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Clinical science
Clinical presentation and survival of retinoblastoma in Indian children
  1. Bhavna Chawla1,2,
  2. Fahmi Hasan1,2,
  3. Rajvardhan Azad1,2,
  4. Rachna Seth2,3,
  5. Ashish Datt Upadhyay2,4,
  6. Sushmita Pathy2,5,
  7. RM Pandey2,4
  1. 1Ocular Oncology & Pediatric Ophthalmology Service, Dr Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi, India
  2. 2All India Institute of Medical Sciences, New Delhi, India
  3. 3Pediatric Oncology Division, Department of Pediatrics, New Delhi, India
  4. 4Department of Biostatistics, New Delhi, India
  5. 5Department of Radiotherapy, Dr. B.R.A.IRCH, New Delhi, India
  1. Correspondence to Dr Bhavna Chawla, Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India; bhavna2424{at}hotmail.com

Abstract

Objective To study the clinical presentation and survival among Indian children with retinoblastoma (RB) and to determine factors predictive of poor outcome.

Methods A retrospective review of children newly diagnosed with RB at a tertiary referral centre was undertaken. Demographic and clinical characteristics and treatment outcomes were studied.

Results A total of 600 patients (unilateral 67.6%, bilateral 32.4%) was studied. 61% was boys. The median age at presentation was 29 months (18 months vs 36 months in bilateral and unilateral cases, respectively, p<0.001). leukocoria was most common (83%), followed by proptosis (17%). Tumours were intraocular in 72.3% and extraocular in 27.7% cases. In the intraocular group, 78% were advanced Group D or E disease. Metastasis to the central nervous system was noted in 15.7% of extraocular cases. A statistically significant difference was seen between intraocular and extraocular groups in the median age (24 months vs 37.5 months, p<0.001) and median lag period (2.5 months vs 7 months, p<0.001). The Kaplan-Meier survival probability was 83%, 73% and 65% at 1 year, 2 years and 5 years, respectively. On univariate analysis, age >2 years (p=0.002), lag period >6 months (p=0.004) and extraocular stage (p<0.001) were associated with poor outcome. On multivariate analysis, extraocular invasion was predictive of low survival (HR 5.04, p<0.001).

Conclusions Delayed presentation is a matter of concern. Improving awareness about the early signs and creating facilities for diagnosing and treating RB at the primary and secondary levels of healthcare are required to reduce mortality and morbidity, and lead to improved outcomes that are comparable with the developed nations.

  • Child health (paediatrics)

https://doi.org/10.1136/bjophthalmol-2015-306672

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    Introduction

    Retinoblastoma (RB) is the most common intraocular malignancy of childhood.1 Leukocoria is the most frequent symptom at presentation, other signs include squint, poor vision, redness or proptosis.2 A potentially curable tumour, the prognosis for survival is dependent on early diagnosis and appropriate therapy. Excellent survival outcomes have been reported from the developed countries where the goals of treatment have shifted towards globe and vision salvage.3 On the other hand, a high mortality rate associated with RB is still a matter of concern in the developing world.4 ,5 Factors that contribute to a poor outcome include delay in presentation, lack of awareness, poor compliance and absence of adequate healthcare facilities.5 ,6

    India is a densely populated country with a large number of children less than 5 years of age. Our centre is a tertiary care centre for eye diseases in North India that caters to referrals from all over the country. This study was undertaken to determine the clinical profile and survival outcomes of Indian children affected by RB. The objective was to assess the magnitude of the problem in our clinical setting and be able to identify priority areas for improving the medical care of children affected by this cancer, and to compare our results with those published from other parts of the world.

    Materials and methods

    Medical records of children newly diagnosed with RB at our centre between January 2009 and June 2013 were retrospectively reviewed. Informed consent was taken from all parents and the study followed the tenets of the declaration of Helsinki. Data noted included demographic information, history, clinical features at presentation, treatment details, survival outcomes and duration of follow-up.

