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PubMed2004

[Management of soft tissue sarcomas in first isolated local recurrence: a retrospective study of 83 cases].

PURPOSE: To analyse the management and clinical outcome of patients treated for a first isolated local recurrence of soft tissue sarcoma (trunk or extremities) and to identify prognosis factors. PATIENTS AND MATERIAL: This is a retrospective study of 83 adult patients treated between 1980 and 1999. Mean tumor size was 6 cm. Most sarcomas were located in extremities (N =74), were deep (N =60), and proximal (N =53). Thirty involved nerves or vessels. Histologic subtypes were mainly grade 2 (42%) or 3 (36%) histocytofibrosarcomas (49%) and liposarcomas (20%). Surgical treatment of recurrences consisted in wide excision (32 cases), marginal resection (46 cases), five patients requiring amputation. Final results were R0 (N =33), R1 (N =47) or R2 (N =3) resection. Beside surgery, six patients received neoadjuvant and seven others adjuvant chemotherapy. Twenty-three patients received postoperative external beam radiotherapy (EBRT) (mean dose 55 Gy) and 26 interstitial (192)Ir low dose rate brachytherapy (BCT) (mean dose 45 Gy for BCT alone, 22 Gy when associated with EBRT), 19 patients being re-irradiated. RESULTS: Mean follow up was 59 months. Thirty-seven (45%) tumors relapsed, 62% locally as first event. Nineteen patients developed secondary distant metastases. Multivariate analysis showed only tumour depth (P =0.05) and re-resection for primary R1 resection for the recurrence (P =0.018) being independent prognosis factors for tumour control, radiotherapy (EBRT and/or BCT) being significant in univariate analysis (P =0.05). Overall survival rate was 73, 54, and 47% at respectively 3, 5 and 10 years, and was 65, 35 and 32% after a further local recurrence. Multivariate analysis showed trunk (P =0.0001) or inferior extremity locations (P =0.023), symptomatic (P =0.001), high grade (P =0.01), deep (P = 0.01) tumours, and the occurrence of a further local failure (P =0.004) as unfavourable characteristics for overall survival. CONCLUSION: Because of the high relapse rate in this series, a first isolated local recurrence of STS increases mainly the risk of a subsequent local relapse. Quality of local treatment for the first local relapse is decisive. When a conservative treatment is feasible, it should combine surgical resection and radiotherapy, brachytherapy being the best suited in previously irradiated patients. Efforts have to be pursued to increase quality of the treatment of primary tumours, at best performed in centers that have expertise in this field.

Adult↗
PubMed2003

[Frequency of genetic diseases and cancer antecedents in 493 adults with visceral or soft tissue sarcomas].

Little is known about epidemiology of adults soft tissue and visceral sarcomas (ASTS). The frequency of previous cancers and associated genetic diseases has been analyzed out of 493 ASTS, treated between 1997 and 2002 at Oscar Lambret Cancer Center. Median age is 51, sex ratio is close to 1. Liposarcomas and malignant fibrous histiocytofibromas are the two main types (respectively 104 and 86 cases). Upper and lower limbs are the two main locations (respectively 176 and 75 cases). Fifteen patients had associated genetic disease, including 12 cases of Recklinghausen diseases. 7 out of those 15 patients have neurosarcoma. 30 patients have previous cancers, including 7 breast cancers, 3 lymphomas and 3 chronic lymphocytic leukemias. Four out of those 30 patients have two different previous cancers. 13 patients have radiation-induced sarcomas, after an average 10-year-period, and an average dose of 53 Gy. Undifferenciated sarcomas are the main histologic type (8/13), followed by angiosarcomas (2/13). Radiation-induced sarcomas are located in the chest wall (7/13), in pelvis (2/13) and head and neck (2/13). Those sarcomas are high grade (10 grade III tumours). ASTS epidemiology is complex with different risk factors depending on histologic type.

Adolescent↗
PubMed2006

Cost analysis of functional restoration surgery for extremity soft-tissue sarcoma.

