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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.

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 (≥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. Cancer 2007;109:603–611. © 2006 American Cancer Society.

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.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.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.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.

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.

Background: Late relapse and solitary lesion are positive prognostic factors in recurrent osteosarcoma. Methods: We reviewed the records of 39 patients treated at three major centres for recurrent osteosarcoma with a single pulmonary metastasis more than 1 year after diagnosis. We analysed their outcomes with respect to clinical factors and treatment with chemotherapy. Results: Median age at diagnosis was 14.6 years. Relapse occurred at a median of 2.5 years (range, 1.2–8.2 years) after initial diagnosis. At relapse, all patients were treated by metastasectomy; 12 (31%) patients also received chemotherapy. There was no difference in time to recurrence or nodule size between the patients who received or did not receive chemotherapy at relapse. Sixteen patients had no subsequent recurrence, 13 of whom survive without evidence of disease. The 5-year and 10-year estimates of post-relapse event-free survival (PREFS) were 33.0±7.5% and 33.0±9.6%, respectively, and of post-relapse survival (PRS) 56.8±8.6% and 53.0±11.0%, respectively. There was a trend for nodules

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 from10 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.

The medical records of boys younger than 11 years and girls younger than 10 years of age with osteosarcoma of the pelvis or extremity were reviewed. Thirty patients were identified who were newly diagnosed but untreated for osteosarcoma. None of these patients had pulmonary metastases. The same four protocols were used to treat the patients in the current study as were used to treat adolescents. The event-free and overall survival was calculated and prognostic factors were assessed. The median followup time was 8 years (range, 6-14 years). The results were compared with the results of older patients treated with the same protocols and with published results. Fourteen patients had pulmonary metastases (47%); among these patients, four also had skeletal metastases (in two of the latter, skeletal metastases appeared before the pulmonary metastases). Event-free survival was 53% and overall survival was 57%. This result is comparable with current survival results in adolescent and older patients. Serum alkaline phosphatase and serum lactic dehydrogenase levels before treatment, height percentile greater than 50%, chemotherapy-induced tumor necrosis, surgical procedure, tumor site, tumor histologic features, and patient gender were not prognostic indicators. The prognosis for prepubertal patients with osteosarcoma is similar to the prognosis of their adolescent and older counterparts. There does not seem to be any indication to treat preadolescent patients with osteosarcoma using alternate therapies.

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

Purpose : The objective of this study was to determine the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/m 2 given in four fractions over 8 h in children with advanced solid tumors. Patients and Methods : Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of high-dose CPA at 7 g/m 2 for the treatment of advanced malignant solid tumor. CPA was given in four 1-h infusions of 1.75 g/m 2 each, with 1 h of rest between each dose. MESNA was used as a uroprotective agent and was continued for 24 h after the final dose of CPA. With only one exception, all patients were discharged at the end of MESNA infusion and received granulocyte colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole. Results : Severe but transient myelosuppression was observed. The median time to neutrophil and platelet recovery was 17 and 19 days, respectively. Fever developed after 13 of the 24 courses, and hospitalization was required. Extramedullary toxicities were mild. No patient showed cardiomyopathy or hemorrhagic cystitis. Forty-six percent of the courses were managed entirely on an outpatient basis. Objective tumor response was seen in five patients. Conclusions : CPA at 7 g/m 2 is well tolerated by children with advanced malignancies and should be considered in earlier phases of antineoplastic therapy.

We attempted to ascertain renal, hematologic, and neurologic tolerance to ifosfamide (IFX) in pediatric patients previously treated with large single and cumulative doses of cis-Diamminedichloroplatinum-II (CDP) for osteosarcoma (OS). Twenty OS patients were treated with CDP: initially 150 mg/m2 was administered every 2 weeks for a maximum of seven courses. Later, other agents, including additional CDP, were also administered. Twelve patients were treated with intra-arterial CDP, one with intra-arterial, and later intravenous CDP, and seven with intravenous CDP. Patients who relapsed were treated with IFX. Renal function was monitored by measuring creatinine clearance, serum electrolytes, total protein, albumin and CO2 content, and urine analysis during IFX therapy. Prior to initiation of IFX, creatinine clearance was above 60 ml/min/m2 in all except one patient who had developed a hemolytic uremic syndrome (HUS). Cumulative CDP doses ranged from 300 to 22,500 mg/m2, and cumulative IFX doses 12 to 128 gm/m2. Myelossupression was monitored by obtaining routine hemograms midway between each course of treatment. Neurologic tolerance was assessed by reviewing the medical records for any abnormality. The interval between CDP and IFX ranged from 1 to 64 months. All patients experienced a progressive reduction in creatinine clearance with CDP. The reduction in creatinine clearance, measured from baseline after three to four courses varied from 10 to 53.7%, after four to seven courses from 19 to 78%, and after seven courses from 12 to 80.5%. In all patients except five, including the HUS patient, creatinine clearance remained above 60 ml/min/m2 during IFX therapy. Twelve patients developed hypomagnesemia in the vicinity of 1.4 to 1.6 mg/dl during CDP treatment and required magnesium supplementation. They were asymptomatic and the abnormality did not affect IFX tolerance. Fourteen patients intermittently displayed variable degrees of glycosuria, phosphaturia, and/or proteinuria during IFX therapy. This was considered to be a forma frustre type of Fanconi's syndrome. Approximately 80% of courses of IFX were associated with reversible myelosuppression. No neurologic abnormalities were detected. The abnormalities detected during IFX treatment were not major, did not give rise to symptomatology, and did not require discontinuation of therapy. Renal abnormalities were considered a forma frustre type of Fanconi's syndrome. Provided a creatinine clearance of 60 ml/min/m2 is accepted as a prerequisite for treatment, and no major preexisting renal disease is present, IFX is well tolerated by most patients previously exposed to very high cumulative doses of CDP. © 1996 Wiley-Liss, Inc.

