Herp Oncology

Question 1

Describe reptile oncology.

How does oncologic treatment differ in veterinary rather than human medicine?

How should neoplasia be diagnosed?

What factors make an ideal treatment candidate?

What is the difference between staging and grading of neoplasia?

What chemotherapeutics should be avoided? What conditions should they be avoided in?

What type of margins need to be taken from reptile tumors?

Answer 1

Oncology

MARMS – 78. Oncology

Veterinary medicine - goal to maximize quality of life rather than cure (typical human medicine goal)

• Remission: partial or complete reduction of any outward evidence of cancer on examination, lab work and imaging, and relief of any clinical signs
• Discussing goals of owner is important

Diagnosis

• Biopsy with bacterial and fungal culture as well as histology to rule out abscess, granuloma, stomatitis, fat, etc
• Parasites that can mimic tumors: plerocercoids, larval dracunculoides, acancephalans, cryptosporidiosis, spiruroids
• FNAs- less costly, less sedation, less risky, less processing (faster results), but more prone to non-diagnostic results
• Biopsy more likely to provide diagnosis - more accurate and representative of tissue, provides information on tissue architecture (and invasiveness), larger sample allows for special stains
  
  • Needle-core or TruCut - externally palpable masses
  • Endoscopic biopsy - internal, should be large (or multiple smaller)
  • Needle tract should be planned with removal in mind, avoid distributing cancer cells to surrounding tissues, sterile technique/change instruments with biopsy
  • Avoid laser and cautery on sample
  • Prolonged fixation in formalin may reduce chances for future successful immunohistochemical staining
  • Mark tissue for orientation
• Definitive diagnosis critical for treatment planning

Suitability of patient for treatment

• General health, secondary conditions
• Organ involvement of tumor
• Individualizing treatment

Staging - quantitate extent of cancer involvement in patient

• Not to be confused with grading (characterizes histopathologic features of the tumor)
• TMN in mammals: the size of the primary tumor, lymph node metastasis, distant metastasis
  
  • Reptiles lack well defined lymphatic system
  • Hematology, serum chemistry (hepatic or renal dysfunction), urinalysis
  • Imaging - CT especially helpful in chelonians, surgical planning, radiation planning
  • Chemotherapy candidates will often have systemic or metastatic disease that is physically evident or presumed (osteosarcoma, hemangiosarcoma) - likelihood of successful outcome depends on drug metabolism, elimination, absorption for oral agents, and sensitivity of tumor -> data lacking in reptiles
• Drugs to avoid
  
  • Cisplatin in patients with renal azotemia
  • Carboplatin in patients with reduced renal excretion - exacerbate myelosuppression
  • Vinca alkaloids, doxorubicin in patients with hepatic dysfunction -> delayed drug elimination and greater toxicity (myelosuppression)
  • Cyclophosphamide (activated in liver) in patients with hepatic dysfunction -> poor efficacy

Treatment

• Palliative - often older patients with other diseases, chemotherapy weighed with risk of toxicity, supportive care and pain relief
• Curative intent - younger patients in good health with no concurrent illnesses

Surgery

• May be curative if tumor localized
• Wide excision - typically 5-10 mm depending on tumor type

Question 2

Describe the use of chemotherapy in reptiles.

How are doses calculated?

What type of tumors is chemo most effective against?

How can side effects be minimized when using multiple drugs?

Describe the safe handling of chemotherapeutics.

What drugs are likely to produce myelosuppresion? How should white blood cell count be used to make decisions to move forward?

What GI and renal side effects may occur?

How is extravasation injury managed?

Answer 2

MARMS – 123. Cancer Chemotherapy

• Used to treat systemic cancers such as hematologic malignancies (lymphoma, leukemia) and metastatic carcinomas or sarcomas
• High incidence of lymphoid neoplasia in reptiles
• Obstacles - lack of scientific literature from which to infer doses and scheduling, toxicity concerns exacerbated
• Drugs are most active against cells that are actively dividing and in a particular phase of the cell cycle.
  
