Historical perspective on the introduction and use of chemotherapy for the treatment of osteosarcoma.

Chemotherapy for treatment of osteosarcoma was demonstrated to be effective in eradicating primary tumor and pulmonary metastases in the mid-twentieth century. The first agents that held promise were doxorubicin and high-dose methotrexate with leucovorin (citrovorin factor) in the mid-1970s. Since then, other agents that can eliminate or cause regression of tumor have been discovered: cis-diamminedichloroplatinum II (cisplatin) and the oxazaphosphorines ifosfamide and cyclophosphamide. Additional agents await further study to define their potential. The effective agents have been utilized in various combination regimens and have escalated the survival rate from <10 to 75 %. They have also enabled pulmonary metastectomy in patients with persistent and/or recurrent pulmonary metastases and tumor ablation and limb salvage in 80 % of newly diagnosed patients. Unfortunately, however, despite these impressive advances no change in survival expectancy of patients with osteosarcoma during the past 40 years has occurred. There have been no new chemotherapeutic agents effective in addressing disease that is resistant to current agents; the few that have been introduced await further study to substantiate their efficacy. This also includes attempts at alternate administration of chemotherapy (intra-arterial and inhalation therapy.) In this chapter, we provide an account of the sequential introduction of the chemotherapeutic agents, review the results of their application in selected regimens, and discuss the role of neoadjuvant chemotherapy.

Sociooccupational and physical outcomes more than 20 years after the diagnosis of osteosarcoma in children and adolescents: limb salvage versus amputation.

BACKGROUND: To the best of the authors' knowledge, there has been relatively little research published to date regarding very long-term survivors of childhood and adolescent osteosarcoma. In the current study, the authors compared the very long-term survival outcomes of patients with osteosarcoma who were treated with either limb salvage procedures or amputation. METHODS: A total of 38 patients with osteosarcoma who survived ≥ 20 years from the time of diagnosis were divided into 2 groups according to whether they underwent amputation or limb salvage. Participants were asked to complete a questionnaire concerning their education, employment, annual income, marital status, health insurance, lifestyle, siblings, and all current and past health issues. RESULTS: Education, employment, marital status, and health insurance were not found to differ significantly between the 2 groups of survivors, who described themselves as being similar to their siblings. Eight percent of survivors underwent secondary amputation because of complications with an endoprosthesis. The cumulative incidence of second primary neoplasms was 13%, and this finding was significantly higher in females and in survivors who underwent radiotherapy and had a genetic predisposition. The second primary malignancies were breast cancer (ductal invasive carcinoma, ductal in situ carcinoma, and leiomyosarcoma), mediastinal leiomyosarcoma, and squamocellular carcinoma of the oral cavity and the uterine cervix. Amputees required more assistive walking support than survivors who received limb salvage treatment (P<.05, chi-square test). CONCLUSIONS: Despite the many challenges that osteosarcoma survivors face, patients who survived ≥ 20 years after their initial diagnosis reported having overall adjusted well to their physical limitations and were productive individuals.

Osteosarcoma: evolution of treatment paradigms.

This paper reviews the contribution of chemotherapy in the conquest of osteosarcoma. It discusses how the treatment of osteosarcoma has evolved over the last five decades, resulting in a more than fivefold increase in survival. Though the initial improvements in survival were dramatic, essentially there has been no change in the outlook for this disease over the past 30 years. The paper also highlights the necessity of a multidisciplinary approach to combat this disease and stresses the need to explore newer treatment agents in order to build on the lessons learnt from the past while striving to achieve greater levels of success.

Comparison of doxorubicin cardiotoxicity in pediatric sarcoma patients when given with dexrazoxane versus as continuous infusion.

Doxorubicin is an effective agent for many malignancies. To limit cardiotoxicity, doxorubicin can be given as prolonged infusion (PIDX) or bolus infusion following dexrazoxane (DZX). The authors report their institutional experience comparing PIDX and DZX in a sarcoma cohort. Retrospective record review for newly diagnosed sarcoma patients at the University of Texas M.D. Anderson Cancer Center from June 1998 to June 2006. There were 23 Ewing's sarcoma (EWS) patients treated with DZX and 40 osteosarcoma (OS) patients treated with PIDX. The DZX group had higher mean cumulative anthracycline dose (510 mg/m(2) [SD 120 mg/m(2)] versus 414 mg/m(2) [SD 99 mg/m(2)], P = .002), however mean lowest left ventricular ejection fraction (EF) values were higher for DZX (52.5% [SD 5.6%] versus 47.2% [SD 10.9%], P = .014). Fifteen of 19 patients with cardiac dysfunction were PIDX patients (P = .15). Five PIDX patients required cardiac medication, and 1 patient died of congestive heart failure (CHF). Sixteen patients with cardiac dysfunction had improvement, demonstrated by EF ≥ 50% at last echocardiogram. Although not statistically significant, there were 4 DZX patients with cardiac dysfunction. Prospective studies are required to determine which strategy has long-term advantages and if certain patients are at increased risk for cardiac dysfunction.

