Winter 2008
The Toronto Protocol:
Saving Lives and Vision
The Global Eye.
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Timothy Murray MD
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What's Happening?
ntroduction
Treatment of retinoblastoma poses an interesting clinical predicament: life-threatening cancer necessitates treatment aimed at obliterating the tumor, yet this may be difficult when one wants also to save vision. Available treatment options for retinoblastoma include enucleation, focal therapy (laser or freezing),
Focal therapy used alone has very poor success except for very small tumors. External beam radiation can cause facial deformities and most importantly increases the risk for secondary cancers, especially in children with germline RB1 mutation. Retinoblastoma tumor cells display properties of multi-drug resistance (MDR), compromising effectiveness of chemotherapy. Since the 1990s, chemotherapy has been increasingly used to treat retinoblastoma, however it cannot cure retinoblastoma alone. The desire to save lives and vision for children with retinoblastoma necessitates comprehensive strategies for treatment.
The Toronto Protocol
In 1991, Drs. Helen Chan (oncologist) and Brenda Gallie (ophthalmologist) at the Hospital for Sick Children in Toronto, Canada initiated a clinical chemotherapy trial for retinoblastoma using three drugs (carboplatin, etoposide and vincristine) supplemented with cyclosporine A (CSA), a drug shown to reverse MDR in retinoblastoma cells. Chemotherapy was combined with focal laser and freezing therapy to further eradicate residual tumor cells that survived the drug treatment. The trial achieved a good cure rate with minimal side effects.
On this trial, it was noted that children who received higher doses of chemotherapy drugs were more likely to achieve cure. At the time, drug dosages were conventionally calculated differently for smaller children than for bigger children, resulting in higher doses and better cure rates for the bigger children. For this reason, the Toronto Protocol was modified to increase doses of 2 of the 3 chemotherapy drugs in an attempt to achieve better cure rates for all children. Preliminary data suggested that the cure rate was indeed better with no significant change in side-effects. This improved Toronto Protocol is now being rigorously tested as a multicenter trial, aimed at determining efficacy and safety in a variety of situations.
What treatment involves
The Toronto Protocol involves intravenous injection of higher than standard doses of carboplatin and etoposide, and standard doses of vincristine for 2 cycles (for medium retinoblastoma) (Group B) or 4 cycles (for large or extra-large retinoblastoma) (Groups C and D), with the potential for additional cycles as necessary. CSA is administered in very high doses at the time that the chemotherapy is given, to combat MDR. The chemotherapy and CSA are given over two days in the outpatient clinic. The children are rarely admitted into hospital. Treatment at home with granulocyte-colony stimulating factor (G-CSF) restores levels of white blood cells, which are decreased by chemotherapy. Eyes are monitored with frequent examinations under general anesthesia (EUA), and after chemotherapy courses are completed, areas suspicious of activity are eliminated with focal therapy using a laser or freezing.
How CSA tackles multi-drug resistance
A specialized protein called p-glycoprotein is normally found on the outer surface of certain cells, where it pumps foreign and toxic substances out of the cell. Retinoblastoma cells contain increased levels of this protein, thus chemotherapeutic drugs are pumped out before they have a chance to work, a phenomenon observed clinically as drug resistance. To combat the p-glycoprotein in retinoblastoma, chemotherapeutic drugs are given between two doses of a ‘decoy’ drug, CSA, which keeps the p-glycoprotein pump busy so that the chemotherapy drugs do not escape, and instead kill the tumor cell.
Safety Issues
The side effects of the Toronto Protocol are similar to side effects of chemotherapy without CSA. At the time of treatment the extra side effects of the CSA, such as abdominal cramps and allergic reactions, are managed in the clinic with supportive medications and large volumes of intravenous fluid. Patients on this protocol are occasionally admitted for fever with low white cell counts (8.3% of cycles). No cases of bacterial sepsis have been observed thus far, and blood or platelet transfusions are occasionally necessary (4.2% and 12.5% of cycles thus far, respectively).
The Toronto Protocol avoids side effects of chronic administration of CSA by administering high doses in short periods of time. Low-dose CSA therapy given during organ transplant reportedly causes renal and liver toxicity, but these serious complications do not occur in the Toronto Protocol, despite the very high doses of CSA.
Eligibility for Toronto Protocol Clinical Trial
Children with bilateral retinoblastoma with at least one eye classified under the International Intraocular Retinoblastoma Classification (IIRC) system as Group B (medium), C (large) or D (extra-large) may be eligible for inclusion in the Toronto Protocol Clinical Trial. The other eye can be Group B, C, D or E (possible/probable extraocular tumor spread; enucleated at diagnosis). Eligibility also requires the patient be older than 30 days old, and all children are tested for mature kidney and liver function, so that they are able to effectively clear the drugs from their system.
Ineligibility for inclusion in the Clinical Trial does not exclude the possibility of treatment with the Toronto Protocol.
Thus far, 93% of eyes treated on protocol have been controlled without need for enucleation or external beam radiation (considered failures of the protocol). Figure 1 shows a retinoblastoma affected eye (A) before and (B) after one cycle of chemotherapy, showing dramatic response by the tumor. Validation of the protocol however still depends on the recruitment of a number of additional cases worldwide. The Toronto Protocol holds promise as an effective and safe treatment of retinoblastoma that has both life-saving and vision-saving potential.
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