Retinoblastoma


Background

Retinoblastoma is the most common primary ocular malignancy (eye cancer) of childhood.

Peter Pawius of Amsterdam provided the first description of a tumor resembling retinoblastoma. He wrote of a malignancy invading the orbit, the temporal region, and the cranium, a picture now strongly suggestive of untreated retinoblastoma. The tumor was described as filled with a "substance similar to brain tissue mixed with thick blood and like crushed stone." [1]

In 1805, William Hey coined the term fungus haematodes, which he used to describe a fungating mass affecting the globe of the eye and destroying its internal organization. [2]

In 1809, the Scottish surgeon James Wardrop pieced together the random isolated facts and observations of previous authors. Despite not having a microscope at his disposal, his meticulous dissection and astute interpretations of some of these eyes led him to conclude that in most instances, the tumor arose from the retina. Wardrop documented the extension of the tumor to the optic nerve and brain. Later, he described metastasis to different parts of the body. [3]

In 1836, Langenbech, Robin, and Nystin of Paris confirmed by microscopic studies that the tumor definitely arose from the retina.

In 1864, Virchow named the tumor a glioma of the retina, supporting glial cells as the cell of origin of the tumor. [4]

In 1891, Flexner of Johns Hopkins was first to notice rosettes within the tumor (shown in the image below). [5A few years later in 1897, Wintersteiner concurred with Flexner and proposed the name neuroepithelioma noting its resemblance to rods and cones and traced one tumor to the photoreceptor cell layer. [6Presently, their names are attached to these rosettes.

Classic histologic finding of retinoblastoma (FlexClassic histologic finding of retinoblastoma (Flexner-Wintersteiner rosettes)

Most cells comprising the tumor histologically resemble the cells of an undifferentiated retina of the embryo called retinoblasts. This resemblance prompted Verhoeff to coin the term retinoblastoma, [7which later was adopted by the American Ophthalmological Society in 1926 as a general term for this entity.

In 1970, Tso and colleagues established that the tumor arises from photoreceptor precursors. [89]

In October of 2007, a team of investigators at St. Jude Children's Research Hospital (Memphis, Tenn) claimed to have identified the specific cell that gives rise to retinoblastoma. [10The major importance of this discovery is the idea that retinoblastoma can arise from fully matured nerves in the retina called horizontal interneurons, disproving the long-held scientific principle that fully formed, mature nerves cannot multiply like young immature cells.

Pathophysiology

The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which have been described as outlined below. (See Causes for more information.)

Endophytic growth

Endophytic growth occurs when the tumor breaks through the internal limiting membrane and has an ophthalmic appearance of a white-to-cream mass showing either no surface vessels or small irregular tumor vessels. This growth pattern is typically associated with vitreous seeding, wherein small fragments of tissue become separated from the main tumor. In some instances, vitreous seeding may be extensive and allow tumor cells to be visible as spheroid masses floating in the vitreous and anterior chamber, simulating endophthalmitis or iridocyclitis, and obscuring the primary mass. Secondary deposits or seeding of tumor cells into other areas of the retina may be confused with multicentric tumors.

Exophytic growth

Exophytic growth occurs in the subretinal space. This growth pattern is often associated with subretinal fluid accumulation and retinal detachment. The tumor cells may infiltrate through the Bruch membrane into the choroid and then invade either blood vessels or ciliary nerves or vessels. Retinal vessels are noted to increase in caliber and tortuosity as they overlie the mass.

Diffuse infiltrating growth

This is a rare subtype comprising 1.5% of all retinoblastomas. It is characterized by a relatively flat infiltration of the retina by tumor cells but without a discrete tumor mass. The obvious white mass seen in typical retinoblastoma rarely occurs. It grows slowly compared with typical retinoblastoma.

Epidemiology

Frequency

United States

An estimated 250-500 new cases of retinoblastoma occur in the United States yearly.

International

Worldwide, the incidence of retinoblastoma is recorded to be about 11 cases per million children younger than 5 years. A more commonly used estimate is 1 case of retinoblastoma per 18,000-30,000 live births, depending on the country.

In the Philippines, unpublished reports have estimated the incidence to be more than 1 case of retinoblastoma per 18,000 live births.