BACKGROUND: Limb-sparing surgery, consisting of wide-margin tumor resection and preoperative or postoperative radiotherapy/chemotherapy, has become the surgical treatment of choice for extremity sarcomas. However, adequate tumor resection can sometimes compromise crucial limb function, necessitating functional restoration surgery. The purpose of this study was to determine the cost impact and functional outcomes of such procedures. METHODS: Patients receiving either functional restoration surgery or soft-tissue-only reconstruction following extremity soft-tissue sarcoma excision were identified. Patients were then compared along several dimensions: overall length of stay and its subdivisions, surgical time, and total charges and its subdivisions. Patients' functional outcomes were assessed with the Toronto Extremity Salvage Score. RESULTS: Sixty-seven patients who underwent 69 limb-sparing procedures were identified. Fifteen of these procedures (eight upper extremity, seven lower extremity) required functional restoration surgery; 54 of these procedures (13 upper extremity, 41 lower extremity) required only soft-tissue coverage. In the upper extremity, there was a statistically significant increase in overall length of stay (2.8 days) and its subdivisions, surgical time (3.7 hours), and total charges (12,484 dollars) and its subdivisions associated with performing functional restoration surgery. In lower extremity cases, statistically significant increases were determined in only the total charges (9190 dollars) and medical supply charges (13,204 dollars) following functional restoration. Patients who underwent functional restoration surgery had better postoperative function (mean Toronto Extremity Salvage Score, 82 versus 80), but this difference was not statistically significant. CONCLUSION: Although functional restoration surgery is more costly than soft-tissue reconstruction alone, the authors believe that the associated better functional outcome justifies its performance.

Adolescent↗
PubMed1994

[The histological features of local recurrences of soft tissue sarcomas].

Local recurrence is a well-recognised problem in soft tissue sarcomas, especially at difficult anatomical locations or after inadequate surgery. It is logical to assume that such recurrence will have an adverse effect on prognosis. In most cases the histological appearance of the recurrence is very similar to that of the primary neoplasm, in view of the fact that recurrence is most common in high-grade (poorly differentiated) sarcomas. However, in some cases, the appearance may change in one of three ways: (1) Gradual progression in grade. This phenomenon is seen most often in leiomyosarcoma or myxofibrosarcoma, in which the tumour shows progressive loss of differentiation and there is increasing risk of metastasis; (2) Abrupt change to a higher grade. This phenomenon, known as dedifferentiation, is commonest (among soft tissue lesions) in liposarcoma and is characterised usually by the emergence of an "MFH-like" pattern and an increased risk of metastasis; (3) Acquisition of differentiation. Some round cell sarcomas in children become better differentiated after chemotherapy, and some dedifferentiated adult sarcomas may revert to their well-differentiated form; occasionally the appearance of greater differentiation reflects sampling error in the primary tumour. Pathologists should be aware that significant morphological changes may occur in recurrent soft tissue sarcomas and, in analysing and diagnosing such lesions, they should always review material from the primary tumour.

Cell Differentiation↗
PubMed1987

Soft tissue sarcoma in Kuwait: a review of 114 patients.

One hundred and fourteen patients with soft tissue sarcoma were seen in the Kuwait Cancer Control Centre over a period of 11 years. Fifty per cent were liposarcomas, fibrosarcomas and rhabdomyosarcomas. The lower extremity was the commonest site involved, followed by the trunk. Treatment was in most cases surgery and adjuvant radiotherapy. The overall rate of local recurrence was 36%. Local failure was highest in abdominal tumours (66%). In extremity lesions, local recurrence was higher in proximal sites than in distal sites. Twenty-eight per cent of the patients had metastases, the lung being the commonest site (68%). The histological type had no bearing on local failure or dissemination. Histopathological grade was found to be an important prognostic indicator, both for local failure and dissemination. The rates of local recurrence and metastases were lower in low grade than in high grade tumours.

Adolescent↗
PubMed2002

Postoperative nomogram for 12-year sarcoma-specific death.

