The risk of tumor dissemination, seeding and extraocular spread has been the biggest obstacle for surgical intervention of retinoblastoma for many years. Honavar SG reported an unfavorable outcome in 75% of patients with retinoblastoma who underwent PPV in 2001(12). This situation may come to an end with the rapid development of local chemotherapy in recent years. The combined use of IViC and PPV for advanced retinoblastoma in small sample cases has been reported in several studies(9, 10, 13). Recently, Zhao, J. has reported planned PPV with IViC in 21 cases of refractory retinoblastoma, with eye preservation achieved in 85.7% (18/21) of the cases with a median of 5.1 years of follow-up(9). In our study, eye preservation was achieved in 100% of cases during an average of 4 years’ follow-up, without any seeding through the surgical tracts or metastasis. These encouraging results revealed that the combined use of IViC (both preoperatively and intraoperatively) had significantly improve the safety of surgical intervention for retinoblastoma. In addition, some safety measures should be taken to reduce the risk of surgical incision seeding, such as using the minimally invasive incision and applying strictly water-tight suture, cryotherapy and subconjunctival injections of anti-tumor drugs at the incision sites. In general, we believe that intravitreal chemotherapy-assisted endoresection by PPV is safe enough and shows promising results as an alternative therapeutic strategy for refractory retinoblastoma patients.
Intravitreal chemotherapy-assisted endoresection should be indicated in refractory ICRB group D cases that are accompanied by obvious vitreous and/or subretinal seeding without any anterior segment or extraocular metastasis, that seem to be the best candidates for this combined treatment at present. The significant superiority of endoresection is the direct and definite removal of tumor, so it is especially helpful for cases with a high burden of vitreous seeding or in refractory cases unresponsive to standard treatments. The intravitreal chemotherapy-assisted endoresection by PPV can reduce tumor size and its resulting burden while facilitating the extensive and uniformed distribution of the chemotherapeutic drug in the vitreous cavity, which would further enhance the efficiency of drug and reduce the amount of treatment required as well as retinal toxicity of repeated IViC.
The contraindication of endoresection for retinoblastoma is any sign of tumor metastasis in the anterior segment or extraocular metastasis which suggests that ICRB group E cases should be excluded. In the study of Zhao, J., the retinoblastoma was not controlled by one-time PPV in 4 patients, all of whom demonstrated tumor metastases in the anterior chamber of the eyes, and only one eye was preserved finally(9). This result is consistent with many previous studies that anterior chamber tumor metastasis is a danger sign that imply poor prognosis and high risk of recurrence and extraocular metastasis(14, 15). Moreover, the attempt to PPV in these eyes may greatly increase the risk of iatrogenic metastasis as the incision is very close to the anterior segment of the eye. In this concern, we also suggest lens-preserving PPV even when there was partial opacity of the lens, in order to minimize disturbance to the anterior segment during surgery and lower the risk of tumor metastasis to the anterior segment. It should be noted that secondary cataract might develop due to silicone tamponade or chemotherapeutic drug toxicity after PPV. In our opinion, cataract surgery should be cautiously considered at least 6 months after PPV when there is no sign of recurrence or metastasis.
Despite the use of many preventive measures, recurrence of the tumor can still occur. Two cases in our study had single or multiple focal subretinal tumor recurrence. Fortunately, the recurrent tumor could all be eradicated by repeated IViC, laser coagulation, or second PPV. The relatively good prognosis was mostly attributed to the absence of recurrent vitreous seeding. We assumed that it is the silicone oil tamponade that helped to confine the tumor as a focal lesion of the retina thus limiting intravitreal tumor seeding. Therefore, intravitreal silicone oil tamponade was recommended during PPV to preventing tumor dissemination, especially vitreous seeding. Since the recurrence of tumor may occur very late after primary surgery, as in case 8 in which tumor recurrence was observed 12 months after PPV, we suggest that the silicone oil removal should not be limited to be done within 6 months after PPV as usually recommended in general PPV, unless there any silicone oil related complication has occurred.
Beside eradicating intraocular tumor, intravitreal chemotherapy-assisted PPV can also help in dealing with sight-threatening vitreoretinal complications of retinoblastoma, such as vitreous hemorrhage and persistent retinal detachment. There were 3 out of 11 eyes in our study that had pre-surgical retinal detachment, and all of them had achieved successful anatomical retinal reattachment after PPV. It is especially crucial for monocular patients whom have no other alternative for retaining visual function and require eye preservation. In our study,10 of the 11 monocular patient had improved vision after PPV, while 4 of them had gained vision of ≥20/200.The favorable outcomes in visual function had also proved the value and good prospect of this treatment strategy.
However, there are still some limitations in this study. Like any new techniques established before, it is difficult to conduct a randomized controlled trial for retinoblastoma, as it is a relatively rare disease. The follow-up period in this study is also relatively short, the longest of which is 83 months and the shortest of which is 12 months. Since the recurrence of retinoblastoma could be years later, further follow up is required to evaluate the long-term effects of this treatment method. Besides, we used Topotecan in this study instead of Melphalan because Topotecan was the only chemotherapy drug currently approved in mainland China to be available for the treatment of retinoblastoma.
In summary, the emergence of IViC in recent years has recovered the role of surgical intervention in the management of retinoblastoma. This study showed encouraging result of intravitreal chemotherapy-assisted endoresection in control of ICRB group D retinoblastoma, which suggested that it might be considered as a supplementary therapeutic strategy for some refractory cases that are unresponsive to standard therapies, especially for the monocular patients whom have had the other affected eye previously enucleated.