Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

divide stages into intraocular tumor, involvement of optic nerve, orbital extension, and finally, distant metastases. There is a new proposed clinical and pathological staging classification for retinoblastoma from the American Joint Committee on Cancer.

A.Incidence of Extension and Metastatic Disease

Previous studies have reported that approximately 10% of patients will develop metastatic disease at a mean age of about 3 years, averaging 12 months from time of diagnosis [7–9]. A retrospective study of 261 patient’s treatment in Saudi Arabia found that 14.9% had metastatic disease, with an average age of 3.1 years [10]. A prospective study in Argentina found that 48% of the 101 eligible patients had extraocular disease, including 9 patients with intracranial or hematogenous metastases [11]. Two studies in the United States reported an incidence of extraocular disease at diagnosis of 3% [12] and 9% [5] respectively.

B.Mechanism of Disease Extension and Metastatic Spread

Invasion of the optic nerve accounts for the most common route of spread, with the potential to involve the optic chiasm or infiltrate into the subarachnoid space to perhaps involve the cerebrospinal fluid and subsequently the brain and spinal cord. Tumor spread from the choroid into the orbit accounts for the second route of dissemination [13]. Once the tumor extension is extraocular, the chances of hematogenous and lymphatic spread increase. The four routes for metastatic spread include the following [14,15]:

1.Direct infiltration into brain or orbit

2.Subarachnoid spread into brain, spinal cord, or the other optic nerve

3.Orbital or lymph node invasion, which may lead to hematogenous dissemination

4.Lymphatic dissemination if the eyelid, conjunctiva, or extraocular tissues are involved

C.Risk Factors and Ancillary Testing

Information regarding sites of metastatic disease in the past has relied on data obtained from autopsy studies, indicating that orbital and cranial bones are the most common sites, with tumor also involving long bones, lymph nodes, and liver and kidney [9,16,17].

Over the past 20 years, many studies have reported the results of ancillary testing for presence of metastatic disease at time of diagnosis. Earlier reports had recommended routine examinations of cerebrospinal fluid and bone marrow in all newly diagnosed patients [18,19], but several large studies have shown that incidence of metastasis at diagnosis or development of metastatic disease can be correlated with certain histopathological risk factors. A multivariate analysis of risk factors found that tumor invasion into the sclera, optic nerve, and orbit were most highly predictive of metastatic disease [20]. Three other studies looked specifically at correlation of invasion of optic nerve and choroid [21], optic nerve invasion [22], and

choroidal involvement of disease [23] with risk of metastatic disease. Conclusions from the two more recent studies are that choroidal invasion alone is not a significant risk factor for development of metastasis [23], while optic nerve invasion beyond the lamina cribrosa is associated with a greater metastatic risk [22].

Three studies have reported incidence of bone marrow involvement of disease from zero to 1.7% [12,24,25], while Karcioglu [10] reported 10% of patients had evidence of disease metastatic to the marrow, all with extraocular disease. Involvement of cerebrospinal fluid in these four studies ranged from zero [12,24] to 1% [25] with 4% of patients in Karcioglu’s study [10].

Current recommendations are magnetic resonance imaging (MRI) of the brain and lumbar puncture be performed in patients with optic nerve extension or choroidal invasion. In addition, bone marrow examination or bone scan reserved for those with clinical signs/symptoms referred to these areas [1].

II.TREATMENT OF EXTRAOCULAR RETINOBLASTOMA WITH STANDARD CHEMOTHERAPY

The previous chapters in this book discuss in detail the treatment options for retinoblastoma. This section focuses on treatment modalities for the patient with extraocular retinoblastoma. The management of patients with trilateral retinoblastoma is discussed separately further on in this chapter.

The goals of therapy for any child diagnosed with cancer is to provide curative treatment with the least possible toxicity, both acute and long-term. Preservation of life, protection of vision, limitation of serious side effects, and not adding unnecessarily to the risk of a second malignancy is the ‘‘gold standard’’ in treating children with retinoblastoma. This becomes more of a challenge with the patients who have extraocular disease, because their survival rates are lower than that of patients with intraocular disease [1,7,11,13,19,20].

Like patients with intraocular disease, the treatment plan for a patient with extraocular retinoblastoma must be individualized and take into account the patient’s age, metastatic risk, likelihood of second malignancy, disease laterality, and size and location of tumor.

Children with extraocular retinoblastoma are not a homogenous group. The survival rate and ideal treatment for each subgroup may vary and, for some situations, there is no clear-cut ‘‘best’’ treatment approach. The therapies utilized for this diverse group of patients have included systemic and intrathecal chemotherapy, external-beam radiation therapy, high-dose chemotherapy with peripheral stem rescue, and combinations of two or more of the above [1,7,11,13,19,26–28].

