Primary Extremity Soft Tissue Sarcoma Research Articles

Body composition predictors of therapy response in patients with primary extremity soft tissue sarcomas.

Background Recent studies have suggested that the quantity and quality of adipose tissue and muscle, assessed on non-contrast computed tomography (CT), may serve as imaging biomarkers of survival in patients with and without neoplasms. Purpose To assess body composition measures that could serve as predictors of therapy response in patients with extremity soft tissue sarcomas treated with radiation therapy and surgery. Material and Methods The study was IRB-approved. Sixty patients had a history of extremity soft tissue sarcoma and underwent FDG-PET/CT prior to radiation therapy and surgical resection. Cross-sectional areas and CT attenuation (HU) of abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and psoas muscle were assessed on non-contrast CT. Clinical information on predictors of tumor recurrence and post-surgical wound infections were recorded. Cox proportional hazard models were used to determine longitudinal associations between body composition and tumor recurrence/wound infections. Results Twenty-three tumor recurrences occurred over a follow-up period of 43 ± 35 months. Higher SAT and lower psoas attenuation were associated with tumor recurrence which remained significant after adjustment for covariates ( P ≤ 0.01). There were 13 post-surgical wound infections. Higher VAT and SAT attenuation were associated with post-surgical wound infections ( P < 0.04); however, VAT attenuation lost significance after adjustment for covariates. Conclusion Abdominal adipose tissue and psoas muscle attenuation assessed on non-contrast CT may predict tumor recurrence and post-surgical infections in patients with extremity soft tissue sarcomas.

Patterns of disease relapse in primary extremity soft tissue sarcoma

Background Extremity soft-tissue sarcomas comprise a range of distinct histological subtypes. This study aimed to characterize the patterns of disease relapse in patients undergoing resection of primary extremity soft-tissue sarcoma. Methods All patients who had resection of primary extremity soft-tissue sarcoma at the Royal Marsden Hospital between January 2004 and January 2014 were identified from an institutional database. Results In the period examined, 556 patients underwent resection. The most common histological subtypes were undifferentiated pleomorphic sarcoma (169 patients, 30·4 per cent), well differentiated liposarcoma (63, 11·3 per cent), myxoid liposarcoma (62, 11·2 per cent), myxofibrosarcoma (54, 9·7 per cent) and leiomyosarcoma (39, 7·0 per cent). Local recurrence-free survival (LRFS) did not differ significantly between histological subtypes (P = 0·222). Distant metastasis-free survival (DMFS) and disease-specific survival (DSS) were found to differ significantly between subtypes (P < 0·001 for both DMFS and DSS), with the worst outcomes in patients with undifferentiated pleomorphic sarcoma (5-year survival rate: 56·8 (95 per cent c.i. 52·5 to 61·1) per cent for DMFS; 60·1 (55·6 to 64·6) per cent for DSS). However, on multivariable analysis, histological subtype was not found to be independently prognostic for LRFS, DMFS or DSS. Metastatic disease developed in 149 patients, with the lungs being the most common site of first metastasis (120 patients, 80·5 per cent). The site of first metastasis differed between subtypes, with extrapulmonary metastases predominant in myxoid liposarcoma (11 of 13 patients; P < 0·001). Conclusion Although histological subtype was not found to be an independent prognostic factor for oncological outcomes, the site of first metastasis differed significantly between subtypes.

Patterns of disease relapse in primary extremity soft-tissue sarcoma.

Extremity soft-tissue sarcomas comprise a range of distinct histological subtypes. This study aimed to characterize the patterns of disease relapse in patients undergoing resection of primary extremity soft-tissue sarcoma. All patients who had resection of primary extremity soft-tissue sarcoma at the Royal Marsden Hospital between January 2004 and January 2014 were identified from an institutional database. In the period examined, 556 patients underwent resection. The most common histological subtypes were undifferentiated pleomorphic sarcoma (169 patients, 30·4 per cent), well differentiated liposarcoma (63, 11·3 per cent), myxoid liposarcoma (62, 11·2 per cent), myxofibrosarcoma (54, 9·7percent) and leiomyosarcoma (39, 7·0 per cent). Local recurrence-free survival (LRFS) did not differ significantly between histological subtypes (P = 0·222). Distant metastasis-free survival (DMFS) and disease-specific survival (DSS) were found to differ significantly between subtypes (P < 0·001 for both DMFS and DSS), with the worst outcomes in patients with undifferentiated pleomorphic sarcoma (5-year survival rate: 56·8 (95 per cent c.i. 52·5 to 61·1) per cent for DMFS; 60·1 (55·6 to 64·6) per cent for DSS). However, on multivariable analysis, histological subtype was not found to be independently prognostic for LRFS, DMFS or DSS. Metastatic disease developed in 149 patients, with the lungs being the most common site of first metastasis (120 patients, 80·5 per cent). The site of first metastasis differed between subtypes, with extrapulmonary metastases predominant in myxoid liposarcoma (11 of 13 patients; P < 0·001). Although histological subtype was not found to be an independent prognostic factor for oncological outcomes, the site of first metastasis differed significantly between subtypes.

