Leading orthopedists fostered drastic changes in osteosarcoma treatment

Patients’ survival rates have more than doubled since the 1960s thanks to chemotherapy and limb-sparing surgical techniques.

During World War II, orthopedic surgeons attempting to treat patients with osteosarcomas often faced bleak prospects. Most of these patients required amputations, and many simply died after their amputation because their bone cancer could not be treated.

So much has changed in the last half-century, particularly with regard to keeping patients alive and saving their limbs, said Eugene R. Mindell, MD, in the department of orthopedic surgery at Buffalo General Hospital.

Mindell took an interest in musculoskeletal oncology starting with his medical training at the University of Chicago, where some of the most respected research in sarcoma treatment took place under the direction of C. Howard Hatcher, MD, Charles B. Huggins, MD, and Dallas B. Phemister, MD.

“The big problem we faced [in the first half of the 20th century] was why did so many of these patients die? Most of these patients were being treated with an amputation, and more than 80% of those patients died anyway,” Mindell told Orthopedics Today. “There weren’t a lot of good options back in those days.”

Nevertheless, orthopedic researchers forged ahead, investigating the benefits of various treatments. In the early 1950s, Phemister reported success treating osteosarcoma cases by local resection and autogenous bone reconstruction, following reviews of his own cases and those by other researchers. He also stressed the importance of diagnosing osteosarcoma and starting treatment early to improve the treatment odds.

Phemister, along with his university orthopedic colleague Hatcher, became early pioneers in limb-sparing surgery as a treatment for bone sarcoma. In turn, Hatcher gained recognition for his classification of bone tumors based on the tissue of origin, which is still used today.

The big turnaround

This patient had an osteosarcoma in the distal femur. This intraoperative image shows the implant in situ. Courtesy of Ernest U. Conrad

But it was not until the first paper on the benefits of chemotherapy for osteosarcoma appeared in 1972 (Cortes et al) that the field of sarcoma treatment suddenly got the boost it needed, said Mindell, who serves on the Orthopedics Today Editorial Advisory Board.

“When chemotherapy was introduced [for osteosarcoma], that’s when things changed completely,” he recalled. “The [researchers] showed that chemotherapy could shrink the size of the metastases and patients could live longer. The survival rate changed from less than 20% to around 70%. Instead of amputation, patients could now receive a limb-sparing operation. It became possible to save lives as well as limbs. That was the big turnaround.”

Further proof of that came in 1974, when Norman Jaffe, MD, an oncologist, treated patients with non-metastatic sarcomas, and the drugs acted on micrometastases while simultaneously shrinking the major bone tumor. As a result, “It made limb-sparing surgery a reasonable thing to do,” Mindell said.

In light of these new developments, orthopedic surgeons who were committed to improving the care of patients with osteosarcoma founded the Musculoskeletal Tumor Society (MTS) in 1977. The first meeting was in 1977 at Harvard University, organized by Henry Mankin, MD, and Hugh Watts, MD.

“The society was very excited in those days to help establish collaborative systems for treating these patients,” said Mindell, one of the co-founders of the MTS. “This multidisciplinary approach in which we work with oncologists, radiologists, nurses, psychologists, etc., addresses the various treatment issues these patients must face as part of their treatment.”

More support for the team

The team approach is at the heart of any successful osteosarcoma treatment team, said William F. Enneking, MD, distinguished service professor of orthopedic oncology at the University of Florida in Gainesville.

In the same patient, here is a close up of the bone graft junction site.

“The multidisciplinary concept is vital because you need so many different disciplines involved in the care of the patient,” Enneking said. “In our facility, we have an entire team that works together to support each other and approach the problem from different angles.”

The multidisciplinary approach grew even more popular over the last 25 years as better drugs and new surgical approaches surfaced, requiring disciplines to provide more unified treatment, he told Orthopedics Today. This approach also influenced the “stage” approach to treatment, whereby the surgeon and other members of the treatment team create treatment plans based on the stage of the bone sarcoma.

At Buffalo General Hospital, orthopedic surgeons rely on the oncologists for extra support in providing limb-sparing surgery, Mindell said.

“When a patient comes in with an osteosarcoma in the distal femur/upper tibia, for example, seeing that tumor is obvious, but what is not obvious are the metastases in the lungs,” he said. “That’s where the oncologist comes in. The chemotherapy will attack those micrometastases in the lungs and make the tumor smaller so that an orthopedic surgeon can do a limb-sparing operation. The chemotherapy will also help prevent local recurrence of the tumor.”

Limb-sparing tumor surgeries are most difficult in the pelvis and spine because of their proximity to the spinal cord and major organs. As a result, the overall outcomes may not be as good as those of similar surgeries performed on the extremities, Mindell said.

