A Comparison of Retinoblastoma Cases in the Philippines

Retinoblastoma is a malignancy that affects the retina during childhood.¹ The Philippines was one of the countries that registered the most cases of retinoblastoma globally in 2013 and was projected to be among the leading sources of retinoblastoma cases in 2023.² From 1977 to 2001, there was a five-fold increase of cases in the country.³ Aside from the increasing number of retinoblastoma cases, available literature highlights the high percentages of advanced and extraocular diseases among retinoblastoma patients in the country. Noguera et al. found advanced intraocular disease in 69% and extraocular disease in 16% among their cohort in 2011.⁴ In 2020, the Global Retinoblastoma Study Group reported a higher percentage of extraocular disease at 37% in their Filipino cohort.⁵ These explain the low survival rates from retinoblastoma in the country, from 53% in northern Luzon to 28% in southern Philippines.^6,7

Programs to improve awareness and survival among retinoblastoma patients in the Philippines have been implemented by the Philippine Academy of Ophthalmology (PAO), the professional society of Filipino ophthalmologists, the Philippine Society of Pediatric Ophthalmology and Strabismus (PSPOS), a subspecialty society of the PAO, and other organizations. The Philippine Health Insurance Corporation (PHIC) has also increased its insurance coverage thru the “No Balance Billing’ policy in 2011, including for cancer treatment in its Z benefits package in 2012. But there has been no direct and updated comparison between demographics, clinical presentation, treatment options, and outcomes of retinoblastoma patients in the country to determine how the diagnosis and management of the disease have changed in the past decade.

Similarly, most available data on retinoblastoma are from Luzon. The Philippines is an archipelago of 7,641 islands divided into 3 major island groups: Luzon in the north, Mindanao in the south, and the Visayas in between. These 3 island groups are further grouped into 17 administrative regions. Given the high number of cases in the country and the severity of the cases upon diagnosis, a comprehensive and a more representative data set are needed.^8-10 This study invited several eye care specialists practicing in different institutions all over the Philippines who diagnose and manage retinoblastoma cases to compare their data on retinoblastoma patients seen between two time periods: from 2010 to 2015 and from 2016 to 2020. The objectives of this study were to compare the demographics, clinical presentation, mode of treatment, and the clinical outcomes of retinoblastoma patients seen at the 11 participating Philippine institutions between the 2 time periods.

METHODS

This was a multicenter, retrospective, cohort study that employed review of medical charts and hospital databases of retinoblastoma patients seen in the Ophthalmology and Pediatrics departments of the participating institutions in the Philippines from 2010 to 2020. This study employed the same data set in a prior publication and analyzed into 2 divided but unequal time periods: from 2010 to 2015 and 2016 to 2020.¹⁰ This study received ethics approval from the Department of Health Single Joint Review Ethics Board and institutional review boards, if present, of each participating institution. The Declaration of Helsinki and the Philippine Data Privacy Act of 2012 were observed in the conduct of this study.

The inclusion and exclusion criteria were described in a prior publication.¹⁰ The following data were collected from the medical charts: institution where the patient was evaluated, age at consult, sex, town and province of origin, ocular involvement (unilateral or bilateral), date of birth, age at initial symptom, date of initial consult, reason for delay of consult (if applicable), presenting symptom, family history, intraocular grading on initial consult, diagnostic imaging and laboratory results (ocular ultrasound, magnetic resonance imaging [MRI], computed tomography [CT] scan, cerebrospinal fluid analysis, bone marrow aspiration), surgical intervention done (enucleation, exenteration, etc), presence of high-risk features on histopatholoic studies, interventions done and number of sessions (chemotherapy, radiotherapy, laser treatment, cryotherapy), latest systemic staging, date at last consult, and status. For geographical origin, the patient’s permanent address was used. For standardization, delay of consult was defined as the interval between the age at onset of symptom and the age at initial consult. Intraocular grading was based on the International Intraocular Retinoblastoma Classification (IIRC) or the International Classification for Retinoblastoma (ICRB), depending on which grading was used by the participating institution. Patients with visible extraocular mass or significant proptosis were assigned to have extraocular disease as their IIRC/ICRB grading. Patients without IIRC/ICRB grading but had available ocular ultrasound results or underwent upfront enucleation with available histopathology report were graded based on these data. Patients without International Retinoblastoma Staging System (IRSS) staging but with available cranial and orbital imaging readings (e.g., CT, MRI scan) and histopathology reports were staged based on the available data. For patients evaluated in more than 1 participating institutions and received different IRSS stages, the latest IRSS stage was used. For bilateral disease, the IRSS stage of the worse eye was used for staging the patient.

