Oral malignant melanomas really belong in a separate category. This type of tumor tends to respond in a similar way to radiation therapy as do late responding tissues. In such cases, when typical standard curative protocols are used to spare the late responding tissues, the tumor cells are also spared. For this reason, a better success rate in tumor control has been achieved with the use of larger and fewer fractions. In human medicine research, an effort has been made to try to differentiate melanoma tumors that respond better to large fractions from those that would respond better to smaller fractions. To date, this remains unresolved and, for the most part, a coarse fractionation protocol is chosen. In veterinary medicine, most protocols consist of fractions between 6 to 10 Gy. Malignant melanomas are usually locally invasive and fairly quick to metastasize. Approximately 75% of cases will die of metastatic disease despite good local control. For this reason, chemotherapy for systemic disease should be considered. Unfortunately, an effective agent for this cancer has yet to be identified.

Benign lesions:

It should be realized that although radiotherapy is mostly used for the control of malignant cancer, certain benign lesions (for example: infiltrative lipomas, Granulomatous meningoencephalomyelitis (GME), and chronic lick granulomas non-responsive to medical treatment?) have been successfully treated as well. Like always, the risks and benefits must all be taken into consideration for each individual case.

T. Control-1 and CompL-1 show the probability of Tumor control and Normal Late Tissue Complications for a protocol of lower fractionation while T.Control-2 and CompL-2 show the probability of Tumor control and Normal Late Tissue Complications for a highly fractionated protocol.

As a general rule, a prescribed treatment protocol should have no more than a 10% probability of inducing serious late complications for most tissues, and no more than a 5% probability of late complications for nervous tissue. Due to improved time-dose fractionation, computer treatment planning, and the use of megavoltage therapy, a serious complication rate of less than 5% exists in most veterinary radiation therapy today.

Various protocols have been applied for palliation in both veterinary and human medicine. The fraction size administered will depend on the site being irradiated and the individual case. The sensitivity of the tissues included in the field must still be taken into consideration, just as they are with curative protocols. For example, a treatment involving brain tissue would be approached slightly differently than one involving a distal extremity. The degree of coarse fractionation and the optimal total dose for palliative protocols is still an area of debate in both human and veterinary therapy. Generally, however, three fractions of 8 to 10 Gy is administered. Approximately 70% of osteosarcoma patients show a positive response to palliative radiotherapy and most show clinical pain relief within 2 to 3 weeks of the start of treatment. Response can occur anywhere between a few hours after the initial dose to 6 weeks after the first course of treatment. When a second course is required for pain recurrence, 80 % of patients who responded well the first time will again
have a positive response.

Palliative therapy of soft tissue tumors may be beneficial when a mass is impairing function or causing discomfort due to tissue compression. This would include masses causing urethral, tracheal or laryngeal/pharyngeal, esophageal colorectal, lymphatic, vascular (ex: Vena Cava), or other types of obstructions or masses inducing painful tissue compression such as pressure on the spinal cord, nerve root, brain tissue or orbital tissue.

Many types of tumors may occur in this area. Examples may include Lymphoma, Osteosarcoma, Mast cell tumor, Reticulum cell sarcoma, Fibrosarcoma, optic nerve Meningioma, Neurofribrosarcoma, Glial,Carcinomas, Undifferentiatedtumors, and others

Periorbital tumors may originate from either the surrounding soft tissues, or bone, or may result from extension of other primary tumors originating in the nasal cavity, maxilla or optic nerve. Many of these tumors cannot be completely resected surgically with good margins because of location and surrounding critical tissues. Response to radiation greatly depends on the type and grade of tumor. Many periorbital tumors are successfully treated with radiation therapy, with or without adjuvant therapy.

Auricular and periauricular tumors:

Theoretically, any cutaneous or soft tissue tumors can occur in the periauricular area. It is not uncommon to find Mast cell tumors, Fibrosarcomas and other Soft tissue sarcomas. As with treating these tumors in other areas of the body, radiation therapy has been successful, although the success rate depends on the grade and type of tumor.

