Multimodality approach to soft tissue sarcomas in dogs and cats (Proceedings)

Canine soft tissue sarcomas

Soft tissue sarcomas comprise 7% and 15% of all skin and subcutaneous tumors in cats and dogs, respectively. The annual incidence of soft tissue sarcomas in companion animals is approximately 17 per 100,000 cats and 35 per 100,000 dogs. In dogs, sarcomas have been associated with radiation, trauma, foreign bodies, orthopedic implants, and the parasite Spirocerca lupi.

Soft tissue sarcomas are a heterogeneous group of tumors whose classification is based on similar pathologic appearance and clinical behavior. Sarcomas arise from mesenchymal tissues and have features similar to the cell type of origin. These tumors originate in connective tissues, including muscle, adipose, neurovascular, fascial and fibrous tissue, and can give rise to benign and malignant entities. Typical soft tissue sarcomas, all of which have a similar biologic behaviour, include fibrosarcoma, peripheral nerve sheath tumor (PNST, also known as malignant schwannoma, neurofibrosarcoma, or hemangiopericytoma), myxosarcoma, undifferentiated sarcoma, liposarcoma, histiocytic sarcoma (or malignant fibrous histiocytoma), and rhabdomyosarcoma.

Diagnosis

Fine-needle aspirates are recommended to exclude other differentials, for example abscesses, cysts, or mast cell tumors. However, cytologic evaluation of fine-needle aspirates is usually not sufficient for definitive diagnosis of soft tissue sarcomas as false-negative results are relatively common because of difficulties in differentiating reactive fibrous tissue from benign and malignant sarcomas, Biopsy methods for definitive preoperative diagnosis of soft tissue sarcomas include needle-core, punch, incisional, or excisional biopsies. The biopsy should be planned and positioned so that the biopsy tract can be included in the curative-intent treatment, whether it be surgery and/or radiation therapy, without increasing the surgical dose or size of the radiation field. Excisional biopsies are not recommended as they are rarely curative and the subsequent surgery required to achieve complete histologic margins is often more aggressive than surgery following core or incisional biopsies resulting in additional morbidity and treatment costs. Furthermore, multiple attempts at resection, including excisional biopsy, prior to definitive therapy has a negative impact on survival time in dogs with soft tissue sarcomas.

Clinical staging

Local tumor

Imaging studies of the local tumor may be required for planning of the surgical approach or radiation therapy if the tumor is fixed to underlying structures or located in an area which may make definitive treatment difficult, such as the pelvic region. Three-dimensional imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI) scans, are particularly useful for staging local disease

Regional lymph node and distant metastasis

Diagnostic tests for staging of metastatic disease should include thoracic radiographs, abdominal ultrasonography or advanced imaging, and fine-needle aspirates or biopsy of the regional lymph nodes. Three-view thoracic radiographs should be performed prior to definitive treatment as the lungs are the most common metastatic site for typical soft tissue sarcomas. Lymph node metastasis is uncommon with typical soft tissue sarcomas. Abdominal imaging is recommended for assessment of metastasis to intra-abdominal organs

Treatment

Surgery

Soft tissue sarcomas are locally aggressive tumors which grow along paths of least resistance and invade surrounding tissue resulting in the formation of a pseudocapsule of compressed viable tumor cells. The pseudocapsule gives the false impression of a well-encapsulated tumor. However, surgical removal of the encapsulated mass without adequate margins will result in incomplete resection and a high risk of local tumor recurrence. The minimum recommended margins for surgical resection are 3 cm lateral to the tumor and one fascial layer deep to the tumor.

The resected tumor should be pinned out to the original dimensions to prevent shrinkage during formalin fixation, the lateral and deep margins should be inked to aide in histologic identification of surgical margins, and any areas of concern should be tagged with suture material, inked in a different color, or submitted separately for specific histologic assessment. Surgical margins and tumor grade are important in determining the need and type of further treatment. For instance, local tumor recurrence is 11-times more likely after incomplete excision of a soft tissue sarcoma compared to complete surgical resection.

Following incomplete excision, the entire surgical wound is contaminated and considered neoplastic. Wide resection of the surgical scar should be performed with the same margins recommended for a primary soft tissue sarcoma, 3 cm lateral to the tumor and one fascial layer deep to the tumor. This is often difficult because normal tissue architecture has been destroyed by the initial surgery resulting in more aggressive subsequent surgeries, increased patient morbidity and treatment costs, increased risk of further local tumor recurrences, and decreased survival time.

