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ARTICLE |
a Departments of Ophthalmology
c Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee; Departments of Surgery
b Divisions of Ophthalmology
d Hematology/Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS. This study comprises a retrospective, noncomparative case series of 25 consecutive patients with multifocal, intraocular retinoblastoma that was treated with primary systemic chemotherapy. Medical charts were reviewed, and the following data were extracted: patients’ age and gender, laterality of disease, and Reese-Ellsworth classification of each eye as well as the number of central venous lines placed, cycles of chemotherapy received, outpatient appointments, examinations under anesthesia, focal therapies administered, computed tomography/MRI, radiation treatments, anesthetic procedures administered, and miles traveled.
RESULTS. Twenty patients with bilateral and 5 with unilateral intraocular retinoblastoma (median age: 9.3 months) had 895 outpatient appointments and underwent 698 examinations under anesthesia with 230 focal therapies, 347 days of radiotherapy, 226 computed tomography scans/MRIs, and 38 central venous line placements. A total of 1272 anesthetic procedures (median: 50) were performed with no major complication. In all, patients traveled 822312 miles (median: 22214 miles) to receive their care. The median follow-up was 82 months.
CONCLUSIONS. Successful retinoblastoma management requires close surveillance, aggressive consolidation, and numerous anesthetic procedures, all of which the patients and the families must endure. There is a significant impact on the patient, the family, and hospital resources.
Key Words: retinoblastoma • chemotherapy • external beam radiotherapy
Abbreviations: EBRT—external beam radiotherapy • RE—Reese-Ellsworth • CT—computed tomography • BCVA—best corrected visual acuity
Retinoblastoma is the most common intraocular malignancy of childhood.1 Approximately 1 in 20000 live births is affected annually, with 300 new cases being diagnosed in the United States each year. One third of these children will have bilateral/multifocal intraocular retinoblastoma. The median age of diagnosis for these patients is <1 year. External beam radiotherapy (EBRT) was the mainstay of treatment for these patients until the 1990s, when the risk for second malignancies led investigators to seek alternative treatment strategies.2 In the past decade, radiation-sparing therapies that incorporate primary systemic chemotherapy and aggressive focal consolidation with cryotherapy, transpupillary thermotherapy, and brachytherapy have evolved; avoidance of EBRT and enucleation have emerged as the main outcomes measured in studies of these newer treatment strategies.3–17
The success of these approaches has been published extensively, and we have debated the differences in our chemotherapeutic protocols in an attempt to move closer to a cure. To date, however, no study has addressed the impact of these new treatment modalities. Each patient must have a central venous line placed, multiple cycles of systemic chemotherapy, serial examinations under anesthesia, focal therapies administered to the eyes, and frequent anesthesia. In addition, there is much time spent traveling to and from the hospital. All of these factors combined place a great burden on the patient and the family as well as a great demand on hospital resources. Although the field of pediatric pyscho-oncology has attempted to address the emotional impact of cancer treatment, true comparative studies are not available.18–21
Herein, we examined the medical care that was provided to a cohort of patients who were treated in a systematic manner as outlined by the St Jude RET3 protocol, a nonrandomized, prospective, clinical trial that was designed to address the efficacy of multiagent chemotherapy alone as primary treatment for intraocular retinoblastoma. As all RET3 patients are now at least 5 years of age and their intraocular disease is stable, we believed that this was an appropriate time to undertake this retrospective review.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Twenty three of the 25 patients successfully completed 8 cycles of chemotherapy; 1 patient completed only 6 cycles, and another completed only 7 cycles. Complications were limited to myelosuppression and fever. Fifteen patients required at least 1 transfusion of packed red blood cells, and 12 patients required at least 1 transfusion of platelets. Thirteen patients were hospitalized at least once for a febrile illness. In all, 197 cycles of carboplatin and vincristine were administered.
The 25 patients underwent 698 examinations under anesthesia. The median number of examinations per patient was 28, with a range of 13 to 53. Focal therapies that were administered during these examinations included transpupillary thermotherapy, cryotherapy, and argon laser photocoagulation. Episcleral plaques for brachytherapy were scheduled during a separate anesthesia. A total of 230 focal therapies were delivered to the 45 eyes, with median of 7 and a range of 0 to 25. Transpupillary thermotherapy accounted for 122 of these procedures, and cryotherapy and argon laser photocoagulation accounted for 83 and 14, respectively. Eleven episcleral plaques were placed.
