Chemotherapy in the multidisciplinary approach to soft tissue sarcomas. EORTC Soft Tissue and Bone Sarcoma Group studies in perspective.
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Antineoplastic Combined Chemotherapy Protocols↗
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Results for “soft tissue sarcomas”
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Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. The EORTC Soft Tissue and Bone Sarcoma Group.
The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft tissue sarcoma. Treatment was doxorubicin 50 mg/m2 followed by a 24 h infusion of ifosfamide 5 g/m2 plus mesna 2.5 g/m2 repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of 203 patients entered, 175 were evaluable for response. The response rate was 35% (95% CI 28-42%), with 9% of the patients achieving a complete remission and 26% a partial remission. The median time to progression was 29 weeks for all evaluable patients, and 67, 40 and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (WHO grade 3 and 4) in 73% of evaluable treatment courses. Other side-effects were rare and usually well manageable.
Adolescent↗
Principles for pathologic-anatomic diagnosis and classification of soft-tissue sarcomas.
Soft-tissue tumors are classified as frankly or potentially malignant, and as benign tumors and tumor-like lesions that can mimic soft-tissue sarcomas and other malignancies. Classification of soft-tissue sarcomas is based on knowledge or assumption of cell and tissue origin and differentiation. New principles and methods are used for the pathologic-anatomic diagnosis of these lesions. With increasing research on chromosomal aberrations and molecular biology, knowledge of the biology of soft-tissue sarcomas will grow, which in turn, will further revise current tumor classifications.
Biopsy, Needle↗
New concepts for the treatment of pediatric nonrhabdomyosarcoma soft tissue sarcomas.
Nonrhabdomyosarcoma soft tissue sarcomas form a group of rare tumors with a different biology and clinical behavior. The recently established European Pediatric Soft Tissue Sarcoma Study Group is organizing a new study devoted specifically to these tumors that were formerly treated according to the principles derived from experience with rhabdomyosarcoma, which is a clearly distinct entity. The new study includes two prospective trials, one for synovial sarcoma and the other for adult-type nonrhabdomyosarcoma soft tissue sarcomas. While surgery remains the mainstay of treatment, the role of adjuvant therapy is not yet clear and our understanding of the biology and natural history of nonrhabdomyosarcoma soft tissue sarcomas is still incomplete. This review presents the latest data on nonrhabdomyosarcoma soft tissue sarcoma treatment and outcome, and the rationale behind a risk-adapted treatment program that investigates the role of full-dose ifosfamide-doxorubicin chemotherapy in improving the response rate of patients with unresectable disease, the chances of avoiding adjuvant chemotherapy in low-risk synovial sarcomas, and the possible role of chemotherapy in high-risk adult-type soft tissue sarcomas.
Antineoplastic Combined Chemotherapy Protocols↗
Molecular determinants of soft tissue sarcoma proliferation.
Soft tissue sarcoma is an extremely rare malignant disease that includes more than 15 distinct histologic subtypes. While all share a propensity for metastasis to the lungs, the clinical presentation and pattern of spread for the specific subtypes are remarkably viable. Little is known about the etiology of soft tissue sarcoma other than several well described epidemiological associations between ionizing and other toxic agents and several of the soft tissue sarcoma histologic subtypes. The key to understanding the etiologic factors driving soft tissue sarcoma proliferation and dissemination lies in understanding the molecular mechanisms underlying these oncologic processes. Progress in this regard has been difficult because of the rarity of this disease. This report reviews the current state of knowledge for three of the most important considerations involving the molecular etiology of soft tissue sarcoma: growth factors and their receptors, nuclear and cytoplasmic oncogenes, and tumor suppressor genes. As we learn more about these molecular mechanisms leading to proliferation and dissemination of soft tissue sarcoma, molecularly based genetic therapies will become a reality for this all too devastating, albeit rare, disease.
Cell Division↗
A phase II study of M-azido-pyrimethamine ethane sulphonate (MZPES) in advanced, recurrent soft tissue sarcoma. An EORTC Soft Tissue and Bone Sarcoma Group Study.
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Adult↗
Feasibility of chemosensitivity testing in soft tissue sarcomas.
