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Research Corner Abstracts by Bruce Shriver and Tom Swartz
In this issue's column:
Diagnosis and Surgical Therapy of Uterine Sarcoma – A Retrospective Study Uterine sarcomas are rare gynecological neoplasms and their classification is complicated. Uterine sarcoma is usually diagnosed in postmenopausal women and the diagnosis is often accidental and postoperative. The aim of this study was to present clinical and pathological characteristics of uterine sarcomas, diagnostic procedures, treatment and two-, three- and five-years cumulative survival rates. This retrospective study of 61 cases of uterine sarcomas was conducted at the Institute of Gynaecology and Obstetric, Clinical centre of Serbia, Belgrade. Cases were distributed into groups based on definitive diagnosis of uterine sarcoma: group of leiomyosarcomas (LMS), carcinosarcoma (CS), endometrial stromal sarcomas (ESS), adenosarcomas (AS) and other rare uterine sarcomas. The authors investigated patients with clinical and pathological characteristics of uterine sarcomas, diagnostic procedures and treatment. Survival rate was calculated by Kaplan-Meier method. The RESULTS were as follows: Of 61 patients 43 patients (70.49%) were postmenopausal. The mean period from menopause until appearance of symptoms was 14.63 years. One or more risk factors were present in 46 (75.4%) patients. The diagnosis of uterine sarcoma was established on average 7.38 months after appearance of symptoms. 50 patients (82.0%) underwent one or more diagnostic procedures. Preoperative diagnosis of uterine sarcoma was established in 42.5% of patients. 53 (86.9%) patients were treated operatively. The most used operative procedure (60.7%) was total hysterectomy with bilateral salpingooophorectomy. Postoperative pathohistologic analysis showed that low grade (LG) leiomyosarcoma were present in 19 (35.9%) cases, high grade (HG) leiomyosarcoma in 1 (1.9%) case, carcinosarcoma in 14 (26.4%) cases, low grade (LG) endometrial stromal sarcoma in 5 (9.4%) cases, high grade (HG) endometrial stromal sarcoma in 9 (17.0%) cases, adenosarcoma in 2 (3.8%) cases, and 2 cases of rare uterine sarcomas: 1 (1.9%) MALT HG lymphoma and 1(1.9%) malignant hemangiopericytoma. In one case of ESS (1.9%) only adenomyosis was found postoperatively suggesting that the whole tumor was removed during diagnostic procedure. Eight patients were not treated operatively. Survival Rates: The Two-year cumulative survival rate was 74.3%, the three-year cumulative survival rate was 71.1%, and the five year survival rate was 64.3%. The authors’ discussion of these results were as follows: The average age, percent of postmenopausal patients and the mean age at the time of menopause in the studied correlate with current data. Clinical presentation of uterine sarcoma is associated with obesity and hypertension in more than 30% of cases. For early diagnostics it is important to notice that risk factors are similar to those connected with far more frequent endometrial carcinoma. Postmenopausal abnormal bleeding was the main reason for medical examination, explaining relatively short period for establishing the diagnosis in this group of patients. The variety of clinical findings in the studied group showed that the diagnosis must be based on preoperative pathohistology. The authors conclude as follows: Adequate diagnosis and treatment of uterine sarcoma is possible with regular yearly or more frequent follow-up, especially in postmenopausal women with known risk factors present. Special attention is needed for unclear symptoms and postmenopausal bleeding and we need to use all diagnostic procedures soon as possible including preoperative histology because early metastases are characteristic for uterine sarcomas. The factor of the most important predictive value is histologic grade.
