"Intralesional Chemotherapy" TUMOR TIDBITS, A BIWEEKLY VETERINARY ONCOLOGY E-LETTER Volume 3; Number 15; April 26, 2002. Editor: Kevin A. Hahn, DVM, PhD, Dipl - ACVIM (Oncology) & Overall Nice Guy! drhahn@gulfcoastvetspec.com ANNOUNCEMENTS * Our clinical trials for dogs with lymphoma are going well. Welcome Kelly to our staff as our Clinical Trials Coordinator. If you have questions about any of our Clinical Trials, please call us or ask for Kelly for additional information. * Our Web Site address has changed for the better, change your bookmarks to www.gcvs.com today! THIS WEEK'S TUMOR TIDBIT: INTRALESIONAL CHEMOTHERAPY! PRINCIPLES * Intratumoral chemotherapy consists of injecting anticancer drugs by needle directly into the tumor and tumor bed. This route of administration has been developed to allow the safe use of high potency anticancer drugs at a reasonable cost in exotic animals, horses, dogs, and cats with localized tumors. * The treatment has several advantages: 1) cancer cells are exposed to high doses of free drug, 2) local distribution of the drug is improved, 3) systemic side-effects are reduced because the general circulation is bypassed, and 4) cost of treatment is acceptable. DRUGS - CISPLATIN: * Cisplatin is a heavy metal compound that inhibits DNA synthesis by directly binding to DNA, which leads to death of actively dividing cells. Cisplatin has been developed for intratumoral administration because of its wide spectrum of activity against solid tumors and its steep dose-response relationship. * Cisplatin is prepared in a water-oil-emulsion to maintain the drug in tissue and prolong local exposure of the tumor cells to high drug concentrations. * NOTE: Recent changes in the availability of Cisplatin have led many to use Carboplatin instead. However, the same principles apply! DRUGS - 5-FU: * 5-Fluorouracil is a metabolized to the nucleotide F-UMP which can be incorporated in RNA blocking the methylation reaction of deoxyuridylic acid to thymidylic acid, therefore, interfering with the synthesis of DNA. * 5-FU comes prepared as a 50 mg/ml solution (5 ml multidose vial). DRUGS - MATRIX: * Medical grade, purified bovine collagen. Used because of protein saturation of drug, minimizing systemic bioavailability. * Medical grade, purified sesame seed oil. Used because of its good safety record for parenteral (intramuscular depot formulations) administration, and its low cost and wide availability. * Autologous serum. Used because of protein saturation properties, low cost, and availability. PREPARATION: * Cisplatin (10 mg/ml), Carboplatin (50 mg/ml) or 5-FU (50 mg/ml) are prepared immediately prior to use. * Sesame oil (2 ml), collagen (0.3 ml), or autologous serum (1 ml) are drawn into individual 3-ml syringes with Luer-lock fittings and mixed with 1 ml of chemotherapy using a stopcock. Remember to: 1) remove air in the mixing unit by gently pushing the matrixl through it (air bubbles disrupt the emulsion) 2) attach the syringe containing chemotherapy to the free end of the mixing unit 3) with both syringes securely fastened, emulsify the chemotherapy by exchanging the syringe contents (pumping method). ADMINISTRATION: * To administer the drug, the needle (20-25 gauge) mounted on the syringe is inserted to the desired length into tissue, and the drug is injected at a constant flow while the needle is withdrawn. * The target volume of tissue to be injected should include all visible tumor and a margin of normal tissue of 1 to 2 cm (as a function of tumor type and tumor size). * The planning of the pattern of injections is critical to achieve a uniform dose distribution. * Depending on the shape and accessibility of the lesion, the target volume is injected via multiple sites using a parallel-row technique or field-block technique. Multiple planes of injections may be needed for large tumor volumes using parallel or orthogonal axes of injection. * In all cases, the treatment field size should remain the same during the course of treatment; the volume of tissue treated should not be decreased if a reduction in tumor size is observed. SAFETY: * Cisplatin, Carboplatin, and 5-FU are mutagenic and carcinogenic at low doses and with repeated exposure. Therefore, strict safety rules must be observed concerning preparation, handling, administration and disposal. * Good technique is critical to maintain product sterility and avoid contamination of the environment or personnel by accidental exposure to cytotoxic dust or aerosols. * The drug mixture should be prepared on a disposable, plastic-backed absorbent liner in a quiet, low-traffic work area, away from drafts and personnel. * Protective garb, i.e., disposable protective gown made of low-permeability fabric, disposable high efficiency respirator, chemical splash goggle, talc- free disposable latex gloves (thickness 7 0.009 inch) is required during drug preparation and treatment. TARGET DOSAGE PER TUMOR: * Tumor dosage is 1 mg of cisplatin, 10 mg of carboplatin, or 10 mg of 5-FU (0.3 ml of mixture) per cm3 of tissue in the target volume (all macroscopic areas of tumor and a margin of normal tissue). * Treatments are done on an outpatient basis. TREATMENT INTERVALS: * Several dose intensity protocols are available. A standard intensity treatment protocol includes 4 intratumoral chemotherapy treatment sessions at 2-week intervals. * A time interval of less than 10 days between treatments may result in an increased risk of local reactions, whereas, a time interval of more than 21 days may allow tumor repopulation and result in a loss of therapeutic effect. A high intensity protocol includes 6 treatments given as a standard