Twenty three (51%) of the 45 eyes could not be salvaged by chemotherapy and focal treatments and required EBRT, enucleation, or both. Nineteen eyes in 14 patients were treated with EBRT. The median dose of radiation delivered was 44 Gy (range: 36-46 Gy). Of the 5 patients who were treated with bilateral EBRT, 4 received treatment to both eyes at the same time. The remaining patient’s second eye was treated 9 months after the first. In all, 347 days of radiotherapy were delivered. The median number of days per patients was 21, with range of 20 to 47 days. Thirteen eyes in 11 patients were enucleated.
The best corrected visual acuity (BCVA) at last examination was 20/40 or better in 16 eyes, 20/50 to 20/100 in 3 eyes, 20/200 to 20/400 in 5 eyes, and count-fingers level or worse in the remaining eyes. Nineteen patients retained 20/40 or better BCVA in the better seeing or remaining eye; this included the 3 patients with unilateral disease, 2 of whom eventually had enucleations. Two patients had BCVA of 20/70, 1 had 20/400, and another was at the hand-motions level; all of these patients had 1 remaining eye. Two patients underwent bilateral enucleation.
Examinations under anesthesia, operative procedures, EBRT, and neuroimaging required anesthesia. In all, 1272 anesthetic procedures were performed with a median of 50 per child (range: 20–88).
Our patients lived a median of 390 miles from the hospital (range: 139–4880 miles). To receive their care, patients traveled 822312 miles to and from the hospital. The median number of miles traveled was 22214, with a range of 3892 to 195200.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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As part of the disease staging, bone marrow aspirates and biopsies as well as lumbar punctures were performed during the first examination under anesthesia. These procedures were incorporated as part of the RET3 protocol for completeness. We acknowledge that their utility in the presence of low-grade intraocular retinoblastoma is limited.22,23 Although no complications resulted from these studies, they were invasive procedures that aroused additional anxiety in the parents as they awaited results.
CT and MRI of the brain and orbits were performed at diagnosis and at scheduled intervals during treatment to screen for central nervous system disease. A median number of 7 studies per child were performed, with each requiring additional anesthesia. Although repeated MRIs are thought to pose no long-term sequelae in this population, concern has arisen over the radiation-related risk of CT.24,25 The need and the efficacy of routine neuroimaging to evaluate the pineal gland remain controversial.26,27 As with the bone marrow and lumbar punctures, anticipation of the results made parents increasingly anxious.
Although the carboplatin and vincristine were well tolerated, the strain that was placed on the child and the family must be acknowledged. Weekly follow-up visits to local pediatricians were needed to monitor adverse effects. Transfusions required additional hospital visits, and for children who developed fever in the presence of neutropenia, hospitalization and broad-spectrum antibiotic coverage were required. Intimately associated with the chemotherapy was the need for central venous access. For our patients, a single-lumen Hickman catheter was placed under anesthesia. A teaching nurse instructed the parents on how to care for the catheter; dressing changes and heparin flushes of the catheter were done daily. In cases in which the catheter became obstructed, the catheter had to be replaced. Five catheter infections required treatment with intravenous antibiotics.
In all, 698 examinations under anesthesia were performed. This finding in itself hallmarks the intensity of treatment in the era of chemotherapy. Examinations under anesthesia were performed every 6 weeks while the child was receiving chemotherapy. Once disease progression was documented, focal therapies were administered and the patients were examined every 3 weeks until their intraocular disease was inactive. The interval between examinations then was lengthened progressively at the discretion of the treating ophthalmologists (M.W.W. and B.G.H.). The psychological trauma to the children and their families as they endured repetitive examinations under anesthesia and multiple focal treatments to the eyes can be presumed. The management of retinoblastoma is unique. Because of the window that the eye provides, retinoblastoma is the only pediatric solid tumor that can be visualized directly. Biopsies are not needed to confirm the diagnosis. We can monitor directly the efficacy of chemotherapy as well as survey for new tumor formation. We can discern new tumors and recurrences as small as 1 mm and treat them under direct visualization. The consequences of such an approach to management are repeated eye drops; anesthesia; manipulation of the eyes; and pain from our lasers, cryotherapy, and episcleral plaques. The patients, who are too young to understand consciously, must endure these procedures as their parents are left to witness their child’s distress and comfort them.