    The diagnosis was based on clinical examination and B-scan ultrasonography. The International Classification System for Intraocular Retinoblastoma and the International Retinoblastoma Staging System were used for staging of intraocular and extraocular RB, respectively. In children with advanced intraocular disease, neuroimaging with MRI was performed to rule out extraocular spread. Extraocular invasion at diagnosis was defined as any extension of the tumour beyond the sclera into the orbit and/or into the optic nerve. The diagnosis of children with extraocular RB was based on clinical examination, MRI of the orbits and brain, and fine needle aspiration cytology/incisional biopsy of the orbital mass, when required. In addition to ophthalmological examination, a general physical examination and systemic examination were carried out. In children with high-risk histopathological features and those with suspected metastasis, metastatic work-up with chest X-ray, liver and kidney function tests and ultrasound of the abdomen were done. In all cases with orbital spread, bone marrow biopsy and cerebrospinal fluid examination were also done.

    Depending on the stage of tumour, unilateral or bilateral presentation and visual potential of the affected eye, a standard protocol-based management was followed. For intraocular disease, globe salvage therapies included transpupillary thermotherapy, cryotherapy, systemic chemotherapy and periocular chemotherapy. For group A–C eyes (unilateral or bilateral) globe salvage therapy was used. For unilateral group D eyes, the options of enucleation as well as globe salvage were offered to the patient. If the parents opted for conservative treatment, close monitoring was performed to assess the response to therapy. For bilateral Group D disease, globe salvage therapy was advised, in an effort to save at least one eye. External beam radiotherapy (EBRT) or enucleation was advised in selected cases that failed chemotherapy and focal therapy. Group E eyes were treated with a primary enucleation. Adjuvant chemotherapy with six cycles of intravenous vincristine, etoposide and carboplatin was given at 3–4 weekly intervals in children with high-risk histopathological characteristics in the enucleated eyeball, based on Children's Oncology Group (COG) guidelines.7 The standard treatment protocol for extraocular tumours included 3–6 cycles of neoadjuvant chemotherapy followed by enucleation, EBRT and adjuvant chemotherapy for a total of 12 cycles. For metastatic cases with a very poor prognosis for survival, palliative care was advised. At completion of therapy; all children were meticulously followed up to look for any local recurrence, adverse effects of treatment or systemic metastasis.

    Data was analysed using Stata 11.2 and presented in frequency (%) and mean (SD)/median (min, max). Categorical variables were compared using the χ2/Fisher's exact tests. Kaplan-Meier survival analysis was carried out to study the survival pattern among different groups and statistical significance was tested by the log-rank test. Univariable and multivariable Cox regression was used to calculate unadjusted and adjusted HR. A p value <0.05 was considered statistically significant. Bonferroni correction t test was considered for multiple comparisons and a p value <0.01 was considered statistically significant.

    Results

    A total of 667 children were newly diagnosed with RB during the study period. Of these, 67 (10%) patients were lost to follow-up. The demographic features of 600 children are presented in table 1. The median age at which the first sign was noted by the parents or family members was 21 months (range, 0–141 months), whereas the median age at presentation was 29 months (range, 1–150 months). The median lag period (time interval between the age at which first sign was noted and age at diagnosis) was 3 months (range, 1–120 months). A significant number of children (7.5%) were older than 5 years at initial diagnosis. Although leukocoria was the most common presenting symptom (83%), 17% of children presented with proptosis of the eye.

    View this table:
    Table 1

    Demographic and clinical features of 600 children with RB

    A third of the children had bilateral involvement. A comparison of clinical characteristics between unilateral and bilateral cases is shown in table 2. The median age at presentation was lower in bilateral cases as compared with unilateral cases (18 months vs 36 months, p<0.001). Figure 1A shows the association between age at diagnosis and laterality. While 66% of bilateral cases were diagnosed before 2 years of age, 68% of unilateral cases were diagnosed after the age of 2 years. Although bilateral cases presented much earlier than unilateral cases, the lag period was comparable between both groups (p=0.056). There was no significant association between gender and laterality.