BACKGROUND: Soft tissue sarcomas comprise less than 1% of all solid malignancies. The presentation and behavior of these tumors differs depending on location and histological characteristics. Standard therapy consists of complete surgical resection in combination with adjuvant radiotherapy. The role of chemotherapy is not clearly defined and is largely restricted to clinical trials. Only a limited number of agents have proved to be effective in soft tissue sarcomas. The use of doxorubicin, epirubicin and ifosfamide allowed response rates of more than 20%. In addition, recent chemotherapy trials did not demonstrate any significant differences in efficacy for various histological subtypes. METHODS: The objective of this study was to gain additional information about the chemosensitivity of soft tissue sarcomas to seven 7 different chemotherapy agents as single drugs and 4 combinations. Therefore we used an established ATP based in-vitro testing system and examined 50 soft tissue sarcomas. Chemosensitivity was assessed using a luciferin-luciferase-based luminescence assay providing individual chemosensitivity indices for each agent tested. RESULTS: The sensitivity varied widely according to the histological subtypes. The tumors state of cellular dedifferentiation played a crucial role for the efficiency of the chemotherapeutic agents. The sensitivity also depended on the presentation of the sarcoma as a primary or recurrent tumor. The highest sensitivity was demonstrated for actinomycin D as a single agent, with 74% of the tumor samples exhibiting a high-grade sensitivity (20% low sensitivity, no resistance). The combination of actinomycin D and ifosfamide yielded a high sensitivity in 76% (2% resistance). Doxorubicin as a mono-therapy or in combination with ifosfamide achieved high sensitivity in 70% and 72%, respectively, and resistance in 6% of the samples. CONCLUSION: Chemosensitivity testing is feasible in soft tissue sarcomas. It can be used to create sensitivity and resistance profiles of established and new cytotoxic agents and their combinations in soft tissue sarcomas. Our data demonstrate measurable discrepancies of the drug efficiency in soft tissue sarcomas, sarcoma subtypes and tumor recurrencies. However, current therapeutic regime does not take this in consideration, yet.
Journal Article↗
Costs of follow-up after potentially curative treatment for extremity soft-tissue sarcoma.
Soft-tissue sarcoma is an uncommon cancer with the potential for high rates of recurrence after initial therapy. Multiple surveillance strategies have been developed to follow patients after primary treatment. The purpose of this study was to quantify the costs associated with various published post-treatment surveillance strategies. A literature review covering the years 1982-2003 was performed to find all modern published surveillance methods for extremity soft-tissue sarcoma. Only articles describing an explicit 5-year follow-up strategy were included. Total costs of 5-year follow-up were calculated for each strategy using Medicare-allowed charges as a proxy. Thirty-four articles depicting 54 strategies were identified. Total Medicare-allowed charges in year 2003 dollars ranged from 485 dollars for follow-up of low-grade sarcoma to 21,235 dollars for follow-up of high-grade sarcoma, a 42.8-fold cost differential. The average charge for these 54 strategies was 6,401 dollars. Physical examination and chest x-ray were the most commonly used screening modalities. Several guidelines have been proposed for extremity soft-tissue sarcoma patient follow-up, most prominently those of the National Comprehensive Cancer Network. The literature has yet to reflect the consensus these guidelines suggest. This study shows wide disparity in the costs of 54 specific methods of following soft-tissue sarcoma patients. Clinical trials are needed to identify an optimal surveillance strategy, one balancing gains in survival, quality of life, costs, and societal willingness to expend resources. Such trials have not been conducted due to the rarity of extremity soft-tissue sarcomas and the costs associated with conducting long-term trials. Alternatively, prospective evaluation of imaging modalities used in follow-up should be assessed as part of other trials. Computer simulation analysis also holds great promise as an assessment tool for surveillance strategies because patient participation is not required.
Extremities↗
Validity and reproducibility of histologic diagnosis and grading for adult soft-tissue sarcomas.
