a relatively short period along with the unavailability of an experienced Neurosurgery setup and advanced radiation techniques (SRS/SRT/HA-WBRT) in this institution during the study period. Moreover, the toxicities (especially late neurocognitive impairment) and QoL of the patients could not be systematically captured owing to the retrospective nature of the study.


  Conclusions Top


BM from solid tumors is a major clinical challenge for oncologists. Our data shows an incidence peaking in the fifth decade with a male preponderance and lung followed by breast cancer as major primary sites, which is congruent with other series. With WBRT, a median OS of 7 months was achievable in our resource-constrained settings. Our study supplements the largely lacking epidemiological data about BM from solid tumors in eastern India and provides foundation for future multi-institutional studies on a larger scale. Better outcomes for these cohort of patients are also expected with the increasing implementation of newer modalities of treatment in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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