PURPOSE: Few published studies have analyzed risk factors for sarcoma-specific death. We developed and internally validated a nomogram that combines the factors to predict the probability of 12-year sarcoma-specific death using a database of 2,136 prospectively followed adult patients treated at a single institution. PATIENTS AND METHODS: Nomogram predictor variables included age at diagnosis, tumor size (< or = 5, 5 to 10, or > 10 cm), histologic grade (high or low), histologic subtype (fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve tumor, synovial, or other), depth (superficial or deep), and site (upper extremity, lower extremity, visceral, thoracic or trunk, retrointraabdominal, or head or neck). Death from sarcoma or treatment complication was the predicted end point. Three prediction methods were compared, Kaplan-Meier analysis of all possible subsets, recursive partitioning, and Cox proportional hazards regression analysis. The concordance index was used as an accuracy measure with bootstrapping to correct for optimistic bias. RESULTS: Sarcoma-specific death at 12 years was 36% (95% confidence interval, 33% to 39%). The bootstrap-corrected concordance indices were as follows: Kaplan-Meier, 0.69; recursive partitioning, 0.74; and Cox regression, 0.77. A nomogram was drawn on the basis of the Cox regression model. This nomogram was internally validated using bootstrapping and shown to have excellent calibration. CONCLUSION: A nomogram has been developed to predict 12-year sarcoma-specific death. This tool may be useful for patient counseling, follow-up scheduling, and clinical trial eligibility determination.

Age Factors↗
PubMed1997

Flow cytometric analysis of P-glycoprotein expression and drug efflux in human soft tissue and bone sarcomas.

Twenty-two fresh surgical specimens of human sarcomas (soft tissue and bone) from 20 patients were analyzed by flow cytometry for the expression of drug resistance-related P-glycoprotein (P-gp) and cellular daunorubicin (DNR) accumulation with or without the presence of DNR efflux blockers. Single-cell suspensions prepared from the tumor specimens were analyzed by dual-color flow cytometry after reaction with MRK-16 (anti-P-gp) and anti-CD45 (pan-leukocyte) antibodies. MRK-16 reactivity of tumor cells was evaluated after exclusion of CD45-positive cells by electronic gates. Parallel samples were incubated with DNR alone or in combination with DNR efflux blockers, verapamil (VPL), or dipyridamole (DPD) for determination of cellular DNR accumulation and the effect of the efflux blockers. Extensive heterogeneity was observed in both P-gp expression and DNR accumulation of the tumor specimens examined. Eight of the 22 tumor specimens had significant numbers of P-gp-positive cells. In three of the eight P-gp-positive tumors, cellular DNR accumulation was significantly increased by co-incubation with the efflux blockers VPL or DPD. These results indicate that both quantitative and functional analysis of P-gp expression may be essential in determining the cellular drug resistance phenotype of tumor cells and its correlation with therapeutic outcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

A clinicopathological study on soft tissue tumors of the head and neck.

The present study consists of 651 cases of soft tissue tumors originating in the head and neck area. Among these tumors 628 were benign (96%), while there were only 23 malignant cases (4%). In the benign group hemangiomas showed the highest incidence (47%) followed by tumors of adipose tissue (19%) and those of peripheral nerves (12%). Rare tumors consisted of nodular fascitis, hibernoma, lipoblastomatosis, glomus tumor, granular cell tumor, and chondroma. The majority of cases in the malignant group were either those of muscle origin or blood vessel origin. Excepting for two cases of rhabdomyosarcoma of the embryonal type and two cases of angiosarcoma, all showed recurrence and/or metastasis and terminated in death. Three cases of liposarcoma of either well-differentiated or myxoid type had a good prognosis with all three living for 3 or more years without any recurrence. Other malignant tumors consisted of malignant schwannoma, fibrosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, and chordoma. The age, sex, anatomical location, and differential diagnosis have also been described.

Adolescent↗
PubMed1976

Comparative pathology of bone tumors in animals, with particular emphasis on the dog.