    View this table:
    Table 2

    Comparison of demographic features at presentation between unilateral and bilateral groups and between extraocular and intraocular groups

    Figure 1
    Figure 1

    Bar diagram to show the association between (A) Age at diagnosis and laterality of disease (B) Age at diagnosis and tumour stage at presentation.

    Extraocular invasion was noted at initial diagnosis in 27.7% cases. A comparative evaluation of intraocular and extraocular groups is shown in table 2. A statistically significant difference was observed with respect to the median age at presentation (24 months vs 37.5 months, p<0.001) and the median lag period (2.5 months vs 7 months, p<0.001). While 51% of intraocular cases were diagnosed before 2 years of age, 78% of extraocular cases were diagnosed after the age of 2 years (p<0.001) (figure 1B). Extraocular spread was more common in the unilateral group as compared with the bilateral group (p=0.033) (table 2).

    Of 600 children, 72.3% (n=434 cases, 585 eyes) had intraocular tumours. These included unilateral cases (65.2%) and bilateral cases (34.8%). The majority of affected eyes were Group E (64%), followed by Group B (15%) and Group D (14%). Figure 2 shows that as the tumour stage increased from Group A to Group E, the proportion of bilateral cases became lower and unilateral cases increased (p<0.001). Among unilateral cases, 95% were Group D or Group E eyes as compared with 5% in Group A–Group C. On the other hand, among bilateral cases, 38.4% were Group A–Group C eyes.

    Figure 2
    Figure 2

    Groupwise distributions (Group A–Group E) of unilateral and bilateral cases with intraocular retinoblastoma.

    The most common treatment for intraocular tumours consisted of a primary enucleation in 289 eyes (49.4%) and secondary enucleation (after failure of systemic chemotherapy and radiotherapy) in 131 eyes (22.4%). For globe salvage, focal therapy by transpupillary thermotherapy and/or cryotherapy was given in 214 (36.6%) eyes, systemic chemoreduction in 203 (34.7%) eyes and EBRT in 31 (5.3%) eyes. At the end of the study, globe salvage rates were 100% in Group A eyes, 94% in Group B eyes, 83% in Group C eyes and 54% in Group D eyes.

    Among extraocular patients (n=166), 123 (74%) children had unilateral disease and 43 (26%) had bilateral disease. Three children had bilateral extraocular RB. The majority of children with orbital RB had Stage III disease (n=140, 84.3%), whereas CNS metastatic disease (Stage IV) was present in 15.7% (n=26) cases. In the extraocular group, the clinical outcomes were as follows—alive and well without any local recurrence or distant metastasis (n=65, 39.2%), alive with metastasis (n=15, 9%) and expired (n=86, 51.8%).