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)

A malignant pleural effusion was diagnosed by thoracentesis in a 12-year-old patient with an established diagnosis of Wilms' tumor. He was treated with chemotherapy and achieved a reduction in the size of the primary tumor and resolution of the effusion. The primary tumor was then resected and chemotherapy continued for a total of 18 months. At the request of the parents, radiation therapy to the thorax was withheld. The patient has remained free of disease for the past 8 years. © 1995 Wi1ey-Liss Inc.

Background. Hemolytic uremic syndrome (HUS) is an acquired disorder largely affecting infants and young children. It is characterized by the triad of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. Although its etiology is unknown, viral and bacterial infections, disseminated malignancies in adults, and a variety of chemotherapeutic agents including cisplatin, have been implicated in its occurrence. The association of HUS with chemotherapeutic agents after its detection in a pediatric patient treated with cisplatin is reviewed. Methods. A 16-year-old male with osteosarcoma was treated with cisplatin as part of a chemotherapy protocol. After the fourth course, his renal function deteriorated and necessitated cessation of cisplatin. Nine months after the initiation of cisplatin, HUS developed. There was no evidence of residual tumor or metastatic disease. He received numerous packed erythrocyte and platelet transfusions for persistent hemolysis and underwent several episodes of hemodialysis. Utilizing this patient as an example, the authors reviewed the incidence of HUS developing subsequent to the use of other chemotherapeutic agents. Results. In the publishing literature, chemotherapy-associated HUS has been described to occur 54 days to 14 months after the initiation of chemotherapeutic regimens. A variety of agents was associated with the phenomenon. Conclusion. Hemolytic uremic syndrome may be a complication of cisplatin, as evidenced by the condition that occurred in a 16-year-old patient with osteosarcoma after cisplatin therapy.

Background: The use of radiotherapy for the treatment of childhood malignancy has improved long-term survival significantly, and many treated children now survive well into adulthood. As a consequence, long-term effects of childhood irradiation are being seen with increasing frequency. Methods: The medical records of 236 patients who had been treated for malignant disease with radiotherapy during childhood were examined to determine the long-term effect of the radiation on their growth and development. Results: Mean treatment dose was 35.5 Gy; mean age at treatment was 7.2 years; and mean follow-up was 14.5 years. Adjuvant chemotherapy was given to 82%. Some degree of bone deformity (usually with overlying soft-tissue hypoplasia) was seen in 40%; 21% developed some type of endocrine deficiency; 30% developed atrophic skin changes; and 7% developed second malignancies. The incidence of bone deformity and hormonal deficiency increased with the radiation dose; the incidence of second malignancy was independent of dose. Bone deformities were more common when radiation was administered before the age of 2 years. Conclusions: The consequences of radiotherapy in childhood are significant and must be considered when planning treatment. Even when treatment is essential, families should be informed of the possibility of growth disturbance to prevent subsequent misunderstanding.

Summary This article has provided an account of the delayed effects after successful treatment for childhood cancer. Particular emphasis has been placed on sequelae induced by radiation therapy. Chemotherapy-related complications that may simulate or aggravate these sequelae also are recorded. The alterations induced by radiation therapy and chemotherapy are not limited to the organs and tissues described in this article. Subtle, and at times psychologically devastating, sequelae also may be encountered (eg, sterility due to radiation and chemotherapeutic effects on the gonads). However, an attempt has been made only to identify those complications that may be more readily detected by means of radiographic studies. It is recommended that ongoing surveillance of the long-term successfully treated childhood cancer survivor be conducted in order to detect such complications. Early detection will assist in implementing appropriate treatment, minimizing delayed effects, and maximizing the quality of life. Periodic radiographic studies of previously radiated areas at regular intervals therefore appears appropriate.