Ceruminous gland adenocarcinoma (CGA) is the most common tumor of the ear canal found in both dogs and cats. In one study, aggressive surgery (ablation of the ear canal and bulla osteotomy) resulted to a median disease-free interval of 42 months. Another study using radiation alone, or in combination with surgery, resulted in a tumor-free survival time of 39 months. In cats, when the tumor invades outside the ear, surgery alone is unlikely to result to a long-term remission and radiation is usually required as an adjuvant treatment for better tumor control.

Squamous cell carcinoma of the ear canal and bulla tend to be more invasive, have a higher metastatic potential, and often compromise the adjacent brain tissue. Thus, the prognosis is significantly poorer than CGA, and these tumors should be thoroughly staged before the type of treatment is considered.

Pharyngeal, laryngeal, thyroid and other:

Common malignant tumors occurring in these areas include: Osteosarcoma, Chondrasarcoma, Undifferentiated carcinoma, Fibrosarcoma, Mast cell, Adenocarcinoma, Squamous cell carcinoma, Plasmacytoma and Lymphoma. Limited data is available on malignant tumors in these regions since few have been reported, but most do tend to be very invasive with significant metastatic behavior. Depending on the tumor type and its expected radiosensitivity (based on treatments at other sites), radiation may help control the tumor while preserving laryngeal function.

Radiation is expected to offer good control of Lymphoma and Plasmacytoma of laryngeal and/or tracheal involvement.

Oncocytoma (also called rhabdomyoma) is a rare benign tumor involving the larynx and usually occurs in the younger mature dog. These tumors are usually successfully resected surgically, have a good prognosis, and are potentially curable. No data is presently available regarding radiation therapy of non-resectable oncocytomas.

Malignant thyroid carcinomas are unfortunately not as responsive to radiation therapy as are benign adenomas. I¹³¹treatment for malignant tumors has been attempted but does not result to the same satisfying success rate achieved in the hyperthyroid cats with benign tumors. Malignant thyroid tumors are best approached with a combination of surgery followed by external beam radiation or I¹³¹radiation treatment and chemotherapy. Although radiation therapy has been attempted on this type of tumor, data is limited due to the small number of reports.

Long-term tumor control has been obtained with surgical resection of Thymomas. However, about 50% are not resectable. Although limited data is available, tumor remission has been reported following radiation therapy alone or combined with surgery (either before or after). When both modalities are used in combination, it is suggested that radiation be performed before surgery to avoid possibly increasing the amount of hypoxic cells created by surgery-induced tumor vasculature damage.

Mediastinal lymphoma refractory to chemotherapy has been treated with radiation therapy with variable results. Many go on to developing systemic signs shortly after treatment. However, while limited data exists, some cases of primary mediastinal lymphoma have responded well to radiation therapy on initial diagnosis with adjuvant chemotherapy for potential systemic disease.

Other thoracic tumors such as Chemodectomas, imcompletely resected Right atrial hemangiosarcomas, incompletely resected primary Lung tumors, and other heart base or mediastinal tumors have been approached with combination of surgery and radiation +/- chemotherapy. Data on treating these tumors is very limited and the decision to treat with radiation alone, or as part of a combination, should be based on a case-by-case basis using the basic principles of radiation oncology.

Abdominal and Perianal tumors:

Very little data is available on radiation therapy of bladder tumors. Transitional cell carcinomasof the bladder have been successfully treated with a combination of radiation and chemotherapy (+/- surgery) with a median survival time of almost 1 year.

As with bladder tumors, data on radiation therapy of Anal sac adenocarcinomas is scarce. They are, however, commonly treated with a combination of radiation and chemotherapy with a median survival time of over1 year. These tumors have a relatively high metastatic potential, with approximately 50% of patients first presenting with evidence of iliac/sublumbar lymphatic metastasis. Therefore, the sublumbar region is included in the radiation treatment field. Chemotherapy is also recommended as an adjuvant to treat metastatic disease even if not clinically evident.

Other Perianal tumors such as Perianal gland adenomas and adenocarcinomas, most often occurring in males, are best treated with surgical resection (aggressive when malignant). When good margins cannot be obtained on adenocarcinomas, radiation therapy is recommended. Regional lymph node metastasis is common. Some 50% are successfully surgically resected, but radiation therapy in combination with chemotherapy should result in a prolonged remission interval in non-resectable cases.

