Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

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7.Moy CS, Albert DM, Diener-West M, et al. Cause-specific mortality coding. methods in the collaborative ocular melanoma study. COMS report no. 14. Control Clin Trials 2001; 22:248–262.

8.Collaborative Ocular Melanoma Study Group. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol 1998; 125:745–766.

9.Collaborative Ocular Melanoma Study Group. Factors predictive of growth and treatment of small choroidal melanoma. COMS report no. 5. Arch Ophthalmol 1997; 115:1537–1544.

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11.Collaborative Ocular Melanoma Study Group. Mortality in patients with small choroidal melanoma. COMS report no. 4. Arch Ophthalmol 1997; 115:886–893.

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and vincristine. Since this meeting, clinicians from a number of countries have embraced this protocol, which uses chemotherapy and local intraocular therapy as the standard of care for a number of patients with retinoblastoma. This treatment protocol needs to be continuously refined to achieve improved visual and systemic results. The treatment for childhood cancers, such as leukemia, has evolved, with high success rates for survival through the process of collaborative research conducted over decades by dedicated investigators in the Children’s Cancer Study Group and the Pediatric Oncology Group, both multicentered clinical research groups using common treatment protocols and evaluating common outcome variables. Networks of clinicians such as the Retinoblastoma Study Group need to be supported and maintained to conduct epidemiological studies and clinical trials in the therapy of retinoblastoma.

II.EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS

Retinoblastoma is a rare ocular disorder with a limited number of patients treated in major clinical centers. For epidemiological studies such as the assessment of associated risk factors and clinical trials to evaluate treatment modalities, multicentered studies are necessary in order to provide sufficient numbers to make meaningful comparisons. Clinical trials may not be necessary to answer all research questions. However, treatment modalities that have small to moderate beneficial effects must be assessed, usually with a controlled clinical trial. Rarely are treatment effects so large that only a small number of patients will be required to be enrolled in a study to achieve statistical and clinical meaningful significance.

By sharing the data, the network of clinician may be able to identify future research questions more readily. It is important to identify future research questions regarding retinoblastoma.

A.Design Issues

1.Interdisciplinary Approach

Treatment strategies in the retinoblastoma require interdisciplinary collaboration among medical oncologists, pediatric ophthalmologist/retinal specialists, and ophthalmic oncologists. The design and conduct of clinical trials require additional team members—statisticians, clinical trialists, and epidemiologists [10]. It is imperative that all such participants of the clinical trial be involved with the process from the conception of the study to the interpretation of the data and drafting of the final manuscript of the study results. Additional expertise in regulatory issues dealing with the Food and Drug Administration (FDA) may be necessary for the conduct of such trials.

Because the number of patients with this rare ocular disorder seen in each major clinical center or major ophthalmic center throughout the United States, Canada, and Europe is limited, a clinical trial is feasible only if the collaborative efforts of a number of investigators in different geographic localities are combined. This requires also the efforts of a coordinating center that is adept in dealing with the issues of clinical trials to provide the necessary support for a large number of clinical

centers providing limited number of participants for trials of a rare condition. In addition, a successful trial requires the direction of a chair and/or an advisory group willing to facilitate such collaborative efforts. Adequate funding to establish the essential infrastructure—i.e., clinical coordinator, data management, data analyses, and others—will also be crucial to the success of a randomized, controlled clinical trial. Clinical trials are unfortunately expensive, but they do provide the ‘‘gold standards’’ for guidance of treatment. It is important for the ophthalmic community to support such efforts of controlled clinical trials by referring patients and contributing in the design and conduct of trials.

2.Standardized Common Protocol

The protocol to be followed by all investigators, who may reside in different parts of the world, must be standardized to ensure that similar patients are receiving the same types of treatment. This requires standardized methods of evaluating eligibility and exclusion criteria and primary as well as secondary outcome measures of interest. Certification of the treating investigators and the technicians may also help with the standardization of the protocol. Monitoring of the trial is needed to determine compliance with the manual of operations of the study. Clinical trials should have an independent data and safety monitoring committee, which will evaluate the data periodically during the course of the study so as to provide protection for the study subjects. If the data indicate a clear beneficial effect of treatment on the primary outcome or if harmful effects are seen with treatment, an early termination of the study should be considered.

3.Eligibility Criteria

Once a clinical research issue has been identified, the study population must be defined, with reproducible methods of classifying the severity, location, and other characteristics of the tumors found in the eye, as well as other patient characteristics. The previously published classification, known as the Reese-Ellsworth classification, is no longer an adequate classification, as it was based on prognosis for mortality. Obviously, the prognostic characteristics for survival of the patient remain important factors to consider in treatment. However, a more refined classification of the status of retinoblastoma in the eye is required. A more recent ocular classification of retinoblastoma involvement, established by Murphree and other investigators, may be a clinically relevant and reproducible system. This classification is currently available at the following website: https://www.unhres.utoronto.ca/abc/. Within the context of a clinical trial, such a classification of ocular lesions of retinoblastoma can be further validated and refined. The classification for diabetic retinopathy as it is used today has its roots in the Airlie House Classification, which predated the beginning of the Diabetic Retinopathy Study (DRS) [11,12]. During the course of the randomized clinical trials of diabetic retinopathy, the DRS, and the Early Treatment Diabetic Retinopathy, the validity and reproducibility of the classification of diabetic retinopathy were further evaluated. This classification has provided the gold standard for all trials of diabetic retinopathy throughout the world.