The effectiveness of chemotherapy in treating retinoblastoma in the setting of extraocular and metastatic disease has previously been reported [7,11,16,19]. The responses of single chemotherapy agents and combination chemotherapeutic agents in patients with measurable extraocular disease treated at St. Jude Children’s Research Hospital included cyclophosphamide and ifosfamide, demonstrating measurable effects as single agents, while the twoor three-drug combinations did show complete responses in some instances [7]. Grabowski and colleagues treated patients with extraocular disease with the combination of cyclophosphamide and doxorubicin and reported a survival of 10 of 12 patients [19].

A phase II study of etoposide and carboplatin administered to 20 patients with extraocular retinoblastoma reported a response rate of 85%, with 9 patients experiencing complete responses [29]. In addition, regimens of carboplatin and etoposide with or without vincristine have been employed in the setting of both intraocular and extraocular disease [1,30].

A.Extraretinal Intraocular Disease

With that background information, the role of standard dose chemotherapy can be explored in various subgroups of patients with extraretinal intraocular and extraocular disease. The first group of patients comprises those with extraretinal spread (choroids, extension to sclera, or disease beyond the lamina cribrosa but not extending to the cut end of the nerve). What appears clear is that extensive invasion of the choroid in the setting of optic nerve invasion beyond the lamina cribrosa warrants prophylactic therapy [1,23,27].

A less obvious subgroup includes those with significant choroidal involvement in the absence of optic nerve invasion in whom prophylactic adjuvant therapy should be considered [1,9,13,23,27,30]. Patients with significant deep involvement of the choroid, optic nerve, ciliary body, or iris have received treatment with chemotherapy including doxorubicin and cyclophosphamide as well as the three-drug combination of vincristine, etoposide, and carboplatin [27,30]. There have been reports suggesting that prophylactic chemotherapy in patients with these high-risk features may lessen the risk of metastases, although the absence of randomized trials to select the best regimen and, as well, no randomized study to prove the benefit of chemoprophylaxis in this group of patients with extraretinal disease makes it difficult to give a definitive recommendation [31].

B.Extraocular Disease—Optic Nerve

For patients with extraocular disease, previous studies have reported results utilizing a combined treatment approach with chemotherapy and radiotherapy [19,26,27,29,32]. The chemotherapeutic agents employed include etoposide, carboplatin, cisplatin, doxorubicin, cyclophosphamide, and vincristine. The overall survival rates ranged from 60–80%. Within this group of patients, there were subsets of patients who had lower survival rates and shared common histopathological features. Invasion of the optic nerve beyond the cut end is a major prognostic factor for relapse and in retrospective studies those patients have fared poorly with a relapse rate of nearly 80% [21,22,33]. Several prospective studies that examined the impact of tumor involving the cut end of the optic nerve have conflicting outcomes with survival rates ranging from 41–80% [29,32]. More recently, chemoprophylaxis appeared to be of benefit in preventing metastasis in patients with optic nerve involvement to the cut end or beyond the lamina cribrosa [34].

Invasion of the optic nerve beyond the lamina cribrosa is not as strong a predictor of relapse, and previous studies have not addressed the question of necessity of adjuvant therapy [11]. It has been suggested that chemotherapy without radiation therapy is sufficient, and Schvartzman and colleagues successfully treated 11 of 12 patients with chemotherapy alone [11,35].

C.Orbital Disease

Radiotherapy and chemotherapy have been successful in the treatment of overt orbital retinoblastoma [29,36].

D.Hematogenous Disease

The group with the poorest prognosis includes patients with hematogenous or central nervous system metastasis [1,19]. Patients with hematogenous spread of disease have responded to different chemotherapeutic agents, but this has not always been long-lasting [7,11,19,26,29,37]. Schvartzman and colleagues reported a 50% survival rate for their patients with hematogenous metastasis who received chemotherapy with vincristine, cyclophosphamide, doxorubicin, cisplatin, and etoposide as well as radiotherapy [11].

E.Central Nervous System Disease

Finally, the patients with metastatic disease involving the central nervous system fare the worst [1,11,19,38]. There are few long-term survivals among patients who present with central nervous system metastasis or develop it. The treatment regimens previously studied have included combination chemotherapy and radiotherapy and intrathecal administration of chemotherapy [7,11,19,26,27,29]. The external-beam radiation therapy given to these patients included focal brain, whole-brain, and craniospinal treatment [7,11,19,26,28,29].

Consensus has not be achieved as to the optimal radiation therapy approach to the patients with evidence of central nervous system metastasis. The morbidity of whole-brain and/or craniospinal irradiation is significant for these patients, who are usually young at the time of their presentation [39,40]. Intrathecal chemotherapy has included methotrexate, hydrocortisone, and cytarabine, with disappointing results [27]. Newer agents under evaluation include topotecan and melphalan [27].

