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Fig. 1 AP radiograph (A) and coronal T1-weighted magnetic resonance image (B) demonstrating osteosarcoma in the distal femur. Postoperative photographs show resection specimen (C) and coronal view (D) of macrosection of distal femur osteosarcoma. E, Postoperative AP radiograph demonstrating reconstruction with intercalary allograft.
Courtesy of Richard M. Turek, MD, FACS Larger image (PDF)

AAOS Now

Published 8/1/2014
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Terry Stanton

Osteosarcoma: Future Strategies for Improving Survival

Researchers review findings in chemotherapy resistance and cancer “stem cells”

Osteosarcoma is problematic. Although it is the most common primary bone sarcoma, it has an incidence of only about 1,000 cases per year in the United States. Its relative rarity constricts the scope of clinical trials that can be conducted and directs researchers to other strategies in their quests to discover effective therapies.

Solid tumors present special challenges in terms of delivery of chemotherapy agents, and these challenges come into sharp focus in osteosarcoma, as demonstrated during a collaborative symposium of the Orthopaedic Research Society (ORS) and the Musculoskeletal Tumor Society.

The current state
According to Richard M. Terek, MD, FACS, of Brown University, osteosarcoma can occur in any bone, although it is most common in the distal femur (Fig. 1), proximal tibia, and proximal humerus. It is typically diagnosed in adolescents, who are experiencing pain and sometimes have a mass, usually around the knee. Radiographs may show a mixed lytic and blastic process involving the metaphysis of the distal femur.

Staging of osteosarcoma, Dr. Terek said, is based on grade, size of the primary tumor, compartmentalization, and presence of metastatic disease. Staging studies include the following:

  • a magnetic resonance imaging scan of the entire bone to evaluate for skip metastases
  • a chest computed tomography scan to evaluate for pulmonary metastases
  • a bone scan to evaluate for distant bone metastases

The diagnosis is made by a biopsy, which demonstrates malignant mesenchymal cells producing osteoid. About 15 percent of patients have metastatic disease detectable by staging studies, and 80 percent of those without detectable metastases actually have micrometastatic disease.

Typical treatment consists of an 8- to 10-week preoperative course of neoadjuvant, multiagent chemotherapy, designed to shrink the tumor; surgical resection; and postoperative adjuvant multiagent chemotherapy for 12 to 27 weeks to lower the risk of recurrence. The usual chemotherapeutic agents are high-dose methotrexate, cis-platin, doxorubicin, and ifosfamide used alone or in combination with carboplatin or etoposide. After the tumor is resected, the pathologist determines the amount of viable and necrotic tumor.

“A good response is more than 90 percent tumor necrosis, which is achieved in 60 percent of patients,” Dr. Terek said. “Although one study showed no difference in survival rates for patients who received neoadjuvant and adjuvant therapy and those who received adjuvant therapy only, neoadjuvant chemotherapy continues, because many clinical trials are based on changing the adjuvant chemotherapy for patients who are poor responders, with the hypothesis that alternative agents might be more effective than the standard agents. Unfortunately, substantially more effective alternatives have not been identified.”

Osteosarcoma is considered radioresistant, Dr. Terek said, but he noted that radiation is used for unresectable axial tumors, and proton beam radiation has been used with some success for local control.

Although amputation was traditionally used for local control, 90 percent of patients today can have limb-sparing surgery consisting of wide resection and reconstruction with rotationplasty, allograft, or an endoprosthesis. Local recurrence rates are 2 percent to 3 percent with amputation and 5 percent to 7 percent with limb salvage and are not statistically related to survival, Dr. Terek said.

Overall survival rates are 60 percent to 70 percent for nonmetastatic, extremity osteosarcoma, he said. “Survival is worse for axial lesions—spine and pelvis,” Dr. Terek said, “and metastases will recur in 30 percent to 40 percent of patients with localized osteosarcoma, with 90 percent of recurrences in the lung.” Most recurrences occur within the first 5 years after treatment.

“The sooner metastases develop after completion of treatment, the worse the prognosis,” he said. “About 25 percent of patients with systemic recurrence can be cured, but it requires the resection of all disease. The role of additional systemic treatment is questionable and the subject of ongoing studies.”

A variety of strategies has been tried with the initial therapy to improve survival, inlcuding dose intensification (higher dose or same total dose over a shorter period of time), adding more drugs to the “backbone of methotrexate, cis-platin, and doxorubicin,” and changing or adding drugs to the adjuvant treatment in poor responders.

The systems approach
“Chemotherapy resistance occurs due to circumstances at all organic levels,” explained John H. Healey, MD, FACS, of Memorial Sloan-Kettering Cancer Center. “Most work has focused on identifying and overcoming the cellular mechanisms of drug resistance, but recently the focus has shifted to the contributions of the local tissue, organ, and entire organism.”

He explained that chemoresistance or drug failure has several causes. “It may be something that prevents the initial action of the drugs. It may be something that directly or indirectly overcomes the actions of the drugs by taking a detour, using redundant pathways to get around the blockage,” he said. “Sometimes the drug may be very effective, but trigger an off-target outcome, such as increased metastasis. Or the patient may have toxicity issues that affect treatment in other ways.”

Dr. Healey espoused a “systems biology approach” that takes into consideration how the patient and the environment interact. “Keep in mind the organism, the organ, the tissue, and the cell,” he advised.