For systemic chemotherapy, the patients were classified into not needed (responsive to local therapy or with surgically resectable and totally resected disease with no high-risk features), completed (completed ≥6 cycles of chemotherapy), and incomplete/abandoned (as stated or those who received less than 6 or the recommended cycles of chemotherapy for reasons not due to death). Follow up interval was the duration between the date of initial consult and the date of last consult.

For outcomes, the patients were classified as alive (confirmed thru phone call or per chart entry, no recurrence on last follow-up after completion of recommended treatment, or was currently undergoing treatment), dead (mortality recorded in the treating institution or confirmed thru phone call or per chart entry) or others which consisted of abandonment, refusal, no additional data and referred. Abandonment was defined as patient having started diagnostic evaluation or treatment but did not complete recommended modes of treatment, number of cycles, or push through with recommended diagnostics during treatment that are not due to death. Refusal was when no consent was provided by the caregivers to undergo any diagnostic or treatment or were lost to follow-up before any diagnostic or treatment was started. Lastly, referred occurred when the patient was transferred to a nonparticipating institution as requested by the patient’s caregiver.

Statistical Analyses

Frequencies, measures of central tendency and dispersion were used to summarize the data using Microsoft Excel Ver. 3 2013 (Microsoft Corp. Redmond, Washington USA). Pearson’s chi-squared test of independence was used to analyze gender and involvement (unilateral vs bilateral). Mann-Whitney U test was used to compare intraocular grading distribution, systemic staging distribution, types of surgery done, high risk features, systemic chemotherapy, radiotherapy, and outcomes between the two time periods. Student t-test was used to compare age at onset of symptom, age at initial consultation, delay in consultation, and length of follow-up between the two time periods. Stata 14 (StataCorp LP, College Station, Texas, USA) was used for statistical analysis. Statistical significance was set at p<0.05.

RESULTS

A total of 636 patients (821 eyes) were diagnosed with retinoblastoma in the 11 participating institutions from 2010 to 2020. Three-hundred thirty (330) retinoblastoma patients (423 eyes) were seen from 2010 to 2015 and 306 patients (398 eyes) from 2016 to 2020. Table 1 lists each participating institution and the number of its patients included in the study. Two were tertiary private hospitals while one was a private ambulatory eye center. The rest were tertiary government-run hospitals. Two had available data from 2016 onwards only.

From 2010 to 2015, a mean number of 55±12 new cases were seen annually versus 61±6 new cases annually from 2016 to 2020. Patients from Luzon accounted for 55% of cases seen from 2010 to 2015 and 58% from 2016 to 2020 (Table 1).

The regional distribution of retinoblastoma patients is summarized in Table 2. In both timelines, Region 4A had the most retinoblastoma cases (18% and 19%, respectively), followed by the National Capital Region (12% and 13%, respectively) and Region 11 at 11% of patients. Region 9 recorded the lowest absolute number of cases in both timelines.

Males accounted for 60% and 51% of patients seen from 2010 to 2015 and 2016 to 2020, respectively. There was a significant change in the gender distribution over time (x2=4.28, p=0.04). There was no significant change in the number of patients with unilateral or bilateral disease between the two time periods (x2=0.44, p=0.51). Median age at onset of symptom (12 [interquartile range{IQR}4,24] for 2010-2015 vs. 12 [IQR 4,24] months for 2016-2020, p=0.9), age at initial consultation at the participating institution (24 [IQR 13,36] vs. 27 [IQR 14,38] months, p=0.6), and delay in consult (8 [IQR 2,16] vs. 10 [IQR4,19] months, p=0.1) between the two time periods were all not significantly different. Among patients with data on reason for delay of consultation, financial issue was the most common reason cited by parents of patients at 60% and 69% over the two time periods, respectively. It was followed by lack of access to a medical facility (11% vs. 9%, respectively) and wrong diagnosis (10% vs. 6%, respectively).

Table 3 summarizes the distribution of presenting symptoms of patients seen from 2010 to 2015 and 2016 to 2020. Leukocoria was the most common presenting symptom in patients seen in both time periods (43% and 55%, respectively). One hundred ninety-five (195) eyes (25%) had no data on presenting symptoms. Of these, 143 patients with bilateral disease had no documented presenting symptom on their better eye.