“The other part that is challenging from an orthopedic standpoint is to do an operation and use an oncologic reconstruction and have it last for decades,” he added. “Many of these patients are young — often teenagers — and they may wear out their oncologic reconstruction in 10 or 15 years, so we are constantly searching for better materials.”

What are the best reconstruction materials? “I think the metal and plastic reconstruction [implants] will continue to be used and improved in the future, and there will still be a place for allografts [that include] cadaver bone. There will always be new techniques for using them, too, as well as improved designs of oncological reconstructions.

“We are currently at a 70% to 75% survival rate at 10 years. That is better than 20%, which is what it used to be before chemotherapy, but we’re still looking at why we aren’t at 90%,” he said.

Pioneers in the field

Mindell cited several surgeons who introduced effective reconstruction methods for patients with osteosarcoma in the last 40 years, he said.

Mankin, from Harvard, used allografts extensively to reconstruct bone defects, and he continues to make great strides in that area, Mindell said. Austin T. Moore, MD, and colleagues reported a case in which they successfully treated a 46-year-old man with a recurrent giant cell tumor of his upper femur and a nonunion pathologic fracture by resection of his upper femur reconstructed with a vitallium proximal femur. Mindell said that many surgeons consider Moore’s surgery to be the first prosthetic reconstruction after skeletal tumor incision.

But perhaps no one had a larger influence on the reconstruction aspect of osteosarcoma treatment than British orthopedist Sir John Charnley, PhD, FRCS, who was “a true innovator for reconstruction after musculoskeletal tumor excision,” Mindell said. “He had a significant impact on the field of artificial joints, and many of our patients eventually need a hip or knee replacement, so you can see how his work has impacted the field.”

Ernest U. “Chappie” Conrad III, MD, FACS, orthopedic surgeon and founder of the Sarcoma Service at the University of Washington and Children’s Hospital in Seattle, said the future looks promising for osteosarcoma treatment.

“Limb salvage was the focus in the 1980s and ‘90s, which followed neoadjuvent chemotherapy, and both approaches significantly reduced the mortality rate of patients with these sarcomas,” he told Orthopedics Today. “The survival rate more than doubled during that time. Today, about 90% of the kids with an osteosarcoma get a limb-sparing surgery, and that has not jeopardized their overall survival. The local recurrence rate is approximately 7% in kids, and kids make up approximately two-thirds of the 1000 to 1500 new osteosarcoma cases each year. We expect the survival rates to continue improving in the near future.”

New questions, challenges

Orthopedic surgeons and musculoskeletal oncologists will face new clinical questions in the next decade, he said.

“Because two-thirds of our osteosarcoma patients are children, and because chemotherapy is successful at eliminating much of the tumor, we have this huge issue of what to put in their legs or hips,” he said. “Today, they either get a graft or an implant, but we are just now getting to understand the aspect of later complications, including implant loosening and infection. A child who has a tumor near the femoral shaft gets an allograft, but a child [with an osteosarcoma] near the knee joint gets a knee replacement. That’s our determining factor right now. The revision rates for these implants is 30% at 10 years, so for many of these kids, they’ll be looking at a revision in the near future.”

Conrad also feels that reconstructing “growth” in pediatric limb salvage patients is perhaps the biggest challenge.

Conrad, who trained with Enneking at the University of Florida, said finding substitute drugs for patients will also be a goal. Likewise, molecular science will play a larger role in future osteosarcoma treatment.

“We’re doing a lot of work in ‘metabolic imaging’ using PET (positron emission tomography) scans to study the tumor at the molecular level,” he said. These PET scans can provide valuable information on whether the tumor is responding to chemotherapy, as well as whether a particular patient’s tumor and condition would be best treated by chemotherapy.

“It can also tell us if an implant is loose, and in the future, we hope it can tell us whether or not there is an infection. Using this technology also reinforces the importance of regular follow-up to detect any changes over time,” he told Orthopedics Today.

Ultimately, the drastic improvements made in the care of these patients over the past few decades “has been a big success for orthopedic surgery, but we’re only halfway there. I believe that, in the near future, we can cut the revision rate in half with some changes in implant designs, how we cement, etc. I really believe that can happen,” Conrad said.

For more information:

• Cortes EP, Wang JW, Sinks L. Doxorubicin in disseminated osteosarcoma. JAMA. 1972;132-1138.
• Jaffe N, Frei E, Traggis D, Bishop Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med. 1974;291:994-1000.
• Mindell ER. Pioneers in musculoskeletal oncology: Musculoskeletal Tumor Society Founders Lecture. Clin Ortho and Rel Res. 2004;426:11-12.