As the cure rate for childhood malignancies increases, the number of patients at risk for development of second malignancies also increases. Due to the potentially long remaining life span, long-term follow-up is difficult and patients are often at risk after presumptive cures. Some authors believe that cure rates for second malignancies are similar to cure rates for primary malignancies. We reviewed the records of 162 patients seen at our institution who had developed a second malignancy after treatment for childhood cancer. Presentation, age at diagnosis, tumor histology, extent of tumor, treatment (including radiotherapy with dosage when available, and chemotherapy) plus outcome were recorded. Mean age at diagnosis of the primary malignancy was 10.3 years. The most common primary malignancy was Hodgkin's disease (33) followed by soft tissue sarcoma (28), retinoblastoma (20), bone tumor (17), central nervous system (CNS) tumor (13), leukemia (8), Wilms' tumor (7), non-Hodgkin's lymphoma (6), neuroblastoma (5), thyroid neoplasm (5), and others (20). The average interval between diagnosis of the first and second malignancy was 10.8 years. These second tumors carried a high mortality. Only 56 patients have no evidence of disease. Five patients are known to be alive with disease and 92 patients have expired due to their second malignancy. Disease status in 8 patients is unknown. The most common second malignancy was osteosarcoma (35) followed by soft tissue sarcoma (24), breast cancer (15), leukemia (14), thyroid carcinoma (14), CNS tumors (12), melanoma (8), nonmelanomatous skin cancer (8), lymphoma (5), and others (27). Eighteen of 35 bone sarcomas developed in irradiated fields and the mean dosage was 44.0±16.3 (10 to 64 Gy). Seventeen of 19 patients who developed a hematologic malignancy received an alkylating agent when treated for their primary malignancy. Of 162 patients developing second malignancies, only 34.6% were cured. When patients with thyroid lesions are excluded, only 28.9% were cured. These poor results are most likely due to two main factors: (1) a high percentage of tumors were not able to be cured due to local unresectability, and (2) the biology of many of these lesions is more aggressive than similar tumors arising "de novo." The more aggressive nature of these neoplasms may in part be due to genetic mutations present at the time of initial diagnosis and/or due to DNA damage resulting from irradiation or administration of alkylating agents.

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.

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.

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.

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.

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.

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 from20% 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.

PURPOSE A phase II trial that uses liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in patients with relapsed osteosarcoma is underway. To determine if in vivo cytokine induction plays a role in the mechanism of action of L-MTP-PE, we investigated the circulating cytokine levels of 16 patients who were undergoing therapy. PATIENTS AND METHODS Patients had histologically proven osteosarcoma and pulmonary metastases that developed either during adjuvant chemotherapy or that were present at diagnosis and persisted despite chemotherapy. Patients were rendered disease-free by surgery. The major goal of the study was to improve the disease-free interval in this high-risk group. L-MTP-PE 2 mg/m2 was infused during a 1-hour period twice a week for 12 weeks, then once a week for 12 weeks. Serial blood samples were collected after L-MTP-PE administration and were assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha] interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-6, interferon-gamma [IFN-gamma], neopterin, C-reactive protein). RESULTS After the infusion of L-MTP-PE, there was rapid induction of circulating TNF alpha and IL-6. TNF alpha levels peaked 1 to 2 hours after infusion in 10 of 16 patients, whereas peak IL-6 levels were detected at 2 to 3 hours in all patients. Induction of circulating TNF alpha and IL-6 was evident only after the first dose of L-MTP-PE. Neither IL-1 alpha nor IL-1 beta was detected in the plasma. Neopterin levels increased at 24 hours postinfusion, which indicated macrophage activation, and were not related to the induction of circulating IFN-gamma. C-reactive protein was elevated in all patients at 24 hours and decreased by 72 hours. Unlike circulating TNF alpha and IL-6, elevations in C-reactive protein and neopterin could be detected throughout the treatment course. CONCLUSION It is concluded that L-MTP-PE has specific biologic effects in patients with osteosarcoma that may be important to the drug's immunostimulatory capacity and its effectiveness as an antitumor agent.

We have recently begun a phase II trial in patients with osteosarcoma who developed pulmonary metastases during adjuvant chemotherapy or who presented with pulmonary metastases that persisted despite chemotherapy. Eligible patients were rendered free of visible disease by surgery. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTP-PE, CGP 19835A lipid) (2 mg/m2) was infused twice weekly for 3 months. In five patients, a single tumor nodule recurred within 6 weeks after completion of therapy. These lesions were resected and submitted for pathological examination. Tissue specimens obtained after therapy were compared to those obtained before therapy. All the patients showed a histological change in the characteristics of the pulmonary tumors. In three patients, peripheral fibrosis surrounded the tumor and inflammatory cell infiltration and neovascularization were present. This is in contrast to central necrosis, with viable peripheral tumor cells and no inflammatory response observed in lesions resected following chemotherapy. In a fourth case, evidence of early fibrotic changes was found. This and the fifth case showed a change in malignant characteristics, from high grade before liposomal therapy to low grade after therapy. The present study provides evidence for a biological effect of liposomal MTP-PE.