III.TREATMENT OF EXTRAOCULAR RETINOBLASTOMA WITH INTENSIVE CHEMOTHERAPY AND AUTOLOGOUS RESCUE

Because of the poor prognosis for patients with metastatic retinoblastoma treated with conventional therapy, there has been interest in intensifying chemotherapy with autologous stem cell or bone marrow rescue. This approach has been successful in other childhood cancers, especially in neuroblastoma [41]. Earlier published work suggests that this intensive approach may be beneficial for this poor-risk population [42,43].

Investigators at the Institut Curie treated 25 high-risk retinoblastoma patients (extraocular disease at diagnosis or relapse, or invasion of cut end of optic nerve) with high-dose carboplatin, etoposide, and cyclophosphamide followed by autologous hematopoietic stem cell rescue (ASCR). The 3-year disease free survival was 67%, and 5 of the 8 patients with metastatic disease (no central nervous system involvement) were event-free survivors with this approach. Central nervous system disease recurrence developed in 3 patients, who died within 20 months of their highdose chemotherapy, and 3 patients experienced progressive disease during the

conventional chemotherapy given during induction and never received the high-dose chemotherapy. For the group of patients with metastatic disease (not initially involving the central nervous system), 5 of the 11 were event-free survivors [28].

Recent reports have described the use of thiotepa, carboplatin, and etoposide with ASCR for patients with metastatic retinoblastoma. Thiotepa was chosen because it penetrates the central nervous system, and the toxicity profile lends it to dose escalation [44]. The five patients treated in this manner are event-free survivors 46–80 months after their diagnosis. The sites of disease included bone, lymph nodes, bone marrow, and liver, but none of the patients had central nervous system disease [45,46].

Radiation therapy was administered to sites of original bulky disease in one study, but in the other two reports no radiation therapy was given to sites of bony metastases; 5 of the 6 patients were event-free survivors in the group not irradiated [28,45,46].

The predominant acute toxicities included myelosuppression and mucositis, with long-term ototoxity related to carboplatin [28,45,46]. These chemotherapy agents are mutagenic and may increase the risk of second cancers. The same can be said for external-beam irradiation [47,48].

IV. TRILATERAL RETINOBLASTOMA

Jakobiec and associates were the first to describe the association of bilateral retinoblastoma with intracranial malignancy, later termed trilateral retinoblastoma by Bader and colleagues [49,50]. Over the decades, more information has become available regarding this entity.

The incidence of trilateral retinoblastoma is approximately eight cases per year in the United States. In nearly all cases, it develops in a subset of retinoblastoma patients harboring germline mutations with the inheritable form of retinoblastoma (bilateral or multifocal, or positive family history). Clinical variants of this presentation have been reported, including lack of ocular involvement or unilateral retinoblastoma [51–53]. The pineal gland is the most common location, but tumors occur in the suprasellar region and typically present earlier than pineal lesions. The histopathological features can be variable, with the majority of tumors undifferentiated and the rest demonstrating degrees of neuronal or photoreceptor differentiation [53,54]. The mean age at diagnosis is 30 months, with signs and symptoms of increased intracranial pressure in the majority of patients [15,53,54].

The vast majority of patients will succumb to their disease, despite multimodality treatment, with a median survival of 6 months. There are reports of long-term survivors who received a variety of treatments, including systemic chemotherapy and intrathecal chemotherapy in some instances. Patients who received treatment experienced a longer median survival than those who received only palliative care. The main pattern of failure was spread to the neural axis [15,53,54]. A comprehensive metanalyses concluded that neuroimaging could improve the cure rate if trilateral retinoblastoma was diagnosed while patients were asymptomatic and tumors were less than 15 mm [15,53]. Because the majority of patients can be detected within 1 year of the diagnosis of retinoblastoma,

screening with brain imaging should be considered in children with bilateral or familial retinoblastoma [15,53,54].

Shields and colleagues performed a retrospective study to evaluate whether neoadjuvant intravenous chemotherapy (vincristine, etoposide, and carboplatin) reduced the risk of development of trilateral retinoblastoma. Comparison was made between the group receiving neoadjuvant chemotherapy versus the nonchemotherapy control group and the development of trilateral retinoblastoma. Based on recent analyses of the prevalence of this disorder, 5–15 patients (in the chemotherapy group) would be projected to develop an intracranial tumor of the 99 children at risk secondary to bilateral and/or family disease. No intracranial tumors were diagnosed in the group receiving chemotherapy, while one patient in the nonchemotherapy control group experienced intracranial development consistent with the expected frequency for that group. Longer follow-up will be necessary to fully appreciate the effect of chemoreduction [55].

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