Chemotherapy for Retinoblastoma

Losing sight of visual outcome.

JASMINE H. FRANCIS, MD · ALLISON E. RIZZUTI, BA · DAVID H. ABRAMSON MD, FACS

Children with small or moderate-sized intraocular retinoblastoma (Reese-Ellsworth Groups 1-3; International Classification A-C) can now be cured by techniques with minimal systemic side effects using lasers (argon, diode), cryotherapy, or brachytherapy. But these techniques cannot be used alone to cure more advanced intraocular tumors (Reese-Ellsworth 4, 5; International Classification D, E). Up until recently there were 3 ways to initially manage the more advanced eyes: enucleation, external-beam radiation (EBR), and systemic chemotherapy; however, recently in New York intra-arterial chemotherapy has largely replaced all of these techniques.¹ Nonetheless, other facilities may not have this latter option, and many of the advanced cases are currently treated with multiagent systemic chemotherapy for 6, 9, or even 12 months.

But when intra-arterial chemotherapy may not be available, how is a parent (or physician) to choose among the 3 other therapies? What are the risks and benefits of each approach? Are the risks of radiation or systemic chemotherapy worth the final result? We have previously shown that, despite nearly 100 publications on the use of systemic chemotherapy for retinoblastoma, there is little information published on its associated systemic side effects.² We really do not know the severity or the frequency of these side effects, and, because of the lack of reporting, we cannot compare a series from one institution (or one approach) with another.

EMPHASIS ON VISUAL OUTCOME

What about vision? What is the visual outcome of eyes treated with prolonged multiagent systemic chemotherapy for advanced retinoblastoma? If different treatments are similarly effective, physicians and families may want to ask if the child will still be able to see even if the eye has been saved. Some may choose to avoid enucleation at all costs, but we need to ask whether, after systemic chemotherapy, the visual outcome for the patient is any better.

Is systemic chemotherapy worth the huge expense in money, time, and anxiety (and associated side effects)? Will the child be able to see and, if so, how much? There may not be sufficient information on final visual results to allow physicians and families to make such a decision. In order to answer some of these questions, we set out to perform a meta-analysis on papers published within the past 12 years on systemic chemotherapy use for ocular retinoblastoma.

METHODS

The literature search was conducted using the following search terms: chemotherapy.mp OR carboplatin OR etoposide OR vincristine OR chemoreduction.mp OR visual acuity OR ocular, vision AND retinoblastoma. Databases were searched from January 1996 until December 2008, using Ovid Technologies software. Further hand-searching of reference lists and related articles of obtained manuscripts was performed. After excluding reviews, comments, manuscripts on intra-arterial chemotherapy, reports on chemotherapy after enucleation, and articles unrelated to retinoblastoma or chemotherapy, 88 papers were available for analysis.

Papers selected for inclusion offered data on visual outcome, whether quantitative or qualitative. Extracted data from these studies were recorded in an electronic database and included: follow-up duration, systemic chemotherapy regimen, dose and number of cycles, local treatment, Reese-Ellsworth group, and International Classification of retinoblastoma eyes. Papers selected for meta-analysis contained quantitative data for eyes that were identified as receiving systemic chemotherapy and as being Reese-Ellsworth Group 4-5 or International Classification D, E. From each of the papers in this latter group, data for individual eyes were further extracted and recorded in an electronic database including Reese-Ellsworth group, confirmation of systemic chemotherapy treatment, and final visual acuity. From this total of 75 eyes, statistical results for the final visual acuities were obtained and aligned to 2 ranges of Snellen vision: 20/40 or better; 20/50 to 20/400; worse than 20/400; no light perception (NLP) and enucleated; and 20/200 or better, worse than 20/200, enucleated.

RESULTS

Based on our literature search of published manuscripts, we identified 88 papers published within the past 12 years on systemic chemotherapy use for ocular retinoblastoma. We hoped to perform a meta-analysis, but to our dismay, 66 articles were eliminated due to their lack of visual outcome reporting, leaving 22 papers that provided visual data, whether quantitative or qualitative (shown in Table 1).

Of the 22 papers with visual data, 16 were less informative for a variety of reasons. For example, 6 papers offered only qualitative data and lacked uniformity: Visual acuity was designated as "yes" or "no"³ or described as "poor," "normal," or "partial"⁴ or even as "saved"⁵ or "blind,"⁶ without more specific definition. Some papers provided numerical visual data but made it nearly impossible to decipher the associated RE Group of the patients or whether they had received chemotherapy. One paper included only RE Groups 1-3.

Of note, 3 papers also included the International Classification for Retinoblastoma.⁷ Therefore, to our surprise, only 6 of the 22 papers provided quantitative visual acuities of systemic chemotherapy-treated patients that could be distinguished by RE classification. Not only was a meta-analysis in its true form difficult to conduct, but we were limited to drawing conclusions from this small selection of articles, which represented only 7% of the total papers — a disappointing realization about a body of literature that prides itself on emerging treatment modalities.

The results are shown in Table 2, but given the dearth of useful data, our conclusions may not be as reliable or informative as hoped. Shields et al. divided their visual data into 2 categories,⁸ prompting us to obtain totals aligned to these groupings for all 4 papers, but also totals for the other 3 papers in which the visual data could be further delineated. For the 6 papers, we found that over half the eyes were enucleated, 11% were worse than 20/200, and 32% were 20/200 or better. Excluding the Shields et al. paper, we found 59% of eyes had no light perception (57% were enucleated and 2% eyes were blind), 2% were 20/400 to light perception, 16% were 20/50 to 20/400, and almost 20% of eyes had 20/40 or better. At least 68% of eyes were in the legally blind category, while 19% had 20/40 or better.