Leiomyosarcoma Metastases to the Spine. Case Series and Review of the Literature Leiomyosarcoma is a rare malignant smooth-muscle tumor that rarely metastasizes to bone. It is extremely uncommon for osseous metastasis to be the initial presentation of leiomyosarcoma or to be the initial manifestation of recurrence in patients with a history of leiomyosarcoma. The authors of this report have treated four cases of metastatic leiomyosarcoma with the lesion initially presenting in the spine, and a fifth case of disseminated leiomyosarcoma that involved the spine. In their report, they highlight the cases of two of these patients and provide tabular data for the remaining three. The authors performed a comprehensive review of the literature on spinal leiomyosarcomas and retrospective chart reviews of five surgically treated patients in whom a spinal metastatic leiomyosarcoma was diagnosed. Their series consists of five women who ranged in age from 36 to 47 years (mean age 43.2 years). Four patients had known, or presumed, uterine primary lesions, whereas one harbored a retroperitoneal primary tumor. These lesions generally appear as lytic foci on imaging studies, but variable imaging characteristics were observed. All cases were managed aggressively: four patients underwent posterior/posterolateral decompression and fusion, and one underwent anterior-posterior en bloc resection and fusion. In all cases preoperative symptoms resolved. Two patients died 9 and 13 years after initial presentation. The remaining patients are alive and neurologically intact. Metastatic spinal leiomyosarcomas tend to symptomatically involve only one spinal level at the time of diagnosis and are known to recur locally. These lesions commonly affect women in early middle age, and long-term survival, even in those with systemic metastatic lesions, is better than that seen in individuals with more aggressive spinal metastases. Attempted gross-total resection with fusion, as opposed to minimal palliative decompression, is recommended by the authors.
Progress Against Synovial Sarcoma University of Utah geneticists have engineered mice that can develop synovial sarcoma -- a significant early step toward developing new treatments for the aggressive, deadly cancer that most often kills teenagers and young adults. The genetically engineered, cancer-stricken mice were used to determine that synovial sarcoma develops in muscle cell precursors known as myoblasts, the researchers report in the April issue of the journal Cancer Cell. The cancer once was thought to arise in synovium, the membrane lining joints like the knee and elbow. That idea fell from favor in recent years, and until now, scientists have not known in which cells the cancer originated. "The only way to develop a therapy that is specific for this cancer is to understand how it works, and the mouse gives you that possibility," says the study's leader, Mario R. Capecchi, distinguished professor and co-chair of human genetics at the University of Utah School of Medicine and an investigator with the Howard Hughes Medical Institute. But as is the case with many basic research advances, Capecchi says a treatment for synovial sarcoma based on the new finding remains at least a decade away. Nevertheless, there also is a wider promise. "First you can design and evaluate new treatments for this specific cancer and, second, you can design therapy for sarcomas in general" because they share many common features with synovial sarcoma, says the study's first author, Malay Haldar, a human genetics graduate student who works in Capecchi's laboratory. Other authors of the University of Utah study are oncologist Stephen L. Lessnick, an assistant professor of pediatrics; Jeffrey D. Hancock, a fellow in pediatric hematology-oncology; and physician Cheryl Coffin, professor and head of pediatric pathology.
Synovial sarcoma accounts for 7 percent to 10 percent of soft-tissue sarcomas, and usually develops in the arms or legs, particularly near the knees or ankles but also near the hips or shoulders. It also can occur on the torso or neck. It often metastasizes, spreading to the lungs, lymph nodes and bone marrow. Even though it most often strikes young adults and adolescents, the most famous synovial sarcoma patient probably was actor Robert Ulrich -- star of such TV shows as "Spenser for Hire," "Vega$" and "Soap" -- who died of the cancer at age 55 in 2004. Haldar says there are about 900 new cases of synovial sarcoma each year in the United States. Five-year survival rates vary wildly in different reports, but as few as 25 percent of patients survive five years. Many synovial sarcomas already have spread by the time they are diagnosed, and about 80 percent of those patients die, Capecchi says. Surgery is the most common treatment to remove a synovial sarcoma that has not spread; chemotherapy and radiation are considered less successful.