    The mean follow-up period of 600 cases was 21 months±15.19 (range, 1–60 months). The overall mortality at the end of the study was 24.3% (n=146). The Kaplan-Meier survival probability was 83%, 73%, 68% and 65% at 1 year, 2 years, 3 years and 5 years, respectively (figure 3A). Association between survival outcomes and variables such as age, gender, lag period, laterality and stage of the disease were studied by univariate and multivariate studies (table 3). On univariate analysis, age at presentation, lag period and stage of the disease were found to be associated with a poor survival outcome. The outcome was significantly better in children diagnosed within the first 2 years of life as compared with those diagnosed after 2 years of age (p=0.002). The survival probabilities at the end of 1 year and 5 years, respectively, was 91% and 70% in Group 1 (<2 years), 77% and 58% in Group 2 (2–4 years), and 80% and 67% in Group 3 (>4 years) (figure 3B). Another factor found to be predictive of poor survival outcome was a lag period of >6 months as compared with a lag period of <3 months (p=0.004) (figure 4A). The survival probability for children with lag period of less than 3 months was 89%, 78% and 68%, respectively, at the end of 1 year, 2 years and 5 years, as compared with 76%, 67% and 59% for those with a lag period of more than 6 months. A statistically significant association was also observed between stage of the disease at initial diagnosis and survival (figure 4B). The survival probability in the extraocular group was 60%, 43% and 35%, respectively, at the end of 1 year, 2 years and 5 years, as compared with 93%, 85% and 78% in the intraocular group (p<0.001). On multivariate analysis, stage of the disease had a significant association with survival outcomes (extraocular vs intraocular, HR 5.04, p<0.001) (table 3). No significant difference in the survival outcomes was observed between unilateral and bilateral cases (p=0.96). In the first 2 years, bilateral cases had a comparatively better survival probability, whereas in the later period, unilateral cases had a better outcome (figure 5A). Gender did not significantly impact the survival outcomes in our study, with no significant difference between boys and girls (p=0.33) (figure 5B). The demographic and clinical features of children who died are shown in table 4. A total of 146/600 children expired, which included 60/434(13.8%) children in the intraocular group and 86/166 (51.8%) children in the extraocular group.

    View this table:
    Table 3

    Association of patient survival with demographic factors and their adjusted and unadjusted HRs

    View this table:
    Table 4

    Demographic and clinical profile of expired children

    Figure 3
    Figure 3

    Kaplan-Meier 5-year survival probability to show (A) The overall survival probability in 600 cases (B) Association between survival probability and age.

    Figure 4
    Figure 4

    Kaplan-Meier 5-year survival probability to show an association between (A) Survival probability and lag period and (B) Survival probability and stage of the disease.

    Figure 5
    Figure 5

    Kaplan-Meier 5-year survival probability to show the lack of association between (A) Survival probability and laterality and (B) Survival probability and gender.

    Regarding the 67 cases (10%) that were lost to follow-up during the study period, the median age at which the first sign of RB was noted was 14 months and the median age at presentation was 23 months. Of these 67 cases, 61% (n=41) were boys and 39% (n=26) were girls. Twenty (30%) cases were bilateral. The stagewise distribution showed that 31.3% (n=21) had extraocular spread at presentation, whereas 68.7% (n=46) had advanced intraocular RB at initial diagnosis (Group E, n=38, Group D, n=8).

    There was no significant difference between the group that was lost to follow-up as compared with the group that followed treatment with respect to age at first sign (p=0.97), age at presentation (p=0.46), gender (p=0.99), laterality (p=0.67) and stage of the disease at diagnosis (p=0.52).

    Of 67 cases, 53 (79%) children were lost to follow-up even before any treatment could be initiated. In the remaining 14 (21%) cases, treatment was initiated, but these patients abandoned therapy during the course of treatment. These included eight children with extraocular disease and six children with advanced intraocular tumours. Of the eight children with extraocular disease in whom neoadjuvant chemotherapy was initiated, five cases abandoned treatment prior to enucleation and the remaining three after undergoing enucleation surgery. Of the six intraocular cases, four children with Group E disease underwent a primary enucleation but were thereafter lost to follow-up. The other two children had Group D disease and were started on systemic chemotherapy but were lost to follow-up during treatment.

    Discussion

    Studies from different parts of the world have shown a wide variation in the clinical presentation and survival outcomes of children affected by RB. In our study, the median age at diagnosis was 29 months, which was comparable with previous studies from Iran (28.5 months), Taiwan (26.3 months) and Malaysia (24.2 months).8 ,9 A relatively higher median age at diagnosis has been reported from African countries like Ghana (36 months) and Kenya (37.5 months).6 ,10 The median lag period was 3 months, which is similar to a study by Butros et al11 who reported a time lag of 2 months. In our series, it was observed that 7.6% of children were older than 5 years at the time of initial diagnosis. Shields et al12 and Karcioglu et al13 have reported that 8.5% and 5.3% cases, respectively, were above 5 years of age at the time of diagnosis. Previous studies have observed that RB has no sex predilection.14 ,15 In contrast, a male preponderance was noted in our patients. This could be attributed to lack of attention given to female children especially in the rural areas of our country, leading to a referral bias.

