Retinoblastoma (RB) is the most common intraocular malignant tumor in infancy and early childhood, seriously endangering the vision and life of children. After more than two decades of efforts, the prognosis of children with RB has improved significantly, and the 5-year survival rate of RB in developed countries has reached more than 90% [1], but compared with developed countries, there is a large gap in the efficacy of RB in China. parents often find it difficult to accept [2]. The main reasons for this gap are, on the one hand, that domestic patients are basically in advanced stages when diagnosed and, on the other hand, that domestic diagnosis and treatment techniques are still relatively backward. To improve the long-term disease-free survival (EFS) of children with RB in China and to reduce the rate of treatment-related disability such as eye removal, the author believes that the following aspects need to be given attention. Liu Qiuling, Department of Pediatrics, Armed Police General Hospital
1 Identifying early patients and improving early diagnosis and treatment rates
RB almost always occurs in infants and young children, some of whom are born with the disease, and the onset of the disease before the age of 3-4 years accounts for more than 80%. Because of the young age of onset and the inability to describe symptoms, RB is often not easily detected by parents, and because the early clinical manifestations of RB are mainly white pupils (commonly known as cataract) or strabismus, it is often not taken seriously by primary care physicians, thus losing a good opportunity for early diagnosis and treatment [3]. Therefore, recognition of early symptoms of RB and timely fundoscopy, orbital ultrasound, orbital CT and MRI are essential for early diagnosis and treatment of RB and thus improving the EFS of RB. early manifestations of RB can be amblyopia, nystagmus, lacrimation, and ocular redness in addition to white pupil syndrome and strabismus. When orbital inflammatory manifestations such as fever and ocular pain are present, there is already extensive infiltration of the choroid. The author believes that fundus screening in newborns and infants, especially in those with family history of RB, strengthening the training of primary care physicians on RB, and educating parents of infants and children on RB science are all essential to improve the early diagnosis and treatment rate of RB. However, in some clinical cases, the presentation is atypical, showing vitreous clouding, hemorrhage and retinal detachment, which often obscure the solid mass.
2 Perform risk assessment and stratify treatment according to different risk levels
2.1 Changing treatment goals Because most children with RB in China are already in advanced stages at the time of diagnosis, traditional RB treatment is aimed at saving the child’s life as the only goal. With the improvement of treatment technology, the goal of modern RB treatment is no longer limited to protecting the child’s life, but to saving the child’s life, preserving the eye, and preserving useful vision.
In order to achieve the goal of saving life, preserving the eye, and preserving useful vision, each child must be accurately assessed in terms of clinical staging and risk level, stratified according to different risk levels, repeatedly re-evaluated during the treatment process, and adjusted according to the treatment response to achieve individualized treatment. The most commonly used clinical staging of intraocular RB was the Reese-Ellsworth (R-E) grading system [4], and its grading criteria were: grade I: tumor <4DD, single or multiple, located in the equatorial part or thereafter, with a very good prognosis. Grade II: tumor 4-10DD, single or multiple, located at or after the equatorial part, with good prognosis. Grade III: Any number of tumors or single tumor >10DD located in front of the equator, with variable prognosis. Grade IV: Tumors >10DD or multiple or single tumors have reached the serrated edge, poor prognosis. Grade V: Large tumors more than half of the fundus and intravitreal implants have poor prognosis. the R-E grading system used to be mainly used to guide external radiotherapy. With the progress of research on RB staging methods, the IIRC grading method has been formed internationally for intraocular RB grading [5]. IIRC grading method classifies intraocular stage RB into five different levels, which are Group A: very low risk, with small tumors and far from important tissue structures. Group B: low risk, regardless of size or location, without implants and diffuse tumors. Group C: Moderate risk, regardless of size or location, with implants and diffuse tumors confined to the vicinity of the tumor. group D: High risk, with diffuse vitreous or subretinal implants, or large endogenous or exogenous tumors. group E: Very high risk, with tumors causing anatomic or functional damage to the eye and one of the following characteristics: (1) neovascular glaucoma. (ii) Massive intraorbital hemorrhage. (iii) Aseptic orbital cellulitis. ④Tumor reaching the vitreous front. ⑤ Tumor touching the crystal. (vi) Diffuse infiltrative RB. (vii) Ocular consumption. Different from R-E grading method IIRC grading method mainly focuses on predicting the prognosis of chemotherapy and local treatment. There is no uniform classification for tumor invasion outside the eye. st. Jude Children’s Research Center classifies extraocular stage RB into: stage I: tumor confined to the retina; stage II: tumor confined to the eye; stage III: tumor with limited extraocular spread; stage IV: distant metastasis. Iris neovascularization, glaucoma, tumor invasion into the anterior chamber, iris and choroidal involvement, and invasion of the optic nerve are risk factors for tumor metastasis [3]. The author believes that comprehensive IIRC grading and St. Jude clinical staging are more instructive for comprehensive assessment of prognosis and determination of risk.