A review of bone tumors in animals, based on cases reported in the literature and on personal examination of cases from several universities in the U.S.A. and Europe, has shown that: 1. The following bone tumors occur in decreasing order of frequency in animals: osteosarcoma, chondrosarcoma, osteochondroma, hemangiosarcoma, fibrosarcoma, and liposarcoma; 2. The dog has by far the highest frequency of bone tumors; and osteosarcomas account for approximately 80 percent of bone tumors in dog, followed by chondrosarcomas and hemangiosarcomas; 3. Bone tumors occur less frequently in the cat than in the dog, and are of essentially the same types and incidence as in the dog; 4. Sheep has a unique propensity for chondrosarcoma and primary bone tumors are rare in other species; 5. Giant cell tumors, reticulum cell sarcomas, and Ewing's sarcomas are exceptional findings in animals.

Animals↗
PubMed1994

Resectable retroperitoneal soft tissue sarcomas. The effect of extent of resection and postoperative radiation therapy on local tumor control.

BACKGROUND: Soft tissue malignancies of the retroperitoneum are rare. Surgery is commonly considered the first choice of treatment. There is still no consensus concerning the precise value of the extent of surgery and the value of additional treatment modalities. METHODS: From 1973 to 1990, 34 patients were initially treated by surgery for retroperitoneal soft tissue sarcomas at the Netherlands Cancer Institute. In a retrospective study, the prognostic effect of extent of primary surgery and postoperative radiation therapy was examined. RESULTS: Liposarcomas (47%) and leiomyosarcomas (29%) were the histologic types most commonly found. Grade of malignancy was defined as medium to high (II/III) in 44% and as low (I) in 38%. Complete (extended or marginal) resection of the tumor was achieved in 29 patients. After complete resection, the 5-year survival rate and the local recurrence rate were 35% and 63%, respectively. Extended surgery (performed in eight patients) showed a local recurrence rate of 50%. Thirteen patients received high-dose postoperative radiation therapy, which was found to have a significant favorable effect on the recurrence-free interval (P < 0.01). CONCLUSIONS: We conclude that complete (extended) resection followed by high-dose postoperative radiation therapy improves the prognostic outcome of patients with retroperitoneal soft tissue sarcomas.

Adult↗
PubMed1981

The continuing challenge of retroperitoneal sarcomas.

Treatment of 158 patients with retroperitoneal sarcomas (1951--1977) resulted in a mean five-year survival of 40% (range 37--45%) after complete excision. Only 22% (range 19--25%) of the patients were free of disease. Survival for five years after incomplete excision was 3%. Operative mortality after complete excision declined from 21 to 2% during this period. Anatomical barriers to wide resection, high-grade histology, and local recurrence were the most important factors determining survival. The need for adjuvant therapy is emphasized by a 77% recurrence rate among patients with apparent complete excision. Brachytherapy (125Iodine, 192Iridium) afterloading techniques and supplemental external radiation are recommended to improve local control and chemotherapy is indicated to diminish the potential for metastatic spread. The contribution of adjuvant therapy after complete excision in this series was difficult to assess because of the number of uncontrolled variables, different histologic types, and limited number of patients treated by multimodality therapy. Although radiation and chemotherapy may be beneficial after incomplete resection, prolonged survival was only seen in patients with liposarcoma and low-grade fibrosarcoma.

Adolescent↗
PubMed1993

Expression of MDR1/P glycoprotein in human sarcomas.