Psychosocial and functional outcomes in long-term survivors of osteosarcoma: a comparison of limb-salvage surgery and amputation.

BACKGROUND: Traditionally, physicians have believed that limb-salvage surgery has functional and cosmetic advantages over amputation, yet the literature is equivocal. Therefore, we sought to compare the psychosocial and functional outcomes in osteosarcoma survivors after limb-salvage surgery and amputation. We hypothesized there to be neither psychosocial nor functional outcome differences between groups. PROCEDURE: Participants received treatment of extremity osteosarcoma, had received their cancer diagnosis at least 2 years prior, and were at least 16 years old. A comprehensive set of validated psychosocial and functional measures was used to assess outcome. RESULTS: Fifty-seven patients participated in this study (33 who underwent limb-salvage surgery and 24 who underwent amputation). Participants had gone 12-24 years since diagnosis and were 16-52 years old at study participation. We used multiple linear regression models to examine differences in quality of life, body image, self-esteem, and social support between the two groups and found no differences. Lower limb function was a significant predictor of quality of life (P < 0.001), whereas surgery type did not impact this relationship. Body image was rated significantly worse by those who underwent late amputation, amputation after failed limb salvage, than by those who did not. CONCLUSIONS: Participants with more functional lower limbs had better quality of life than did those with less functional lower limbs regardless of whether they underwent amputation or limb-salvage surgery.

The epidemiology of osteosarcoma.

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons. Among childhood cancers, osteosarcoma occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). The incidence rates of childhood and adolescent osteosarcoma with 95% confidence intervals areas follows: Blacks, 6.8/year/million; Hispanics, 6.5/year/million; and Caucasians, 4.6/year/million. Osteosarcoma has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood. The first peak is in the 10-14-year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second osteosarcoma peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget's disease. The incidence of osteosarcoma has always been considered to be higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites (4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur (42%, with 75% of tumors in the distal femur), the tibia (19%, with 80% of tumors in the proximal tibia), and the humerus (10%, with 90% of tumors in the proximal humerus). Other likely locations are the skull or jaw (8%) and the pelvis (8%). Cancer deaths due to bone and joint malignant neoplasms represent 8.9% of all childhood and adolescent cancer deaths. Death rates for osteosarcoma have been declining by about 1.3% per year. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference. The age of the patient is correlated with the survival, with the poorest survival among older patients. Complete surgical excision is important to ensure an optimum outcome. Tumor staging, presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome.

The etiology of osteosarcoma.

Studies to determine the etiology of osteosarcoma involve epidemiologic and environmental factors and genetic impairments. Factors related to patient characteristics include age, gender, ethnicity, growth and height, genetic and familial factors, and preexisting bone abnormalities. Rapidly proliferating cells may be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Genetic aberrations that accompany osteosarcoma have received increasing recognition as an important factor in its etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of complexity which has made it difficult to determine whether any recurrent chromosomal aberrations characterize osteosarcoma. Although extremely rare, osteosarcoma has occasionally been observed in several members of the same family. No other clinical abnormalities in the proband or the affected members were reported. Pathologic examination of the tumors revealed no unusual features. Genetic testing was not available in most of these reports. The patients generally responded to conventional therapy. A genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma, characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. The Rothmund-Thomson syndrome is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash, small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and gastrointestinal disturbance including chronic emesis and diarrhea; its molecular basis is the mutation in the RECQL4 gene in a subset of cases. The Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a high risk of developing osteosarcoma and has been found in up to 3% of children with osteosarcoma. It is associated with a germline mutation of the p53, a suppressor gene. The following three criteria must be met for a diagnosis of Li-Fraumeni syndrome: (1) A proband diagnosed with sarcoma when younger than 45 years; (2) A first-degree relative with any cancer diagnosed when younger than 45 years; (3) Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age. A second recessive p53 oncogene on chromosome 17p13.1 may also play a role in the development and progression of osteosarcoma. Osteosarcoma has also been associated with solitary or multiple osteochondroma, solitary enchondroma or enchondromatosis (Ollier's disease), multiple hereditary exostoses, fibrous dysplasia, chronic osteomyelitis, sites of bone infarcts, sites of metallic prostheses and sites of prior internal fixation. Ionizing radiation is a well-documented etiologic factor. Osteosarcoma has also been associated with the use of intravenous radium and Thorotrast. Exposure to alkylating agents may also contribute to its development ,and it is apparently independent of the administration of radiotherapy.