DISCUSSION

It is common for reports on conservative treatments to describe 3 idealized endpoints: patient survival, ocular survival, and visual survival. However, the current reporting on tumor response to systemic chemoreduction in retinoblastoma is most often defined by outcome variables associated with ocular and patient survival and avoidance of EBR,⁹ not with whether the patient can see or how well. The studies overwhelmingly concentrate on a new globe-sparing treatment but do not consider the functionality of the eye. Visual results are crucial in enabling physicians and families to measure retaining an eye with no useful vision against the side effects of treatment — or even the risk of maintaining a potentially malignant source. We need to consider not only saving the eye but whether vision can be saved as well.

Few of the authors who fail to provide visual outcome data deny the importance of vision. Almost a quarter, or 17 of the 88 articles, make claims for its significance: "an increasingly important second priority to life prognosis is the salvage of the eye and vision"¹⁰ or "the objective is to try to improve the visual prognosis"¹¹ and "dramatic tumor regression… after use of full chemotherapy and focal treatment… resulting in useful vision."¹² Despite these assertions, none of these cited papers make any mention of visual data. Our understanding of visual outcome in systemic chemotherapy treatment could be improved by adopting common reporting standards. We invite authors to establish and incorporate a standard protocol for visual assessment, including: visual acuity (Cardiff vanishing objects, Teller cards, Snellen chart), pupil responses, electroretinogram recordings, and even visual field, color vision, and cognitive function in older children.

Visual acuity predictors in systemic chemotherapy-treated eyes remain controversial. The adverse visual effects of macular involvement by tumors are obvious, but the extent of these consequences on vision loss in systemic chemotherapy-treated eyes is unclear. Two groups demonstrated a negative influence of macular proximity on visual prognosis,^13,14 while 4 other papers contested this: "satisfactory visual acuities were obtained in most of the patients, despite the fovea being involved."^8,9,15,16 The Reese-Ellsworth classification system is an unreliable predictor of visual acuity since it was developed in the era of EBT: It may accurately predict if an eye will be salvaged after radiation, but it is not designed to predict visual outcome. Patients selected to have systemic chemotherapy may have high visual risk factors not accounted for in the RE classification (such as a macular lesion in a Group 2 eye), thus distributing visual outcomes nonlinearly among RE Groups. Disputes about the outcomes of local treatments are common: One group attributes the maculopathy complicated by their local treatments as a cause of vision loss,¹⁴ while another found that aggressive local therapy (and more local complications) had little bearing on visual outcome, which was "surprisingly good."⁹ It is unclear whether reduced visual outcome is a factor of not treating aggressively enough and allowing for local recurrence and disease progression or whether the complications of aggressive local therapy have any bearing on visual compromise.

Certain chemotherapeutic agents may be more damaging to the retina and therefore have greater impact on visual potential than others. For instance, at high local levels, carboplatin can damage photoreceptors and inner retinal layers as demonstrated by ERG B-wave suppression.¹⁷ Likewise, vincristine interrupts the synaptic transmission between photoreceptors and their second-order neurons, thereby resulting in symptoms similar to night blindness.¹⁸

It is imperative for us to gain a deeper understanding of the impact of chemotherapeutic agents on retinal function; more specifically, our understanding should tease apart a number of variables, such as agent delivery, threshold dose, and both short- and long-term damage. If we are given the choice of effective chemotherapeutic agents, perhaps the more retinal toxic agents can be avoided so as to maximize retinal health and possibly visual promise.

One group recently attempted to further our knowledge on visual potential in systemic chemotherapy-treated retinoblastoma eyes by publishing data on multifocal electroretinogram (mERG) responses after treatment, which included systemic chemotherapy in three-quarters of the eyes.¹⁹ These eyes were subsequently enucleated due to retinal detachment or poor vision and vitreous seeding. The group demonstrated extinguished mERG in half their patients, attributing this to retinal atrophy from prolonged retinal detachment or complete retinal replacement by tumor. Residual response in the other half of patients was histopathologically correlated to partial preservation of the photoreceptor and inner nuclear layers.

The authors suggest the use of mERG in evaluating the visual promise of the eye and using this to guide future treatment. Perhaps systemic chemotherapy would be opted for over enucleation in an eye with preserved retinal function on mERG. It would be most convincing to have ERG information pre- and post-treatment; and while there is no such paper on ERGs with systemic chemotherapy, we have published ERG data before and after intra-arterial chemotherapy.²⁰ Based on our results, it should be noted that a pretreatment flat ERG is not necessarily a lost cause for future visual potential, since post-treatment ERG amplitudes were recovered in 3 of our patients. Therefore, pretreatment mERGs may not have as much predictive value as one would have thought.

CONCLUSION

We encourage all authors to report on visual acuity (at least) and other accepted tests of visual function in children who receive treatments for retinoblastoma. Future studies need to be designed to determine if the explanations for good (or poor) visual outcomes are due to the tumor or to its treatment. Physicians and families may decide to aggressively treat eyes with no visual prognosis, but without this information, an informed decision weighing the risks and benefits is impossible.

We hope that the recognition of inadequate visual outcome reporting in the chemotherapy literature will serve as a lesson for future bodies of research. As newer treatments are explored and eyes are saved that would have previously been enucleated, we urge that visual acuity reporting become standard. The new era of globe-sparing efforts in retinoblastoma treatment should include a rigorous recording and evaluation of visual outcome. RP

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