Primary Extremity Soft Tissue Sarcomas: Does Local Control Impact Survival?

The objective of this study was to evaluate the adequate margin in the local treatment of extremity soft tissue sarcomas (ESTS) and understand the relationship between local control and overall survival (OS). All consecutive patients treated for a primary ESTS at a single center from 1993 to 2012 were reviewed. In all, 531 patients were included. Twelve (2%) underwent a first-line amputation. The resections were R0/R1/not available in 434 (82%), 92 (17%), and 5 patients (1%). The median tumor size was 8cm, and the tumor grades were 1 (n=132), 2 (n=201), and 3 (n=195). The median size of the minimal margin was 2mm on fixed specimen. Preop or postop chemotherapy was administered to 222 patients, and 414 received radiotherapy. With a median follow-up period of 7 years, the 5-year actuarial local recurrence (LR) rate and OS were 8% (95% CI, 6-11%) and 80% (95% CI, 76-83%). Predictors of worse OS were grade 3, leiomyosarcoma, male gender, and age >60 years, whereas tumor size, margin status, and LR were not. Among patients requiring re-excision (n=252), the presence of residual cells correlated with OS but not LR. After preoperative treatment, a percentage of residual cells ≥10% correlated with OS but not LR. In the multivariate analysis, specific subtypes (epithelioid sarcoma and myxofibrosarcoma) and margin size <1mm correlated with LR, whereas grade and the tissue constituting the surgical margins did not. Specific subtypes and surgical margin size <1mm were correlated with a higher LR. Neither the margin status nor LR affect OS.

Chemotherapy, Irradiation, and Surgery for Function-preserving Curative Therapy of Primary Extremity Soft Tissue Sarcomas

To determine if aerosol granulocyte macrophage-colony-stimulating factor (GM-CSF) decreases the 2-year pulmonary metastasis rate for soft tissue sarcoma. Patients with high-grade soft tissue sarcomas were treated with 2 cycles of ifosfamide, mitomycin, doxorubicin, and cisplatin plus GM-CSF subcutaneous followed by 45 Gy irradiation with concurrent 2 cycles of mitomycin, doxorubicin, and cisplatin followed by surgery +/- intraoperative radiation or brachytherapy. Aerosol GM-CSF (250 mcg twice a day) was administered for 1 week every other week 3× during neoadjuvant therapy and beginning 4 weeks postoperatively every other week 5×. A total of 39 patients were enrolled between November 2001 and April 2006. The median age was 51 years (range, 19 to 65 y). The median lesion size was 9 cm (range, 2.3 to 26.7 cm). Seventy-six percent experienced grade 3-4 hematologic toxicity. Twenty-four of the first 35 evaluable patients (69%; 95% CI, 41%-84%) were free of pulmonary metastasis at 2 years. A total of 82% (95% CI, 70%-95%) of patients were still alive after 3 years, with a median follow-up of 5.5 years (range, 3.4 to 7.6 y). A total of 58% (95% CI, 44%-76%) of patients remained progression free after 3 years. The addition of aerosol GM-CSF to combined chemotherapy, irradiation, and surgery for soft tissue sarcomas did not achieve the study endpoint to decrease the 2-year pulmonary metastasis rate.

The Impact of Perioperative Chemotherapy Timing in Conjunction With Postoperative External-Beam Radiation Therapy on Extremity Soft-Tissue Sarcomas Outcome.