2.3 Stratified treatment Current RB treatment methods that have been applied clinically include: chemical reduction, external radiation radiotherapy, ophthalmic removal, orbital content enucleation, systemic chemotherapy for metastatic tumors, and a combination of multiple methods. Since removal of the eye can cause disability and affect the quality of survival due to the developmental disorder of the child’s heart, and external radiotherapy can cause ocular complications, orbital malformations and second malignant tumors, the treatment of RB has gradually adopted conservative therapies such as chemotherapy and local treatment in recent years. It has been found that although chemotherapy can significantly reduce the size of the tumor, it does not cure RB. Therefore, modern RB treatment emphasizes chemotherapy combined with local treatment, the latter including laser photocoagulation, scleral dressing radiotherapy, warm heat therapy, cryotherapy, etc. The current more consistent stratified treatment plan is: ① chemotherapy combined with local treatment for grades I-IV in R-E grading can achieve satisfactory control, and only 10% of affected eyes need external radiotherapy at 5 years of follow-up, and nearly 15% of affected eyes need ophthalmopexy [6]. Among the chemotherapy regimens, the CEV regimen consisting of vincristine, carboplatin, and onychomycin has been widely adopted internationally because of its efficacy and low side effects. This regimen is administered at 3-4 week intervals for a total of 6 courses of treatment. It has been found that too many courses of chemotherapy not only do not increase the efficacy but also increase the toxic side effects of the drugs [7].RB is usually subject to multidrug resistance during chemotherapy, and short-term high doses of cyclosporine A (CsA) can enhance the antitumor effects of carboplatin and VP16 and inhibit multidrug resistance [8]. Interspersed local treatment between chemotherapy sessions can effectively eliminate residual tumor lesions and is a good complement to chemotherapy. (ii) In recent years, interventional chemotherapy by direct injection of chemotherapeutic drugs through the femoral artery to the local tumor through the ophthalmic artery has enabled the local blood concentration of the tumor to reach 200-300 times that of systemic intravenous chemotherapy, which not only can rapidly control the huge tumor but also has little systemic toxic side effects, and its combined application with local therapy is a good choice for patients with grade V in R-E classification [9]. (iii) A high-dose chemotherapy followed by hematopoietic stem cell transplantation regimen for children with extraocular stage RB who have metastases at diagnosis can significantly improve their prognosis [10]. (iv) External radiotherapy and/or ophthalmic removal is still required to save the lives of patients who relapse and develop metastases during chemotherapy and local treatment.
3 Development of new treatment techniques to further improve the EFS of RB
3.1 Use of new drugs Some of the new drugs currently used for RB treatment are still largely in the experimental stage, and once these drugs are used in the clinic they will certainly improve the current status of RB treatment. There are many new drugs, mainly anti-tumor drugs and pro-apoptotic drugs. For example, (i) phenylalanine azide, a cell cycle non-specific antitumor drug, has been used in the interventional treatment of RB and has obtained certain efficacy [9]. (ii) Bortezomib, a novel antitumor agent, was found to induce apoptosis in RB cells in in vitro experiments [11]. (iii) Trimethoprim: an anti-folate agent, which was found to inhibit RB tumor cell growth in in vitro experiments [12]. (iv) Topotecan: in vitro animal experiments demonstrated the ability to shrink RB tumors [13]. In addition, there are N4-hydroxyphenyl vincristine, 2-deoxy-D-glucose, paclitaxel, and bittersweet, all of which can inhibit RB cell proliferation and induce apoptosis.