Osteosarcoma multidisciplinary approach to the management from the pathologist's perspective.

Osteosarcoma is a primary malignant tumor of the bone in which proliferating neoplastic cells produce osteoid and/or bone, if only in small amounts. This histological principle defines a tumor that usually affects young males more frequently than females, and disproportionately involves the long bones of the appendicular skeleton. These tumors are generally locally aggressive and tend to produce early, lethal systemic metastases. However, osteosarcoma is not a single disease but a family of neoplasms, sharing the single histological finding of osseous matrix production in association with malignant cells. The majority (i.e., 75%) of cases are relatively stereotypical from the demographic, clinical, radiographic and histologic points of view. These tumors generally occur in the metaphyseal portion of the medullary cavity of the long bone and are referred to as "Conventional Osteosarcoma." The group is sub classified by the form of the dominant matrix present within the tumor, which may be bone, cartilage or fibrous tissue, and it is correspondingly referred to as osteoblastic, chondroblastic and fibroblastic osteosarcoma. The remaining 25% of cases have unique parameters that allow reproducible identification of tumors which are biologically different from conventional osteosarcoma and are referred to as "Variants." The parameters identifying Variants fall into one of three major groups: (1) clinical factors, (2) histologic findings and (3) location of origin--within or on the cortex. Because of their inherent biological difference from Conventional Osteosarcoma, the Variants identify cases which must be excluded from analysis of data pertaining to the treatment of the majority of cases: Conventional Osteosarcoma. The diagnostic parameters of osteosarcoma must be sufficiently inclusive to identify all the members of this potentially lethal tumor. Conversely, criteria for sub classification must be restricted to assure homogenous populations of tumors productively incorporating different biological behavior and the potential for development of unique treatment strategies which are different from those for Conventional Osteosarcoma. This can be designated "Classification Based Therapy" or "Therapy Based Osteosarcoma." With this background, we will discuss the highly disciplined approach to the management of osteosarcoma from the pathologist's perspective. Factors governing the assessment of the response to preoperative chemotherapy will also be reviewed.

Conditions that mimic osteosarcoma.

A variety of conditions may mimic osteosarcoma. The differential diagnosis includes benign and malignant tumors, infection and inflammatory processes arising from the musculoskeletal system. An accurate clinical history, imaging studies, and pathological evaluation are essential to establish the exact diagnosis. This chapter describes many of the conditions which may mimic the diagnosis of osteosarcoma. For convenience, the conditions are divided into several categories.

Osteosarcoma: review of the past, impact on the future. The American experience.

Major advances have been achieved in the treatment of osteosarcoma with the discovery of several chemotherapeutic agents that were active in the disease. These agents comprise high-dose methotrexate with leucovorin rescue, Adriamycin, cisplatin, ifosfamide and cyclophosphamide. The agents were integrated into various regimens and administered in an effort to destroy silent pulmonary micrometastases which are considered to be present in at least 80% of patients at the time of diagnosis. Their efficacy in achieving this goal was realized and their use was further extended to the application of preoperative (neoadjuvant) chemotherapy to destroy the primary tumor and achieve safe surgical resections. Disease free survival was escalated from <20% prior to the introduction of effective chemotherapy to 55-75% and overall survival to 85%. Further, the opportunity to perform limb salvage was expanded to 80% of patients. Of interest also was an attempt in one series to treat the primary tumor exclusively with chemotherapy, and abrogation of surgery. Adding to these advances, varieties of subsequently discovered agents are currently undergoing investigations in patients who have relapsed and/or failed conventional therapy. The agents include Gemcitabine, Docetaxel, novel antifolate compounds, and a liposome formulation of adriamycin (Doxil). A biological agent, muramyl tripeptide phosphatidyl ethanolamine (MTPPE) was also recently investigated in a 2x2 factorial design to determine its efficacy in combination with chemotherapy (methotrexate, cisplatin, Adriamycin and ifosfamide).In circumstances where the tumor was considered inoperable, chemotherapy and radiotherapy were advocated for local control. High dose methotrexate, Adriamycin and cisplatin and Gemcitabine interact with radiation therapy and potentiate its therapeutic effect. This combination is also particularly useful in palliation. Occasionally, the combination of radiation and chemotherapy may render a tumor suitable for surgical ablation. Samarium153, a radio active agent, is also used as palliative therapy for bone metastases.However, despite the advances achieved with the multidisciplinary application of chemotherapy, radiotherapy and surgical ablation of the primary tumor over the past 3(1/2) decades, the improved cure rate reported initially has not altered. Particularly vexing is the problem of rescuing patients who develop pulmonary metastases after receiving seemingly effective multidisciplinary treatment. Approximately 15-25% of such patients only are rendered free of disease with the reintroduction of chemotherapy and resection of metastases. Extrapulmonary metastases and multifocal osteosarcoma also constitute a major problem. The arsenal of available agents to treat such patients has not made any substantial impact in improving their survival. New chemotherapeutic agents are urgently required to improve treatment and outcome. Additional strategies to be considered are targeted tumor therapy, anti tumor angiogenesis, biotherapy and therapy based upon molecular profiles. This communication outlines sequential discoveries in the chemotherapeutic research of osteosarcoma in the United States of America. It also describes the principles regulating the therapeutic application of the regimens and considers the impact of their results on the conduct in the design of future investigations and treatment.

