Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

Harbour et al. demonstrated that transgenic mice with retinoblastoma experienced significant tumor control accompanied by little or no local toxicity using subconjunctivally injected carboplatin [88,89]. Our group reported that periocular carboplatin was well-tolerated in non-tumor-bearing primates and that higher levels of carboplatin were achieved in the vitreous after periocular administration than after intravenous administration [90]. These preclinical data prompted our group to study the efficacy and toxicity of subconjunctival carboplatin for intraocular retinoblastoma in a phase I/II trial with retinoblastoma patients. In the trial, a response was observed in some eyes with vitreous disease or retinal tumors but not in eyes with subretinal disease. In most patients, minor local toxicity and no systemic toxicities were observed. However, one patient did develop optic atrophy with decreased visual acuity. For patients who are treated with this modality for vitreous seeding, the source of the vitreous seeds must be treated with another method in order to achieve a cure. Further study and longer follow-up are needed to determine fully the safety and applicability of subconjunctival administration of carboplatin and other potential agents.

III.ADDITIONAL NONOCULAR CANCERS

A.Background

In 1949, it was first recognized that some retinoblastoma patients developed second nonocular neoplasms years after the successful treatment of the eye cancer [14]. Since then, the incidence of additional nonocular cancers in survivors of retinoblastoma who carry the RB1 mutation has been reviewed extensively [91]. Previous analyses have also shown that additional nonocular cancers are the leading cause of death in survivors of germinal retinoblastoma. These patients are not at an increased risk of dying of any other causes when compared to patients who have never had retinoblastoma [92].

B.Incidence and Timing of Additional Cancers

Nearly 95% of all children in the United States who develop retinoblastoma survive the disease. Of the survivors of germinal retinoblastoma, cumulative incidence reports of second cancers vary, but it is estimated that a rate of 1% per year of life approximates the rate [93]. Patients who develop a second cancer and then survive that cancer have an increased risk for the development of additional nonocular tumors of approximately 2% per year from the time of second tumor diagnosis [91]. The average latency period between subsequent tumor diagnoses becomes progressively shorter with each additional cancer that develops. Because females have a higher overall risk of dying of second tumors than males, more males are at risk for developing third tumors [91,92].

C.Risk Factors

A necessary risk factor for the development of additional nonocular tumors in retinoblastoma survivors is the presence of the germinal RB1 mutation. All patients

with bilateral retinoblastoma are carriers of the germinal mutation and are at risk for additional nonocular cancers [91]. Identifying unilateral patients who carry the germinal mutation is less straightforward, but the following patients should be considered high risk for carrying the germinal mutation: most unilateral patients with a family history of retinoblastoma (including a family history of retinoma), unilateral patients who are diagnosed under the age of 6 months, and unilateral patients who present with multifocal tumors (not one tumor with seeding).

EBR is also a contributing factor to the development of additional cancers in retinoblastoma survivors. Children radiated during the first year of life are between two and eight times as likely to develop second cancers as those radiated after the age of 1 year [94,95]. Patients treated with higher doses and older methods of radiation delivery that lead to increased superficial skin and bone exposure are at higher risk for subsequent tumor development in the radiation field [91]. The radiation-induced risk for additional cancers applies only to patients with germinal retinoblastoma. Unilateral retinoblastoma patients who do not carry the constitutional mutation are at no increased risk for developing other cancers, even if they received EBR [6].

Additional nonocular cancers develop both within and outside the field of EBR. Our group has reported that in radiated patients who develop second malignancies, the tumors are within the radiation field two-thirds of the time and outside the field one-third of the time. In nonradiated patients who develop second tumors, the tumors are outside the hypothetical field two-thirds of the time and within the hypothetical field one-third of the time [94,96].

D.Types and Locations of Additional Malignancies

Second nonocular neoplasms observed in survivors of germinal retinoblastoma include, in order of most common to least, osteogenic sarcomas of the skull and long bones, soft tissue sarcomas, pineoblastomas, cutaneous melanomas, brain tumors, Hodgkin disease, lung cancer, and breast cancer [96,97]. Survivors of hereditary retinoblastoma are also at increased risk for the development of lipomas throughout the body. Patients who develop lipomas are at an even higher risk of developing second cancers [98].

Figure 3 demonstrates the timing of the development of each type of second cancer in retinoblastoma survivors. EBR treatment changes the age distribution of some of these cancers in two different patterns: one pattern if it was given before the age of 1 year and another if it was given afterward. In general, however, patients who have not received EBR are at highest risk for developing soft tissue sarcomas of the head and cutaneous melanomas beginning in their late twenties or early thirties. These patients are at highest risk for osteogenic sarcomas of the long bones and osteosarcomas of the skull during the mid-teenage years. Finally, retinoblastoma survivors at an equally elevated risk throughout their lives for developing brain tumors.