Conflicting reports of MDR1 gene expression in human tumours are observed according to whether studies are performed at the mRNA or P-glycoprotein level. We have investigated this expression in 22 clinically drug-resistant sarcomas at the mRNA level by Northern blot (NB), Dot blot (DB), in situ hybridisation (ISH), and at the protein level by immunohistochemistry (IHC) using three monoclonal antibodies (MoAbs): C219, JSB1, MRK16. Increased MDR1 mRNA expression was detected by NB, DB, and ISH in 1/22 sarcoma (an Ewing's sarcoma). ISH was perfectly correlated with DB hybridisation and confirmed the expression of tumoral cells alone. Specific staining of 100% of tumoral cells was obtained with the three MoAbs in the same sarcoma. Expression in tumoral cells of 12 other sarcomas was detected with MRK16, and positive staining of stromal cells with both C219 (1/22) and MRK16 (8/22) was observed. This study confirms that MDR1 overexpression occurs in human sarcomas but is not the principal mechanism of drug-resistance. Furthermore, positivity with one antibody does not necessarily imply the presence of P glycoprotein (P-gp) and a disparity may exist between the levels of P-gp and its mRNA in the same sample. So care must be taken in interpreting results and more sensitive techniques such as the polymerase chain reaction (PCR) could prove useful.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766.

Trabectedin [Ecteinascidin 743, Yondelis, ET 743, NSC 684766] is a tetrahydroisoquinoline alkaloid derived from the Caribbean marine tunicate, Ecteinascidia turbinata. The drug is being developed by PharmaMar (Zeltia) in partnership with Johnson & Johnson Pharmaceutical Research & Development LLC. It was synthetically isolated and developed by the University of Illinois and licensed to PharmaMar; the company has completed the hemisynthesis of agent. Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G(2) phase, while cells at the G(1 )phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. PharmaMar and Ortho Biotech Products (Johnson & Johnson) entered into an agreement in August 2001 for the joint development and commercialisation of trabectedin. PharmaMar retains commercialisation rights in Europe, including Eastern Europe. Ortho Biotech will market the product in the US, Japan and the rest of the world; Tibotec Therapeutics (a division of Ortho Biotech) will commercialise it in the US. PharmaMar will receive an initial payment from Ortho Biotech plus future milestone and royalty payments linked to development targets and sales; the upfront payment would be approximately 20 million US dollars with royalties contributing 10-20% of total sales of the drug. Although details of the licensing transaction for trabectedin were undisclosed, analysts estimate the figure to be around 100 million US dollars. Previously, PharmaMar signed an agreement granting Bristol-Myers Squibb the option to evaluate and develop as many as 12 of PharmaMar's marine-derived anticancer compounds on an exclusive worldwide basis. However, it appears that Bristol-Myers Squibb had chosen not to exercise the option. Trabectedin is undergoing clinical trials in soft tissue sarcoma (Sarcoma in the Phase table), ovarian, breast, endometrial, prostate and non-small-cell lung cancers. PharmaMar indicated in January 2004 that it intends to launch trabectedin in one of these indications in 2006. PharmaMar raised funds from a round of financing in June 2005 that will be used to fund further clinical trials of its anticancer products, including trabectedin. The US FDA granted trabectedin orphan drug status for ovarian cancer in April 2005. Trabectedin also received orphan drug status from the European Commission for the treatment of ovarian cancer in October 2003. This followed a positive opinion by the Committee for Orphan Medicinal Products (COMP) of the EMEA. Trabectedin has undergone a phase II study for the second- or third-line treatment of ovarian cancer in Europe (England and Belgium), the US and Canada. The trial was initiated in October 2002 and evaluated a weekly schedule of trabectedin (0.58 mg/m(2)) via IV infusion for 3 weeks followed by a week of rest. Final results from this study have been presented. A separate phase II trial evaluating the antitumour activity of trabectedin as a second-line therapy in advanced ovarian cancer was conducted by researchers at the Southern Europe New Drugs Organization (SENDO) in Milan, Italy. PharmaMar and Johnson & Johnson are conducting a pivotal (STS-201) trial to compare a weekly and daily dosing regimen of trabectedin among patients with advanced or metastatic soft tissue sarcoma who are unresponsive to standard chemotherapy of doxorubicin and ifosfamide. The randomised, multicentre, open-label trial has completed enrolment of 270 patients during the second quarter of 2005. Positive data from the STS-201 trial have been announced. An independent data monitoring committee has found that interim data supports a positive trend in time to disease progression favouring patients receiving the daily dosing regimen. Consequently, all patients have been offered the option of switching to the daily regimen. Final results from the STS-201 trial will form the basis of MAA re-submission with European regulatory authorities. PharmaMar has held a pre-submission meeting with the EMEA and has presented a formal letter of intent to file for approval of trabectedin for soft tissue sarcoma. Previously, PharmaMar first filed for EU registration of trabectedin for treatment of advanced soft tissue sarcoma in November 2001, which was accepted for review by the EMEA and Swiss Health Authorities. However, the CPMP confirmed its recommendation not to grant trabectedin marketing authorisation in November 2003 following PharmaMar's appeal against the CPMP's negative opinion first announced in July 2003; the opinion was adopted by a majority vote rather than by consensus. Trabectedin was granted orphan drug status in Europe for recurrent soft tissue sarcoma in 2001. It was also granted orphan drug status by the FDA for the same indication in October 2004. Phase I studies are being conducted to evaluate trabectedin in combination with doxorubicin and liposomal doxorubicin for the treatment of soft tissue sarcoma. PharmaMar is also conducting a phase I study of sequential paclitaxel followed by trabectedin in patients with soft tissue sarcoma. At additional dose levels, patients with other tumour types will be enrolled to assess the antitumour activity of the combination. The US NCI has approved and is partially funding a phase I clinical programme to determine the feasibility of using trabectedin to treat children with soft tissue sarcoma and bone sarcoma who are resistant to conventional therapies. PharmaMar has reported that trabectedin can be safely administered to children at doses up to 1100mg given as a 3-hour infusion, and that this dose will be used in further paediatric studies. Trabectedin has completed phase II studies for small round cell sarcoma and rhabdomyosarcoma, which are aggressive tumours occurring predominantly in children. A phase II study evaluating two dosing schedules of trabectedin has been conducted in patients with leiomyosarcomas or liposarcomas refractory to standard doxorubicin + ifosfamide chemotherapy. The study was conducted in Australia, Canada, Russia and the US.