Acute nonlymphocytic leukemia (ANLL) developed in 2 of 142 pediatric patients with osteosarcoma treated with a cis-diamminedichloroplatinum-II (CDP)-based regimen: acute monomyelogenous leukemia (M4) with a normal female karyotype in one and acute myelogenous leukemia (M2) with t (8,21) in the other. The ANLLs occurred, respectively, in each patient 3 and 4 years after the initial diagnosis of osteosarcoma. In contrast to most of the adult experience and consistent with the majority of reported ANLL in children, the disease was characterized by an absence of the smoldering phase and cytogenetic findings similar to those seen in de novo ANLL.

Osteosarcoma is the most common primary malignant bone tumor affecting children and adults. The etiology is unknown, although a higher incidence occurs in patients with bilateral retinoblastoma, Paget’s disease of bone, the Li Fraumeni syndrome, and those who have received therapeutic radiation. The biologic behavior is consistent with the premise that silent pulmonary micrometastases are present in at least 80% of patients at diagnosis. These metastases are not visible on imaging studies, but in the absence of effective systemic therapy, they generally surface 6 to 9 months after surgical ablation of the primary tumor. If untreated, they will be responsible for the patients demise within 2 to 3 years of their appearance. Historical controls reveal a survival of 5% to 20%. There are currently four major classes of chemotherapeutic agents with established efficacy that are used in the therapy of this malignancy: doxorubicin, cisplatin, ifosfamide/high-dose cyclophosphamide, and high-dose methotrexate with leucovorin rescue (MTXL). Doxorubicin and MTX-L were discovered first in the early 1970s. Doxorubicin, and the other agents when discovered later, were accepted without query; not so for MTX-L. It was initially subjected to intense scrutiny, 1,2 rebuffed intermittently, 3 and later incorporated with variable degrees of indifference or enthusiasm into therapeutic regimens seemingly for want of a more effective agent. During this interminable period of probation (still extant 4 ), support for its efficacy and confirmation of its activity emanated from various publications. It was shown to be effective in eliminating overt pulmonary metastases, improving the opportunity for limb salvage, healing pathologic fractures, and enhancing the effect of radiation therapy for palliation and control of inoperable tumors. 5 When administered postoperatively as the sole agent after ablation of the primary tumor, it increased survival to 40%, 6 and in combination with other agents (pre- and postoperative therapy), it increased survival to 65% to 75%. 6-12

Ninety-eight pediatric patients were treated with three separate protocols (Treatment and investigation of Osteosarcoma [TIOS] I, II, and III) and 47 developed recurrent disease (metastases and/or local recurrence). Actuarial overall disease-free survival (hereafter designated survival) was 43%. Over 90% of the patients were treated initially with preoperative intraarterial cisplatin (CDP). Postoperative chemotherapeutic regimens comprised high-dose methotrexate with leucovorin rescue (MTX-CF), Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide. Primary definitive treatment comprised amputation or limb salvage (TIOS I and TIOS III). Patients treated with preoperative CDP and surgery (TIOS I and III) had a 62% survival. Patients in TIOS II refused surgical extirpation; they were treated exclusively with chemotherapy and had a 23% survival. Survival in patients treated with amputation was 55% and limb salvage 58%. Prognostic factors considered significant in relation to development of pulmonary metastases comprised tumor burden (P = .04) and the percentage of tumor necrosis induced by preoperative chemotherapy (P = .01). Histopathologic subtype was marginally significant: chondroblastic was more favorable as opposed to osteoblastic (P = .05). These findings are compared with results and prognostic factors published in the literature.

Six patients with extremity osteosarcoma initially underwent successful treatment of the primary tumor with four to seven courses of intraarterial cis-diamminedichloroplatin-II (IA-CDP; 100 to 150 mg/m2/course). The primary tumors in two patients were then extirpated by limb salvage. However, a local soft tissue recurrence occurred in both patients several months later. The other four patients refused surgical intervention and later also developed local bony recurrences. Reinstatement of three to five courses of IA-CDP in all six patients induced a complete response in five. The local recurrences (bony and soft tissue) in all six patients were excised. This included limb-salvage procedures in three patients. Additional postoperative chemotherapy was administered. Four patients remain alive and continuously free of disease 3.5+ to 4.5+ years after retreatment with IA-CDP.

Sarcoma of the thymus is exceedingly rare, especially in children. We report a case of thymic sarcoma in a child, including the imaging findings which have not been previously described.

Adolescence is characterized by inter-related physiologic and emotional development. It is a particularly vulnerable period of life culminating into emergence as an adult. The majority of malignant bone tumors in pediatrics affect the adolescent patient. As a part of the treatment, amputation may be required for cure. This often creates a "grieving process. " Adjustment to this process is described. At the M. D. Anderson Cancer Center to assist in functional and emotional rehabilitation, an annual ski trip for amputees has been held over the past two decades. The accomplishments of this trip are outlined. Motivated by the success of the program, preadolescent amputees and blind and paraplegic cancer patients were also invited to participate. The adolescent amputee paved the way for rehabilitating other physically challenged cancer patients!