All synovial sarcomas (but not other sarcomas) contain what is known as a SYT-SSX fusion gene, a mutant gene created by "translocation," which occurs when two chromosomes break due to sunlight, oxygen radical chemicals or other causes of DNA damage. Part of one chromosome combines with part of the other. In synovial sarcoma, the SYT gene on chromosome 18 breaks and part of it combines with part of a broken SSX gene from the X chromosome, either SSX1 or SSX2.The SYT-SSX1 fusion gene results in synovial sarcoma that progresses more quickly and is deadlier, but the study involved SYT-SSX2 because that gene was the first Haldar was able to extract from a human tumor, which was difficult to obtain. SYT normally activates other genes, while SSX normally turns off other genes. Capecchi says the fusion gene's precise role in causing synovial sarcoma is unknown.
To learn where synovial sarcoma originates, Capecchi, Haldar and colleagues genetically engineered mice so that the researchers could activate the SYT-SSX2 fusion gene in various muscle cells or their precursors. They suspected some sort of muscle cell or precursor cell was where synovial sarcoma originates because "these tumors arise near joints, and the other thing you have near joints is muscle," Capecchi says. The researchers used an enzyme named Cre to activate the human cancer-causing SYT-SSX2 fusion gene in the precursor and muscle cells. Cre "is a switch that allows us to turn the fusion gene on and off when and where we want it," says Capecchi. In less mature muscle cell precursors, the SYT-SSX2 gene disrupted normal development of mouse embryos, and they died, but there was no cancer. When the cancer gene was activated in mature muscle cells, cancer did not appear, but there was myopathy or muscle damage. Capecchi says that may spur research to learn if SYT-SSX genes play a role in any of the numerous forms of myopathy. The researchers discovered that when the SYT-SSX2 fusion gene was expressed or activated in myoblasts, the cells became cancerous 100 percent of the time. Myoblasts are not stem cells, which can become any kind of tissue, but are precursor cells that are committed to becoming muscle cells. "What's surprising here is that the fusion gene itself is sufficient to start the cancer process so that every mouse gets the cancer," Capecchi says.
The study also indicated that myoblasts become cancerous with help from some favorable, yet-unidentified factor in nearby joint cartilage. Based on the findings, Capecchi believes myoblasts are the likely source of synovial sarcoma in humans. "Usually what we learn in mice is applicable to humans, but we have to prove it," although such experiments could not be conducted ethically in people, he says. Nevertheless, the tumors in mice with the SYT-SSX fusion gene "strongly resemble human synovial sarcoma" in appearance, tumor architecture and proteins produced by genes in the cancer cells, Capecchi says. "They look the same and they also are expressing the same set of genes. It says the human tumor and the mouse tumor are similar." Capecchi says that is why mice with synovial sarcoma can serve as a model for humans when testing possible new treatments. Chromosome translocations probably create fusion genes quite often, but if the SYT-SSX fusion gene forms too early or too late in muscle cell development, cancer does not develop. "You have to hit the right place in the right time to get the tumor," Capecchi says. The new study shows the SYT-SSX fusion gene is needed to initiate synovial sarcoma. Capecchi says he plans to study whether the gene must continue working for the tumor to keep growing and eventually spread. If that proves true, the SYT-SSX gene itself would be a target for possible new drugs to treat synovial sarcoma. But other genes that are overactive in synovial sarcoma tumors were identified in the new study, and they also may be potential targets for anticancer medicines, he adds.
The Biology of Metastasis to a Sanctuary Site Metastasis to the brain is prevalent in solid tumors and lymphomas, and is associated with shortened survival. The brain is regarded as a sanctuary site for metastatic tumor cells where they exist partially protected from drugs by the blood-tumor barrier. Model systems for brain metastasis have been developed and are now yielding mechanistic insights into the roles of angiogenesis, energy metabolism, the Her-2 and Stat3 signaling pathways, and dormancy. Specific, new approaches to combat brain metastatic disease are needed. This review article summarizes progress in the development and validation of model systems for brain metastases of cancer. Recent advances in defining the molecular underpinnings of brain tropism are discussed, and future needs enumerated. Because brain metastases represent an unmet medical need, the authors hope that information from these models can be rapidly translated to the clinic.