  • Shedding could change risks of cutaneous toxicity
  • Implications for patient (efficacy, toxicity), owner and veterinary staff safety
  • Side effects may be delayed in reptiles
• Avoid caudal injections

Dose calculation

• Metabolic basis, should decrease risk of toxicity
• mg/M2 (mg per body surface area)
• Not much is known about these formulas for reptiles, and systemic chemotherapy is often based on assumptions about drug metabolism and excretion
  
  • There are Meeh coefficients specifically for reptiles, the published literature uses mg/kg dosing, and that is what is recommended by the authors of this chapter.

Strategy

• Larger tumors - may have poor blood supply, don’t grow as rapidly, and can become resistant through mutation, so chemo may be less effective
• More active against small tumors (early detection, after debulking
• Exception is combo therapy for lymphoid neoplasia (affects different metabolic pathways)
• When using multiple drugs - vary toxicity types and scheduling
  
  • Myelosuppressive agent - doxorubicin, cyclophosphamide
  • Non suppressive - vincristine, L-asparaginase

Drug handling

• Most toxic and mutagenic
• Organ damage, increased risk of fetal loss without safety measures during prep, admin and disposal
• PPE: eye ware, respiratory, gown, latex (not vinyl) gloves
• closed -system transfer device for avoiding aerosolization and leakage
• Cleaning cage done with gloves for minimum 1 month after each tx, but could be longer
• Not recommended for immunocompromised or pregnant women to handle reptile waste during tx

Myelosuppression

• Interval bt myelosuppressive drugs in mammalian species is usually every 2-3 weeks, which have been used in some publications
• Lomustine and carboplatin have delayed or prolonged nidirs (dosing intervals longer)
• Hematology monitored every 2 weeks or longer in reptiles
• Some normal white cell counts may be low, so serial testing is important
• one report recommended that hematology be performed prior to each chemotherapy, and if the heterophil count was 1.5 x 109 cells/L (1.5 x 1012 cells/µL), the treatment was delayed until the heterophil count exceeded 2 x 109 cells/L (2 x 1012 cells/µL)
• Treatment before marrow recovery may lead to stem cell depletion and prolonged potentially irreversible recovery
• A nadir count of less than 0.5 x 109 /L is sufficient reason to reduce all subsequent dosages by 25% of that myelosuppressive drug
• Thrombocytopenia rarely severe and normal ranges not readily available in lit, but caution with use of lomustine, carboplatin and cisplatin

GI toxicity

• Renewing tissue, especially in predatory reptiles during episodic feeding - careful scheduling helpful
• Signs - nausea, vomiting, inappetence, anorexia, ulceration, diarrhea
• Vomiting common in snakes, but terminal event in turtles and lizards
• Diarrea - concern for sepsis, antibiotics recommended

Nephrotoxicity

• Lower number of nephrons in reptilian kidney
• Administer fluids with potentially nephrotoxic drugs

Extravasation necrosis

• non-DNA binding drugs (vinca alkaloids): may be benefit to diluting drug with saline and warm compress, hyaluronidase to improve absorption
• DNA binding (doxorubicin): restrict after extravasation with cold packs, dexrazoxane
• Surgical debridement may be needed
• Use IV catheter
• Don’t use these drugs intralesionally

Hypersensitivity

• Occurs with rapid administration
• Drug or carrier
• L-asparaginase in mammals
• Discontinue drug
• No reports in reptiles

Therapy - systemic, intralesional (injected into tumor with vehicle such as oil)

• Subcutaneous vascular access port (VAP) placed surgically may be suitable for larger reptiles (iguanas)
• 10% complications in mammals
• Central line placement tortoises

Consultation with veterinary oncologist recommended

• We recommend starting with established dog dosages reduced by one-third and at intervals as used in dogs.

The chapter includes relevant literature and examples that are clinically relevant

Question 3

Describe the use of radiation therapy in reptile species.

What types of radiation are most commonly used?

How do x- and gamma rays kill cells?

What types of tumors are ideal for radiation?

What are the side effects of radiation?

What types of reptile neoplasia respond well to radiation?

When is strontium 90 indicated?