Soft-tissue sarcomas in adults show great variations in histologic type and grade. A valid and reproducible prognostication system is needed to select patients with soft-tissue sarcomas who could benefit from adjuvant chemotherapy. This study was conducted to assess the validity and reproducibility of diagnosis of the histologic type, MIB-1 grade, and mitosis grade, as well as of the 3 components of these grading systems. MIB-1 grade is a recently proposed grading system for predicting the prognosis of patients with adult soft-tissue sarcomas on the basis of 3 criteria (tumor differentiation, necrosis, and MIB-1 score) and replaces the mitotic count in the French system with MIB-1 immunohistochemical staining. Four surgical pathologists from 4 institutions who had experience in diagnostic soft-tissue tumor pathology reviewed 130 cases of soft-tissue sarcoma and independently determined histologic type and grade. The validity of histologic diagnosis was measured by sensitivity and specificity, and that of grading was measured by kappa statistics and percentage agreement with the diagnosis of the expert panel at the National Cancer Center, which was defined as a gold standard. Interobserver reproducibility was measured by kappa and by percentage agreement between the diagnoses of the 4 pathologists. The validity of the diagnosis of histologic type was high for synovial sarcoma, small round-cell sarcoma, and liposarcoma (sensitivity 89% to 100%; specificity, 98% to 100%) but low for malignant fibrous histiocytoma (MFH) and spindle-cell sarcoma (73% to 75%; 93% to 95%). For the grading, the validity of the MIB-1 grade was substantial (kappa = 0.68; agreement, 79%) and higher than that of the mitosis grade (0.54; 69%). The most valid component was tumor differentiation (kappa = 0.79), followed by tumor necrosis (0.66), MIB-1 score (0.59), and mitotic score (0.37). Interobserver reproducibility of histologic diagnosis was high for small round-cell sarcoma, synovial sarcoma, and liposarcoma (kappa = 0.92, 0.90, 0.87; percentage agreement = 99%, 97%, 96%, respectively); for grading, reproducibility was highest for tumor differentiation (0.78; 87%) and second highest for MIB-1 grade (0.68; 79%). We conclude that diagnosis of the type of soft-tissue sarcoma for synovial sarcoma, small round-cell sarcoma, and liposarcoma and the MIB-1 grading system based on tumor differentiation are highly valid and reproducible among Japanese pathologists who are familiar with the grading system, whereas re-evaluation of histologic criteria is essential for other histologic types such as MFH and spindle-cell sarcoma.
Antigens, Nuclear↗
Prognostic factors for recurrence and survival in head and neck soft tissue sarcomas.
BACKGROUND: Soft tissue sarcomas of the head and neck represent uncommon malignant neoplasms. With the exception of orbital and parameningeal sites, the treatment of sarcomas in the head and neck has not been standardized. The authors used a prospectively collected database of adult soft tissue sarcomas to identify prognostic factors for local control and survival. METHODS: A prospectively collected database of adult soft tissue sarcoma from 1982 to 1989 was analyzed for the impact of prognostic factors on local control and survival. Factors examined included histologic type, tumor grade, size, and resection margins. RESULTS: The overall and disease free survival at 5 years was 71 and 60%, respectively. Local control was 70% at 5 years. On univariate analysis, grade and margin status were predictors for local control. Analysis based on the Cox proportional hazard model revealed that margin status was the only significant factor in predicting local control. Grade and margin status were significant prognostic indicators for survival both on univariate analysis and in the Cox proportional hazard model. CONCLUSION: Patients with head and neck sarcomas should undergo wide excision with the removal of all gross disease and the acquisition of negative, microscopic surgical margins. Patients with positive margins should receive adjuvant radiotherapy for local control. High grade lesions place patients at risk for local recurrence and distant dissemination. Investigational regimens designed to prevent metastatic disease should be performed.
Adolescent↗
Altered expression of G1 regulatory proteins in human soft tissue sarcomas.
CONTEXT: Soft tissue sarcomas constitute a heterogeneous group of tumors for which tumorigenesis is not fully understood. Altered cell-cycle regulation may underlie the development and/or progression of human malignancies. However, data concerning the occurrence of cell-cycle aberrations in soft tissue sarcomas are very limited. OBJECTIVES: To detect the abnormal features of cell-cycle regulatory proteins in soft tissue sarcomas and to determine the potential role of these proteins in clinical behavior. DESIGN: The p53 and Rb-cyclin D pathways were investigated by immunohistochemical studies of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins, respectively. RESULTS: Of the 67 sarcomas analyzed, nuclear accumulation of p53 was detected in 25 samples (37%), and overexpression of mdm2 was found in 16 samples (24%). Both p53 and mdm2 expression correlated with tumor grade. Abnormalities involving the Rb-cyclin D pathway were identified in all of the tumors by the altered expression of either pRb (72%) or p16 (94%). Fourteen (21%) and 64 (96%) cases demonstrated cyclin D1 or cdk4 expression, respectively. Overexpression of cyclin D1 showed an association with pRb and p53. There was no correlation between pRb, p16, cyclin D1, or cdk4 and tumor grade or relapse. CONCLUSION: Disturbance in the cell-cycle regulatory system involving the p53 pathway and the Rb-cyclin D pathway is relatively frequent in soft tissue sarcomas and may be a contributing factor in the tumorigenesis of these tumors. The alterations in the Rb-cyclin D pathway probably constitute an early event, whereas the abnormalities in the p53 pathway seem to be involved in tumor progression. It is noteworthy that cyclin D1 may play a key role in linking both pathways.