Staging resections are a relatively new concept being used for the management of incompletely resected soft tissue sarcomas and mast cell tumors. Staging resections are a decision-making surgery. Unpublished research has shown that up to 40% of incompletely resected soft tissue sarcomas have no evidence of neoplastic cells following subsequent surgical resection. The reason for this finding is unknown. Staging surgical resections, which involve resection of the surgical scar with 5-10 mm margins, have minimal wound tension and postoperative morbidity because the surgery is not aggressive. Following staging resection, wide surgical resection or radiation therapy should be used to manage the wound if there is evidence of residual tumor. If there is no evidence of residual tumor, then no further local treatment is required and the dog should be managed appropriately depending on clinical stage and histologic grade.

Surgery and radiation therapy

Radiation therapy can be used as an adjunct to surgery following either planned marginal resection or unplanned incomplete resection. Marginal surgical resection combined with full-course postoperative radiation therapy is an attractive alternative to limb amputation for soft tissue sarcomas of the extremities

This multimodality approach requires additional planning but preserves the limb and limb function. Surgery involves complete removal of all grossly visible tumor and then marking the lateral, proximal, and distal extents of the surgical field with radiopaque clips to assist in planning of radiation therapy. Migration of the radiopaque clips has been reported but does not significantly influence the planned radiation field.

Radiation therapy

The use of radiotherapy alone as a single modality treatment is not recommended because of poor rates of tumor response and long-term control. Measurable and palpable soft tissue sarcomas are resistant to long-term control with conventional doses of irradiation alone (40-48 Gy). Although one study reported a 30% complete response rate with radiation therapy alone, these tumors do not rapidly regress after radiation, or if there is significant tumor shrinkage, it is not a durable response. One-year tumor control rates of 50% are reported with cumulative doses of 50 Gy, and this decreased to 33% at 2 years. As a single modality, radiotherapy is generally considered palliative with control defined as a slowly regressing or stable-in-size tumor mass. 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. In one study the overall median survival time for incompletely resected non-oral soft tissue sarcomas treated with postoperative radiation therapy is 2,270 days with 2-, 4-, and 5-year survival rates of 87%, 81%, and 76%, respectively.

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. Preoperative radiation is not utilized in every clinical situation. 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. There is currently widespread use of treatment planning computers, allowing two- and three-dimensional visualization of the dose within the entire patient based on CT or MRI imaging. However, it is the information provided by the referring veterinarian that provides the most valuable planning information especially if surgery has already been performed.

Chemotherapy

The role of chemotherapy in the management of dogs with soft tissue sarcoma is unknown. The metastatic rate for cutaneous soft tissue sarcoma is grade-dependent and varies from less than 15% for grade I and II soft tissue sarcoma to 41% for grade III soft tissue sarcoma. Metastasis often occurs late in the course of disease, with a median time to metastasis of 365 days, and this may minimize the beneficial effects of postoperative chemotherapy on the development of metastatic disease. However, there are clinical situations in which postoperative chemotherapy should be considered, including dogs with grade III soft tissue sarcoma, metastatic disease, intra-abdominal soft tissue sarcoma (e.g., leiomyosarcoma and splenic sarcoma), and histologic subtypes with a higher rate of metastasis, such as histiocytic sarcoma, hypodermal hemangiosarcoma (stage II or III), synovial cell sarcoma, rhabdomyosarcoma, and lymphangiosarcoma.

Doxorubicin-based protocols, either alone or in combination with cyclophosphamide, have shown the most promise in dogs with soft tissue sarcoma with an overall response rate of 23%. Mitoxantrone, a chemotherapeutic drug related to doxorubicin, has a variable effect against soft tissue sarcoma in dogs in phase II trials with response rate varying from 0% in six dogs to 33% in 12 dogs. Ifosfamide has also shown some potential with a complete response rate of 15% in 13 dogs with solid sarcomas of the skin, bladder, and spleen. Doxorubicin and ifosfamide are the most effective single agents in the management of soft tissue sarcoma in humans, but response rates are less than 30% and meta-analyses show single- and multiple-agent chemotherapy protocols do not significantly increase overall survival times compared to surgery alone. Recently low dose oral metronomic chemotherapy showed some promise for high grade disease in an incomplete margin setting but it is too soon to know if this is of real clinical value

Feline vaccine-associated sarcomas

Vaccine-associated sarcomas are relatively common in North America, but less common in other regions. These sarcomas are believed to be associated with the administration of certain vaccines, but have also been reported with other injections such as microchips and luferon. The development of soft tissue sarcoma at sites of vaccine administration of FeLV or rabies is believed by some to be as high as 1/1,000. Vaccine-associated sarcomas are comparably more prevalent than fibrosarcomas at non-vaccine sites, with the latter accounting for 20/100,000 cases.

