Nonsurgical Treatment for Bone Cancer

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By Morgan Stanfield

Osteosarcoma, the most common primary bone cancer, strikes about 900 people per year in the United States, 400 of them children. According to the American Cancer Society, its five-year survival rate is only 60-65 percent, and in the three years after initial treatment, 50-75 percent will have at least one recurrence. The first-line treatment for osteosarcoma is removal of the entire cancerous area, its replacement with a cadaver-bone or metal implant when possible, and chemotherapy. Sometimes the surgical resection (removal) is preceded and followed by radiotherapy (radiation treatment), which can provide pain relief and treat microscopic tumors but can also be associated with adverse radiation effects to the skin and healthy tissue and weaken healthy bone to the point of fracturing.

Ironically, osteosarcoma is also the most common bone cancer among our closest nonhuman companions, dogs and cats. According to Steven Withrow, DVM, it is ten times more common in dogs than in humans, disproportionately striking the large and giant breeds--Dobermans, Rottweilers, greyhounds, great Danes, and Irish wolfhounds. The irony is bittersweet, however, because the disease's prevalence among pets, especially dogs, has led to some of the most important advances in its treatment for humans.

Since the 1980s, veterinary oncologists at the Animal Cancer Center at Colorado State University (CSU), Fort Collins, have been pioneering treatments and discoveries that have saved hundreds of human lives and limbs. In the 1980s, they developed groundbreaking limb-sparing techniques. In 2004, they developed a system for implantable, slow-release chemotherapy. In 2005, they discovered that post-osteosarcoma-surgery infections actually stimulate the immune system to attack osteosarcoma cells, resulting in longer survival times. And this year, they are embarking on canine studies of a radiotherapy technique that could potentially lead to an effective, non-surgical limb-sparing technique for both humans and their animal companions.

Why a New Method?

Currently, complete surgical resection of the cancerous bone via amputation or limb-salvage surgery, plus chemotherapy, sometimes preceded and followed by radiation, is the best available treatment for people with osteosarcoma. According to cancer.gov, at least 80 percent of patients treated with surgery alone will experience metastases, and chemotherapy alone is considered ineffective. Radiotherapy alone is useful only for pain relief in unresectable tumors or, combined with resection and chemotherapy, for killing microscopic tumor cells. However, resection inevitably brings a high risk of complications, particularly in children. Infection, rejection of grafts, and complications with metal implants are common problems that often lead to further surgeries and, in some cases, amputations. Children who receive metal implants also need to have the implants replaced as they grow in order to avoid uneven limbs, gait problems, disfigurement, and pain. Resection of facial and pelvic osteosarcomas are particularly troublesome, with a 30-percent higher risk of complications and metastases.

The Trilogy Stereotactic
System Linear Accelerator

The Varian Trilogy Stereotactic System Linear Accelerator.
The Varian Trilogy Stereotactic System Linear Accelerator.

Osteosarcoma has traditionally been considered relatively resistant to the effects of radiation therapy. In 2002, CSU veterinary researchers attempted curative radiotherapy on osteosarcoma in dogs using fractionated radiotherapy--radiotherapy in which small radiation doses are given daily, spread out over three to four weeks. The attempt failed. Not only did the tumors continue to grow, there were serious bone-fracture and skin complications. For the time being, the less-than-ideal conventional therapies were re-proven as the best available. Then, in 2004, University of Florida, Miami, researcher James Farese, DVM, DAVCS, and his colleagues published a paper in the Journal of the American Veterinary Medicine Association (JAVMA) that outlined their success in treating osteosarcoma in dogs through stereotactic radiosurgery-radiation therapy produced by a linear accelerator that targets the tumor in three-dimensional space, using multiple, overlapping radiation beams to send highly concentrated radiation directly into the tumor while delivering minimal dosage to surrounding tissues. The dogs experienced good local tumor control, durable pain reduction, high tumor-necrosis rates, and survival times comparable to conventional therapies. While the canine patients still experienced higher than desirable fracture rates, the treatment showed promise. In later work, with more refined dosing techniques and patient selection, the rates of fractures were reduced.