Cell Cycle Proteins↗
Treatment options for children with nonrhabdomyosarcoma soft tissue sarcoma.
Nonrhabdomyosarcoma soft tissue sarcomas account for approximately 40% of all soft tissue sarcomas in children. Although these tumors are typically grouped together, individual tumor types with different biological characteristics have been found that may impact on the optimal therapy for each type of sarcoma in the future. Most of the current information regarding this tumor comes from the adult literature. Wide local excision appears to provide the best chance of cure. Future studies are needed to determine which adjuvant therapies are most useful in improving local control and overall survival in the different subsets of patients.
Chemotherapy, Adjuvant↗
Chromosomal analysis and the classification of soft tissue sarcomas.
Seventeen soft tissue sarcomas were karyotyped and the chromosomal findings were compared with those in the literature. Some cases were easily classified (immuno)histologically, whereas others defied classification. In four cases with unequivocal histology, a "characteristic" chromosomal abnormality was found. In one case a diagnosis that was doubtful on histologic grounds was supported by the chromosomal findings, whereas in three other cases, the chromosomal pattern led to reconsideration of the histologic diagnosis. The remaining cases either showed chromosomal abnormalities with hitherto undescribed breakpoints or breakpoints described in tumors with different histology. The results extend the knowledge of chromosomal abnormalities in soft tissue sarcomas. Most importantly, the present approach demonstrates that close collaboration between the surgical pathologist and the cytogeneticist may improve the classification of soft tissue sarcomas.
Adolescent↗
Minimal residual disease in soft-tissue sarcomas.
Soft-tissue sarcomas are characterized by the development of disease recurrence in a distinct subgroup of patients. Despite intense efforts in applying multimodal treatment, the risk of local recurrence or distant metastases remains a considerable threat to patients with soft-tissue sarcoma. This review focuses on the efforts aimed at defining local and systemic tumor extent at the level of minimal residual disease (MRD) tumor cell detection. Examination of MRD in soft-tissue sarcomas has experienced a significant boost from the definition of fusion transcripts resulting from stable chromosomal translocations. The sensitivity and exclusive specificity of the reverse-transcription polymerase chain reaction (RT-PCR) protocols have given insights into tumor cell residues in nearly all body compartments. The accumulated data demonstrates that even after oncologic resections most patients will still harbor a significant tumor burden. Clinical concepts arising out of these new data are under way. One of these concepts is the targeting of the fusion transcript for therapy. However, this approach is still restricted to the experimental setting. The development of clinical applications remains a challenging task, requiring the treatment of as many patients as possible in centers specializing in all of the affected disciplines.
Adult↗
Incidence, investigations and staging of soft-tissue sarcoma.
Soft-tissue sarcomas account for only 1% of all malignant lesions. The Canadian Sarcoma Group encourages the investigation and management of these tumours at tertiary institutions, where a multidisciplinary team can handle the complex problems. Staging of these tumours implies accurate anatomic determination of the extent of disease, the histogenesis and grade of the tumours and the presence of regional or distant metastases. Arteriography, computed tomography and magnetic resonance imaging can accurately define the tumour before biopsy. The biopsy should be muscle-splitting to minimize contamination of additional compartments and should allow inclusion of the biopsy site at definitive surgical resection. It should be done at the institution where definitive management will be performed. Regional lymph-node involvement can be detected using magnetic resonance imaging or gallium scanning, whereas for distant metastases, specifically of lung, computed tomography is the method of choice. To date no one staging system for soft-tissue sarcomas has been universally accepted. A hybrid, encompassing the advantages of each system, is being formulated.
