US Pharm. 2008;33(1)(Oncology suppl):5-8.

ABSTRACT: The frequency of bone cancer is very rare, with only 400 to 700 new cases diagnosed annually. Bone cancer may take three different forms: osteosarcoma, chondrosarcoma, and Ewing's sarcoma.1-3 Current treatment recommendations include high-dose methotrexate, cisplatin, ifosfamide, and doxorubicin in combination with surgery.2 Multiple regimens have been utilized for pre- and postoperative chemotherapy, along with trials evaluating high-dose or dose-intensive regimens. This article seeks to focus on the diagnosis, presentation, and treatment of osteosarcoma. In particular, this article will review recent literature evaluating the benefits of dose-intensive regimens.

Bone cancer is extremely rare, representing approximately 0.001% of all new cancers, with an annual diagnosis of 400 to 700 primary bone tumors in the United States.1-3 There are multiple forms of bone cancer, with the three most common being osteosarcoma (35%), chondrosarcoma (30%), and Ewing's sarcoma (16%).2 Chondrosarcoma, a malignant cartilage tumor, is most often found in older adults. It is generally considered a low-grade malignant tumor since metastasis is less frequent. Ewing's sarcoma, a malignant small-cell tumor, primarily affects children and adolescents. Osteosarcoma, the focus of this article, primarily affects children and adolescents but may also develop in elderly adults.3 Most patients with osteosarcoma are cured with the appropriate multimodality therapy.2,3

Pathophysiology

Osteosarcoma has a bimodal distribution. The first peak in incidence occurs in children and adolescents coinciding with rapid bone growth (i.e., growing spurts) and is considered a primary tumor. The second peak in incidence occurs in elderly adults and is considered a secondary tumor, which is most commonly associated with a history of radiation therapy. Osteosarcoma tumors consist of malignant mesenchyma, or spindle, cells and osteoclasts that produce immature bone, or osteoid.2,3 The malignant tissue grows in a radial manner to form a ball-like mass, which may be felt on physical examination. As the mass grows, it penetrates the bony cortex and compresses the surrounding muscle, creating the pseudocapsular reactive, zone-containing microscopic extensions, or satellites, of the main tumor mass. Although osteosarcoma can occur in any bone, the metaphyseal regions of the distal femur, proximal tibia, and proximal humerus are the most frequent regions affected. Osteosarcomas are typically classified as high-grade tumors due to their rapid growth and early metastasis.1,4 The tumor can metastasize regionally, to the same extremity, or systemically. The most common site of systemic metastasis is to the lungs.3

Clinical Presentation
Pain is the most common symptom upon presentation and may be accompanied by swelling. The pain, which may begin several months prior to presentation, is usually dull and/or achy.2,3 Patients may experience a sudden worsening of pain, causing them to seek medical attention; however, it is also common for patients to present after experiencing a trauma, but no cause and effect relationship for this has been demonstrated.

Diagnosis
Diagnosis of osteosarcoma requires a detailed patient history along with physical examination. Plain radiographic films of the suspected area are helpful in determining anatomic site, border or growth rate, visualization of bone destruction, matrix or new bone formation, and any periosteal reactions. 1,4 If initial radiographic films indicate an aggressive or malignant tumor, additional studies such as MRI, CT scans, bone scintigraphy, angiography, thallium scans, and PET scans should be performed prior to a biopsy.1 A core needle biopsy is the preferred method and should be performed at the site where definitive treatment will take place.2,4 Laboratory data are often unremarkable; however, elevated alkaline phosphatase and lactate dehydrogenase (LDH) have been reported to have prognostic significance.2,3

Staging

Staging of osteosarcoma is multifaceted and is typically performed upon diagnosis and again after induction, or pre-operative, chemotherapy. Presurgical staging systems are available via the Musculoskeletal Tumor Society (MSTS), American Joint Committee on Cancer (AJCC), and the International Union Against Cancer (Union Internationale Contre le Cancer [UICC]).1 The MSTS staging is based on the "GTM" classification scheme of grade (G), location (T), and lymph node involvement/metastases (M).1 By this system, grade is categorized as low or high. High-grade tumors are those with "a poorly defined reactive zone that may be invaded and destroyed by the tumor" and have nodules that are not continuous with the main tumor (skip metastases). To differentiate, low-grade tumors are not typically found to have skip metastases.1 Location of the tumor is either categorized as intra- or extracompartmental. Intracompartmental tumors are typically easier to characterize and have a lower likelihood of removal that does not require amputation.1 Due to the lack of lymphatic system throughout the bone, metastasis is rare; therefore, any metastasis is denoted as M1 and the absence of metastasis as M0. 1 Using the grade, location, and extent of metastasis, the MSTS system then stages the sarcoma. See TABLE 1 for a description of the MSTS staging system.