Functional, psychosocial and professional outcomes in long-term survivors of lower-extremity osteosarcomas: amputation versus limb salvage.

As the number of osteosarcoma survivors increases, the impact of quality of life and function needs to be addressed. Limb salvage is the preferred treatment when patients have treatment options; yet, the questionable long-term durability and complications of prostheses, combined with ambiguous function, leave some doubt regarding the best clinical and surgical options. Comparisons between limb salvage patients, amputees and controls also require further investigation. Amputation would leave the patients with a lifelong requirement for an external prosthetic leg associated with an overall limited walking distance. While artificial limbs are much more sophisticated than those used in the past, phantom limb sensations remain a substantial and unpredictable problem in the amputee. Complications such as stump overgrowth, bleeding, and infection, also require further elucidation. Limb salvage surgery using endoprosthesis, allografts or reconstruction is performed in approximately 85% of patients affected by osteosarcoma located in the middle and/or distal femur. One drawback in limb-salvage surgery in the long-term survivor is that endoprostheses have a limited life span with long-term prosthetic failure. The inherent high rate of reoperation remains a serious problem. Replacing a damaged, infected or severely worn-out arthroplastic joint or its intramedullary stem is difficult, especially in the long-stem cemented endoprostheses used in the 1980s. Limb lengthening procedures in patients who have not reached maturity must also be addressed. Periprosthetic infections, compared to other indications for joint reconstruction, were found to be more frequent in patients treated for neoplastic conditions and their outcome can be devastating, resulting in total loss of joint function, amputation, and systemic complications. Quality of life in terms of function, psychological outcome and endpoint achievements such as marriage and employment apparently do not differ significantly between amputee and nonamputee osteosarcoma survivors. Amputee patients nonetheless appear to have made satisfactory adjustments to their deficits with or without a functional external prosthesis. It also appeared that amputee patients had a similar psychological and quality of life outcome as limb salvage patients. There was no evidence of excessive anxiety or depression or deficits in self-esteem compared with the normal population or matched controls. A number of long-term survivors also achieved high ranking in the professional and commercial work place. These positive aspects should be recognized and emphasized to patients and their parents when discussing the outcome.

Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma.

BACKGROUND: Local recurrence in Ewing sarcoma is associated with a poor prognosis. The purpose of the study was to determine the factors that predict local recurrence after surgical treatment of the primary tumor. METHODS: Between 1990 and 2001, 64 patients underwent surgical resection of Ewing sarcoma. Surgical margins were assessed histologically and radiologically. Response to preoperative chemotherapy was determined by detailed specimen mapping. Local recurrence-free survival (LRFS) was calculated by Kaplan-Meier analysis. Multivariate analysis was performed with the Cox proportional hazards model. RESULTS: A number of factors were found to be associated with local recurrence on univariate analysis. Patients with a good response to chemotherapy (> or = 90% tumor necrosis), had superior LRFS at 5 years (86% vs 51%, P = .015). Central site of disease was associated with an increased rate of recurrence. The LRFS at 5 years was 50% for the chest wall, 74% for pelvic/scapular, and 86% for extremity tumors (P = .083). Positive surgical margin was not a strong predictor of recurrence (P = .72). A critical analysis of minimal surgical margin based on preoperative magnetic resonance imaging (MRI) and computed tomography (CT) scans also failed to reveal an association between margin and local recurrence. In multivariate analysis, the 2 independent predictors of local recurrence were histological response to chemotherapy and central site of disease. CONCLUSION: Local recurrence after surgical resection is a complex phenomenon. An important predictive factor is the response to chemotherapy. In the current study, this seems to have the largest impact. Central site of disease may be a second independent predictive factor.