Biopsy↗
[Results of oncological reoperation in primary soft tissue sarcomas].
BACKGROUND: Soft tissue sarcomas (STS) are frequently resected incompletely or without an adequate margin. In such clinical situations an oncological re-resection (wide or compartmental resection or amputation) is recommended. Here, we evaluate the results of oncological re-resection for STS. METHODS: Prospectively gathered data on 67 patients who underwent oncological re-resection after inadequate (intracapsular or marginal) surgery for primary soft tissue sarcomas were analyzed. RESULTS: STS were located in the extremities (85%) and trunk (15%). Advanced UICC stages (1992, 4th edn., 2nd Rev.), IIB-IIIB predominated (66%). Twenty-five patients received intraoperative radiotherapy. Morbidity of re-resection was 28.4%. Residual tumor was detected in 64% of the specimens and clear margins were obtained in 60 patients (90%). With a median follow-up of 57 months the overall local control in patients with tumor-free resection margins was 88% (UICC IA-IIA 100%, IIB-IIIB 82%). Patients treated by adjuvant intraoperative radiotherapy for UICC stages IIB-IIIB with clear margins achieved 90% local control. The 5-year overall survival rate was 87% in patients with tumor-free resection margins. CONCLUSIONS: These findings support the strategy of oncological re-resection after previously non-oncological surgery of STS and imply that re-resection is the prerequisite for any effective adjuvant therapy modality.
Adult↗
[Place and technical aspects of external beam radiation therapy in the treatment of adult soft tissue sarcomas].
In soft tissue sarcoma, surgical resection remains the cornerstone of therapy for localized disease. Quality of margins is very important to evaluate. In case of marginal or incomplete resection, a new enlarged surgical resection should always be discussed before administration of any adjuvant treatments. Many retrospective studies and 2 randomized studies (one of adjuvant brachytherapy and one of external beam radiotherapy) have shown that adjuvant radiotherapy after complete surgery reduces significantly the risk of local recurrence in extremity soft tissue sarcomas. Combination of surgery and pre- or postoperative radiotherapy has therefore become the standard treatment with a local recurrence rate <or=25% and very few amputations. A recent randomized study has compared pre-op to postoperative radiotherapy. The results in terms of local control are similar in both arms (93 and 92% at 5 years) but the risk of early complications is higher in the preoperative arm and the risk of late sequela is higher in the postoperative arm. Surgical resection without radiotherapy may be considered after discussion at best within a multidisciplinary meeting, if surgical margins are considered satisfactory, in superficial, small tumours and low-grade. In retroperitoneal sarcomas, adjuvant radiotherapy is not a standard. It may decrease the risk of local recurrence but at the price of an increased gastro-intestinal toxicity. A randomized trial is warranted. Because of its rarity, and the risk of recurrence both local and metastatic, treatment should preferentially be discussed with a multimodality specialized approach.
Adult↗
Adult soft tissue sarcoma.
BACKGROUND: Soft tissue sarcomas (STS) are a group of anatomically and histologically diverse tumours. They account for about 1% of adult malignancies, and about 50% of patients diagnosed with sarcoma eventually die of the disease. These tumours are grouped together because of shared biological characteristics and treatment responses. METHODS: A review of the key literature on STS was undertaken, complemented by data taken from the prospectively accumulated database of 3442 patients treated for STS at Memorial Sloan-Kettering Cancer Center (MSKCC) from July 1982 to December 1997. RESULTS: Despite advances in knowledge of the molecular genetics of STS, the aetiology in most cases remains elusive. Management has been gradually refined over the last two decades. Core biopsy usually provides enough material for diagnosis. Computed tomography and magnetic resonance imaging provide a similar amount of information, which is usually adequate for surgical planning. Amputation as standard treatment for extremity lesions has been replaced by limb-sparing surgery in about 90% of patients. The role of adjuvant radiation has been further defined: it has been shown to be unnecessary for completely excised tumours less than 5 cm in diameter, but effective in decreasing local recurrence for others. Adjuvant chemotherapy has been controversial for many years. Recent meta-analysis of randomized trial results has found a small reduction in local and distant relapse, and a trend to better overall survival. Recurrent or metastatic disease should be completely excised if possible. CONCLUSIONS: Soft tissue sarcoma requires multidisciplinary care tailored to the individual patient and tumour for optimal results.
Adult↗