Mortality/Morbidity

Survival rates for patients with retinoblastoma range from a reported 86-92%. However, these figures must be kept in the context of the retinoblastoma cancers. In actuality, the survival rate drops with each decade of life for patients with the genomic mutation.

The genomic mutation is a gene mutation within every cell of the individual's body. These patients typically present with either bilateral disease or unilateral-multifocal (one eye with multiple distinctly separate tumor foci) disease. These individuals have a predisposition for developing second cancers later in life.

Mortality in these individuals is consequently much higher than rates for those with somatic mutations (ie, affecting one retinal cell only and unilateral-unifocal disease). The greatest predictor of death is extraocular extension, either directly through the sclera or via extension along the optic nerve.

Race

No racial predilection appears to exist for retinoblastoma.

No difference in incidence exists among blacks and whites.

Sex

Studies show no significant difference in the incidence of retinoblastoma by sex for children aged 0-14 years.

The estimated boy-to-girl ratio is reportedly 1.12:1.

Age

Retinoblastoma is diagnosed in patients at an average of 18 months, with 90% of cases diagnosed in patients younger than 5 years.

Children who are affected bilaterally are diagnosed at an average age of 13 months, while patients with unilateral retinoblastoma are diagnosed at an average age of 24 months.

When a known family history of retinoblastoma exists, patients with bilateral retinoblastoma are diagnosed at an average age of 11 months.

A few cases of retinoblastoma in adults (aged 20 y and older) have been reported in the literature. Some theorize that these lesions arise from a previously existing retinocytoma that underwent malignant transformation.

Prognosis

In a study of 69 adult survivors of retinoblastoma assessed at an average of 31 years after diagnosis, Brinkman et al found that subjects performed within normative expectations on various measures of verbal intelligence, attention, memory, processing speed, and executive functioning; they performed above expectations in nonverbal reasoning abilities and ability to learn new information and below expectations in fine motor dexterity. [1112 Survivors reported more problems with working memory and task completion than adults of similar age did.

Patients who had had bilateral disease performed significantly better than those with unilateral disease on measures of verbal learning and short- and long-term verbal memory. [12 Diagnosis at less than 1 year of age was associated with better performance on a number of verbal domains, Total brain radiation exposure was negatively correlated with performance on measures of verbal learning and memory.

The prognosis in retinoblastoma is good where prompt medical care is available. The overall survival rate of retinoblastoma in the United States and Great Britain is presently greater than 85%.

The cure rate is almost 90% if the optic nerve is not involved and enucleation is performed before the tumor passes through the lamina cribrosa.

Survival rates decrease to 60% if the tumor extends beyond the lamina cribrosa even if the cut end of the nerve is free of tumor cells.

Survival rates decrease to less than 20% if the tumor cells are found at the surgical transection sight.

Death occurs secondary to intracranial extension. Treatment with EBRT results in an 85% cure rate.

Visual preservation occurs in 90% of children with group I and II disease (Reese-Ellsworth classification); 30-40% for group IV and 10-15% for patients with advanced group V disease.

Of patients previously treated with EBRT, 60% require further therapy with cryotherapy or photocoagulation.

Of patients requiring treatment with EBRT, 20% eventually require enucleation.

Patient Education

Genetic counseling for retinoblastoma

In 1979, Vogel published his review on the genetics of retinoblastoma in the Journal of Human Genetics. He reviewed the likelihood for the recurrence of retinoblastoma in close relatives of a patient with the disease, based on clinical criteria, as shown below. It is the physician's responsibility to inform the patient's family that retinoblastoma can be hereditary. The methods for screening and estimation of risks are highly improved with use of molecular genetics techniques, although this sometimes can prove to be very expensive.

Genetic counseling for retinoblastoma. (This tableGenetic counseling for retinoblastoma. (This table is modified from Vogel F. Genetics of retinoblastoma. Hum Genet 1979; 52:1.)

Normal individuals have 2 copies of the retinoblastoma gene, 1 coming from each parent. However, in patients with retinoblastoma, one copy of the gene is inactivated by an initial mutation.

When the initial mutation arises from a somatic cell (retinal), the patient has the nonhereditary type of retinoblastoma and the relatives have a low risk for the disease. These individuals have 1 abnormal gene in all their cells, and the mutation in the other gene (in the retinal cell) allows the expression of the tumor.