Background Sixteen pediatric osteosarcoma patients, previously treated with conventional chemotherapy (including ifosfamide (IFX), 9 g/m2) were retreated with high-dose ifosfamide (HD-IFX, 14 g/m2 per course), following relapse or development of a new bone tumor. The objective was to obtain responses and an improved event-free survival (EFS). Procedure HD-IFX was administered as described by Patel SR: J Clin Oncol 1997;15:2378. Efficacy of treatment was assessed initially after two to four courses. The interval between the courses was 3 to 4 weeks. Provided a response was obtained after two to four courses, treatment was continued for an additional eight courses unless progressive disease or an untoward event, for example, renal failure occurred. Tumor sites were: lung, (10) bone (9), and bone and soft-tissue (1). Results Response after two to four courses was 62.5%: CR 6 and PR 4. A total of 84 courses were administered to the 16 patients: (range 2–10, median 5.5 per patient). Median interval between courses was 28.5 days (range 15–90). Five patients were disease free at 15+ to 63+ months after induction and maintenance therapy. Fever and neutropenia occurred in 12 courses. Nephrotoxicity was a major toxic event and was characterized by creatinine levels at or above three times the upper limit of normal. It was unpredictable and occurred in four patients: two were reversible. The other two patients developed full-blown renal failure; one was treated with renal dialysis, but both eventually succumbed to osteosarcoma. Our past experience also indicated that two patients treated with IFX (9 g/m2/course) developed renal failure: one recovered and the other required a renal transplant. Conclusions HD-IFX is effective in patients who have failed conventional chemotherapy including IFX (9 g/m2). Improved disease-free survival was achieved in 30% of patients. However, renal failure constitutes an important life-threatening complication and its development is unpredictable. © 2004 Wiley-Liss, Inc.

BACKGROUND The objective of the current study was to determine the incidence, clinical and pathologic characteristics, and outcome of patients with conventional osteosarcoma who developed metachronous tumors after treatment for the primary tumor and prevention of pulmonary metastases. METHODS The medical records of 270 pediatric patients (younger than age 18 years) were reviewed. The prevention and absence of pulmonary metastases was confirmed by chest radiographs and computerized scans of the lungs. Radionuclide bone scans were used to confirm the absence of skeletal metastases. RESULTS Eleven patients with metachronous tumors were identified. Index primary tumors involved the femur (n = 8), the tibia (n = 2), and the radius (n = 1). Single metachronous tumors developed in the femur (n = 6), in the humerus (n = 1), and multifocal in multiple bones (n = 4). Two patients later developed second metachronous tumors. The interval between identification of the primary tumor to development of the single metachronous tumors varied from 11 months to 78 months and from 12 months to 42 months for synchronous multifocal tumors. Metachronous tumors were treated with single-agent cisplatin or ifosfamide. Only 1 patient experienced > 90% tumor necrosis. Pulmonary metastases were not detected in 10 of 11 patients at the time metachronous tumors were discovered. In the 11th patient, synchronous pulmonary metastasis with the metachronous tumor was noted. Three patients had a prior history of bilateral retinoblastoma. The Li–Fraumeni syndrome may have been present in another patient. Six patients died. Five patients have survived for 20+ to 50+ months after the appearance, treatment, and resection of metachronous tumors. CONCLUSIONS With improvement in the cure rate, metachronous osteosarcoma should be recognized as an important sequela in long-term survivors. The etiology of this disease is unknown. Speculation rests on a skeletal multicentric origin, which includes an inherited predisposition to develop osteosarcoma in retinoblastoma and in the Li–Fraumeni syndrome. Meticulous follow-up is required to permit early detection and successful therapeutic intervention. Cancer 2003. © 2003 American Cancer Society.