Prostatic tumors and Testicular tumors of retained testicles or lymphatic metastasis of either type can be treated with radiation therapy. Primary testicular tumors and testicular tumor lymphatic metastasis has been successfully treated with radiation therapy. The prognosis greatly depends on the extent of the local invasion and the degree of metastasis at presentation. Prostatic tumors, on the other hand, usually have a poor prognosis no matter what treatment modality is used. Approximately 70-80% already have advanced skeletal metastatic disease of the lumbar spine, sacrum and/or pelvis on presentation, or extensive local invasion of the urethra, bladder or colon. Radiation therapy has been attempted on occasion, however data is limited. For the most part, treatment of these cases are usually geared toward a palliative intent.

Osteosarcoma (OSA) is by far the most common primary bone tumor. Other primary bone tumors, such as Chondroma/chondrosarcoma, Hemangiosarcoma, Fibrosarcoma, and Multilobular osteochondrosarcoma (MLO, Chondroma rodens) may occur. A definitive diagnosis is not possible without a bone biopsy – but performing a biopsy risks causing a pathologic fracture at the biopsy site (because of the bone is so friable with tumor destruction). Thus, a final diagnosis is not always available. OSA tumors have a very high metastatic potential, and most patients already have microscopic pulmonary metastasis on presentation. Therefore, while radiation therapy is not usually curative and does not increase survival time, it is a very effective palliative treatment when surgery or amputation has been declined. Approximately 70% of these patients have a positive response to palliative radiotherapy. (Refer to handout subtitle Palliative radiation therapy for more detailed information.)

MLO generally occur on canine skulls and will often recur if not fully resected. Approximately 50% will metastasize (usually within the first year after treatment) and the median survival time is about 21 months. Although both chemo and radiation therapy have been administered to these patients, the exact role and efficiency of these adjuvant modalities are not yet well defined.

Feline osteosarcomas have a lower metastatic potential and, thus, a significantly better prognosis, compared to the same tumors in dogs. Median survival time in cats with osteosarcoma, with no evidence of metastatic disease, treated with amputation alone, is 2 years. Their better prognosis may make radiation therapy (not as a palliative approach) more reasonable in cases where complete surgical resection is not an option.

Multiple myeloma, Lymphoma of the bone marrow and bone metastases can be painful, and may be successfully managed with palliative treatment. As with primary bone tumors, radiation is not used to increase survival time but to control pain and offer local comfort in sites non-responsive to conservative medical treatment.

The prognosis of Synovial cell carcinoma is greatly dependent on the grade and stage of the tumor. Approximately 22 % have evident metastatic disease on presentation, and require chemotherapy. Grade III tumors (most malignant) are best treated with amputation +/- chemotherapy. When amputation is declined, aggressive local surgical resection followed by radiation therapy (+/- chemotherapy) is the most appropriate treatment. One reported isolated case, treated with surgery and radiation, showed no evidence of neoplastic disease 2 years after treatment (deceased from unrelated cause).

Spinal bone tumors (primary or secondary) have been treated with palliative radiotherapy – often on an emergency basis when they cause significant neurological signs and paralysis. Just as bone tumors of the limbs show a pain relief response to radiation, neurological improvement and pain relief has been observed as soon as a few hours to a few weeks following the initial radiation treatment of spinal bone tumors.

Normal lymphocytes are extremely radiosensitive. However, resistance to chemo and radiation therapy has also been noted. Little is reported regarding the response of Spinal lymphosarcoma to radiation. In one study one three cases of feline lymphosarcoma treated with chemotherapy and radiation therapy, two cats had a positive response to radiotherapy while one continued to deteriorate.

Tumors of the spinal nervous tissue – like brain tumors – generally respond to radiation in a similar fashion. When feasible, surgery combined with radiation should offer the best long-term prognosis. If both are combined as a treatment the total radiation dose is slightly decreased to reduce potential late complications. Therefore, these options need to be thoroughly discussed if initiating radiation before surgery.

Maxillary, mandibular, lingual, tonsilar and salivary glands.

Aggressive surgical excision, whenever feasible, usually yields the highest survival times and tumor control. Adequate surgical margins are often difficult to achieve in the oral cavity, so adjuvant radiation therapy is required for residual disease. Radiation therapy is effective for incompletely resected or for non-resectable oral tumors (either due to critical tissue involvement or due to declination of the procedure by the owners).