An example of a possible clinical trial may include subjects with eyes manifesting the most severe form of retinoblastoma, in which there is vitreous

seeding and tumors of large volume, resulting in exudative retinal detachment. The eligibility criteria for a trial of such eyes may require specific tests—i.e., ultrasonography, fundus photography, optical coherence tomography (OCT), and others. Standardization of the protocol that establishes both eligibility criteria is essential. When possible, the grading of some of these tests should be done at a centralized reading center that has no prior knowledge of the patients’ characteristics or the assigned treatment.

4.Outcome Measurements

The main measurements of outcome would include the assessment of visual function in a standardized fashion. In order to obtain best-corrected visual acuities, the pediatric patients other methods of visual acuity measurement in addition to the traditional best-corrected visual acuity measured on the logarithmic visual acuity charts (Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts) may be required [13–15]. Secondary outcome measurements include ultrasonography, which will measure both the tumor height and volume as well as the presence of exudative retinal detachment in these cases. All of these assessments should be done with masked examiners who have no knowledge of the treatment modalities to be used.

B.Adverse Effects

Immediate adverse side effects associated with treatment of retinoblastoma will be collected as part of the clinical trial, with adverse report forms that must be submitted to central agencies such as the FDA if the drug/device is an investigative new drug or an approved drug with a new indication for use in this ocular disease.

An important adverse side effects associated with chemotherapy is the potential to develop secondary tumors. Patients with retinoblastoma already have this propensity, which is accelerated by radiation. It is important to gather such data during the course of the clinical trial and many years following the completion of the trial. This propensity may result in increased mortality decades following the administration of the chemotherapy. It may not be feasible to provide decades of follow-up in a clinical trial. Creative design of simple trials may be able to gather data on these long-term adverse effects. Alternative methods of obtaining such information may include periodic assessment of potential deaths of this cohort of individuals through agencies such as the National Death Index from the National Health Statistics. This means that essential information required for such surveys must be gathered at baseline. It is also important to obtain informed consents from all subjects and their families for the future collection of this information. With increasing scrutiny of the Institutional Review Boards (IRBs), these procedures may not be possible. It is important, however, for these studies of children, that the devastating effects of such adverse events be collected.

C.Masking of Treatment

Depending on the research question to be addressed, it may be difficult to mask the patient, his or her parents, and the treating ophthalmologists and oncologists as to

the randomly assigned treatment. The placebo effect is real and, whenever possible, both the treating physician and the patient and his or her family should be masked. The technicians who are evaluating the major outcome measures, however, can and should definitely be masked to assigned treatment to prevent a biased assessment of the treatment effects. If possible, the patient care chart should not be available to the technicians who measure outcomes such as visual acuity, tumor regression measured by ultrasonography or optical coherence tomography, etc.

D.Natural History Data

Like all controlled clinical trials, studies in retinoblastoma will be valuable in providing important longitudinal clinical data. It is unexpected that trials in retinoblastoma will provided a pure placebo treatment group because no investigators would be willing to participate in such a trial. However, the natural history of the ‘‘standard of care’’ provides important information for the care of patients with retinoblastoma. In addition, risk-factor analyses of baseline characteristics as predictors of treatment outcome may also be valuable.

III.CONCLUSION

To further our knowledge of treatment for retinoblastoma, well-designed, controlled clinical trials are needed to provide data on both the beneficial effects as well as the long-term adverse effects of treatment. Such efforts deserve the support of the ophthalmic community because, in the case of such a rare ocular condition, it is imperative to evaluate treatment modalities within the context of a multicentered study. Establishing a retinoblastoma network will also enhance the chance of sharing precious tissues, which may lead to further tests at the basic science level to elucidate tumor formation as well as possible leads for new treatment techniques.

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formidable obstacle to progress in their descriptive pathology. By contrast, dermatologists and dermatopathologists collaborated to develop precise clinicopathological correlations, and long-term follow-up studies provided information on the biological behavior of many of types of pigmented cutaneous lesions.

When precise clinicopathological correlations are possible, as in iris melanomas, which are easily visible during slit-lamp examination and accessible to excision, a robust pathological classification is possible. The classification of iris melanomas proposed by Jakobiec and Silbert [2] is remarkable because it addresses not only the issue of prognosis for life but also the prognosis for retention of vision. Melanomas confined to the iris are seldom life-threatening unless there is invasion into the filtration angle or involvement of the ciliary body. One of the principal contributions of the Jakobiec and Silbert [2] classification is the recognition of a surface plaque—a thin layer of melanoma cells that may extend from a stromal thickening along the surface of the iris—as a risk factor for recurrence (Fig. 1). Clinical effacement or flattening of iris crypts and folds on slit-lamp examination by an ‘‘invisible’’ membrane may be the only clinical clue to the existence of the surface plaque histologically. When present, excision of the easily visible nodule may leave the thin membrane of tumor behind: there may be no clinically visible recurrence in the form of a nodule or tumefaction. However, a recurrence may appear many years after resection, or the flat membrane may grow over the trabecular meshwork and contribute to peripheral anterior synechiae and extensive spread of tumor, reminiscent of the diffuse spreading of the membranes of epithelial downgrowth.

Figure 1 Iris nevus with surface plaque. The iris stroma is distended by nevus cells. A plaque of bland spindle cells lines the anterior surface of the iris. (H&E.)