Donald E. Thrall, DVM, PhD, DACVR (Radiology, Radiation Oncology)
RADIATION THERAPY TECHNIQUE
Considerable knowledge has been gained in the past 10 years about the best way to administer radiation therapy. Guidelines for total dose, the size of dose per fraction, and overall time are now developed. In earlier days, it was common to give relatively large fractions (4-5 Gy) three days per week, for a total of 10-12 fractions (40-50 Gy total dose). We now know this total dose is too low, and the fraction size is too big. It is also known that prolongation of treatment time is disadvantageous and administration of daily fractions has become common.
Large fraction sizes predispose to serious complications in slowly proliferating normal tissues, such as spinal cord or heart. These complications are life threatening and limit the dose of radiation that may be administered. By using smaller doses per fraction, the probability of these complications in slowly proliferating tissues can be avoided. Use of smaller fraction sizes necessitates prolongation of overall time to administer a sufficiently large total dose. This will increase stress on animal owners and the expense of treatment but shortcuts around this basic fact are not realistic.
Increasing the intensity of dose administration by giving small fractions, but on a daily basis, may increase the frequency of complications in rapidly proliferating tissues, such as skin. Unfortunately, the tumor behaves like a rapidly proliferating tissue and it is not generally possible to give a dose of radiation likely to control the tumor and not have some demonstrable change in proliferating normal tissue. Fortunately, although temporarily discomforting, these reactions in rapidly proliferating tissues heal and do not generally limit the dose of radiation that may be administered.
Prolongation of treatment time allows tumor proliferation during treatment. This proliferation increases the number of tumor clonogens that must be killed by the radiation. The biologic basis for proliferation during protracted treatment schemes being detrimental to radiation response of the tumor is indisputable and unnecessary gaps in treatment or prolongation of treatment should be avoided.
Typical definitive radiation therapy protocols in veterinary medicine involve daily administration of 3.0 Gy fractions for a total dose of 57-60 Gy.
When one considers therapeutic options for a tumor, typically only one modality is chosen. Often this is a bad decision, making permanent local control of the tumor impossible. The first therapy administered should be the optimal therapy, and this may entail combinations of modalities. Clearly, combination therapy will be more expensive than one single therapy, but in treating recurrent tumors considerable additional expense will be incurred. Additionally, recurrent tumors are more refractory to local control and the best chance for curing the tumor is administration of the optimal therapy the first time the tumor is treated.
The tumor factors that should be considered when selecting the initial therapy are: 1) location; 2) volume; 3) grade; and 4) histologic type. Many individuals place the greatest significance on histologic type, but the other three factors often play a bigger role in determining response to therapy.
With any single modality, killing less than 10% of the tumor cells will result in a partial response where the tumor will be visibly smaller, but still grossly apparent. Killing 99% of the cells will result in a complete response where there is no gross evidence of the tumor. However, cell killing 99% of cells is far from a cure. Assume that a tumor contains 1010 cells, not an unreasonable assumption. If one kills 99% of 1010 cells, there are 108 (100,000,000) cells remaining. Clearly this tumor is going to recur. A complete response lulls the clinician into thinking that an effective therapy has been administered. Therapy of solid tumors should be aimed at permanent local control, not obtaining a complete response. This requires killing 10 to 12 logs of cells, not just 2 or 3.
Efficacy of Radiation Therapy Alone
Very few macroscopic tumors can be controlled with radiation therapy alone. Some examples are: 1) acanthomatous epulides10; 2) canine gingival carcinomas2; 3) small grade II mast cell tumors4; and 4) transmissible venereal tumors9. This small list is the result of the overwhelming negative effect of tumor volume on the probability of solid tumors being controlled with radiation therapy. The detrimental effect of increasing tumor volume occurs at surprisingly small volumes4. Thus, for gross tumors where complete surgical excision is not possible, combinations of therapy should be considered as the first-line therapy rather than trying a less aggressive, and ineffective, treatment.
Surgery and Radiation Therapy
The combination of surgery and radiation therapy is one of the most effective cancer treatment options available. Optimal use of this combination requires thoughtful preplanning, communication among involved parties, and adherence to good surgical oncologic principles. Surgery can be used before or after irradiation and there are indications for each sequence. This will not be discussed here, but more information is available6.
By judicious combination of surgery and radiation, permanent local control of various solid tumors may be achieved. These include: 1) grade I and II mast cell tumors; 2) canine and feline soft tissue sarcomas1,5; and 3) miscellaneous soft tissue tumors such as thyroid, perianal tumors, ear canal tumors.
Chemotherapy and Radiation Therapy
The combination of chemotherapy and radiation therapy is clearly superior to radiation therapy alone for some human tumors. Controlled clinical trials documenting this principle in veterinary medicine have not been performed. Nevertheless, in theory this may be useful in some patients. Problems relate to the uncertainties of scheduling of the two agents, possible chemotherapy dose reductions, and unexpected toxicity.
Some chemotherapeutic agents are actual radiosensitizers, but in reality, one should expect only an additive interaction in vivo. Even with additivity, increased tumor response is a reasonable expectation if chemotherapy kills cells that would not have been killed by radiation. Agents that have been used in combination with radiation in veterinary medicine include cisplatin, carboplatin, and doxorubicin.
Chemotherapy has been added to the combination of surgery and radiation therapy in treatment of canine nasal tumors, feline vaccine associated sarcomas, and high grade canine soft tissue sarcomas.
Conclusive results documenting the superiority of these combinations are not yet available.