E.Third, Fourth, and Fifth Cancers

Our group recently published a report on the largest series of retinoblastoma survivors who developed a second cancer, survived, and went on to develop third, fourth, or fifth nonocular tumors [91]. Survivors of retinoblastoma who develop

Figure 3 Patients who carry the germinal mutation for retinoblastoma are at risk for the development of additional nonocular cancers well into their adult lives.

second malignancies and survive are at an even higher risk for the development of additional cancers than they were for the development of a second tumor. The distribution of tumor sites in the second-tumor group suggests a nonrandom pattern of third, fourth, and fifth tumor development. Of patients with skin cancers as their second tumors, skin cancers also represent most of the third, fourth, and fifth tumors that develop in this group. Of patients treated for a second tumor in the skull in whom a third tumor develops, most are diagnosed with a soft tissue sarcoma in the head as the third tumor. The locations and expected ages at which soft tissue sarcomas of the head and osteogenic sarcomas of the long bones develop are consistent with the patterns observed in second tumors (see Fig. 3).

F.Recommendations to Patients to Minimize Subsequent Cancers

In order to minimize the role of subsequent cancers, retinoblastoma survivors at our center are advised to refrain from smoking, minimize their exposure to sunlight, and avoid unnecessary CT scans or x-rays. Although the relationship between degree of sunlight exposure and the development of cutaneous melanomas in the retinoblastoma survivor population is unclear, we continue to recommend limiting sunlight exposure because of the clear association with cutaneous melanomas in the general population. Regarding CT scans, our recommendation is based on a recent

study that has demonstrated an increased risk for radiation-related cancers in children who undergo CT scans [15].

IV. CONCLUSION

The survival of retinoblastoma patients in the United States has improved significantly over the past century, while survival rates remain low in developing countries, where patients commonly present with metastatic disease. The implementation over the past 30 years of effective focal therapies such as photocoagulation, cryotherapy, and brachytherapy have helped prevent many patients from undergoing enucleation and EBR. Newer techniques such as transpupillary thermotherapy and chemoreduction hold additional promise for patients with intraocular disease. Unresolved issues in the treatment of retinoblastoma include effective screening protocols for additional nonocular malignancies, indications for chemoreduction, and appropriate therapies for widespread metastatic disease.

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patients between study treatment arms. Prior to the implementation of a clinical trial, several factors must be considered, including (1) the clinical relevance of the study outcomes; (2) the ethical rationale to treatment randomization; (3) the existence of pilot data establishing a framework for accuracy of diagnosis, perceived efficacy of each treatment, and acceptable treatment associated complications; (4) the absence of definitive existing clinical data documenting a clear treatment benefit; (5) and the willingness of the medical community (and at risk patients) to participate in the proposed clinical trial. For the Collaborative Ocular Melanoma Study (COMS), the existing literature describing outcomes for uveal melanoma was investigated utilizing metanalysis techniques to determine a range of expected mortality for patients with small, medium, and large choroidal melanoma as defined by a standardized grading criteria focused on both tumor basal dimension and apical height. This information was combined with clinical parameters to establish an expected clinically relevant difference between each of two different treatments for the Medium Choroidal and Large Choroidal Melanoma Treatment Trials [1]. Preliminary safety and efficacy data for pre-enucleation external-beam radiotherapy, enucleation, and 125-iodine brachytherapy were also reviewed and standardized for the proposed clinical trials.

This information was integrated into the (COMS) planning phase beginning in 1984 and aimed at establishing the framework for submission of a series of three clinical studies to evaluate small, medium, and large posterior uveal (choroidal/ ciliary body) melanoma treatment [2]. The overall design of the COMS incorporated six centralized units consisting of the chairman’s office, a coordinating center, radiological physics center, echography center, photographic reading center, pathology center, and 41 individual clinical centers targeted toward patient screening for eligibility, randomization, treatment, and follow-up. The Small Tumor Trial was constituted to observe the outcome, in a nonrandomized fashion, for patients meeting the eligibility criteria with small choroidal melanoma. The second two arms of the COMS were constituted as prospective, randomized, multicentered clinical trials to evaluate the outcomes for patients with medium and large choroidal melanoma. Standardized inclusion criteria for these clinical trials included a primary, unilateral, unifocal choroidal tumor in an individual over the age of 18 years and competent to provide informed consent. The tumor was required to meet size eligibility criteria and to be evaluable by echography to accurately delineate the tumor height [3,4].

Patients were excluded from the COMS if 50% or more of the tumor volume involved the ciliary body; if extrascleral extension of 2 mm or more was present; if previous biopsy or treatment had been performed; if coexisting disease was expected to compromise survival; if other primary or metastatic malignancy was known; or if the patient had contraindications to surgery, radiation therapy, or general anesthesia. Specific to the medium tumor trial were exclusions that precluded plaque radiotherapy for tumors within 2 mm of the optic disc, media opacity that precluded indirect ophthalmoscopic visualization of the tumor, visual loss in the fellow eye of 20/200 or worse and involvement of the iris/angle by the tumor, or secondary/ neovascular glaucoma.

The COMS utilized a manual of procedures, aimed at assuring uniformity throughout each individual study center that standardized all aspects of the two randomized trials [3,5]. This manual incorporated standard certification for each