3.2 Cell therapy Although chemotherapy combined with local therapy and hematopoietic stem cell transplantation have led to remission in more than 90% of children with RB, some children still relapse because chemotherapy is powerless against residual tumor cells present in the body. Cytokine-induced killer T lymphocytes (CIK cells) and dendritic cell-activated CIK cells (DC-CIK cells) have been widely used in the clinical treatment of many malignancies due to their broad-spectrum antitumor effects [14-15]. There is no clinical data on the treatment of RB with CIK or DC-CIK cells, but it is expected to be a complementary treatment to chemotherapy, local therapy, and stem cell transplantation.
3.3 Gene therapy The pathogenesis of RB is generally believed to be the result of secondary mutations in the Rb gene. More than 40% of RB patients have a family history of genetic predisposition, and coupled with the increased risk of secondary tumors with chemotherapy and radiotherapy, gene therapy is safer and could be the direction of RB treatment in the future. At present, a lot of in vitro research work has been carried out in RB gene therapy internationally [16-19], and the main gene therapy methods used are: ① suicide gene therapy; ② oncogenic gene therapy; ③ anti-angiogenic gene therapy; ④ lytic virus gene therapy; ⑤ pro-apoptotic gene therapy, etc. Each method has shown its effectiveness on RB, and it is hoped that it will enter clinical treatment in the near future.
4 Improving EFS of RB while focusing on survival quality
Although chemotherapy combined with local treatment has reduced the rate of eye removal and external radiotherapy in RB, some advanced patients still have to remove their eyes or implement external radiotherapy; chemotherapy or local treatment also brings certain toxic side effects, such as bone marrow suppression, nephrotoxicity, ototoxicity, and the occurrence of second tumors, which will affect the quality of survival of children. Therefore, at this stage, the treatment of RB should find a balance between obtaining EFS and reducing treatment-related toxic side effects. Studies have demonstrated that shortening the duration of drug administration and reducing the cumulative dose of chemotherapy drugs are effective ways to reduce the toxic side effects of chemotherapy. Monitoring the children’s hearing and isotope nephrogram during treatment and adjusting the treatment plan according to the monitoring results at any time, using stimulation factors and installing prosthetic eyes reasonably can help to reduce the toxic side effects and reduce the degree of disability.
5 Establishment of multidisciplinary joint work mode
The treatment of modern RB involves multiple disciplines such as ophthalmology, pediatric oncology, pathology, imaging and radiotherapy. Before each treatment, ophthalmology needs to evaluate the efficacy of the previous treatment and the risk of metastasis under fundoscopy; pediatric oncology needs to decide the next treatment plan based on fundus changes and the risk of metastasis as well as the systemic condition; imaging and pathology need to provide the corresponding lesion data to help the decision. Therefore, the treatment of each patient requires the cooperation of multiple disciplines. The establishment of a multidisciplinary model and the formation of a collective consultation system to discuss and adjust the treatment plan for each patient will undoubtedly have a positive effect on the treatment of patients.
In conclusion, the key to RB treatment is early detection, early diagnosis and early treatment. The strategy of RB treatment should be stratified according to the clinical and pathological stages of the child to determine the risk level. Each child should be treated individually under a multidisciplinary joint work model that integrates the size, location, number, unilateral or bilateral onset, contralateral eye, risk of metastasis, possibility of secondary tumors, and the child’s general condition. As far as possible, conservative therapy of chemotherapy combined with local treatment should be used to avoid eye removal and external radiotherapy. The application of other new anti-tumor drugs, cell therapy, gene therapy and other therapies are expected to enter the clinic as a supplement to the existing treatments, thus providing a guarantee to further increase the survival rate of RB and improve the quality of survival of RB patients.