Chemotherapy in combination with radiation is also used in canine melanoma. Canine melanoma cells have been characterized by a large capacity to accumulate and repair sublethal radiation damage. This large repair capacity is similar to that of slowly proliferating normal tissues as described above. As a result, there have been melanoma trials using large fractional doses of radiation, sometimes in combination with chemotherapy. However, in a study of 140 dogs, fraction size was not found to be associated with local tumor control and systemic chemotherapy had no impact on survival, though drug dosages were suboptimal7. Importantly, radiation was found to be effective in local control. The following factors were associated with increased survival following radiation therapy: 1) rostral tumor location, 2) lack of bone lysis, and 3) microscopic tumor burden7. Metastasis remains a serious issue.
The Future of Radiation Therapy
In radiation therapy in both humans and animals, improvements in tumor control have been sought and the main focus has been alteration of technology with administration of higher and more conformal radiation doses.
Though this approach will, at least in theory, result in a greater probability of tumor control, one must ask whether the gain in outcome can be justified Sophisticated collimation systems enabling delivery of dynamic intensity modulated radiation doses may cost $500,000. The trend is to bigger and better technology. Less attention has been paid to modulation of tumor biology in combination with more standard approaches to irradiation as a way to improve tumor response. Clearly more attention should be directed toward this area. For example, cycloxygenase-2 (COX-2) and the epithelial growth factor receptor (EGFR) are parts of the cellular machinery that when upregulated, or overexpressed, lead to events that promote tumor growth and resistance to treatment. These include a decrease in apoptosis, increased propensity for metastasis and resistance to radiation. There are ways to modulate each of these agents that could improve response to therapy that does not rely on highly sophisticated radiation therapy technology. Recently we have shown that COX-2 is upregulated in canine nasal tumors3 and EGFR is overexpressed in feline oral squamous cell carcinomas. Both of these tumors are very difficult to control with radiation therapy, alone or in combination with surgery, but the addition of inhibitors of COX-2 or EGFR are clearly worthy of assessment as a way to improve outcome. In the future, investigations into the molecular nature of canine and feline cancer hold great promise as a way to improve treatment outcome.
Palliative Radiation Therapy
Often, patients have tumors where the chance for definitive control is very low regardless of the modality or modalities used. Many of these patients can benefit from palliative radiation therapy. The intent of palliative radiation therapy is alleviation of discomforting clinical signs associated with the tumor, not prolongation of survival. This intent must be made perfectly clear to the pet owner. Palliative irradiation involves administration of fewer fractions (typically 1-5) with larger doses per fraction (4-8Gy) than employed in definitive irradiation. Palliative irradiation has been used for treatment of bone and soft tissue tumors with some success and in osteosarcoma, factors associated with long remission times have been identified (8). These include length of bone involved and degree of tumor lysis.
The knowledge of technical aspects of delivering radiation therapeutically and the biologic aspects of interaction of radiation with tissue have increased considerably in the past 10 years. The limitations of any single modality are well understood. There are some tumors that may be controlled with radiation therapy, but many are best treated with a combination of modalities. It is important that the first therapy administered be the absolute best therapy. Radiation has a role in palliation of signs associated with advanced bone and soft tissue tumors. A focus on tumor biology will be necessary for real gains in tumor control to be achieved; this will likely be more successful than bigger and more sophisticated treatment machines or strategies to increase the dose of radiation delivered.
1. Cronin, K.; Page, R.; Spodnick, G.; Dodge, R.; Hardie, E.; Price, G.; Ruslander, D.; Thrall, D. Radiation therapy and surgery for fibrosarcoma in 33 cats. Vet Radiol & Ultrasound 39:51-56; 1998.
2. Gillette, E.; McChesney, S.; Dewhirst, M.; Scott, R. Response of canine oral carcinomas to heat and radiation. Int J Radiat Oncol Biol Phys 13:1861-1867; 1987.
3. Kleiter, M., Malarkey, D.E., Ruslander, D.E., Thrall, D.E.: Expression of Cyclooxygenase-2 in Canine Epithelial Nasal Tumors. Vet Radiol & Ultrasound, In Press, 2004
4. LaDue, T.; Price, G.; Dodge, R.; Page, R.; Thrall, D. Radiation therapy for incompletely resected canine mast cell tumors. Vet Radiol & Ultrasound 39:57-662; 1998.
5. McKnight, J.; Mauldin, G.; McEntee, M.; Meleo, K.; Patnaik, A. Radiation treatment for incompletely resected soft-tissue sarcomas in dogs. J Am Vet Med Assoc 217:205-210; 2000.
6. McLeod, D.; Thrall, D. The combination of surgery and radiation in the treatment of cancer: A review. Vet Surg 18:1-6; 1989.
7. Proulx, D.R., Ruslander, D.M., Dodge, R.K., Hauck, M.L., Williams, L.E., Horn, B., Price, G.S., Thrall, D.E.. A Retrospective Analysis of 140 Dogs with Oral Melanoma Treated with External Beam Radiation. Vet Radiol & Ultrasound 44:352-359, 2003.
8. Ramirez III, O.; Dodge, R.; Page, R.; Price, G.; Hauck, M.; LaDue, T.; Nutter, F.; Thrall, D. E. Palliative Radiotherapy of Appendicular Osteosarcoma in 95 Dog. Vet Radiol & Ultrasound 40:517-522; 1999.
9. Thrall, D. Orthovoltage radiotherapy of canine transmissible venereal tumors. Vet Radiol 23:217-219; 1982.
10. Thrall, D. Orthovoltage radiotherapy of acanthomatous epulides in 39 dogs. J am Vet Med Assoc 184:826-829; 1984.