The AJCC and UICC systems are identical and utilize the same three categories as MSTS (grade, location, and presence of metastasis) and include a fourth category: nodal status (N), or lymph node involvement.1 In addition to including lymph node involvement, the AJCC system differs in that it considers lesion size, presence of skip metastases, and type of metastasis.1,2 Considering these four factors, the sarcoma is then staged. TABLE 2 provides a summary of the AJCC/UICC staging system.




It is common for cancer registries to apply the AJCC/UICC staging system; however, the MSTS system is most utilized among the majority of orthopedic oncologists.1 After induction chemotherapy, restaging of the sarcoma is typically performed utilizing the same studies (MRI, CT scan, etc.).1 The surgical procedure to remove the sarcoma is then categorized as intralesional, marginal, wide, or radical.1 An intralesional procedure is commonly done by curettage and may leave behind macroscopic disease.1 In a marginal procedure, the entire lesion is removed in one piece; however, skip metastasis may be missed.1 A wide, or intracompartmental, excision is a partial amputation that removes the entire lesion in addition to a small portion of normal tissue. Again, skip metastasis may be missed, particularly if the sarcoma is of high grade.1

Treatment

While surgery is a major component of the treatment for sarcomas, a full discussion of the advantages and disadvantages of limb-sparing surgery versus amputation are beyond the scope of this paper. For purposes of this paper, we will focus on recent clinical trials that have explored the use of dose-intensive regimens to treat nonmetastatic and metastatic disease.

Practice guidelines from the National Comprehensive Cancer Network (NCCN) state chemotherapy should include at least two of the following: doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate.2 There are a multitude of suggested regimens for pre- and postoperative use. The use of adjuvant chemotherapy was originally researched due to the extraordinary high recurrence rate of 80% to 90%.5 Evidence regarding the use of chemotherapy in addition to surgery was conflicting until two clinical trials performed in the 1980s.5 The results of these two trials, and multiple trials afterward, have established that the combination of chemotherapy and surgery improve disease-free and overall survival rates of >60%.5 A multitude of trials have studied various regimens with the four recommended therapies. A comprehensive review of osteosarcoma treatment by Ferguson and Goorin in 2001 concluded that "the optimal schedule of therapy is still being investigated, as is the role of dose intensification."5

As methotrexate is already recommended to be used at a high-dose for osteosarcoma, several trials have evaluated the effectiveness of various regimens that include high-dose ifosfamide.6-11 TABLE 3 outlines the various regimens used in the trials discussed below.




One of the earlier trials to evaluate high-dose ifosfamide did so in patients that were initially diagnosed with metastatic osteosarcoma. This trial combined high-dose ifosfamide with etoposide and granulocyte colony-stimulating factor (G-CSF). The combination of therapy was given twice over the course of six weeks to 41 patients. After the six weeks of therapy, patients underwent surgery, then received 34 weeks of continuation therapy. Sites of metastasis for these patients included pulmonary (n=28), bone (n=6), bone and pulmonary (n=6), and liver and pulmonary (n=1). Of the 39 patients evaluated for response, 59% had a complete or partial response to treatment. Overall survival was found to be 55% for two years. This regimen was associated with severe toxicities. While the majority of adverse effects were hematologic, several patients experienced a variety of infections (including sepsis), electrolyte imbalances, and congestive heart failure. Two patients expired during remission.6

Two recent trials by McTiernan et al. in 2006 and Le Deley et al. in 2007 evaluated the combination of ifosfamide and etoposide: one in metastatic disease and one in nonmetastatic disease.7, 8 The trial conducted by McTiernan included 13 patients with metastatic disease. Patients received a combination of ifosfamide, etoposide, and doxorubicin with interval doses of methotrexate. Patients were also given G-CSF. Of the seven patients with definitive pulmonary metastasis, three had either a complete or partial response to therapy (43%). Median survival was found to be 13 months (5-53+). As in the previous study, the most common adverse effects were hematologic.