When the initial mutation arises from the germline, the patient has the hereditary type of retinoblastoma and the relatives of the patient have a significant risk for retinoblastoma. In these individuals, both mutations occur only in the retinal cell that has become malignant.



History

At the time of initial examination, obtain a careful family history.

Specifically ask parents about the occurrence of retinoblastoma in the family.

Elicit a history of eye tumors, previous enucleation, or any malignancy in childhood in any of the family members.

Only about 5% of patients who develop this disease have a positive family history.

A large number of patients with retinoblastoma (95%) have no previous family history, including those who have the bilateral hereditary form of the disease.

Physical

The clinical findings in all the stages of retinoblastoma are numerous and varied. The image below presents an overview of the presenting signs in retinoblastoma.

Presenting signs or symptoms in retinoblastoma. (TPresenting signs or symptoms in retinoblastoma. (This table is modified from Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J Pediatr 1998 Mar; 132(3 Pt 1): 505-8.)

Leukocoria (white pupillary reflex or cat's eye reflex) is the most common presenting sign, accounting for about 56.1% of cases. Leukocoria is shown in the image below.

Retinoblastoma, intraocular stage (leukocoria). HiRetinoblastoma, intraocular stage (leukocoria). History: NB, 1-year-old male from Quezon Province, Philippines, with chief complaint of opacity, left eye. Born full-term spontaneous vaginal delivery (FTSVD) to a 27-year-old gravida 3, para 2 (2002) at home. Four months prior to admission (PTA), opacity was noted in the left eye (no consultation/medications). Five days PTA, consultation with an ophthalmologist. Examination: (+) leukocoria with visual acuity of central, steady, and maintained fixation on right eye, (-) dazzle on left eye; (+) Marcus Gunn (MG) reflex. Diagnostics: Ocular ultrasound was performed, revealing intraocular retinoblastoma. Management: Patient underwent enucleation of left eye. Examination under anesthesia of right eye: E/N retina. Histopathology: Retinoblastoma, intraocular stage left eye.

Strabismus, which occurs as a result of visual loss, is the second most common mode of presentation. Thus, funduscopic examination through a well-dilated pupil must be performed in all cases of childhood strabismus.

Retinoblastoma can cause secondary changes in the eye, including glaucoma, retinal detachment, and inflammation secondary to tumor necrosis.

Pseudouveitis, with a red eye and pain and associated hypopyon and hyphema, is a rare presentation. It is characteristic of an infiltrating type of retinoblastoma in which the tumor cells invade the retina diffusely without forming a discrete tumor mass.

Orbital inflammation mimicking orbital cellulitis may occur in eyes with necrotic tumors and does not necessarily imply extraocular extension.

The glaucomatous stage is shown in the image below.

Retinoblastoma, glaucomatous stage. History: AB, 2Retinoblastoma, glaucomatous stage. History: AB, 2-year-old female from Marikina City, Philippines, with chief complaint of proptosis, right eye. The patient is an adopted child. Prior to admission (PTA), with child aged 6 months (time of adoption), surrogate mother noted an opacity in the right eye. No medical consultation. One year PTA, physician consultation; told AB had an "eye mass" and needed to see an ophthalmologist. No compliance. One month PTA, proptosis was noted in the right eye. Examination: Visual acuity (VA) of right eye is no light perception; VA of left eye is central, steady, and maintained fixation. Sensorium: Awake but irritable. Diagnostics: Intracranial extension on CT scan. Skeletal survey: E/N. Management: The patient underwent exenteration (right side).

The extraocular stage is shown in the image below.

Retinoblastoma, extraocular stage (neglected with Retinoblastoma, extraocular stage (neglected with necrosis). History: RC, 2-year-old male with chief complaint of left orbital mass. Born full-term spontaneous vaginal delivery (FTSVD) to a gravida 3, para 2 (2001) at home. Three months prior to admission (PTA), an inward deviation of the left eye was noted. No consultation. Six months PTA, opacity in the left eye was noted. Five months PTA, proptosis of the left eye with pain and bleeding was noted. Family/Social History: Indigent family. Youngest of 3 siblings; eldest sibling had no retinoblastoma; second sibling had retinoblastoma and underwent enucleation, dying after 2 sessions of chemotherapy. A cousin passed away with retinoblastoma. Examination: Indirect ophthalmoscopy of right eye revealed a large intraocular mass occupying the inferior half of the retina. Mass on left side. Management: The patient was scheduled for exenteration, left side. The mother and child went home against medical advice; what happened to the patient is not known.