Table 4 shows the distribution of retinoblastoma patients based on IIRC/ICRB grading. Based on the IIRC and ICRB grading systems, retinoblastoma patients seen from 2010 to 2015 had significantly different grade distribution compared to those seen from 2016 to 2020 (p<0.0001).

Based on the IRSS , the stages of retinoblastoma patients seen from 2010 to 2015 were also significantly different from those seen from 2016 to 2020 (p<0.0002) [Table 5].

Enucleation was the most common surgery performed for both timelines at 65% and 66%, respectively for 2010 to 2015 and 2016 to 2020. There was no significant difference in the type of surgery done over time (p=0.54) [Table 6]. Table 7 shows the distribution of enucleated eyes based on presence of high-risk features. There was a significant difference in presence of high-risk features of enucleated eyes (p<0.0001) over time.

There was a significant difference in the retinoblastoma patient distribution based on systemic chemotherapy received between the two timelines (Table 8). The Philippine General Hospital (PGH) and the Southern Philippines Medical Center (SPMC), the two institutions with data on radiotherapy on 109 patients, noted significant difference in the status of patients needing radiotherapy (p<0.04) (Table 9). There were 8 and 16 eyes treated with cryotherapy in 2010 to 2015 and 2016 to 2020, respectively. There were 8 eyes in 2010 to 2015 while 33 eyes in 2016 to 2020 treated with laser therapy.

The median length of follow-up was correspondingly longer in patients seen from 2010 to 2015 than those seen from 2016 to 2020 (17 [IQR 5,54] months vs. 10 [IQR5,24], respectively, p<0.0001). There was a significant difference in the distribution of outcomes of patients over time (p<0.0001) (Table 10). A total of 57 (7%) globes were salvaged, 23 and 34 globes from 2010 to 2015 and 2016 to 2020, respectively.

Discussion

This study compared the largest and most comprehensive data on retinoblastoma patients in the country in terms of the number of patients included, geographical coverage, and the number and type (private and public) of participating institutions. The authors initially aimed to divide the cohort into 2 equal groups with 6 years duration each (from 2010 to 2015 and from 2016 to 2021) to determine if there are changes in the patterns on demographics, clinical presentation, treatment, and clinical outcomes over time. However, due to logistical issues, data collection was only done up to 2020. Aside from the shorter duration of the second timeline (5 versus 6 years), the lower absolute number of cases from 2016 to 2020 could be due to the mobility restrictions imposed during the COVID-19 pandemic in 2020. However, the annual average of new cases was still higher from 2016 to 2020 and can be attributed to the increasing national population over time.¹¹ The changes in the number of cases recorded from Regions 6, 7, 8 and 10 between the two timelines can be from better record keeping with less number of patients without data on province of origin in the later timeline. For the same reason, missing data was reduced from 56 in 2010 to 2015 to 5 in 2016 to 2020.

More males (60%) were affected in the earlier time period despite the country’s equal sex distribution for the age group based on the Philippine Statistics Authority’s National Census in 2015 and 2020.¹² Fabian et al. reported a similar finding of high male-to-female ratio in their global retinoblastoma cases and attributed it to gender discrimination in access to healthcare in Asia, particularly India.¹³ However, the Philippines is not known to have similar issues like in India.^13,14 The male predominance in the 2010-2015 timeline is less than the 1967 to 1977 and the 1985 to 1995 series of Espiritu and company.³ It was similar though to their 1996-2001 series.³ The sex distribution in this cohort eventually equalized over time, similar to the study by Noguera et al. covering the years 1998 to 2008, reflecting the general global finding of no sex predilection for retinoblastoma.^4,13 This can then be a recurring pattern as was noted in the previous local series.^3,4

Eight (8) out of the 11 participating institutions were located in Luzon and this largely accounted for the predominance of retinoblastoma patients from Luzon. Region 4A and the National Capital Region were the regions with the most retinoblastoma cases as they are the most populated in the country, with 15% and 12%, respectively, of the national population living in these 2 regions based on the 2020 Philippine Statistics Authority Population census.¹¹ However, Region 11 ranked third at 11% despite being only the 8th most populated region in the country, suggesting a higher incidence of retinoblastoma in the region.¹¹ On the other hand, Region 9 registered the lowest number of cases at 2 for each timeline, despite being 13th of the 17 regions in terms of share in the national population.¹¹

The percentages of unilateral disease did not differ between the two timelines and were even similar to Espiritu et al.’s 1996-2001 series.³ However, they were lower than that of the Global Retinoblastoma Study Group (78%).⁵ Espiritu et al. attributed the increasing percentage of patients with bilateral retinoblastoma to increased survival of retinoblastoma patients from prior generations who eventually passed the disease to their offspring, a common pattern seen among those with bilateral disease.³ Based on this, more patients with bilateral disease may be expected as there was significant difference in the outcomes of retinoblastoma cases over time.