While Acanthomatous epulides do not metastasize, they are often locally aggressive and destructive; requiring an aggressive response. They are very responsive to radiation therapy either as a sole modality or as a complement to surgery. Median survival times of over 3 years have been reported (with an 85% 1 year survival rate).

Low-grade fibrosarcoma, nodular fascitis, invasive fibroma and granulation tissue. Be particularly cautious if one of the above is listed as originating from an oral or facial mass. There is a form of fibrosarcoma that behaves very aggressively while appearing very benign histologically. If this clinical behavior is noted, another histopathological opinion is recommended. An aggressive approach to these tumors is mandatory because they progress very quickly and are extremely locally invasive. Ideally, these are best approached with a combination of radiation followed by surgery.

Canine Squamous cell carcinomaSSC is best treated with a combination of radiation therapy, surgery and chemotherapy. A 1-2 year survival time has been achieved with radiation and surgery, while radiation alone had a median survival of approximately 16 months. Prognosis and tumor response depends on location (the most rostral lesions have a higher success rate than caudal lesions), which is also true for Lingual SCC.

Good tumor control is not as successfully achieved in Feline SCC as in canine SSC. The most aggressive approach combining radiation, surgery and chemotherapy yields the best results. Radiation alone, radiation plus chemotherapy, and surgery plus radiation do produce positive results but survival times are not as long as achieved in treating canine SCC.

Malignant melanomas do respond to radiation, but tend to respond better to fewer but larger doses. While local control is usually gained with radiation therapy, many of these cases metastasize and are best treated with radiation and some form of chemotherapy and/or immunotherapy. Unfortunately, an agent to systemically control this particular cancer has yet to be identified.

Normal lymphocytic cells are generally very radiosensitive. Radiation therapy is very effective in treating Focal lymphosarcoma and particularly effective as an emergency treatment of obstructive oral lymphoma of the tongue and pharyngeal region.

Mycosis fungoides is a cutaneous neoplastic process involving helper T-cells. A variation of mycosis fungoides limited to the oral cavity and mucocutaneous margins has been successfully treated with radiation therapy alone. In widespread cases involving both the oral cavity and multiple cutaneous sites, radiation therapy has successfully treated the oral cavity and certain painful cutaneous lesions that are non-responsive to chemotherapy.

Local recurrence of Salivary tumors commonly results within 6 months following surgery alone, suggesting the need for adjuvant therapy. Limited data is available regarding radiation therapy, but a report on three cases treated with radiation and surgery obtained tumor control durations of 12, 25 and 40 months. Chemotherapy should also be considered for metastatic disease.

(Meningiomas, pituitary macrotumors, other brain tumors and GME)

Meningiomas and pituitary tumors are generally more radioresponsive than other types of brain tumors.

The treatment of choice for Feline meningioma is surgery when feasible (depending on location). Radiation therapy is effective when surgical resection is not possible.

The treatment of choice for Canine meningioma is either a combination of surgery and radiation therapy, or radiotherapy alone.

Radiation therapy is an effective treatment of Pituitary macrotumors and has become the safest and most common treatment. The response and survival time is usually dependent on the severity of neurological signs.

While not a neoplastic process, some GME (granulomatous meningoencephalo-myelitis) cases unresponsive to cortico-steroids have responded well to irradiation.

Irradiation of other Intracranial tumors (most without a definite diagnosis) has significantly increased survival time compared to strictly medically-treated cases. Response to treatment is usually dependent on the severity of neurological signs (the more neurological impairment, the worse the prognosis).

Nasal tumors:

Nasal, paranasal sinuses, and nasal plenum

For the most part, studies on tumors of thenasal cavity and paranasal sinuses in canines have been grouped together. Aggressive surgery followed by orthovoltage therapy has produced the best survival times (median of approximately 23 months). When using megavoltage therapy, prior surgery decreases the success rate (mean and median survival of approximately 21 and 13 months respectively).

In a recent study, megavoltage therapy combined with (OPLA)-cisplatin (not yet available on the market) has increased survival times to a median of some 24 months.