Proptosis is a more common presenting symptom in most underdeveloped countries.

Causes

Retinoblastoma is caused by the so-called retinoblastoma gene, which is a mutation in the long arm of chromosome 13.

This gene name is actually a misnomer because the gene does not actively lead to retinoblastoma. The unaffected gene actually suppresses the development of retinoblastoma.

When both homologous loci of the suppressor gene become nonfunctional by either deletion error or by mutation, retinoblastoma develops.

A positive family history is present in 5-10% of children who develop this disease.

Castera et al identified MDM2 as the first modifier gene for retinoblastoma. [13MDM2 increases p53 and pRB catabolism, both of which are involved in the development of retinoblastoma. A study of 326 individuals in 70 retinoblastoma families found that MDM2 is strongly associated with bilateral and unilateral retinoblastoma development.


Differential Diagnoses



Medical Care

Medical therapy should be directed toward complete control of the tumor and the preservation of as much useful vision as possible. Treatment is usually individualized to the specific patient.

External beam radiation therapy

Incidence of local control is high and retinal late effects are minimal with radiation doses of 4000-4500 cGy used with 200 cGy fractions. However, morbidity and mortality associated with external beam radiation therapy (EBRT) are significant. EBRT results in cessation of bone growth. Therefore, children with retinoblastoma who are treated with EBRT have significant midface hypoplasia. (The younger the child is when EBRT is instituted, the more dramatic the outcome.) More importantly, EBRT has been shown to increase the risk of developing second cancers almost 6-fold during the lifetime of these patients. Today, neoadjuvant chemotherapy (chemoreduction) has superseded EBRT in order to (hopefully) circumvent these terrible adverse effects of EBRT. Nevertheless, EBRT is still indicated in selected circumstances, as follows:

  • For eyes with significant vitreous seeding

  • For children who have progression of disease while undergoing chemoreduction

  • For tumors extending up to or beyond the cut margin of the optic nerve of an enucleated eye (The best method of treatment is being debated in such a case.)

Radioactive isotope plaques

Use of radioactive 60 Co (cobalt); radioactive 125 I (iodine), which is presently the most used; radioactive 192 Ir (iridium); or radioactive 106 Ru (ruthenium)

Radioactive 125 I plaque treatment is recommended for treatment of one larger tumor or a limited number of moderately sized tumors (< 3) present in noncritical areas.

Advantage - Locally directed treatment to the tumor, minimizing radiation to the normal tissue

Disadvantage - Incomplete treatment, high dose to local sclera, significantly less irradiation for anterior lesions, and difficulty placing posterior plaques

Chemotherapy

Primary neoadjuvant chemotherapy or chemoreduction has been the most significant recent advance in the treatment of retinoblastoma. This is typically the principle mode of treatment for eyes in intraocular groups C and D. However, our understanding of dose, duration, and end points are still evolving with this relatively new treatment modality.

Prophylactic chemotherapy is recommended if a tumor is in the optic nerve past the lamina cribrosa because these cases have a poor survival prognosis.

Use of neoadjuvant chemotherapy has the advantage of limiting the necessity for EBRT and reducing the possibility of EBRT-related complications.

Chemotherapy also may be used prior to EBRT, as completed by Kingston and associates in an attempt to improve local control and visual outcome in children with group V tumors, using carboplatin, etoposide, and vincristine, followed by 40-44 Gy of EBRT. [17]

Shields and associates used carboplatin, etoposide, and vincristine chemotherapy, followed by cryotherapy, photocoagulation, and 125 I plaque treatment in an attempt to improve outcome for eyes with more advanced retinoblastoma commonly treated with enucleation. [18]

Current studies completed by the Retinoblastoma Study Group show the promising use of chemotherapy (carboplatin, vincristine sulfate, and etoposide phosphate) as a primary mode of treatment in reducing tumor bulk, followed by various forms of local approaches (radiotherapy [external beam or plaque], cryotherapy, thermotherapy, and photocoagulation) that can be used for final tumor control.

