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Advancements in Veterinary Radiation Oncology and Commonly Irradiated Tumors

dr-lynsday-kubicekby Lyndsay Kubicek, DVM DACVR (Radiation Oncology)
oncology@angell.org
angell.org/oncology
617-541-5136

 

Early publications by Austrian veterinarian Alois Pommer in 1958 describe the use of radiation therapy in veterinary medicine1. Many advances in technology have occurred since 1958, both involving radiation delivery and imaging. Alongside our technologic changes, our understanding of medical physics, radiation and molecular biology of cancers have drastically improved. Present day treatments have the fundamental goal of delivering a tumorical dose of radiation therapy while sparing the adjacent normal tissues.

More than half of treatment protocols for human cancer patients will include radiation therapy2.  The need for multimodal cancer treatment does not stop with human patients, and the benefits of complimentary treatments are evident in our veterinary population when looking for disease control and potential cure. The option of radiation therapy is becoming increasingly available in veterinary hospitals throughout the world3. Clients are becoming more aware of what treatments are offered in human medicine and the demand for translational treatments with radiotherapy for pets with cancer is increasing.

With the advances in diagnostic imaging and computerized treatment planning, radiation oncology has made massive strides in designing state-of-the-art treatment plans. These developments along with technological improvements of the radiation delivery units have allowed for delivery of higher conformal doses while sparing critical normal structures.

The diagnostic imaging advancements in clinical veterinary radiation oncology include the use of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) for both tumor imaging and radiation treatment planning.  The integration of newer imaging modalities has led to the use of three-dimensional conformal radiation therapy (3D-CRT) for treatment planning. Newer technologies in treatment planning and delivery are being used in numerous veterinary oncology services including inverse-treatment planning, intensity modulated radiation therapy (IMRT), stereotactic radiation therapy (SRT), dynamic-adaptive radiation therapy (DART) or planned adaptive technology, and image guided radiation therapy (IGRT).

In order to reap the potential benefits of more precise planning, we must be able to perform well-executed delivery of a prescribed radiation dose. The two key factors here are immobilization and on board imaging to verify patient position. Immobilization that is reproducible is the key; there is no sense in an elaborate setup that cannot be reproduced, or leaves room for error. To aid in the immobilization, general anesthesia is needed. Various devices are used to position the patient into an easily reproducible position. Such devices include dental molds and bite blocks (see picture 1), vac-lock mattresses, troughs, thermoplastic facemasks, rectal balloons and urinary catheters.

Picture 1. A canine patient in a bite block system.

Picture 1. A canine patient in a bite block system.

Three-dimensional conformal radiation therapy is a sophisticated type of external beam treatment planning used for radiation treatment. Computers calculate a three-dimensional virtual model of the tumor volume. The information from that virtual model is then used to plan the radiation treatments. During 3D-CRT, multiple beams of radiation will conform to the tumor’s size and shape, limiting exposure to nearby tissue and organs. 3D-CRT is designed to give a high dose of radiation to a targeted area while limiting side effects to healthy tissues. This form of delivery does not incorporate IMRT however.

Intensity modulated radiation therapy is an advanced form of high-precision radiation therapy that refers to the modulation (adjustment) of the intensity of the radiation beams across the treatment field with the aid of a multileaf collimator (MLC) system moving in and out of the beams. They are computer-controlled devices that use up to 120 movable “leaves” to conform the radiation beam to the shape of the tumor from any angle, while protecting normal adjacent tissue as much as possible. MLCs allow the dose of radiation to vary within a single beam. The radiation dose intensity is elevated near the tumor volume while radiation among the neighboring normal tissue is decreased or avoided completely. The customized radiation dose is intended to maximize tumor dose while simultaneously protecting the surrounding normal tissue. IMRT also improves the ability to conform the treatment volume to concave tumor shapes, for example when a tumor is wrapped around a vulnerable structure such as the spinal cord or a major organ or blood vessel. The ability to vary the radiation dose with MLCs is accomplished by delivering different doses to many subfields (beamlets) or using variable width “sliding windows” of radiation beams across the target volume. The net effect is that radiation doses can be “wrapped” around tumors, or “painted” within tumors, far more precisely than was previously possible.

Stereotactic radiation uses highly conformal and focused irradiation beams directed precisely at a target and is typically delivered over 1-5 closely scheduled doses. SRT can be delivered with a linear accelerator based system or using multiple Cobalt-60 beams focused at a point. There is a different biology associated with stereotactic radiation compared to fractionated radiation, in that sparing normal tissue is accomplished by avoidance of normal tissue structures, not by delivering smaller doses of fractions over a course of therapy (fractionation).