Contemporary therapy for osteosarcoma is comprised of initial treatment with chemotherapy and surgical extirpation of the primary tumor in the affected bone. In view of the major advances forged by chemotherapy in the treatment of the primary tumor, an attempt was made to destroy the tumor exclusively with this therapeutic modality and abrogate surgery.Thirty-one consecutive patients were treated. All had localized disease (absence of metastases) at the time of diagnosis. Initial treatment with chemotherapy was comprised of high-dose methotrexate and leucovorin rescue (MTX-LF) in 3 patients and intraarterial cisplatin in 28 patients. Clinical, radiologic, angiographic, radionuclide, and histologic investigations were utilized to assess the efficacy of treatment. After a response at 3 months, entry into the study was permitted and treatment was maintained for a total of 18-21 months with a combination of agents comprised of MTX-LF, intraarterial cisplatin, and doxorubicin. Patients were monitored closely for disease recurrence with the investigations outlined earlier. Two informed consents were required: one at the time of diagnosis and another at 3 months after the initial response had been attained.Only 3 of 31 patients were cured with the administration of chemotherapy alone. Local recurrence and pulmonary metastases were not reported to develop in these 3 patients during a follow-up period of 204+ to 225+ months. Four other patients also possibly were cured with chemotherapy alone. At their request, several months after the cessation of chemotherapy, they underwent surgical extirpation of the tumor. No evidence of viable tumor was found. These patients remained free of disease for 192+ to 216+ months. Thus, only seven patients did not develop local recurrence and/or pulmonary metastases. Among the remaining 24 patients, 9 developed local recurrences without pulmonary metastases 14-74 months (median, 30 months) after the initial response. Eight of the nine patients were rendered tumor free by extirpation of the local recurrence. Two of these eight patients subsequently died, one of the acquired immunodeficiency syndrome (AIDS) and the other of varicella septicemia. The ninth patient refused amputation and died of metabolic complications. Three other patients developed local recurrences 20-69 months and pulmonary metastases 10-98 months after achievement of the initial response. These patients were rendered tumor free by extirpation of the local recurrence and metastasectomy. One of these patients also later died of AIDS. In the remaining 12 patients, local recurrences developed 5-29 months (median, 14 months) after the initial response was achieved. The patients also developed pulmonary metastases 11-60 months after the initial response. In eight patients the local recurrences were extirpated and metastasectomy was performed; however, these patients later died of recurrent pulmonary metastases. The remaining four patients refused to undergo extirpation of the local recurrence. The pulmonary metastases were not resected. They failed to respond to alternate therapy. Thus, the tumor-free survival rate was 23% (7 of 31 patients): 3 patients who were treated with chemotherapy only and 4 patients who were treated with chemotherapy plus surgery. The overall survival rate (patients who remained free of disease and those who underwent resection for local recurrence and metastasectomy) was 48% (15 of 31 patients). Prior to the deaths from AIDS and varicella septicemia, the overall survival was 58% (18 of 31 patients).Utilizing the regimen employed in the current study, only 3 of 31 patients with osteosarcoma (10%) were cured exclusively with chemotherapy. Four additional patients who underwent extirpation of the primary tumor without disease recurrence and in whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50-65% with "conventional" sin whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50-65% with "conventional" strategies, the results of the current study do not justify the adoption of current forms of chemotherapy as exclusive treatments for osteosarcoma.

We retrospectively reviewed the medical records of 97 children (59 boys and 38 girls) with a median age of 13 +/- 4 years who had been treated with continuous infusion of doxorubicin at a dosage of 60 mg/m2 over 24 h (61 patients) or at a dosage of 75 mg/m2 over 72 h (36 patients). The drug was administered every 3 weeks. The cardiac status of patients was evaluated as a baseline and every 6 months during, and following therapy (median, 30.5 months). The evaluations included M-mode and two-dimensional echocardiography. Congestive heart failure developed in only one patient in this series, an 8-year-old girl who ultimately died of her cardiac complication. This incidence of doxorubicin-induced cardiotoxicity was compared with that seen in a control group of pediatric patients previously treated with doxorubicin at similar dosages but with a rapid infusion. The result compared favorably to the 13% incidence of cardiotoxicity (p = 0.03) and 7% mortality (p < 0.01) in the control group. No changes in the levels of tumor response were noted in children treated by continuous infusion when compared with historical controls. Continuous-infusion schedules of doxorubicin thus result in fewer incidences of cardiotoxicity in children and should be considered for wider application in pediatric cancer patients receiving doxorubicin.

The clavicle is frequently incorporated into the radiation field in the treatment of malignant tumors located in the head and neck. From 1954 to 1995, 499 pediatric patients were treated with moderate to high-dose radiation therapy to the head and neck at the University of Texas M.D. Anderson Cancer Center. The medical records of 312 of these patients were available and were reviewed. The period of observation ranged from 5 to 30 years. Five late radiation-induced abnormalities of the clavicle were encountered: osteosarcoma; osteochondroma; malignant fibrous histiocytoma; radionecrosis and impaired healing following trauma and radionecrosis and lysis. The doses of radiation therapy which induced the abnormalities varied from 35 to 60.5 Gy (median 34.75 Gy). The interval from radiation therapy to discovery of the complications varied from 6 to 11 years. Two patients died: one from malignant fibrous histiocytoma and another from a radiation-induced meningioma of the brain (which accompanied radionecrosis of the clavicle). We conclude that the incidence of radiation-induced abnormalities of the clavicle in pediatric long-term survivors is low (1.5%). However, some of the late sequela are potentially fatal. The clavicle should be considered a vulnerable bone to radiation therapy and should be monitored in long-term survivors of childhood cancer. The experience is compared to radiation-induced abnormalities recorded in the literature.