Animals↗
PubMed2007

Retroperitoneal and truncal sarcomas: prognosis depends upon type not location.

BACKGROUND: Prognostication of truncal and retroperitoneal soft tissue sarcomas has traditionally been predicated on tumor location and grade. OBJECTIVE: To compare outcomes for patients with retroperitoneal or truncal sarcomas. METHODS: Retrospective analysis of a prospective cancer data registry from 1977 to 2004 was performed and outcomes were determined. RESULTS: The study group numbered 312 patients (median age 58 years, 54% male, 56% Caucasian, 14% black, 29% Hispanic). The most common tumor types were liposarcoma (35.9%), leiomyosarcoma (30.1%), and malignant fibrous histiocytoma (MFH) (19.5%). Tumor distributions were retroperitoneal (38.9%), pelvic (24.7%), abdominal (18.6%) and thoracic (17.9%). Median overall survival was 74 months. Operative resection was undertaken in 89.4% of cases and multiple surgeries (range 2-5) in 42.2%. Negative resection margins were obtained in 72.7% of patients. Univariate analysis comparing retroperitoneal versus truncal location demonstrated no significant differences in survival. Survival was improved in lower grade tumors (P < 0.02). Liposarcoma and fibrosarcoma were associated with improved survival (P < 0.0001). Multivariate analysis of pre-treatment variables showed increasing age, grade, histopathology (leiomyosarcoma and MFH) and metastasis to be associated with worse outcomes. Multivariate analysis of the treatment variables showed that surgery and negative resection margins were associated with improved survival (P < 0.001). No advantage for chemoradiotherapy could be demonstrated. CONCLUSIONS: Successful operative resection can confer prolonged disease-free survival and cure for truncal and retroperitoneal sarcomas. Histological subtype, not location, is predictive of long-term survival. Future studies should focus on histological subtype rather than tumor location for truncal and retroperitoneal sarcomas.

Adult↗