For our 25 RET3 patients, 1272 anesthetic procedures were performed with a median of 50 per child. No adverse complications other than bronchospasm were encountered. The safety of such frequent anesthesia was reported previously.28,29 Under our protocol, the needs for anesthesia, including the route of administration, are left to the discretion of the anesthesiologists; we acknowledge that other centers may use a different practice. The trauma that is associated with mask induction clearly is apparent to those who work in this environment. The child’s apprehension and anxiety increase with repetition. The agitation persists in the recovery room. Although we are aware of the induced psychological stress, the long-term neurocognitive effects of repeated anesthesia in a population so young remain unclear. Although we have not observed and parents have not reported such defects, detailed psychological testing is needed.
In cases in which we were unable to control tumor activity with chemotherapy and focal treatments, patients underwent a median of 23 days of EBRT with each fractionation requiring a separate anesthesia. During this time, patients and their parents stayed in temporary housing near the hospital. Spouses and families were separated, and days from work were missed. Children who long were removed from chemotherapy and whose central venous line had been removed required placement of another line for the repeated anesthesia that would be given. These stressors further taxed families that already endured months to years of treatment (the median time to EBRT was 9.5 months, with a range of 6–21 months). Ultimately, in cases in which all treatment options were exhausted and the intraocular disease remained uncontrolled, parents were left the finality of enucleation. After >1 year of treatment (the median time to enucleation was 14 months, with a range of 8–33 months), the parents’ disappointment was compounded by the hardships that they and their child had endured.
As is the case with most retinoblastoma referral centers, our patients traveled far and frequently for their care. For most families, the trip to and from the hospital added at least 1 day to their time away from home and work. None of our patients lived in the metropolitan Memphis area, and only 3 of the 25 lived in the mid-southern United States. The median distance from the hospital was 390 miles. Our closest patient lived in Little Rock, Arkansas, 139 miles away, and our most remote lived in Cordoba, Argentina, 4880 miles away. The total number of miles traveled was 822312. Although assistance with airfare was provided for some patients and 1 of their parents, at least 13 families regularly drove, absorbing the cost in gasoline and wear on their automobiles.
The data reported reflect our unique experience with a cohort of patients who were treated with the St Jude RET3 protocol. However, the trends that we observed are applicable to other centers that specialize in the treatment of retinoblastoma. Multiple studies on outcomes in the modern management of retinoblastoma stress the need for close surveillance and aggressive focal consolidation.3–17 Chemotherapy and screening for trilateral retinoblastoma subject the child and the family to more medical procedures. Furthermore, frequent anesthesia is needed. Because centers that specialize in retinoblastoma are remote, patients must travel great distances to receive their care. In the end, patients and families have endured an arduous journey, and hospitals’ resources have been relied on heavily to treat their retinoblastoma, the socioeconomic impact of which cannot be ignored.
Greater hardships will be encountered as our patients mature. Late complications related to their treatment, such as cataracts, will develop, but more important, our patients’ mutations of the retinoblastoma gene place them at risk for second, third, and fourth malignancies, all of which will require more invasive procedures. For now, our RET3 patients continue with their oncology and ophthalmology appointments.
Because chemotherapy necessitates greater utilization of resources in retinoblastoma management, it is associated with a greater economic impact. As our study was retrospective, we cannot assess fully the impact of our treatment on the children and the families who were enrolled in our RET3 protocol. We used objective data that were retrieved from the medical chart to reach our conclusions. Our perceptions therefore are based on a myriad of medical procedures and thousands of miles traveled, not on our patients’ and families’ subjective responses to what they have experienced. Quality-of-life assessments and survivorship studies are needed as we go forward.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Matthew W. Wilson, MD, Hamilton Eye Institute, 930 Madison, 4th Floor, Memphis, TN 38163. E-mail: mwilson5{at}utmem.edu
This work was presented at the annual meeting of the American Academy of Ophthalmology; October 16, 2005; Chicago, IL.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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