Childhood Cancer Survivors At Increased Risk Of Sarcoma Survivors of childhood cancers have a ninefold increased risk of developing a secondary sarcoma compared with the general population, according to a study in the February 21 Journal of the National Cancer Institute. Treatments for childhood cancer have resulted in a current overall cure rate of over 70 percent. However, long-term survivors of childhood cancer are at a higher risk of developing a secondary cancer than the general population. Previous studies have shown that these survivors are specifically at a higher risk of secondary sarcomas, such as soft tissue sarcomas and osteosarcoma. Radiation therapy is associated with secondary sarcomas, but other specific risk factors are largely unknown. Tara Henderson, M.D., of the University of Chicago Department of Pediatrics, and colleagues examined the incidence of secondary sarcomas and the risk factors associated with that risk among the 14,372 participants in the Childhood Cancer Survivor Study. Overall, there were 751 second cancers diagnosed among the participants, 108 of which were secondary sarcomas such as soft tissue sarcoma, malignant peripheral nerve sheath tumors, and osteosarcoma. These sarcomas were diagnosed an average of 11 years after patients were diagnosed with their primary cancer. The authors found that patients with secondary sarcomas were more likely to have received primary radiation therapy; to have received higher doses of drugs called anthracyclines or alkylators; to have had a primary diagnosis of soft tissue sarcoma, bone tumor, or Hodgkin lymphoma; to have a family history of cancer; or to have a history of other second cancers. The authors calculated that the excess number of cases of secondary sarcomas among childhood cancer survivors over those in the general population is 32.5 cases per 100,000 person-years of follow-up. "As the childhood cancer survivor population ages and expands in number, clinicians and researchers must carefully identify patients who are at risk for secondary morbidities, particularly for secondary cancers," the authors write.
Outcomes of Older Patients with Localized Ewing’s Sarcoma Similar to Younger Patients Researchers from Italy have reported that patients over the age of 40 with localized Ewing’s sarcoma have outcomes similar to that of younger patients and should be treated on the same protocols. The details of this study appeared in the February 15, 2007, issue of Cancer. Ewing sarcomas occur most frequently in the second decade of life and account for 3-4% of childhood and adolescent malignancies. The peak age appears to be approximately 14 years. However, Ewing’s sarcoma can occur at any age even in the very elderly. Most observers suggest that 75% of patients with Ewing’s sarcoma present with localized disease, which may be curable in up to 75% of patients with combined modality therapy. For those who present with metastatic disease, the cure rate is 25-30%. These figures represent results from the most recent treatment strategies, which are significantly better than in the past. Treatment for patients whose cancer was diagnosed before 1986 strongly relied on radiation therapy and amputation, while treatments after 1986 tended towards a multi-modality strategy, including surgery, chemotherapy, radiation, and/or amputation as a last resort. Overall, rates of survival for patients with Ewing’s sarcoma of the bone have improved significantly during the time period of this study. As a generality, most patients with Ewing’s sarcoma are treated in pediatric oncology centers and less is known about this disease in older patients. Researchers in the current study reviewed the outcomes of 35 patients between the ages of 40 and 60 treated between 1972 and 2000. Local treatment was surgery alone, radiotherapy or surgery plus radiotherapy. All received adjuvant and neoadjuvant chemotherapy. Fifteen of the 36 patients remain disease-free. They reported a 5-year event-free survival of 43% and an overall survival of 46%. They compared these outcomes to 586 younger patients treated in the same time period and concluded that the outcomes were comparable. Older patients received less chemotherapy and had more toxicity than younger patients. These authors suggest that older patients be treated the same as younger patients.