Eighty-five patients (37 female, 48 male; median age 14 years) with non-metastatic Ewing's sarcoma received definitive treatment at the University of Texas M.D. Anderson Cancer Center between 1969 and 1988. Multidisciplinary therapy was administered as follows: combination chemotherapy (CC) and local radiotherapy (XRT): 65 patients; CC, XRT and surgery, 19 patients; and XRT and surgery, 1 patient. This permitted a 10-20 year follow-up for 75% of our patients. The overall survival at 5 and 10-20 years was 46.1%, and 37.2%, respectively. At 5 years, 80.5% of live patients had control of local disease. The influence of sex, age, ethnicity, primary site, size, lactic dehydrogenase (LDH) level, presence or absence of systemic symptoms, and XRT dose (

Between January 1993 and December 1996, 21 children with advanced solid tumors were entered in a dose-escalating study of high-dose sequential chemotherapy followed by autologous stem cell transplantation. The diagnoses included neuroblastoma (NB) for 13 patients; Ewing's sarcoma (ES) for six patients and osteosarcoma for two patients. Nine patients received therapy as consolidation for primary metastatic disease, and 12 patients had had previous relapses. Treatment consisted of CY given i.v. at a dose of 7 g/m2 on day 1, followed by G-CSF until myeloid recovery. After 3 weeks of rest, all patients were given thiotepa i.v. on days 22-24. The total dose of thiotepa was 450 mg/m2 in three patients, 600 mg/m2 in six patients, and 750 mg/m2 in 12 patients. Melphalan was given i.v. at a dose of 180 mg/m2 i.v. on day 27 followed by stem cell infusion on day 28. Major toxic reactions included stomatitis, esophagitis, diarrhea and dermatitis. Three patients died of treatment-related complications. Twelve patients have had a relapse. Six patients (five with NB and one with ES) are alive in continuous remission 5-50 months (median 36) after transplantation. The results of this study show that it is feasible to administer high-dose sequential chemotherapy to children with advanced solid tumors.

PURPOSE A prospective study was conducted to assess the effects of chemotherapy for cancer on children's long-term neuropsychologic status. PATIENTS AND METHODS Ninety-nine children who received no cranial radiation therapy (CRT) completed four annual neuropsychologic assessments. Fifty-one patients received intrathecal (IT) chemotherapy (ITC); 48 received no CNS treatment. These two groups were compared using repeated-measures analysis of variance on IQ, memory, language, freedom from distractibility, academic achievement, executive functions, and fine-motor, perceptual-motor, and tactile-spatial skills. In addition, 51 of the sample of 99 patients had been examined 5 to 11 years after diagnosis. Their data were analyzed to evaluate the longer-term effects of chemotherapy. The predictability of demographic and medical variables on neuropsychologic outcome at 3-year and long-term follow-up study were assessed using multiple regression techniques. RESULTS Overall, the effects of chemotherapy in the absence of CRT appear to be slight. Patients who received ITC and intravenous (IV) methotrexate declined slightly on perceptual-motor skills, but were still well within the normal range. Both groups, regardless of treatment, declined on academic achievement tests, although not to a statistically significant degree. Age effects were found on performance IQ (PIQ) and perceptual-motor skills. Socioeconomic status (SES) correlated with a large number of variables. Sex effects were not significant. CONCLUSION The present results are largely consistent with previous findings for nonirradiated groups. Treatment effects from ITC are slightly more apparent 5 to 11 years after diagnosis than at 3-year follow-up evaluation but this does not constitute a clinically meaningful difference. More noticeable are academic declines among all groups, regardless of treatment.

BACKGROUND The spectrum of side effects induced by chemotherapy includes skin hyperpigmentation. This is prone to occur following treatment with alkylating agents and doxorubicin. More recently, hyperpigmentation was discovered in patients treated exclusively with intra-arterial cisplatin and was likely to develop over the dorsal surfaces of the hands and feet, elbows and knees, and operative incisions (trauma). METHODS We followed the clinical course of a patient with osteosarcoma treated with intravenous (i.v.) cisplatin, doxorubicin, and high-dose methotrexate. RESULTS Following two courses of chemotherapy, hyperpigmentation developed along the sides of the thorax juxtaposed to the rubber shoulder pads of the patient's crutches. It appeared that the pigmentary change was due to localized pressure in the skin of the patient exposed to i.v. cisplatin. CONCLUSIONS Factors associated with skin hyperpigmentation as a complication of chemotherapy are discussed. We believe that cisplatin was the major contributing factor. The mechanism for cisplatin-induced hyperpigmentation is undetermined. However, it has occurred in patients treated exclusively with intra-arterial cisplatin and can possibly be attributed to an effect on the melanocytes. This is supported by experiences in which cisplatin extravasated into the tissues and resulted in a similar phenomenon. Reasons for excluding doxorubicin and methotrexate as causative agents are presented. Cancer 1996; 77:1578-81.

Three principal environmental causes of hemolytic anemia in malignancy have been identified: (1) hemolysis mediated by auto-antibodies to red cells; (2) hemolysis due to microangiopathic disorders; and (3) chemotherapy-induced red cell destruction. These three environmental stressors occur rarely in cancer patients, and they form the subject of this review.