Some reports suggest the addition of cyclosporine in combination with the chemotherapy regimen of carboplatin, etoposide, and vincristine. These reports showed that this addition enhances the efficacy of chemotherapy and eliminates the need for radiation.

Abramson and colleagues have demonstrated successful salvage of eyes typically enucleated for advanced disease. [19Intra-arterial chemotherapy for advanced retinoblastoma offers another weapon in the arsenal of therapies for retinoblastoma. However, there are still potential complications to consider, and, consequently, this procedure should be performed at tertiary care institutions that specialize in the care of patients with retinoblastoma.

Novel therapy

A study by Yi Qu et al used immunohistochemical analysis of normal retina and retinoblastoma tumor specimens acquired from multiple centers in order to evaluate the pathological associations of the nuclear factor-κB (NF-κB) subunits and retinoblastoma. The data point to the fact that therapeutic strategies targeting NF-κB together with other therapies may represent a novel approach to retinoblastoma therapy. [20]

Suzuki et al conducted a study with selective arterial injection involving a balloon catheter and melphalan. It achieved a success rate of 98.8% and had few severe adverse events, including secondary neoplasms. The rate of preservation was more than half for treated eyes, and more than half of the eyes without macular tumors maintained a visual acuity of more than 0.5. No severe eye damage or severe systemic events were detected; secondary neoplasms were observed but no more frequently than otherwise expected. [21]

Surgical Care

Surgical removal of the tumor has been the standard management of very unfavorable retinoblastoma cases.

Enucleation

Enucleation is performed when there is no chance of preserving useful vision in an eye.

Patients generally requiring enucleation are those who present with total retinal detachments and/or the posterior segment is full of the tumor, in which case it is clear the patient cannot retain any form of useful vision.

Kletke et al found that macular sparing, optic nerve visibility, and/or less than one quadrant of retinal detachment at diagnosis were predictors of low-risk histopathologic features at primary enucleation, suggesting safe trial eye salvage. [22]

Significant orbital growth retardation remains after enucleation for retinoblastoma. [23The younger the patient is at the time of surgery, the more growth retardation occurs.

Cryotherapy

Cryotherapy can be used primarily for small anteriorly located tumors, remote from the disc and macula but also may be indicated for recurrence after radiation therapy.

Cryotherapy is performed transsclerally. Under direct visualization, freezing is carried out until the ice ball incorporates the entire tumor. A refreeze-thaw cycle is repeated 3-4 times.

Complete disappearance of the tumor with a flat pigmented scar is the sign of successful treatment. This can be repeated if the tumor does not respond initially.

Photocoagulation

Photocoagulation can be used as primary therapy for small posteriorly located tumors.

There is a danger of producing large field defects near the disc and decreased vision resulting from macular pucker by photocoagulation near the macula.

The technique is performed by placing a double row of confluent burns around each tumor using a photocoagulator.

It is important not to do direct treatment on the tumor itself because the light color of the tumor generally precludes absorption of sufficient energy and there is a danger of exploding the tumor with spread of viable tumor debris into the vitreous and other parts of the retina.

Successful treatment with photocoagulation takes weeks to evolve and consists of complete disappearance of the tumor, which is replaced with a flat area.

Photocoagulation can also be used for tumor recurrences after EBRT.

Exenteration

Exenteration is still performed, especially in most underdeveloped countries, when extension of the tumor into the surrounding areas is considerable.

Status post (S/P) enucleation for retinoblastoma, Status post (S/P) enucleation for retinoblastoma, right eye retinoblastoma, recurrence, right eye. History: IJ, 3-year-old male with chief complaint of right orbital mass. At age 2 months, opacity in right eye is noted. Five months prior to admission (PTA), consultation with an ophthalmologist for proptosis, right eye. Four months PTA, the patient underwent enucleation, right eye, with no alleged tumor involvement of the tumor resection margins on histopathology. One month PTA, gradually enlarging orbital mass, right side, was noted. Examination: Visual acuity right eye, not applicable (S/P enucleation); visual acuity left eye, at least 6/12 (20/40). No masses are seen in left eye on indirect ophthalmoscopy. Diagnostics: Skeletal survey showed lytic lesions on the humerus, femur, and pubic bones.