In the cat, similar survival times have been achieved as found in the dog.

Little data is available on Solitary nasal lymphoma in dogs, due to the rarity of cases. Nasal lymphoma in cats is well documented and has been successfully treated with radiation therapy, with and without chemotherapy, resulting to a median survival time of approximately 2 years. A similar survival time was achieved in an isolated canine case treated with megavoltage radiation combined with (OPLA)-cisplatin.

Squamous cell carcinoma (SCC) of the nasal plenum in felines is most successfully treated with surgery (the use of radiation therapy depends on the tumor margins). Cases treated with radiation therapy alone have also responded well. The prognosis and disease-free interval depends largely on the clinical stage at the start of treatment.

Unfortunately, SCC of the nasal plenum in canines is more resistant to radiation therapy than SCC of the nasal cavity. Ultimately these tumors are best approached very aggressively with a combination of radiation, surgery and chemotherapy. They may be treated with aggressive surgery (+/- radiation depending on the margins) if found when still relatively superficial. Radiation alone does not appear promising.

Cutaneous and soft tissue tumors of the trunk and extremities:

Mycosis fungoides (see Oral Tumors)

Cutaneous and soft tissue tumors of the trunk and extremities are best approached in most situations by aggressive surgical resection. However, complete resection is not always possible because of location. This is particularly difficult when distal limbs are involved and the amount of normal skin to close the incision becomes limited. Adjuvant radiation therapy is an effective approach to treat the residual tumor cells.

Mast cell tumors and Soft tissue sarcomas (fibrosarcoma, hemangiopericytoma, malignant fibrous histiocytoma, Neurofibrosarcoma, myxosarcoma, malignant giant cell tumors etc) are the most common tumor types treated with a combination of surgery and radiation. A cooperative study published in the proceedings of Veterinary Cancer Society reported disease-free intervals of 2 – 5 years in 88% of patients with mast cell tumors (MCT) treated with surgery and radiation. A 5-year survival rate of up to 86% was reported in a study of soft tissue sarcomas (STS) treated with surgery and radiation at the Animal Medical Center, New York.

The histological grade of MCT has a great impact on prognosis and should always be obtained before considering radiation. Because MCT will most commonly metastasize to the local lymph nodes and abdominal organs, and less commonly to the lungs, an abdominal ultrasound and radiograph is more critical than a thoracic radiograph for the staging work up. Local lymph nodes should also be evaluated for staging as they are often included in the treatment field.

A grading system has not been well established for Soft tissue sarcomas and is therefore not yet a routine part of the histopathology report of most laboratories. However, it is important to recognize that undifferentiated and fast growing STS have a significantly higher metastatic potential, and adjuvant chemotherapy should be strongly recommended with a significantly more guarded prognosis.

The Vaccine-induced Feline sarcomas are more aggressive tumors with a higher metastatic potential than sarcomas unrelated to vaccination, and need to be approached very aggressively. Presently, the best treatment is radiation therapy administered FIRST combined with chemotherapy, then followed by aggressive surgery.

Squamous cell carcinoma (SCC) on the trunk and extremities in canines is most commonly treated with surgical resection and generally has a good prognosis. The histopathologic characteristics should be thoroughly determined for prognostic purposes and chemotherapy is recommended for poorly differentiated tumors. For incompletely resected tumors, radiation therapy of residual disease is recommended.

Many other Cutaneous tumors (basal cell, plasma cell, etc…) have been effectively treated with radiation when incompletely resected. Only limited published data is available because of their infrequent numbers. This is because many such tumors are successfully treated with surgery alone. Like all other cases, these should be approached individually with a thorough diagnostic and staging work up before determining the most appropriate treatment.

Like most benign tumors, Infiltrative lipomas should be approached first with aggressive surgical resection (many lipomas will recur if the resection is incomplete – as it may be when they occur in limbs and infiltrate around critical structures like vessels, nerves and tendons). Recurring lipomas have been effectively treated with radiation therapy when complete resection is impossible due to extensive infiltration.

Fractionation – which requires a higher total dose than single port protocols – allows for an increased repair capability of late responding tissues. This, in turn, results in greater tumor control, and different levels and types of radiation side effects.