Addressing the special challenges involved with dealing with the dense mass of the osteosarcoma tumor, he noted, “There are no lymphatics to ‘mop up’ fluid. It’s a rigid, closed system, especially with its mineralized matrix. The vasculature is abnormal in number, shape, and orientation of vessels. Vessels are leaky and disorganized. There is a lack of connectivity with incomplete endothelial lining, blind vascular endings, and increased resistance to blood flow.”

The physical properties of the tumor have implications for drug delivery. “There are differences in tissue hydrostatic pressure and solid stress within the tumor,” he said. “The tumor acts like a compartment syndrome, generating central necrosis, with a peripheral gradient force metastasis. This induces gene expression differences in various parts of the tumor, which is partly why tumors mutate in different fashions, and reduces the effectiveness of chemotherapy. The solid cellular mass effect that the tumor creates compounds all of these effects.”

The vascular distribution within a tumor is significant, noted Dr. Healey. Some parts have intense areas of vascularity and perfusion while adjacent areas get nothing. However, this is not due to an abundance of vessels in some areas; blocked areas have just as many vessels, but the solid stress of the tumor bulk itself hampers perfusion, preventing drug delivery.

After treatment, the vessels repair, the number of tumor cells diminishes, and fluid flow is restored. Combined treatment is essential, he said, to improve vascularity, alleviate solid stress, and optimize perfusion and drug delivery.

The microenvironment also affects distribution of drug and antibodies in tissues. “Pressure affects sensitivity to common chemotherapy agents,” he said. “The surrounding cells, such as monocytes, have an influence. Small molecules—10 nanometers (nm) or less—as in conventional chemotherapy have a low binding affinity and distribute in the tumors by diffusion. The larger the molecule, the less diffusion. Antibodies—7.5 nm to 15 nm—are large enough to severely alter distribution, particularly if they are sticking to something, which is what antibodies are designed to do. They don’t disseminate at all.

“The hydrostatic pressure in a tumor also alters the chemotherapy activity,” he continued. He noted the success of using dipalmitoyl phosphoethanolamine to activate monocytes and macrophages in some clinical trials. “It works by changing the activity of these cells within the microenvironment effectively.” However, it is not approved yet in the United States.

Going “inside the cell,” he said, mechanisms that are important in drug resistance include reduced folate carrier, and the multidrug resistance gene manifesting through P-glycoprotein, one for drug delivery and the other for drug
retention.

In summary, said Dr. Healey, “Our current dilemma is that because there are so few patients (fewer than a thousand), we have lots of possibilities but we can’t deal with this in clinical trials. It takes too long. Models—natural animal models, cell lines, and patient-derived xenograft models—are needed.”

Osteosarcoma stem cells
Addressing the intriguing but elusive possibility of cancer stem or stemlike cells in osteosarcoma was C. Parker Gibbs, Jr, MD, of the University of Florida. In stem cell biology, the concept of self-renewal and asymmetric division comes into play, said Dr. Gibbs.

“The cancer stem cell (CSC) theory holds that within a tumor, a subpopulation of cells has the ability to self-renew like normal stem cells,” Dr. Gibbs said. “During tumor growth, CSCs are thought to divide asymmetrically, producing not only an identical daughter cell but a more differentiated cell that, with further divisions, generates most of the tumor bulk, which is essentially benign. The stemlike tumor-initiating cell is considered to be responsible for initiating and maintaining the growth of the tumor.”

This subpopulation of cells within the tumor establishes a functional heterogeneity, so that all cells do not behave in the same way. “These cells are then responsible for driving the malignant phenotype as well as initiating tumorigenesis. They may be therapy-resistant and they may be responsible for recurrence and metastasis, which is why we are so interested in them,” he explained.

Because osteosarcomas most often occur around active growth plates, they may be good candidates for verifying the existence of cancer stem cells. If the existence of such cells can be confirmed, it could lead to an improved understanding of how they work, and subsequently to advances in therapies for osteosarcoma and other cancers.

Disclosure information: Dr. Terek—Clinical Orthopaedics and Related Research (CORR); Musculoskeletal Tumor Society; Rhode Island Orthopaedic Society; New England Orthopaedic Society; Lippincott Williams & Wilkins. Dr. Healey—CORR; Journal of Bone and Joint Surgery (JBJS); Association of Bone and Joint Surgeons; Musculoskeletal Tumor Society; ORS; Orthopaedic Research and Education Foundation; Musculoskeletal Transplant Foundation; AAOS. Dr. Gibbs—JBJS; Orthopedics.

Terry Stanton is a senior science writer for AAOS Now. He can be reached at tstanton@aaos.org

Bottom Line

  • Osteosarcoma is rare—with an incidence of 1,000 new U.S. cases annually—hindering the scope of clinical research.
  • Response to therapy varies from poor to good, leading to an overall survival rate of about 70 percent.
  • A systems approach to chemotherapy resistance focuses on the cell, the tissue, the organ, and the environment; accounts for the physics of the tumor mass; and examines all the factors preventing effective and complete drug delivery.
    The theory of the cancer stem cell may lead to a better understanding of what drives the malignant phenotype and what causes tumorigenesis, as well as why such a cell is therapy-resistant and how it is responsible for recurrence and metastasis.