    In developed nations, leukocoria is the most common symptom at presentation, followed by strabismus.2 ,16 In our study, strabismus was seen in only 5.5% of cases, with proptosis as the second most common presenting symptom (17%). A study from Taiwan5 has also reported proptosis in 17% cases, whereas another study on Nigerian children found proptosis in 85% cases.17

    Extraocular RB is rare in the developed world and its frequency ranges between 2% and 5%.18 On the other hand, orbital invasion remains a challenge for developing countries.19 ,20 In our study, extraocular spread was seen in 28% cases, which falls in the range of 26–50% in studies from different parts of the world.9 ,10 ,21 This figure reflects a lack of awareness regarding early signs of RB, inadequate healthcare facilities at the primary and secondary levels of healthcare, delays in the referral system and poor compliance to treatment, a feature common to most developing nations.

    A third of the children had bilateral disease in our series. The median age at diagnosis was 18 months for bilateral cases and 36 months for unilateral cases. Bilateral and unilateral tumours were diagnosed at a relatively earlier age in developed countries like USA (13 months and 23 months)11 and Australia (5 months and 21 months).22 This could be attributed to greater awareness and access to better medical facilities in the developed world. Interestingly, a study from Iran found a slightly earlier age of diagnosis among unilateral cases as compared with bilateral cases (27.4 months and 30 months, respectively).8 Our results showed that 66% of bilateral cases were diagnosed during the first 2 years of life whereas 68% of unilateral cases were diagnosed after the age of 2 years. An association between age and laterality has also been previously reported by Sanders et al.23

    Delay in presentation was observed in the majority of cases. Advanced Group D or Group E tumours were present in 78% cases in the intraocular group. Less advanced tumours (Group A–Group C) were less frequently picked up among unilateral cases as compared with bilateral cases (5.3% vs 38.4% in unilateral and bilateral groups, respectively). The majority of children with early tumours were picked up either due to advanced disease in the fellow eye or due to screening of siblings with a positive family history. Our observation of identifying less advanced disease more often in bilateral RB is consistent with that reported by Zhao et al24 in Chinese children.

    Primary enucleation is considered as an ideal treatment for Group E eyes to save life and prevent metastasis. Due to advanced stage at presentation, the most common treatment was enucleation. A similar high rate of enucleation has also been reported from China24 where the majority of children presented with advanced disease. Globe salvage rates for Group A–Group D disease were 100%, 94%, 83% and 54%, respectively, which were comparable with those reported by Shields et al25 (100%, 93%, 90% and 47%).

    In developed nations such as Europe, Canada and USA, mortality due to RB varies between 3% and 5%.3 ,23 However, in the developing countries, this rate increases to 40%–70% owing to late presentation.4 In our series, the overall mortality was 24% and the cumulative 5-year survival probability was 65%, which is similar to the figure of 64.4% reported from Taiwan.5 This survival rate is considerably lower than the 5-year survival rate seen in the USA (95%),26 Japan (93%)27 and Iran (83%).8 ,9 In one study from the UK, the 3-year survival rate was 88%,23 however, only 1.6% of children had extraocular spread in contrast to 28% in our series. An extremely low 3-year survival of 26% has been reported from the Kenyatta National Hospital, which was attributed to late presentation and delay in the referral system.6 In our study, the Kaplan-Meier survival probability was 83%, 73%, 68% and 65% at 1 year, 2 years, 3 years and 5 years, respectively, showing that most deaths occurred within the first 3 years of diagnosis, which has also been observed in another series.23