Radiation side effects are generally categorized as acute and late. Acute effects are defined as those occurring during the course of radiation treatment or soon after the completion of treatment. Late effects only become clinically evident at least six months or more following the completion of treatment.

The greater tumor control created by fractionation creates in a beneficial decrease in late complications. However, fractionation can also slightly increase the severity of acute side effects. Despite this, the protocol is justified because early side effects tend to be reversible (if the damage to the cells is repairable). The damage caused by late side effects, however, tends to be permanent as it results from slowly to non-proliferating cell loss. Once these cells have died, the chance of replacement is virtually non-existent (this is especially important when irradiating critical tissues like the brain and spinal cord). For this reason, late effects are of more concern medically than early ones.

As a general rule, a prescribed treatment protocol should have no more than a 10% probability of inducing serious late complications for most tissues, and no more than a 5% probability of late complications for nervous tissue. Due to improved time-dose fractionation, computer treatment planning, and the use of megavoltage therapy, a serious complication rate of less than 5% exists in most veterinary radiation therapy today.

Repair: Radiation’s attack on cells appears to be primarily on the DNA level. Radiation damage to DNA can be described in a grossly simplified manner by limiting the discussion to two patterns: single strand breaks and double strand breaks. One single strand break is usually relatively easy to repair by the cell. Two, separate, single strand breaks are each similarly and individually repaired. However, the closer the two breaks are to one another, the more likely the chromosome or chromatid will break into two separate pieces, becoming a double strand break. A detached piece of chromosome or chromatid can either rejoin the strand in its normal position or in an incorrect one, leading to an aberration. Thus, double strand breaks are less likely to be correctly repaired and may result to lethal damage.

Sublethal damage usually refers to single strand breaks that can easily be repaired – as long as a second break does not occur too close by before repair is completed. When a small dose of radiation is administered, sublethal damage occurs in multiple areas in a cell. If the cell is not saturated by this damage, and has enough time to repair itself before cell division (or before the next radiation dose), the cell will survive.

Slowly proliferating cells are better able to repair sublethal damage, making them less susceptible to radiation cell death following a fractionated protocol. The time required for completion of the repair is a minimum of 6 hours for most tissues, but tissues from the nervous system usually require additional time. Although all cells will achieve a certain degree of repair during this interval, more slowly proliferating cells will survive than fast proliferating cells. Re-assortment: Cells have varying radio-sensitivities at different phases in their cycle. As a rule, cells tend to be most sensitive during mitosis and the G2 phase of their cycle, and most resistant during the S (synthesis) phase. During the interval between treatments, some cells in the resistant S-phase will cycle through to more sensitive phases, becoming more susceptible to cell death on the following treatment. Again, this is more likely to affect fast proliferating cells, resulting in an increased cell kill of the more rapidly dividing cells.

Re-population: Some cells survive mitosis between treatments and continue to multiply, making up for at least part of the radiation-induced cell loss. In this instance, the fast proliferating cells regain more cell population than the slowly proliferating cells, and the tissues they make up are more likely to survive. Since tumors generally consist of fast proliferating cells, the likelihood of tumor control is greatly decreased when the radiotherapy schedule is interrupted – and, thus, why such interruptions are strongly discouraged.

Re-oxygenation: Hypoxic tissues (those lacking oxygen) are more radio-resistant than
well-oxygenated ones. Tumor cells often have multiple areas of poorly oxygenated tissue due to a poor vascular system, and longer diffusion distances, causing tumor necrosis.

Radiation (ionizing photons) interacts with water molecules to form highly reactive free radicals that are responsible for breaking strong chemical bonds, most importantly in DNA, leading to eventual cellular destruction. It appears that oxygen “fixes” or secures the radical damage on the DNA, making it unrepairable. Therefore, the damage is less likely to be ‘fixed’ if the environment lacks oxygen, rendering cells in hypoxic areas more resistant to radiation. As the surrounding cell population decreases following cell death, hypoxic areas will re-oxygenate between doses in a fractionated course of treatment. This re-oxygenation causes some initially resistant cells to become more sensitive to the next dose administration, which may improve tumor control by decreasing the radio-resistance caused by hypoxia. Since normal tissues are generally well oxygenated, re-oxygenation does not affect their cells.