Consultations

Patients with retinoblastoma should be evaluated and treated by a team of medical professionals, including an ophthalmologist (preferably an ocular oncologist), pediatrician, oncologist, radiologist, and pathologist. Given that this is a relatively uncommon disease, patients should try to seek attention from physicians with subspecialty training and experience in retinoblastoma, and who are actively participating in organizations that explore up-to-date treatments for retinoblastoma.

The pathologist plays a special role in the treatment of a patient with retinoblastoma. The surgical specimens should be evaluated with care to guide the clinicians with the appropriate postsurgical management.

Appropriate consultations are needed to provide much needed information to each other. In some instances, frozen sections are requested after enucleation or exenteration.

Complications

Secondary nonocular tumors can develop in survivors of retinoblastoma. In order of decreasing frequency, they are as follows: osteosarcoma, various soft tissue sarcomas, [24 malignant melanoma, various carcinomas, leukemia and lymphoma, and various brain tumors. (See Special Concerns.)

Cataract formation: Radiation doses of 800 cGy to the lens using dose rates of 150-300 cGy/min usually lead to cataract formation in 18 months to 3+ years.

Vascular complications: Retinal vascular damage and hemorrhage may be seen after external beam radiation using 70-75 Gy with 200-350 cGy per fraction.

Bone, dental, and soft tissue effects: Hypoplasia of bone and soft tissue structures after treatment with radiation doses exceeding 3500 cGy may occur. The maxillary molar tooth buds located high in the maxilla just inferior to the posterior apex of the orbit may become irradiated with treatment. Numerous reports of failure of tooth eruption have been noted in patients with retinoblastoma treated with irradiation.

Prevention

Frequent ophthalmologic examination is indicated for children at elevated risk.

Estimation of risk can be completed using molecular genetics.

DNA testing can be a cost-effective component of the care of patients with retinoblastoma and their relatives.

Diagnosing the tumor as early as possible is important to prevent progression leading to metastasis and ultimately death.

Long-Term Monitoring

Patients with treated retinoblastoma as well as siblings who are at risk of inheriting the tumor need to be monitored indefinitely.

Patients and siblings of patients in whom the risk of retinoblastoma cannot be ruled out by genetic studies should be monitored with examination under anesthesia every 3-4 months until age 3-4 years, after which they are examined under anesthesia every 6 months until age 5-6 years and then annually thereafter. At about age 8 years, most patients are able to tolerate a dilated fundus examination in the office without anesthesia and can be examined annually in the office thereafter.

Visual acuity, alignment, and general ocular health should be should be periodically examined in office. The patient and parents should be questioned about and warned about signs of secondary nonocular tumors during these examinations.

Formal examination under general anesthesia is completed 6 months after completion of radiation therapy.

For classic regression patterns, see the image below.

Classic regression patterns of retinoblastoma Classic regression patterns of retinoblastoma

As long as the tumor is not enlarging, it can be considered to be locally controlled by radiation therapy.

Further Inpatient Care

Inpatient care is mostly supportive during the period of recuperation after surgery or during chemotherapy.

Daily attention to the cleansing and dressing of a postenucleated eye or postexenterated orbit is necessary.

Inpatient & Outpatient Medications

Only supportive medications during chemotherapy or after surgery are needed. These include antinausea agents, broad-spectrum antibiotics, and painkillers.



Medication Summary

Use of chemotherapeutic drugs should be limited to specific group of patients for whom the benefits outweigh the potential disadvantages.

Anticancer drugs

Class Summary

Used for management of metastasis but also used as adjuvant therapy for patients with high-risk retinoblastoma.

Vincristine (Vincasar, Oncovin PFS)

Cycle-specific and phase-specific, which blocks mitosis in metaphase. Binds to microtubular protein, tubulin, GTP dependent. Blocks ability of tubulin to polymerize to form microtubules, which leads to rapid cytotoxic effects and cell destruction.

Carboplatin (Paraplatin)

Inhibits both DNA and RNA synthesis. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.

Etoposide (Toposar, VePesid)

Blocks cells in the late S-G2 phase of the cell cycle. Binding of drugs to enzyme-DNA complex results in persistence of transient cleavable form of complex and, thus, renders it susceptible to irreversible double strand breaks.

Immunosuppressants

Class Summary

The addition of cyclosporine in combination with chemotherapy regimen of carboplatin, etoposide, and vincristine reportedly have showed enhanced efficacy of chemotherapy.

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight.

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