Answer 3

MARMS – 124. Radiation Therapy

• Linear accelerator most common - produces highly penetrating x-rays
• Gamma rays - cobalt-60 sources, radioactive isotopes
• X and gamma rays kill the cell by knockin out electrons from atoms orbit, react with water and turn into free radicals -> damage DNA, breaks ->lethal chromosomal aberrations with division -> cell death
• Lymphocytes and lymphoma cells undergo apoptosis (rapid reduction of tumor size within 24-48 hours
• Large tumors resistant - hypoxic

Side effects - acute and late

• Acute - days to weeks
• Late - months, years, most permanent/non healing (necrosis)

CT or MR helpful with planning

Linear accelerator and Cobalt-60 cases listed

• Indian rock python with recurrent lymphoma in oral cavity - treated 15 Gray with cobalt-60 and tumor regression observed 16 days later, when treated again with 35 Gy -> 6 mo follow up no evidence of recurrence, but did die a month later -> necropsy showed lesions in liver and gi with lymphoma cells; side effect - elimination of dententition at irradiated site
• Green iguana with localized lymphoma in cranial cervical area treated with single 10 Gy and tumor reduced in size by 90% the next day and chemo was initiated -> in remission at recheck after 1008 days - like mammals lymphomas in reptiles may also be very sensitive to RT
• Caution when exposing entire snake to radiation - a snake treated with 20 Gy to a field when including lung -> pulmonary vasculitis -> euthanized for dyspnea
• LD50 in box turtles is approximately 850 Roentgen (7.5 GY), 800 R in goldfish, 700 R in frogs and 1486 R in newts, but lower in snakes (300-400 R, 2.6-3.6 Gy)
• Some reptiles may tolerate RT better than mammals
• Sungazer lizard with acute lymphoblastic leukemia was treated with whole body radiation with 1 GY and decreased WBC count within 3 mo; lizard was previously treated with prednisone; died 11 mo after RT due to femoral pore abscess, which was present prior to RT
• Less success with nonlymphoma
  
  • Boa constrictor with sq fibrosarcoma, surgically excised and treated 3 weeks later (cobalt-60 16x3 Gy fractions, total dose 48 Gy over 3 wks) - leukopenia with severe lymphopenia resulted from combo of factors (neoplasia, multiple coelomic surgeries, RT, stress) -> tumor increased in size during RT, intralesional chemo was performed after RT, but culture of tumor revealed Mycobacterium chelonei (snake was euthanized)
  • Madagascar ground boa with SCC treated with 2 doses of x-ray radiation a week apart (10 Gy each, total 20 Gy), tumor increased in size, euthanized 5 days after second RT (open mouth breathing, dysecdysis), MRI revealed suspected RT related edema and vasculitis
  • Yellow rat snake with subcutaneous malignant chromatophoroma mid body initially treated with 2 surgical procedures, then RT (4 x 15 GH over 15 days by 6 MeV electron beams); dry scales in irradiated area 10 days after start, snake reportedly irritable for months and anorexic for 20 wks (sx site healed normally), snake died after 10 months (abscess in site of previous tumor, coelomic tumor)
  • Anaconda with SCC near cloaca- irradiated with 6 weekly doses of 6 Gy electron beams; By last tx, patient more comfortable (lesion regressed, gained weight), but at 6 week follow up, edema and loss of scales noted (acute radiation effects); lesions persisted for 16 weeks (tx with antibiotics and buprenorphine); tumor recurred and snake was euthanized for nonhealing wound near vent (severe constipation, weight loss, depression)
• Stereotactic radiation therapy (SRT) is emerging method that involves a high dose of (usu 6-17 Gy/fraction in mammals)
  
  • Delivered in 1, 3 or 5 fractions instead of daily treatments
  • Advanced imaging systems with linear accelerator (CT before tx) to allow accurate and conformal beam delivery (intensity modulated radiation therapy)
  • To treat superficial tumors, linear accelerates with limited penetration depth of 1.5-5 cm is helpful
  • No documented reptile reports at time of publishing

Strontium 90

• Electrons emitted from strontium-90 ophthalmic probe (8mm diameter)
• Limited penetration, high dose to surface (100 Gy or higher) without causing significant effects in mammals
• Caution if tumor exceeds 3-4 mm thickness as deeper portion will be underdosed
• Case report - bearded dragon with myxosarcoma surgically debulked on medial canthus OD, followed by RT with 100 Gy -> tumor recurred 5 mo later (locally infiltrative nature)
• Anecdotally successful in other reptiles (oncologists ACVR listserv)

Radioactive implants (seeds, straws)

• Less common in vet med
• Not successful for treatment of melanoma in common death adder or mast cell tumor in eastern kingsnake