The trial to evaluate the ifosfamide/etoposide combination in nonmetastatic disease was much larger: a total of 239 patients were enrolled. Patients were randomized to receive either doxorubicin and high-dose methotrexate or etoposide-ifosfamide and high-dose methotrexate. This study found that significantly more patients had a histologic response to therapy with the etoposide-ifosfamide regimen (P =0.009) compared to the standard treatment with doxorubicin. However, overall three-year survival rates were similar between the doxorubicin arm and the etoposide-ifosfamide arm (84% and 83%, respectively) and were found to be nonsignificant (HR=0.95, 95% CI: 0.6-1.6, P=0.85). Significantly more patients in the etoposide-ifosfamide arm experienced hematologic adverse effects than the doxorubicin arm (80% and 65%, respectively, P=0.01). Conversely, there were significantly more nonhematologic adverse effects, such as hepatotoxicity, in the doxorubicin arm (P=0.005).8

Survival rates for patients presenting with metastatic disease have been reported to be approximately 20% to 50%.1,5 For patients with nonmetastatic disease, survival rates are typically greater than 60%, with reports of different regimens reaching 80%.1, 5 The trials combining the use of etoposide and ifosfamide demonstrate similar survival rates for metastatic disease and may improve survival for those patients with nonmetastatic disease. However, further clinical trials are needed to support routine use of this combination.

Several trials have sought to examine the utility of high-dose ifosfamide in combination with doxorubicin, cisplatin, and high-dose methotrexate. One study group from Italy has evaluated this regimen multiple times in patients with and without metastasis. 9-11 One of the first trials that was conducted evaluated 68 patients with nonmetastatic disease. Fifty-six percent of patients were found to have a good histological response to chemotherapy.

The Italian study group additionally explored this therapy combination in 57 patients with metastatic disease. The authors report that they previously experienced overall survival rates of 53% in a small study of similar design.11 Sites of metastasis for this trial were largely only pulmonary. Few patients had bone metastasis (n=3), lung and bone (n=9), and lymph nodes (n=2). At the end of treatment, 63% of patients were disease free. Of note, the authors found that the site of metastasis played a significant role in the prognosis of the patient (P=0.003). A single site metastasis was shown to have a higher proportion of patients that were in a disease-free state after treatment. Overall two-year survival for all patients in the study was found to be 55%; for patients in remission, survival increased to 79%. Twenty-one percent of patients experienced severe hematologic adverse events, resulting in hospitalization for 4% of patients.11

Conclusion

Osteosarcoma is a complex diagnosis. With the combination of chemotherapy and surgery, prognosis and survival for patients has increased dramatically.1,5 As recommended by the NCCN, the mainstay of therapy should be a regimen that includes doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate.2

REFERENCES

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2. Practice guidelines in oncology ñ v.1.2007: bone cancer. National Comprehensive

Cancer Network, Inc. Available at: www.nccn.org/professionals/ physician_gls/default.asp. Accessed August 18, 2007.

3. Marina N, Gebhart M, Teot L, et al. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist . 2004;9:422-441.

4. Wittig JC, Bickels J, Priebat D, et al. Osteosarcoma: a multidisciplinary approach to diagnosis and treatment. Am Fam Physician. 2002;65:1123-1132,1135-1336.

5. Ferguson WS, Goorin AM. Current treatment of osteosarcoma. Cancer Invest. 2001;19:292-315.

6. Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol. 2002;20:426-433.

7. McTiernan A, Meyer T, Michelagnoli MP, et al. A phase I / II study of doxorubicin, ifosfamide, etoposide and interval methotrexate in patients with poor prognosis osteosarcoma. Pediatr Blood Cancer. 2006;46:345-350.

8. Le Deley MC, Guinebretiere JM, Gentet JC, et al. SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007;43:752-761.

9. Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high dose methotrexate, adriamycin, and cisplatin in the neoadjuvant treatment of extremity osteosarcoma. J Chemother. 2002:14;198-206.

10. Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian sarcoma groups. J Clin Oncol. 2005;23:8845-8852.

11. Bacci G, Briccoli A, Rocca M, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003;14:1126-1134.

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