protocol with a 4-week rest, followed by 2 treatments given also at 2-week intervals. EFFICACY: * Factors affecting efficacy may be classified as tumor-related and technique-related. The most important factor is tumor size. For a given size, tumor response is a function of histologic type and tumor proliferative activity. * Tumor types responsive to the treatment include squamous cell carcinoma/papilloma, sarcoid, soft tissue sarcoma (neurofibrosarcoma, fibrosarcoma, hemangiosarcoma, schwannoma), melanoma, lymphoma, and hamartoma. * The most responsive tumors include fibroblastic ulcerated sarcoids and lymphomas, the least responsive tumors include flat sarcoids and melanomas (benign and malignant). REASONS FOR TREATMENT FAILURE: * Drug resistance, intrinsic or acquired, is not clinically significant because less than 2% of all tumor types treated do not respond initially to treatment and recurrent tumors are retreated successfully. * The technique of injection is critical to the success of the treatment. Because the chemotherapy drug does not diffuse in tissues farther than 3-5 mm from the site of injection, the rows of injections should be 0.6-0.8 cm apart. * If the injections are farther apart, the dose distribution is not uniform and some areas of the tumor may be underdosed which would result in tumor recurrence. If the injections are too close, the tissue at the site of puncture are exposed to excessive doses of drug which would result in excessive local normal tissue reactions. SIDE EFFECTS: * The side-effects of treatment are strictly local. All acute reactions including inflammation, swelling and focal ulceration are self-limiting and resolve quickly. Perioperative treatment does not appear to compromise the healing of normal skin, mucosa, or subcutaneous tissue. * Treatment of grossly infected lesions should be postponed until the infection has resolved. Permanent damage to nerve, muscle or blood vessels has not been observed. The treatment does not produce chronic tissue fibrosis or necrosis and does not affect hair growth and color. INDICATIONS - AS SOLE MODALITY: * The treatment is ideal for tumors in locations where a complete surgical resection would result in a cosmetic or functional deficit. * The most commonly indicated sites include the face (eyelid, lip, pinna, nose), distal extremities and genitalia (male and female). A treatment with standard dose intensity is used for tumors less than 3 cm in their greatest dimension, corresponding to a volume of tissue of about 20 cm3. * 2-year relapse-free rates range from 80 to 90% for all locations, 70 to 80% for periorbital carcinomas and 90-100% for carcinomas of the genitalia. * High dose intensity treatment is indicated for large (3-5 cm in largest dimension) inoperable tumors. INDICATIONS - IN COMBINATION THERAPY: * Intratumoral chemotherapy can be used alone or in combination with other treatment modalities including surgery or radiotherapy. * The goals of a combined approach are to improve the efficacy and reduce the morbidity of the treatment. A combined treatment is aimed at a single target, the local-regional tumor and is used for tumors where treatment failure results from the inability of a single treatment to control the primary tumor. WITH SURGERY: * The central idea in combining surgery and intratumoral chemotherapy is that conservative surgery and adjuvant intratumoral chemotherapy is as effective as radical surgery. * The 2 treatments are complementary: conservative surgery removes the tumor bulk and chemotherapy treatment eradicates the residual disease (microscopic or macroscopic). * Depending on tumor location, type of surgical wound (open vs. closed), volume of residual tumor (microscopic vs. macroscopic), and tumor proliferative activity, several treatment protocols are feasible. * A protocol is defined by the timing of the 2 treatments and the dose intensity of chemotherapy treatment. * Chemotherapy treatment may be done perioperatively when the treatment is initiated at the time of surgery, or postoperatively when the first administration of drug is planned 2-3 weeks after surgery when the wound has healed. * For tumors with visible residual disease that cannot be surgically closed (open wound < 5 cm in largest diameter), the perioperative protocol of choice is best. * For larger tumors (open wound > 5 cm in largest diameter), perioperative treatment with a high dose intensity protocol is recommended. When primary closure is possible, the choice of peri- versus post-operative treatment depends on the risk of surgical complications, and the surgical margin status. * Postoperative treatment is recommended after extensive surgery when there is a high risk of skin wound dehiscence (skin tension) or after microscopically incomplete surgical resection. Perioperative treatment is recommended after incomplete removal of gross tumor (tumor removed in fragments) with grossly positive margins and when the risk of postoperative complications is low. * Combined surgery and intratumoral chemotherapy is the most effective approach for treatment of cutaneous tumors in horses, birds, and reptiles. * It is indicated for large operable tumors of any histologic type located on the face, genitalia, distal extremities, and perineum where a wide surgical resection would result in a substantial functional deficit. MORE QUESTIONS?: Don't hesitate to call or email us at Gulf Coast Veterinary Oncology! ALL THE BEST, Kevin A. Hahn, DVM, PhD Diplomate ACVIM (Oncology) & Overall Nice Guy Gulf Coast Veterinary Specialists 1111 West Loop South, Suite 150 Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 http://www.gcvs.com