The results were so promising that the team of researchers at the CSU Animal Cancer Center decided to initiate its own studies of stereotactic radiotherapy. According to Stewart Ryan, BVSC, MS, Dip. CVM, the CSU Animal Cancer Center purchased in 2007 the most advanced linear accelerator in the world, the Trilogy© Stereotactic System, produced by Varian Medical Systems, Palo Alto, California. One of only 1520 Varian Trilogy systems in the United States, the $3 million machine looks like a prop from the Star Trek medical deck, with a sleek gray body and electronics-packed head and arms surrounding an integrated, motorized patient couch. Ryan, a soft-spoken native of Australia, told The O&P EDGE , "A unique advantage of this machine is that is has on-board imaging capabilities, including diagnostic-quality kilovoltage peak (kVp) x-ray imaging and a cone-beam CT, as well as mega-voltage radiation for portal radiography used by traditional linear accelerators. The ability to accurately image the patient at each treatment session is key to ensuring correct positioning and safe delivery of the radiation dose." The Trilogy machine can sculpt the radiation beam based on the computer-enhanced, three-dimensional diagnostic images, which means that the Trilogy can work with tumors of almost any size and complexity of shape. Previous-generation machines, such as the Leksell Gamma Knife©, Elekta AB, Stockholm, Sweden, are designed for intracranial tumors and don't efficiently handle tumors of odd sizes and shapes. The Gamma Knife is limited to a treatment area just 3cm across and, according to Ryan, "tends to like a spherical-shaped tumor."

Targeted Dosages

The Trilogy's imaging capabilities are just part of its power. Ryan says, "Its real advantage comes with the treatment planning software. The Varian Trilogy has an inverse planning system' that allows us to identify structures within the treatment field. Then we can assign a maximum radiation dose, a range of radiation, or a minimum dose to each structure. The software then...comes up with the optimal algorithm and number of treatment beams to achieve delivery of a maximum dose to the tumor volume and a limited dose to the surrounding normal tissue structures. Once the optimal treatment plan is reviewed, the algorithm and images are integrated into the Trilogy's on-board guidance system. Small adjustments are made with the patient on the couch to perfectly align the patient's tumor with the radiation beams by comparing the treatment planning images and the treatment session images." Then, the Trilogy sends multiple, overlapping beams of killer radiation into the tumor with accuracy down to two millimeters or less, barely affecting the surrounding tissue.

Shaping the Radiation

How does the Trilogy concentrate the radiation? "The Varian has what's called multileaf collimators, lead shields that we can use to attenuate the radiation beams," Ryan explains, "so that the shape of the beams is made according to the three-dimensional imagining.... We can conform the radiation so that it's very tight to the tumor." A typical dosage from the Trilogy is eight to ten times greater than with typical radiotherapy, but it spares the patient the two most prohibitive side effects of high-dose radiation-fractures in previously healthy bone, and tissue burns, particularly on the skin. Doses this high that don't damage surrounding tissue could lead to Ryan's goal for this technology. He told The O&P EDGE, "Part of developing this technology is that we're aiming to see if we can develop it as a nonsurgical limb-salvage option," one that can kill tumors in a wide variety of anatomical locations while preventing amputations, dangerous infections, and unnecessary surgeries.

Saving Human Limbs and Lives

Ryan and his colleagues are veterinarians, and in November they began two studies of the Trilogy's effectiveness at treating osteosarcoma in dogs. However, Ryan says, "The big potential impact is in the potential translational research aspect. We will be helping our canine patients, and our ultimate goal will be to introduce this into human clinical practice as a possible nonsurgical limb-salvage option. At the very least, this treatment modality may decrease the number and intensity of neoadjuvant [presurgical] chemotherapy treatments in kids, and get them to limb-salvage surgery much sooner."

Ryan and his colleagues can't estimate a time frame in which this technology might translate into clinical trials, but the U.S. Food and Drug Administration (FDA) has previously given special early approval to experimental bone cancer treatments, citing "immediate humanitarian need," and the American Society of Clinical Oncology says that more than 60 percent of children treated for osteosarcoma are part of a clinical trial. The CSU researchers regularly collaborate with Ross Wilkins, MD, founder of the Denver Clinic for Extremities at Risk, Colorado. Wilkins has used techniques developed at CSU for more than ten years on his human patients. He told CBS News that he justifies the use of a veterinary procedure on a human patient because major problems require major or valiant solutions. Thanks to the work of CSU researchers like Ryan and his colleagues, the Trilogy may be treating humans within just a few years.

Morgan Stanfield can be reached at morgan@opedge.com