Dynamic-adaptive radiation therapy (DART) or planned adaptive therapy is the ability to make day-to-day changes to a radiation plan quickly while the patient is being treated. This technology is needed when drastic changes to a tumor or normal shape occur during therapy with the goal to minimize normal tissue radiation exposure.

Image guided radiation therapy uses images of the patient at the time of treatment to determine the accuracy of setup so that corrections can be made in real time before the treatment is delivered. By verifying the actual location of the tumor target and relying less on an external landmark, we are more likely to deliver the necessary dose to sterilize the disease and avoid inadvertently delivering dose to adjacent critical structures. Image-guided radiation therapy can also be used for adaptive modifications based on changes in tumor size and shape, thus IGRT is the basis when dynamic adaptive radiation therapy is employed.

What types of tumors do we treat?

Each veterinary oncology patient must be evaluated locally and systemically (staging) to best practice individualized medicine. Radiation therapy can be used as a stand-alone therapy or in conjunction with other therapies such as surgery and chemotherapy. Consultation with a veterinary oncologist is the first step in designing such a tailored protocol. For the discussion of the article, we will go through the most common tumors where radiation is utilized.

Oral tumors:

Most oral tumors are locally invasive which require aggressive surgery with wide margins. The complex anatomy of the oral cavity renders this approach very difficult. A combined approach of surgery and radiation therapy has shown improved local control rates for oral tumors4-6. Most of the canine oral tumors are responsive to radiation therapy; the epulides, melanoma, fibrosarcomas and squamous cell carcinoma (SCC). Feline SCC has proven to be a poor responder to radiation therapy delivered in various fractionation schemes7,8.

Nasal tumors:

Again, the anatomy proves challenging for surgical interventions with nasal tumors, with studies showing no benefit to survival time with surgery alone9-14. Chemotherapy studies are lacking for the sole treatment of nasal tumors. Radiation therapy is the primary treatment modality for canine and feline nasal tumors. Most nasal tumors are radioresponsive with histologic types and subtypes being prognostic. In general, palliative or curative intent radiation therapy can improve the quality of life in this patient population. Two recent publications of curative intent protocols have shown survival times of 446 and 420 days respectively15,16.  With the newer technologies such as IMRT at Angell Animal Medical Center, the side effects associated with the irradiation of the sino-nasal cavity is very well tolerated with mild side effects.

Brain, pituitary and spinal cord:

Brain tumors can be successfully treated with radiation therapy, and histologies do play a role in prognosis although the data with treatment and histologic samples is lacking and most treatments are based on imaging diagnosis alone. The highest survival times are reported when a combination of surgery and radiation are used together17. However, not all tumors are amendable to surgical reduction and radiation as a sole therapy has shown good responses and survival times.  One study of 46 dogs with neurologic signs were treated with radiation alone and had a median survival time of 23.3 months18. Stereotactic radiation therapy has been evaluated in one study for canine brain tumors and has shown similar results to full course radiation therapy19.

Canine and feline pituitary tumors are also responsive to radiation therapy. Radiation therapy for canine pituitary tumors associated with hyperadrenocorticism has shown improvement in neurologic status and can aid in controlling hormone secretion. Feline pituitary tumors associated with acromegaly, hyperadrenocorticism, and insulin-resistant diabetes have shown marked improvement in terms of controlling endocrinopathies.

Overall there is limited information on the results of dogs and cats treated for spinal tumors, however there are smaller studies that we can draw some information from. Treatment of meningiomas with surgery and radiation therapy can result in a fair to excellent prognosis20. Another study showed that surgical cytoreduction and radiotherapy are effective at improving survival in dogs with spinal cord nephroblastoma21. A small report for dogs with spinal lymphoma showed long term control of greater than a year.

Thyroid and thymoma:Both thyroid carcinoma and thymomas are responsive to radiation therapy and are typically treated if surgery is not an option. Both have reported survival times with radiation alone for greater than 1 year22, 23.