The perioperative management of primary extremity soft-tissue sarcomas (ESTS) is multidisciplinary including radiation therapy and chemotherapy (CT). The interplay between these modalities and the relative importance of each remain unclear. Our study aims to determine the relative impact of CT and radiotherapy on the outcome of ESTS patients treated with limb-sparing surgery. A retrospective review of ESTS registry yielded 97 patients who received neoadjuvant chemotherapy (NCT) and/or adjuvant CT with or without external-beam radiation therapy (EBRT) from January 1, 1999 through December 31, 2009. The cohort comprised 56 males and 41 females whose age at surgery ranged from 17 to 83 years (median, 56 y). Tumor characteristics included the following: 73 lower ESTS; 70 grade 3 lesions; 63 American Joint Committee on Cancer stage III tumors; and 27 lesions with positive microscopic margins. The following outcome parameters were evaluated for the patients' subgroups: overall survival (OS), locoregional control (LRC), and disease-free survival (DFS). EBRT was delivered postoperatively to 81 patients and 49 received CT. Median EBRT dose was 63 Gy (range, 50 to 72 Gy). At median follow-up of 54.6 months, the 5-year OS, LRC, DFS was 68.9%, 87.1%, 66.5%, respectively. On multivariate analysis, positive surgical margins negatively impacted LRC, DFS, and OS (hazard ratio [HR]=10.43, P=0.004), (HR=2.37, P=0.03), (HR=2.26, P=0.038), respectively. EBRT use improved LRC (HR=0.24, P=0.018) and DFS (HR=0.36, P=0.021). The impact of EBRT on DFS was retained (HR=0.28, P=0.006) in the high-grade ESTS subgroup who received CT. The 5-year local failure rate was 6.5%, 28.6%, and 22.2% (P=0.019) for patient receiving NCT, adjuvant chemotherapy, and no CT, respectively. Our data support the use of NCT followed by limb-sparing surgery and adjuvant EBRT in ESTS for local failure reduction with a trend toward improved DFS.

Anticipated Intraoperative Electron Beam Boost, External Beam Radiation Therapy, and Limb-Sparing Surgical Resection for Patients with Pediatric Soft-Tissue Sarcomas of the Extremity: A Multicentric Pooled Analysis of Long-Term Outcomes

To perform a joint analysis of data from 3 contributing centers within the intraoperative electron-beam radiation therapy (IOERT)-Spanish program, to determine the potential of IOERT as an anticipated boost before external beam radiation therapy in the multidisciplinary treatment of pediatric extremity soft-tissue sarcomas. From June 1993 to May 2013, 62 patients (aged <21 years) with a histologic diagnosis of primary extremity soft-tissue sarcoma with absence of distant metastases, undergoing limb-sparing grossly resected surgery, external beam radiation therapy (median dose 40 Gy) and IOERT (median dose 10 Gy) were considered eligible for this analysis. After a median follow-up of 66 months (range, 4-235 months), 10-year local control, disease-free survival, and overall survival was 85%, 76%, and 81%, respectively. In multivariate analysis after adjustment for other covariates, tumor size >5 cm (P=.04) and R1 margin status (P=.04) remained significantly associated with local relapse. In regard to overall survival only margin status (P=.04) retained association on multivariate analysis. Ten patients (16%) reported severe chronic toxicity events (all grade 3). An anticipated IOERT boost allowed for external beam radiation therapy dose reduction, with high local control and acceptably low toxicity rates. The combined radiosurgical approach needs to be tested in a prospective trial to confirm these results.

Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity

A joint analysis of data from three contributing centres within the intraoperative electron-beam radiation therapy (IOERT) Spanish program was performed to investigate the main contributions of IORT to the multidisciplinary treatment of high-risk extremity soft tissue sarcoma (STS). Patients with an histologic diagnosis of primary extremity STS, with absence of distant metastases, undergoing limb-sparing surgery with radical intent, external beam radiotherapy (median dose 45 Gy) and IOERT (median dose 12.5 Gy) were considered eligible for participation in this study. From 1986-2012, a total of 159 patients were analysed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316 years), 5-year local control (LC) was 82 %. The 5-year IOERT in-field control, disease-free survival (DFS) and overall survival (OS) were 86, 62 and 72 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 5.20, p < 0.001). With regard to IOERT in-field control, incomplete resection (HR 4.88, p = 0.001) and higher IOERT dose (≥ 12.5 Gy; HR 0.32, p = 0.02) retained a significant association in multivariate analysis. From this joint analysis emerges the fact that an IOERT dose ≥ 12.5 Gy increases the rate of IOERT in-field control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo- and adjuvant systemic therapy.