    The child's age at diagnosis had an impact on survival, with a better outcome in children <2 years of age. Other studies have also reported a higher age at diagnosis to be associated with poor outcome.6 In contrast, a study from Iran found a comparatively better survival rate if the disease was diagnosed after 24 months of age.8 In the current series, a lag period of >6 months had an adverse impact on the survival outcomes This finding is consistent with a study by Chang et al9 in which a lag period of more than 2.5 months was associated with poor survival. Survival outcomes in unilateral and bilateral groups were comparable, although bilateral cases had a comparatively better survival in the initial period. A similar trend has also been previously reported by other studies.9 ,22 Regarding gender and survival, the overall survival for the male child was found to be better than the female child in a previous study,22 although no such association was observed among our patients. On multivariate analysis, stage of the disease (intraocular versus extraocular) had a significant impact on the survival outcomes, which is consistent with previous studies that reported an association between severity of disease and the survival outcome.9 ,27 ,28

    While extraocular disease at presentation is expected to be the primary driver of mortality over a 5-year period, in our cohort, 13.8% (60/434) of children with intraocular tumours expired, with a Kaplan-Meier survival probability of 93%, 85% and 78% at 1 year, 2 years and 5 years, respectively. These figures are higher than those reported from developed nations. Multiple factors were responsible for deaths occurring in the intraocular cases. First, the majority of intraocular cases (82% of unilateral and 46% of bilateral cases) had advanced Group E disease that was treated by an upfront enucleation. Of the 60 children that expired, 38% deaths (n=23) occurred in children with high-risk histopathological features including microscopic residual disease. Another factor responsible for mortality in the intraocular group was poor patient compliance leading to inadequacy of treatment as most of the children came from remote areas and belonged to a poor socioeconomic background. Lack of compliance towards treatment was noted in 25% cases (n=15) that expired. Treatment-related complications such as myelosuppression leading to subsequent neutropenia and infection were responsible for 6.6% of deaths (n=4). Another important factor is that conditions such as malnutrition, lack of immunisation, viral infections, respiratory disorders and gastrointestinal diseases are responsible for many deaths in children under the age of 5 years in India. In 13 cases, (21.6%), the deaths occurred due to these additional factors. In five cases (8.3%), the exact cause of death could not be ascertained as the death occurred at remote places and was confirmed by telephonic conversation.

    We also studied the reasons that led to abandonment of treatment. Ten per cent of our cases were lost to follow-up. One reason for abandonment included reluctance for enucleation, which was the most commonly advised treatment due to advanced stage of the disease. Among extraocular cases, the lengthy protocol of treatment and poor prognosis for survival were major factors that resulted in abandonment. Other reasons included poor socioeconomic conditions and long distances of travel to our centre.

    To summarise, the present study on a large series of Indian children affected by RB describes the outcomes in Indian children, although it probably represents about 10% of all cases seen in the country. Our results showed that delayed presentation due to lack of awareness and inaccessibility to proper medical facilities at the primary and secondary levels of healthcare were a major impediment in achieving high cure rates. This hurdle needs to be overcome by making concerted efforts towards facilitating early diagnosis and avoiding delays in the referral system. A nationwide awareness campaign to educate the public and healthcare professionals about early signs of RB and its implications is required. Strengthening of medical facilities for diagnosing and treating RB at the primary and secondary levels of healthcare is also important to reduce mortality and morbidity associated with the disease, and lead to improved outcomes that are comparable with the developed nations.

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    View Abstract

    Footnotes

    • Correction notice This article has been corrected since it was published Online First. The p value in the following sentence has been corrected from 0.02 to 0.002, ‘The outcome was significantly better in children diagnosed within the first 2 years of life as compared with those diagnosed after 2 years of age (p=0.002).’

    • Contributors All authors included in this paper fulfil the criteria of authorship.

    • Competing interests None declared.

    • Ethics approval All India Institute of Medical Sciences.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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