Mast cell tumor:

Radiation therapy can be used for local therapy of mast cell tumors following cytoreductive surgery, or in a gross disease setting. In a study of 37 dogs with incompletely excised grade 2 mast cell tumors treated with radiation therapy had tumor control at 1 and 2 years that exceeded 90% 24. In another study of 57 dogs with incompletely resected mast cell tumors, the median disease-free interval was 32.7 months25. Radiation can also be used when regional lymph nodes are involved; a study of 19 dogs with surgical reduction of the primary mass, followed by radiation to the primary and metastatic lymph node and prednisone had a median disease free survival time of 1240 days26. In the gross disease setting, 17 dogs were treated with a palliative fractionated radiation protocol combined with Palladia and had a median progression free interval of 316 days27.

Soft tissue sarcoma:

Soft tissue sarcomas are a group of tumors with similar biologic behavior, in that local control is the primary concern with low and intermediate grade tumors. This group includes hemangiopericytomas, fibrosarcomas, neurofibrosarcomas, myxosarcomas, and nerve sheath tumors. Radiation can be used in the pre or post-operative setting. Soft tissue sarcomas incompletely excised not followed up with radiation therapy have a local recurrence rates of 17-40%28-33. By comparison, one study of 48 dogs with soft tissue sarcomas treated with surgery and radiation had a local recurrence rate of 16% and a 5-year survival of 78%34.

Injection site sarcoma:

Injection site sarcomas in cats (previously called vaccine associated sarcomas) pose a challenge for local control due to high recurrence rates following surgery or radiation therapy alone. Local tumor control is frustrating with 28-45% local recurrence rates following surgery and radiation therapy35-39.  Like soft tissue sarcomas, the role of pre or postoperative radiation therapy is controversial, however we do know that the combination offers better control. The median survival times associated with the combination therapy have been reported to range from 600 to 1300 days35-37, 39.

Osteosarcoma:

Radiation is primarily used in a palliative setting when amputation is not an option for patients with appendicular osteosarcoma. Pain relief is seen in 80-100% of cases and median survival times have been reported between 4-6 months40-43.

Bladder and prostate:

A recent study of dogs with primary disease of the urinary bladder, urethra or prostate were treated with full course intensity modulated radiation therapy (IMRT) in additional to other treatments such as chemotherapy or non-steroidal anti-inflammatory drugs and had a progression free interval of approximately 300 days and survival time of 654 days. Side effects were very mild and treatment was well tolerated44.

Perianal adenocarcinoma and anal sac adenocarcinomas:

Both can be challenging to obtain good local control with surgery alone and there is a high likelihood of spread to local lymph nodes. Radiation is used to control local recurrence and treat regional lymph nodes. Survival times are reported at 544 days with radiation, surgery and chemotherapy for aporcine gland anal sac adenocarcinoma45. Protocols are typically longer when treatingthis region to lower the risks of late term side effects. Overall with IMRT we are able to reduce such side effects.

Lymphoma:

Lymphoma is extremely radiosensitive and responds very quickly. Radiation is very useful for localized lymphoma such as nasal, brain and spine, retrobulbar, mediastinal, mandible, maxilla, and subcutaneous tissues. Reports show a response rate of greater than 80% and median remission for cats with complete responses to be 114 weeks46. Radiation therapy has also been used to treat cutaneous and mucocutaneous lymphoma of dogs with prolonged remission times47, 48.

If you have a patient who may benefit from radiation treatment, please feel free to contact the Angell Oncology Service with questions (617 541-5136 or e-mail oncology@angell.org).

Chart 1

Abbreviations:

  • CT computed tomogram
  • CTV clinical target volume
  • DART dynamic-adaptive radiation therapy
  • GTV gross tumor volume
  • FRT fractionated radiation therapy
  • IGRT image-guided radiation therapy
  • IMRT intensity-modulated radiation therapy
  • kV-CBCT kilovoltage cone-beam CT
  • MRI magnetic resonance imaging
  • MLC multileaf collimator
  • PTV planning target volume
  • PET positron emission tomography
  • RT radiation therapy
  • SCC squamous cell carcinoma
  • SRT stereotactic radiation therapy
  • 3D-CRT three-dimensional conformal radiation therapy

 

Chart 2

Clinical Radiation therapy:

  • Very Radiosensitive
    • Round cells
    • Epulides
  • Radiosensitive-moderate radiosensitive
    • Nasal tumors
    • Soft tissue sarcomas
    • Brain tumors
    • Urogenital tumors
    • Thyroid tumors
    • Anal sac tumors
    • Oral tumors
    • +/- Osteosarcoma
  • Poorly radiosensitive
    • Feline SCC

 

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