Impact of Margin Status and Local Recurrence on Soft-Tissue Sarcoma Outcomes

The impact of local recurrence and surgical resection margin status on survival in extremity soft-tissue sarcomas remains to be clearly defined. Our aim was to conduct a retrospective analysis of prospectively collected data to determine the prognostic relevance of positive resection margins and local recurrence for extremity soft-tissue sarcomas for survival. Three hundred and sixty-three patients who underwent resection of localized primary extremity soft-tissue sarcomas with curative intent were selected from the United States Department of Defense Automated Central Tumor Registry. Outcomes for local recurrence, distant recurrence, disease-specific survival, and overall survival were analyzed according to clinical, pathological, and treatment variables with use of the Kaplan-Meier method (log-rank test) and the multivariate Cox regression model. Positive margins (hazard ratio, 1.99 [95% confidence interval, 1.15 to 3.45]), local recurrence (hazard ratio, 2.93 [95% confidence interval, 1.38 to 6.23]), and distant recurrence (hazard ratio, 12.13 [95% confidence interval, 5.97 to 24.65]) were significantly associated with overall survival on multivariate Cox regression analysis. However, for disease-specific survival, local recurrence was not significant and tumor size of >10 cm (hazard ratio, 2.83 [95% confidence interval, 1.15 to 6.95]), positive margins (hazard ratio, 1.95 [95% confidence interval, 1.05 to 3.63]), and distant recurrence (hazard ratio, 9.46 [95% confidence interval, 4.37 to 20.47]) were independent adverse prognostic factors. The disease-specific survival rate for patients with localized soft-tissue sarcomas was 89% (95% confidence interval, 85% to 92%) for five years and 75% (95% confidence interval, 70% to 81%) for ten years. Positive surgical margins are consistently associated with adverse survival-related outcomes in localized soft-tissue sarcomas of the extremity. Local recurrence had a significant impact on overall survival, but not on disease-specific survival.

Liver Metastasis of Extremity Pleomorphic Liposarcoma Treated with Hepatic Resection

The WHO defines pleomorphic liposarcoma as a pleomorphic, high-grade sarcoma containing a variable number of pleomorphic lipoblasts. Pleomorphic liposarcoma represents the rarest subtype of liposarcoma, accounting for approximately 5 % of all liposarcomas and 20 % of pleomorphic sarcomas [1]. Clinically, pleomorphic liposarcoma represents an aggressive neoplasm most often occurring in the limbs of older adults (the lower extremity, particularly the thigh, is the most frequent location) with a peak incidence between the fifth and sixth decade of life. The trunk and the retroperitoneum represent less frequently affected anatomic sites [1].There is an equal sex distribution. Liver as the first and sole site of metastases from a primary extremity softtissue sarcoma is extremely rare [2]. There are only two case reports in English literature with the liver as the first site of spread from an extremity myxoid liposarcoma [3, 4]. To the best of the author's knowledge, there are no case reports of liver metastasis of pleomorphic liposarcoma. There is limited information regarding the appropriate management of these lesions. We report an extremely rare and unusual case of a pleomorphic liposarcoma of the left thigh with hepatic metastasis, treated by liver resection. The patient is well at 3 months after liver resection. Case Report

Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution

BackgroundTo assess changes in survival over time of extremity soft tissue sarcoma (ESTS) patients treated at a single reference institution. Patients and methodsPatients with primary localized adult-type ESTS surgically treated at our institution between 1987 and 2007 were retrospectively reviewed. Patients were categorized into four 5-year groups according to the timing of their first operation. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DMs) were calculated for each time period. ResultsA total of 1094 patients were identified. Median follow-up was 81 months. CCI of SSM and LR were significantly better in period 4 in comparison to periods 1–3 (P < 0.001 for both end points), dropping, respectively, from 15% to 6% and from 23% to 9%. An overall improvement of DMs-free survival at 5 years could be detected in the latter period, as well as a better postmetastasis survival. ConclusionsReference institutions for sarcomas may have improved their outcome in the last years. Although biases of retrospective analyses as well as the effect of institutional learning curves need to be discounted, it is possible that optimal exploitation of a series of subtle improvements in sarcoma treatment may make a difference in results currently achievable.