Benefit of Surgical Treatment of Lung Metastasis in Soft Tissue Sarcoma The above linked study was a retrospective review at an academic tertiary care center. Between January 1, 1991, and December 31, 2002, 61 patients (33 men and 28 women; median age at initial diagnosis, 42 years [age range, 18-74 years]) were surgically treated for pulmonary metastases of soft tissue sarcoma at University Hospital, Hamburg-Eppendorf, Germany. Interventions used were: Sternotomy or anterior lateral thoracotomy was performed for metastasectomy, including wedge resection or lobectomy. The effects of clinical and pathologic factors on disease-specific survival were analyzed using the log rank test and a multivariate Cox proportional hazards model. The Results were as follows: Primary tumor size was pT1 in 13 patients and pT2 in 48 patients. The differentiation was high in 7 patients, intermediate in 19 patients, and low in 35 patients. The mean number of resected pulmonary metastatic lesions was 5 (range, 1-48). An anterolateral thoracotomy was performed in 39 patients, and sternotomy in 22 patients. There were no significant postoperative complications that required surgical revision. The perioperative mortality was 0%. At a mean follow-up of 60 months, the mean survival time after metastasectomy was 33 months (range, 2-125 months). The 5-year survival was 25%. The number of resected lung metastatic lesions had no prognostic relevance (P=.37). The authors thus conclude that patients with lung metastasis from soft tissue sarcomas benefit from surgical excision. This treatment has low complication rates and has a favorable influence on the course of the disease. Long-term survival is possible even when recurrent pulmonary disease is resected.
The fully human monoclonal
antibody to anti–
The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). From 1991 to 2003, 73 patients (36 men, 37 women, median age 54 [range 14–80] years) with biopsy-proven STS underwent 77 perfusions followed by delayed surgical resection, with or without adjuvant radiation. Limb salvage and overall survival curves were calculated by the Kaplan-Meier method. The Results were as follows: A total of 21 amputations (28%) were performed. Overall 1, 5, and 10 years’ limb salvage was 80.1% ± 4.8%, 68.2% ± 6.5%, and 60.6% ± 9.2%, respectively. The investigators found that the risk of amputation was linked to three time periods. The first was within a year after perfusion, mainly as a result of massive necrosis of the tumor and overlying skin, resulting in soft tissue deficit or recurrent disease (n = 17). The second was within 5 years, with two amputations performed for late local recurrence. The third occurred 10 years after perfusion, with two amputations performed for critical leg ischemia. Another two patients developed a pathological fracture of the femur due to radiation osteonecrosis. These four patients received adjuvant radiotherapy. Overall, 1, 5, and 10 years’ survival was 82.9% ± 9.2%, 58.7% ± 13.1%, and 42.5% ± 18.2%, respectively. The investigators Conclude: ILP treatment with tumor necrosis factor alpha and melphalan followed by delayed surgical resection and adjuvant radiation treatment is an effective limb salvage treatment regimen for locally advanced STS. However, they observed late morbidity, with two amputations performed for critical leg ischemia and two pathological fractures of the femur in patients receiving adjuvant radiotherapy.
Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of dasatinib in mesenchymally derived tumors has yet to be shown. Based on previous findings of Src activation in human sarcomas, the investigators of this study evaluated the effects of dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130CAS), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing's subset of bone sarcomas at nanomolar concentrations of dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, the investigators conclude that dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients.
Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. The investigators of this study conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewing's sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation. Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. Harmacokinetic and pharmacodynamic studies were done during cycle 1. The Results were as follows: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m2; 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m2. Dose limiting toxicities were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 ± 6.21 (mean ± SD) L/h/m2 and 2.6 ± 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels. The investigators Conclude: 17-AAG was well tolerated at a dose of 270 mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.
Prospective Multicentric Randomized Phase III Study of Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors Comparing Interruption Versus Continuation of Treatment Beyond 1 Year: The French Sarcoma GroupImatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled. This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses. The Results were as follows: Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients. Thus, the investigators Conclude: Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity.