Long-term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma.

PURPOSE: Although survival without resection of pulmonary metastases from osteosarcoma is unlikely, not all surgeons agree on an aggressive surgical approach. We have taken an approach to attempt surgical resection if at all feasible regardless of number of metastases and disease-free interval (DFI). This study presents information on long-term follow-up after this aggressive approach to resection. METHODS: A single-institution retrospective cohort study of osteosarcoma patients younger than 21 years with pulmonary metastases, limited to the contemporary chemotherapeutic period (1980-2000), was conducted. RESULTS: In 137 patients, synchronous (23.4%) or metachronous (76.6%) pulmonary nodules were identified. The median follow-up was 2.0 years (5 days to 20.1 years) for all patients. Overall survival among patients who had pulmonary nodules was 40.2% and 22.6% at 3 and 5 years, respectively. Ninety-nine patients underwent attempted pulmonary metastasectomy (mean survival, 33.6 months; 95% confidence interval, 25.1-42.1) and 38 patients did not (mean survival, 10.1 months; 95% confidence interval, 6.5-13.6; P < .001, t test). Characteristics that were associated with an increased likelihood of 5-year overall survival after pulmonary resection were primary tumor necrosis greater than 98% after neoadjuvant chemotherapy (P < .05) and DFI before developing lung metastases more than 1 year (P < .001). No statistically significant difference in overall survival or disease-free survival was found based on the number of pulmonary metastases resected. Characteristics including primary tumor size, site, or extension; chemotherapy; early vs late metastases; unilateral vs bilateral metastases; and resection margins did not significantly affect survival. CONCLUSIONS: Most patient and tumor characteristics commonly used by surgeons to determine utility of resection of pulmonary metastases among patients with osteosarcoma are not associated with outcome. Biology of the particular tumor (response to preoperative chemotherapy, measured by tumor necrosis percentage, and DFI), as opposed to tumor burden, appears to influence survival more significantly. We would advocate considering repeat pulmonary resection for patients with recurrent metastases from osteosarcoma.

Ewing's sarcoma of the mobile spine.

STUDY DESIGN: A retrospective analysis was performed. OBJECTIVES: To determine the oncological outcome of patients with nonmetastatic Ewing's sarcoma of the mobile spine treated with systemic multiagent chemotherapy combined with radiation therapy for definitive local control. SUMMARY OF BACKGROUND DATA: To our knowledge, there are no studies that evaluate the oncological outcome of patients with nonmetastatic Ewing's sarcoma of the mobile spine treated with systemic chemotherapy and radiation therapy for definitive local control. METHODS: Thirteen patients with nonmetastatic Ewing's sarcoma of the mobile spine were treated with high-dose multiagent chemotherapy combined with radiation therapy for definitive local control from 1971 to 2000 at a single institution. Patients were observed for a minimum of 2 years or until death. Neurological function, local recurrence, distant relapse, and treatment-related complications were evaluated. RESULTS: There were 8 females and 5 males with a mean age of 19 years (ranging from 7-26 years). The mean follow-up time was 65 months (median 28 months; ranging from 2 to 218 months). All patients presented with pain. Motor deficits were present in 6 patients. Ten patients had a decompressive laminectomy. Improved pain control, as determined by narcotic use, was noted in 12 (92%) patients. Ten patients maintained or improved motor function by at least 1 Frankel grade, while 3 had deterioration of motor function. The disease-free survival rate was 49% and 36% at 5 and 10 years. Five (38%) patients were free of disease at last follow-up. Seven patients developed metastatic disease. Three (23%) patients developed a local recurrence. One of these patients had paraplegia associated with the local recurrence. Five patients developed 8 treatment-related complications. Four of the 10 (40%) patients that had a laminectomy developed progressive kyphosis. Two of these patients also developed late-onset cauda equina syndrome along with the deformity. One of these patients also developed cardiomyopathy associated with adriamycin cardiotoxicity. One patient developed a nonhealing pressure ulcerover a prominent spinous process. CONCLUSIONS: The current study provides historical data on a relatively homogeneous group of patients withEwing's sarcoma of the mobile spine treated with multiagent chemotherapy combined with radiation therapy for definitive local control. Systemic chemotherapy combined with current spinal resection and reconstruction techniques may lead to improved oncological and clinical outcomes.