Multimodality care in veterinary oncology (Proceedings)

Surgical oncology

A chance to cut is a chance to cure

Most primary tumors are best treated by surgical excision. Most benign tumors, low grade cutaneous mast cell tumors, odontogenic tumors, or solitary mammary tumors are perhaps best treated by wide surgical excision. Some tumors, however, due to their more aggressive biologic behavior are best treated with other therapeutic modalities in combination with surgery such as oral malignant melanomas, feline fibrosarcomas, and canine appendicular osteosarcomas.

Palliation

Palliation refers to reducing the severity of or mitigating the clinical signs of a disease. Palliative surgery in regards to cancer usually involves removal of a non-functional or painful part without being curative. Treatment of appendicular osteosarcoma by amputation is the best example of such a surgery.

Cytoreductive surgery

Surgical excision is performed knowing that residual disease remains in the surgical site. Such treatment would be combined with adjuvant treatment to control local and distant invasion. An example of this might be a large oral fibrosarcoma which will be treated with radiation.

Management of metastasis

Surgical removal of metastatic disease with a curative intent is part of an increasing role the surgeon will play. Adjuvant chemotherapy for the treatment of canine appendicular osteosarcoma has extended survival times, but it also has changed the biologic behavior of the tumor. Surgical excision of pulmonary and other metastatic lesions may further prolong quality of life and long term survival as in the case of iliac lymph node resection in apocrine gland adenocarcinoma of the anal sac in dogs.

Oncologic emergencies

The presence of a neoplasm may not be fully appreciated until the biopsy results are available btu surgical intervention is needed immediately. Upper airway obstruction and acute paralysis due to spinal cord compression are other examples of oncologic surgical emergencies.

Reconstruction and patient supportive care

Wide excision of en bloc resection of neoplasms can be challenging, but reconstruction of the resulting defects can be even more difficult. Plans for excision of a mass should include the method of reconstruction (along with a backup plan should that fail. Oncologic abdominal surgery may be accompanied by placement of a feeding jejunostomy tube for alimentation of the patient during the recovery period.

Radiation oncology

Radiation therapy is local therapy for local disease and is utilized when surgery cannot be performed or will not entirely remove 100% of the tumor. There is a constant balance between dose to the tumor and dose to the surrounding tissues.ff Only cells that are radiated are at risk for the treatment-related sequela. The higher the dose, the more likely a biologic effect (tumor cell death or normal tissue toxicity) will be seen. Standard doses used to treat tumors have evolved by attempting to use a dose that is associated with a high probability of tumor control and an acceptable probability of normal tissue toxicity. Acute effects are seen in the proliferating cells of the body such as bone marrow, epidermis, enterocytes, mucosa (and tumor!) and are seen during or within the first few months following radiation therapy, reflecting damage to stem cells needed to maintain these structures. Factors associated with the development of acute effects include total dose, overall treatment time (dose intensity) and volume of tissue irradiated. Skin effects range from mild erythema to confluent moist desquamation. Erythema is thought to be an inflammatory reaction and can be seen as early as 24 hours following the first treatment. Desquamation, both dry and moist is seen later (2-3 weeks) in the course of therapy. This reaction can persist for 2-4 weeks following completion of therapy with reepithelialization within 1-2 months.

The major acute effect of radiation in the oral cavity is stomatitis or mucositis, starting 2-3 weeks after therapy is initiated, progressing to a confluent mucositis with superficial ulceration, tissue edema and bleeding. Goals of supportive care include pain management, maintenance of adequate hydration and nutrition and treatment of secondary bacterial infection including temporary feeding tubes (gastrostomy or esophagostomy tubes)

The eye is often in a radiation field especially in veterinary patients given the anatomy of the head, leading to conjunctivitis, keratoconjunctivitis sicca (KCS) and corneal ulcers in some patients. Permanent KCS, cataracts and retinal damage are all potential late consequences to radiation. Cataracts are the most sensitive structure in the eye and can be seen even if receiving a low dose. Management of these problems includes tear replacement, corneal ulcer management and cataract removal, depending on the clinical situation.

Late effects of radiation are seen in slowly proliferating tissue such as nerve or muscle. Damage to these cells appears to be related to damage to the vascular and connective (stromal) tissue in slowly or non-proliferating tissue such as the brain, spinal cord, muscle, bone, kidney, and lung. Damage is often progressive and non-reversible and limits the dose that can safely be given. The development of a late effect can have devastating and potentially life threatening consequences on the patient and should be considered as a treatment failure, similar to tumor recurrence. The development of late effects is related to dose and treatment volume and is significantly impacted by dose per fraction, necessitating the use of fractionated radiation therapy.

The goal of definitive radiation therapy is eradication of all viable tumor cells within the patient. Its intent is to cure the patient of the tumor whenever possible and even if not possible to prolong survival as long as possible. It often involves the combination of surgery, radiation therapy and chemotherapy. Patients with distant metastatic disease or significant underlying problems may not be candidates for definitive radiation therapy and would be best managed with a palliative course of therapy.

Palliative radiation is playing a larger role in veterinary oncology as owners are seeking to improve quality of life, decrease pain and minimize hospitalization rather than achieving a cure and prolonging survival. Most palliative protocols use lower total doses and a higher dose per fraction to accomplish the goals listed above.