It is alarming that despite having similar age at onset of symptom over time and continuing efforts from organizations like the PAO and the PSPOS to increase awareness on the disease, there was no improvement in the age at initial consult and delay of consultation over time. Financial concerns remained the major cause in the delay despite improvement in healthcare financing through increased coverage by the PHIC, as cost particularly the non-medical ones (fare, food and accommodation) remained high or are even increasing.^15,16 Majority of the patients were seen in institutions located outside their regions of residence as availability of properly equipped institutions remained limited and are concentrated in the metropolitan areas.^17,18

Leukocoria remained the most common presenting symptom in both timelines. This should help with the early detection of retinoblastoma as it is easily identifiable with the use of portable phone cameras.¹⁰ There were significant differences in intraocular grading and systemic staging over time despite similar delay in consultation. However, the difference in systemic stages may have resulted from improvement in surgical technique when doing enucleation as a result of increasing attention to train residents to perform the procedure on affected eyes.

The percentages of grade E eyes in both timelines were less than those from India, Indonesia and Pakistan, the first, 3rd and 4th leading countries with the most reported retinoblastoma cases globally.^{2,14, 19-25} In the same report, the Philippines ranked 6th.² Patients with IRSS Stages 2 to 4 in both timelines were both lower compared to those in Indonesia since their series had a longer delay in consultation.²⁵ However, the results of this study are still high especially when compared to developed countries. These data should keep clinical practitioners and policy makers aware of the national situation and guide them in implementing programs and policies to help improve the local situation on retinoblastoma detection and management.

Enucleation remained the most common treatment mode in both timelines as opposed to other countries like India which has shifted to systemic chemotherapy as its most common treatment modality for retinoblastoma.²⁶ This is secondary to the similar percentages of patients with unilateral advanced disease, for which enucleation is favored over systemic chemotherapy.²⁷ Changes in the distribution of patients needing systemic chemotherapy between the two timelines reflect the changes in the number of eyes without high-risk features and did not need adjuvant systemic chemotherapy over time. Increased awareness on the benefit and acceptance of systemic chemotherapy over time may have contributed to the change in proportion of patients who completed their cycles, from 34% to 44% in 2010 to 2015 and 2016 to 2020, respectively. Although there was change in patients’ status on systemic chemotherapy, a quarter of the 2016 to 2020 cohort was still a high number. Efforts to educate the parents of patients are still needed to address the stigma associated with systemic chemotherapy. Financial issues, especially over nonmedical ones, need to be addressed as well since the systemic chemotherapy regimen for retinoblastoma is given for at least 6 cycles spaced almost a month apart.²⁷ The costs incurred by patients while receiving interval treatments in a facility away from their place of residence remain high.¹⁶ Some transient houses provide free to low-cost accommodations in Manila to patients of PGH and similar programs can be implemented in other cities.²⁸ The increase in the absolute number of eyes from 8 to 16 and 8 to 33 which underwent cryotherapy and laser therapy, respectively, can be a result of increased availability of the human resources and equipment to deliver them.

Follow-up periods for both timelines were short as a result of the overall high percentages of patients who died (28 and 31%), abandoned (17% and 9%) and who were lost to follow-up (14.0 and 14.5%). The percentage of living patients (35% and 43%) were still lower than the series from Pakistan (64-66%), India (83-94%) and China (81-98%) which highlight the need for improvement in the management of retinoblastoma cases.^20-26,29-35

This study is limited by its retrospective nature. Incomplete data ranged from 10% to 17% which highlight the need for better recordkeeping by medical staff who evaluate retinoblastoma patients in the country. A prospective study may also better address the high number of incomplete data as the latter can significantly alter the findings of this retrospective study. Four institutions used established digital databases which can serve as an example to follow for other institutions. A national retinoblastoma registry can then be established from these digital databases. There are also regions with limited representations; several institutions from different regions were invited to participate in this study but were unable to do so. Funding can also be explored in the future to be able to incentivize institutional investigators as well as hire research assistants for data collection.

In conclusion, there was no improvement in early health seeking behavior based on similar age at initial consult and delay in consult over time. Enucleation remained the most common treatment mode as opposed to chemotherapy due to similar percentages of patients with unilateral disease, an indication for enucleation rather than chemotherapy.

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