There are significant differences between vaccine-associated sarcomas and non-vaccine-associated sarcomas. Vaccine-associated sarcomas have histologic features consistent with a more aggressive biologic behavior than non-vaccine-associated sarcoma, such as marked nuclear and cellular pleomorphism, increased tumor necrosis, high mitotic activity, and the presence of a peripheral inflammatory cell infiltrate consisting of lymphocytes and macrophages.

Treatment

Surgery

Vaccine-associated sarcomas are poorly encapsulated tumors with extension and infiltration along fascial planes. Marginal resection or excisional biopsy should not be attempted. The median disease-free interval and survival time are significantly decreased with marginal resection, increased number of surgical interventions, and surgery performed by non-referral surgeons. The median time to first recurrence following marginal resection is 79 days compared to 325-419 days for wide resection or radical surgery

Similar to dogs with soft tissue sarcomas, biopsy tracts and any areas of fixation, including bone and fascia, should be resected en bloc with the tumor. In cats with vaccine-associated sarcoma, wide surgical resection of tumors located in the interscapular region will often involve excision of dorsal spinous processes and perhaps the dorsal aspect of the scapula for tumors, while thoracic and/or body wall resection is often required for truncal tumors. Amputation or hemipelvectomy are usually required to achieve adequate surgical margins and local tumor control for vaccine-associated sarcoma located on the extremity.

Local tumor control is still disappointing with curative-intent surgery. Despite attempting aggressive surgical margins, complete resection is achieved in less than 50% of cats. Median disease-free interval and survival time are both greater than 16 months following complete histologic resection and significantly better than incompletely resected tumors.

Surgery and radiation therapy

In two studies investigating preoperative radiation therapy, local tumor recurrence was reported in 40%-45% of cats at a median of 398-584 days postoperatively. In both studies, complete resection significantly improved the time to local recurrence with a 700-986 day median disease-free interval for completely excised tumors and 112-292 day median disease-free interval for tumors resected with incomplete margins. However, despite the prolonged interval to local tumor recurrence, complete resection following preoperative radiation therapy does not appear to improve local control rates as local tumor recurrence was reported in 42% of 59 cats with complete margins and 32% of 33 cats with incomplete margins.

The outcome following postoperative radiation therapy is similar to preoperative radiation therapy. In one study, local tumor recurrence was reported in 41% of 76 cats at a median of 405 days postoperatively. In another study investigating the effects of chemotherapy in cats treated with surgery and postoperative radiation therapy, local tumor recurrence occurred 28% of 25 cats with median time to first recurrence not reached in cats treated with surgery and radiation therapy alone and 661 days in cats also treated with doxorubicin. Local tumor control is still disappointing with 28%-45% of tumors recurring following treatment with surgery and radiation therapy.

Chemotherapy

The role of chemotherapy in the management of cats with vaccine-associated sarcoma remains undefined. Metastasis has been reported in 12%-26% of cats with vaccine-associated sarcomas, despite the aggressive histologic appearance and prevalence of high-grade lesions in these tumors, with a median time to metastasis of 265 days. Clinically, partial and complete responses to doxorubicin, either alone or in combination with cyclophosphamide, have been reported in 39%-50% of cats with gross tumors, but these responses are often short-lived with a median duration of 84-125 days. However, median survival times are significantly prolonged in cats that respond to chemotherapy with 242 days for responders and 83 days for non-responders. Recently, an overall response rate of 41% was reported in cats treated with ifosfamide and these responses persisted for a median of 70 days.

Postoperative chemotherapy has minimal impact on survival in cats treated with curative-intent surgery and radiation therapy. Chemotherapy may, however, have beneficial effects on local tumor control and time to local tumor recurrence. Doxorubicin and liposome-encapsulated doxorubicin significantly prolongs the disease-free interval following surgery, with a median disease-free interval of 393 days for cats receiving chemotherapy and 93 days for those in which chemotherapy was not administered. The completeness of surgical margins may be a confounding factor in this analysis as the median disease-free interval was not reached and greater than 449 days in cats with complete surgical margins compared to 281 days following incomplete resection. Carboplatin was associated with an insignificant but numerically superior median disease-free interval of greater than 986 days in cats treated with preoperative radiation therapy and surgery. Other studies have shown no effect of adjunctive chemotherapy on either local tumor control or survival time.

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