Determination of the precise treatment volume is based on the tumor type in addition to the surgery and pathology reports. The medical record should provide information regarding initial location, size and extent of the tumor, extent of surgical excision and involvement of surrounding tissues. Preoperative imaging is extremely important for radiation therapy planning purposes and knowing the original extent of the tumor. The surgical scar may or may not be representative of the underlying mass especially in situations where advanced reconstructive surgery (advancement flaps, etc.) is performed. Surgiclips can be placed at the time of surgery to better define the tumor bed. Historically, radiation therapy has been delivered to patients when complete excision is not possible or if surgery would result in functional or cosmetic compromise. It is becoming clear however, that there are situations where radiation therapy can be given before or during surgery. Therefore, consultation with a radiation oncology is indicated at the time of diagnosis prior to definitive therapy, especially in situations where a complete excision is unlikely. Incisional biopsies can provide the histopathologic diagnosis without a highly invasive or costly procedure. Preoperative radiation therapy has some potential advantages over postoperative radiation including treatment of well oxygenated tissue rather than a scar, decreased tumor seeding a smaller treatment volume and in some situations a less aggressive surgery. Potential disadvantages of preoperative radiation include increased wound complications and delayed surgical extirpation. The decision to pursue such a course is based not only on tumor type, but also location, surgeon preference, risk of wound complication as compared to risk of radiation toxicity. A preoperative course of radiation may allow sparing of critical structures such as spinal cord or eye that would invariably be included in a postoperative field.

Medical oncology

Chemotherapy can be grouped into 3 main categories. Primary or sole chemotherapy which is used for lymphoma or other systemic diseases such as leukemia, myeloma, systemic mastocytosis, disseminated histiocytic sarcoma. Patients with metastatic disease especially to to the lungs fall into this category especially if surgery and radiation therapy are not to be administered given the metastatic nature of the disease. Adjuvant chemotherapy is utilized after the local disease is controlled either with surgery, radiation therapy or a combination. The purpose of adjuvant therapy is to delay or prevent the development of metastatic disease and to a lesser extent control local disease. Examples of adjuvant chemotherapy in veterinary medicine include post operative chemotherapy for osteosarcoma, hemangiosarcoma mammary carcinoma, thyroid carcinoma, Grade III mast cell tumors, high grade soft tissue sarcoma and many others. Unfortunately with the exception of a few diseases (OSA, HAS, STS) the benefit of such chemotherapy has not been proven to prolong survival times. As such the decision to treat with chemotherapy is often complex and based not only on tumor factors such as grade, mitotic index and overall biologic behavior, but also on owner considerations and comfort of taking a "wait and see" approach vs treating as aggressively as possible. A final often forgotten form of chemotherapy is neoadjuvant chemotherapy which is chemotherapy given prior to (and potentially after) local therapy in order to shrink tumors and make them more surgically resectable. Testing of new agents prior to removal will also guide the clinician in his/her choice of chemotherapy if a dramatic response is seen. Recently newer agents and strategies have been utilized including low dose oral chemotherapy (so called metronomic chemotherapy) and targeted therapies using recently approved tyrosine kinase inhibitors such as masitinib (Kinavet) and toceranib phosphate ( Palladia )

Selected references

Arthur JJ, Kleiter MM, Thrall DE, et al. Characterization of normal tissue complications in 51 dogs undergoing definitive pelvic region irradiation. Veterinary Radiology Ultrasound 2008: 49:85-89.

Collen EB, Mayer MN. Acute oropharyngeal effects of full-course radiation treatment of tumors of the head. Canadian Veterinary Journal 2008:509-512.

Fan TM, Charney SC, de Lorimier LP, et al. Double-blind placebo-controlled trial of adjuvant pamidronate with palliative radiotherapy and intravenous doxorubicin for canine appendicular osteosarcoma bone pain. Journal of Veterinary Internal Medicine 2009:23:152-160.

Gieger T, Rassnick K, Siegel S,et al. Palliation of clinical signs in 48 dogs with nasal carcinomas treated with coarse-fraction radiation therapy. Journal of American Animal Hospital Association 2008;44:116-123.

Hahn KA, Ogilvie G, Rusk T, Devauchelle P, Leblanc A, Legendre A, Powers B, Leventhal PS, Kinet JP, Palmerini F, Dubreuil P, Moussy A, Hermine O. Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Intern Med. 2008 Nov-Dec;22(6):1301-9

Hahn KA, Legendre AM, Shaw NG, Phillips B, Ogilvie GK, Prescott DM, Atwater SW, Carreras JK, Lana SE, Ladue T, Rusk A, Kinet JP, Dubreuil P, Moussy A, Hermine O. Evaluation of 12- and 24-month survival rates after treatment with masitinib in dogs with nonresectable mast cell tumors. Am J Vet Res. 2010 Nov;71(11):1354-61.

Lana S, U'ren L, Plaza S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. Journal of Veterinary Internal Medicin 2007:21:764-769.

Selting KA, Powers BE, Thompson LJ, Mittleman E, Tyler JW, Lafferty MH, Withrow SJ. Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy:39 cases (1996-2004).J Am Vet Med Assoc.2005 Nov ;227(9):1442-8.

London CA, Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosenberg MP, Henry CJ, Mitchener KL, Klein MK, Hintermeister JG, Bergman PJ, Couto GC, Mauldin GN, Michels GM. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res. 2009 Jun 1;15(11):3856-65.