Phase I Study of Inhaled Doxorubicin for Patients with Metastatic Tumors to the Lungs The purpose of this study was to evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung. The OncoMyst Model CDD-2a inhalation device aerosolizes compounds to particles of 2 to 3 µm and prevents exhaled aerosol from escaping into the environment. Deposition efficiency of inhaled Technetium 99m was used to predict deposition of doxorubicin and calculate dose. Treatment was repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (forced expiratory volume in 1 s, forced vital capacity, and diffusing capacity for carbon monoxide, all >50% predicted; resting SaO2 >90%). The Results were as follows: Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4 mg/m2. The most common histologic diagnoses were sarcoma (n = 19) and non–small cell lung cancer (n = 16). Dose-limiting toxicity (DLT) was observed at the 9.4 mg/m2 dose level when two of four patients experienced pulmonary DLT. Of 11 patients treated at the 7.5 mg/m2 dose level, only one showed DLT consisting of a decline in forced vital capacity of >20% from baseline. No significant systemic drug-related toxicity was observed. Several patients experienced declines in pulmonary function test variables, which were attributed to progressive disease. Observed activity included a partial response in a patient with metastatic soft tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide. The authors Conclude: Inhaled doxorubicin is safe up to a dose of 7.5 mg/m2 every 3 weeks in patients with cancer who had normal to moderately impaired pulmonary function.
The treatment of small-round-cell tumors (SRCT) in adult patients remains a challenge to clinicians. In this study, the investigators analyzed the feasibility and efficacy of high-dose chemotherapy (HDCT) followed by autologous peripheral blood stem-cell rescue as a consolidation therapy exclusively for patients with good disease control through a single regimen of induction chemotherapy and local therapy. Twenty-one patients (12 females, median age 22.0 years) were analyzed, including seven cases with rhabdomyosarcoma (RMS) and 14 cases with Ewing’s family tumors (EFT). Overall, survival was 46% and failure-free survival (FFS) was 33% at 3 years. Patients with EFT had better FFS than those with RMS, with an estimated 3-year FFS of 50% (Po0.01). There was a single case of possible treatment-related death and two cases of secondary malignancies. The investigators conclude that this study cannot conclusively determine the beneficial effects of HDCT for improving treatment outcomes in adult SRCTs due to the small number of subjects. However, the study findings suggest that a subgroup of patients with EFT may obtain prolonged survival benefits from this therapy.
Therapeutic Advances in the Treatment of Brain Metastases Brain metastases continue to pose a formidable challenge in the treatment of solid tumors. In the United States, approximately 170,000 new cases of brain metastases are diagnosed annually. The risk varies according to primary tumor type. Although the mainstay of treatment for brain metastases remains whole-brain radiotherapy (WBRT), the role of other approaches including surgery, radiosurgery, chemotherapy, and targeted biologic therapies continues to evolve. This review article focuses on recent and ongoing advances in the therapy of brain metastases from solid tumors.
V4N2 ESUN Copyright © 2007 Liddy Shriver Sarcoma Initiative. |
v
Integrin Monoclonal Antibody (CNTO 95) in Patients with Advanced
Solid Tumors 
v
integrins (CNTO 95) has been shown to inhibit angiogenesis and
tumor growth in preclinical studies. Thus, the purpose of this
study was to assess the safety and pharmacokinetics of CNTO 95 in
patients with advanced refractory solid tumors. In this phase I trial, CNTO
95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0,
28, 35, and 42, and clinical assessments, dynamic
contrast-enhanced magnetic resonance imaging (DCE-MRI), and [18F]-2-fluorodeoxyglucose
positron emission tomography (FDG-PET) were done. Patients achieving
stable disease or better were eligible for extended dosing every
3 weeks for up to 12 months. The Results were as follows: Among
the 24 enrolled patients, CNTO 95 was associated with one episode
of grade III and four episodes of grade II infusion-related fever
(all responded to acetaminophen). Of the six patients who
received extended dosing, one patient (10.0 mg/kg), with
cutaneous angiosarcoma, had a 9-month partial response. Pre-
and post-treatment lesion biopsies confirmed tumor cell 