BACKGROUND The experience of one institution in treating soft tissue sarcomas of the head and neck in a pediatric population is presented. METHODS Case materials of 134 patients younger than 20 years who were referred to the University of Texas M. D. Anderson Cancer Center between 1970 and 1989 for treatment of sarcoma of the head and neck were retrospectively reviewed. Patients with rhabdomyosarcoma underwent multimodality treatment consisting of surgery, irradiation, and chemotherapy. Wide resection was the treatment used for patients with nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS). Adjuvant chemotherapy and irradiation were used to treat high grade neoplasms and residual disease. The clinical response to therapy was measured in terms of the disease-specific survival rate. RESULTS Seventy-nine of 134 patients presented with untreated or biopsy-proven disease. Fifty-six had rhabdomyosarcoma and 23 had NRSTS. At 2 and 5 years, the disease-specific survival rates for patients with rhabdomyosarcoma were 74% and 63%, respectively, and patients with NRSTS had 80% and 75% disease-specific survival rates at 2 and 5 years, respectively. CONCLUSIONS Rhabdomyosarcoma of the head and neck in children is effectively treated with multimodality therapy. Prognostic indicators for rhabdomyosarcoma include completeness of tumor resection and the development of recurrent disease. Aggressive surgical resection is the treatment of choice for patients with NRSTS. Prognostic indicators for NRSTS include completeness of tumor resection and the development of recurrent disease. Cancer 1996;77:193-200.

Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthesized lipophilic analogue of muramyl dipeptide. MTP-PE encapsulated in liposomes (L-MTP-PE) allows selective delivery to pulmonary macrophages and circulating monocytes. In vivo administration has resulted in tumor regression in mice with B16 melanoma lung and lymph node metastases and a 40% long-term disease-free survival in dogs with osteosarcoma. Phase I studies have demonstrated that the drug is well tolerated. A Phase II trial using L-MTP-PE was undertaken in relapsed osteosarcoma patients to determine whether L-MTP-PE therapy could improve the progression-free interval in this high-risk group of patients. Patients had histologically proven osteosarcoma and pulmonary metastases that had developed during adjuvant chemotherapy or that were present at diagnosis and had persisted despite chemotherapy. Patients were rendered disease free by surgery. L-MTP-PE, 2 mg/m2, was infused over a 1-hour period twice a week for 12 weeks in 12 patients (Group 1). Sixteen patients (Group 2) received 2 mg/m2 L-MTP-PE twice a week for 12 weeks, then once a week for 12 weeks, for a total of 24 weeks of therapy. Progression-free intervals in each group were calculated from the day of surgery to the day of relapse and compared with the progression-free interval of a historical control group (Group 3) treated postoperatively with chemotherapy at M. D. Anderson Cancer Center between 1980 and 1990. Patients who received 24 weeks of L-MTP-PE therapy had a significant prolongation in time to relapse but those who received 12 weeks of therapy did not. The median time to relapse for group 2 patients was 9.0 months compared with 4.5 months for the control group (Group 3). These data suggest that L-MTP-PE deserves further investigation in a more appropriate adjuvant setting. A nationwide randomized Phase III trial is now underway in newly diagnosed osteosarcoma patients in conjunction with the Children's Cancer Study Group and the Pediatric Oncology Group.

We report an unusual case of anaphylaxis and hepatitic dysfunction in a child with the administration of the twenty-third course of high-dose methotrexate. The latter had been used as an adjuvant to prevent pulmonary metastases and the prior 22 courses had been well tolerated. An attempt to reinstate methotrexate after the twenty-third course was again followed by a similar reaction. © 1995 Wiley-Liss, Inc.

The purpose of the study was to compare systolic and diastolic function in pediatric patients treated with doxorubicin. Left ventricular function was evaluated in 61 children prior to and following chemotherapy. None had clinical evidence of cardiac decompensation prior to treatment. All received relatively low cumulative doses of doxorubicin; the majority received the drug by continuous infusion. Systolic function was estimated using fractional shortening; diastolic function was estimated using A wave velocity, E wave velocity, E to A ratio, and deceleration time. There was a small but significant decline in systolic cardiac function as estimated from changes in fractional shortening that could not be appreciated in any of the measured parameters of diastolic function. A variety of reasons that could be responsible for the absence of significant changes in diastolic function are discussed. For the present, estimations of systolic function are preferred over the studied parameters of diastolic function in the evaluation of cardiac status in pediatric patients receiving doxorubicin containing regimens.

The records of 50 selected pediatric patients who were treated and followed at M. D. Anderson Cancer Center were reviewed to study the late effects of nonsurgical treatment of cancer in children. There were 26 girls and 24 boys ranging in age between 2 months and 16 years. Patients with head and neck cancer received chemotherapy and radiotherapy for rhabdomyosarcoma (n = 27), retinoblastoma (n = 8), or nasopharynx cancer (n = 2). Median follow-up was 13 years. The most severe side effects were noted in the fields of radiation and included hypoplasia of the jaw, orbit, or hemi-face with varying degrees of atrophy of the overlying soft tissues. A wide range of endocrine, dental, and psychologic abnormalities was also documented. Since 1 in every 1,000 adults older than 20 years today is likely to be a survivor of childhood cancer, recommendations are made for this "new" class of patients whom the head and neck surgeon will be seeing in the future.