RTOG Sarcoma Radiation Oncologists Reach Consensus on Gross Tumor Volume and Clinical Target Volume on Computed Tomographic Images for Preoperative Radiotherapy of Primary Soft Tissue Sarcoma of Extremity in Radiation Therapy Oncology Group Studies

To develop a Radiation Therapy Oncology Group (RTOG) atlas delineating gross tumor volume (GTV) and clinical target volume (CTV) to be used for preoperative radiotherapy of primary extremity soft tissue sarcoma (STS). A consensus meeting was held during the RTOG meeting in January 2010 to reach agreement about GTV and CTV delineation on computed tomography (CT) images for preoperative radiotherapy of high-grade large extremity STS. Data were presented to address the local extension of STS. Extensive discussion ensued to develop optimal criteria for GTV and CTV delineation on CT images. A consensus was reached on appropriate CT-based GTV and CTV. The GTV is gross tumor defined by T1 contrast-enhanced magnetic resonance images. Fusion of magnetic resonance and images is recommended to delineate the GTV. The CTV for high-grade large STS typically includes the GTV plus 3-cm margins in the longitudinal directions. If this causes the field to extend beyond the compartment, the field can be shortened to include the end of a compartment. The radial margin from the lesion should be 1.5 cm, including any portion of the tumor not confined by an intact fascial barrier, bone, or skin surface. The consensus on GTV and CTV for preoperative radiotherapy of high-grade large extremity STS is available as web-based images and in a descriptive format through the RTOG. This is expected to improve target volume consistency and allow for rigorous evaluation of the benefits and risks of such treatment.

Quality of surgical margins and local recurrence in primary extremity soft tissue sarcoma (STS).

10068 Background: In previous studies, quality of margins after resection of primary STS of extremity was only defined by their size. Methods: We analyzed all patients (pts) with primary limbs STS addressed for surgery in our institution from 1997 to 2008 in a prospective data base. All histological specimens were reviewed and quality of margins prospectively evaluated. The minimum margin (in mm) and the type of surrounding tissue (muscle, aponevrosis, fat, periosteum) were registered on fixed specimen. The endpoints were mortality, local recurrence (LR) and distant metastasis analyzed by Cox multivariate models. Results: There were 450 pts: 50% were operated at first after pre-operative biopsy (Group A) and 50% had a second extended resection after unplanned surgery (Group B). 81% were deep. Mean tumor size was 12cm in group A and 7cm in group B (p<.0001). Grades were: 1 (21%), 2 (33%), 3 (47%). 99% had limb sparing surgery with 14% flap reconstruction. Margins (mm) were 0 in 14%, [0 – 1]: 28%, [1 – 5]: 37%, [5 – 10]: 11%, >10: 10%. Clear median minimum margin was 2mm (0.5 – 35). Tissue type varied according to width, with higher proportion of aponevrosis and periosteum below 2mm (61%) than above (29%) (p<.0001). In group B, residual tumor was found in 61% of pts. 36% of pts received chemotherapy (neo-adjuvant 88%, adjuvant 12%), 18% had neo-adjuvant isolated limb perfusion. 74% of pts received radiotherapy (post op 93%, pre op 6%) with a median dose of 50Gy (30 to 70Gy). Among pts who had neo adjuvant ILP/CT/RX, the mean% of viable cells was 36, 44 and 46 respectively. With a median follow up of 4.2 yrs, the 5-yr OS, LR and metastatic rates were 79%, 8% and 22% respectively. In the multivariate analysis, high grade (p<.0001) and large tumor size (p<.002) were the only predictive factors for shorter OS. Absence of clear margins (0mm) was significantly predictive of LR (p<.001). Conclusions: In this high risk series, a very low rate of local recurrence was observed despite a small median minimum margin. This suggests that the quality of margins should integrate the quality of the tissue involved. A planned extended surgery associated with combined treatments guarantees a very low risk of amputation or re intervention. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer, PharmaMar Novartis, Pfizer, PharmaMar

Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity

Evolving evidence suggests that, in selected patients with tumour category 1 (T1) extremity soft tissue sarcoma (ESTS), surgery alone offers satisfactory results without decreasing survival. This study assessed the effect of sarcoma treatments on survival outcomes of T1 ESTS in a population-based data set. Using the Surveillance, Epidemiology, and End Results database, 1618 patients with primary ESTS underwent limb-sparing surgery. Multivariable analysis was used to assess the impact of radiotherapy on overall survival (OS) and sarcoma-specific survival (SSS), adjusting for co-variables. Some 803 patients (49.6 per cent) underwent surgery alone for T1 ESTS. Radiotherapy in patients with low- and high-grade tumours did not result in any significant difference in OS or SSS. When stratified by grade, multivariable analysis showed that adjuvant radiotherapy was not an independent predictor of SSS (hazard ratio (HR) 1.05; P = 0.906) or OS (HR 0.89; P = 0.695) in low-grade tumours. Neither was radiotherapy a significant predictor of SSS (HR 0.87; P = 0.608) or OS (HR 0.67; P = 0.071) in high-grade tumours. This population-based appraisal validated previous evidence supporting a role for surgery alone in the treatment of T1 ESTS. Future policies should be tailored to offer patients minimal yet effective therapy, rather than maximum tolerated therapy.

Extremity Soft Tissue Sarcoma in a Series of Patients Treated at a Single Institution

To improve understanding of what is adequate in local treatment of extremity soft tissue sarcomas (ESTS), to maximize the ratio between local control, limb preservation and prognosis. Nine hundred ninety-seven consecutive patients affected by primary ESTS were reviewed. Size, depth, histotype and grade of the tumor, margin status (R0, R1, R2) of surgical resection, and adjuvant treatments were analyzed. Univariable and multivariable analysis were carried out. For the subgroup of R1 resection the presence/absence of the tumor at the inked surface and the presence/absence of an anatomic barrier were also considered. Five- and 10-year mortality estimates (95% confidence interval) were 0.29 (0.20-0.38) and 0.38 (0.28-0.49) in R1 cases, and 0.16 (0.13-0.19) and 0.19 (0.16-0.23) in R0 cases (P = 0.0003). Size, grade, depth, and histologic subtype were also significant predictor of mortality. Significant determinants for local relapse were surgical margins, radiation therapy, and histologic subtype. In the subset of R1 resections trends towards a better local control for R1 negative cases and histology other than myxofibrosarcoma were identified. Significant determinants for distant metastases were size, grade and histologic subtype of the tumor but not surgical margins. Quality of surgical margins independently predicted local control and survival. The effect on survival was directly mediated by local recurrence to proximal sites invading the abdomen/thorax, and this may indeed be the main way by which quality of surgery directly impacts the final prognosis of ESTS patients.

Comparison of conventional radiotherapy and intensity-modulated radiotherapy for post-operative radiotherapy for primary extremity soft tissue sarcoma

Introduction Doses in conventional radiotherapy for extremity soft tissue sarcoma (STS) potentially exceed normal tissue tolerances. This study compares 3D-conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) in optimising target volume coverage and minimising integral dose to organs-at-risk (OAR). Methods and materials Ten patients undergoing post-operative radiotherapy for extremity STS were assessed. PTV 1 was defined as tumour bed plus 5 cm superiorly/inferiorly and 3 cm circumferentially, PTV 2 was defined as 2 cm isotropically. OAR were defined as whole femur, neurovascular bundle, tissue corridor and normal tissue outside PTV 1. For each patient 2-phase 3D-CRT was compared to 2/3 field (2/3f) and 4/5 field (4/5f) IMRT with simultaneous integrated boost (SIB). The primary planning objective was to minimise femur and skin corridor dose. Volumetric analysis and conformity and heterogeneity indices were used for plan comparison. Results A planning protocol containing dose/volume constraints for target and OAR was defined. 4/5f IMRT showed greatest conformity and homogeneity. IMRT resulted in significantly lower femur V45 using 2/3f ( p = 0.01) and 4/5f ( p = 0.0009) than 3D-CRT. 4/5f IMRT resulted in significantly lower normal tissue V55 ( p = 0.004) and maximum dose ( p = 0.04) than 3D-CRT. Conclusions A reproducible set of planning guidelines and dose–volume constraints for 3D-CRT and IMRT planning for extremity sarcomas was devised. 4/5f IMRT with SIB resulted in better target coverage and significantly decreased OAR dose. Further evaluation of this technique within a clinical trial is recommended to demonstrate that the technical benefit of the more complex technique translates into patient-derived benefit by reducing late toxicity.

Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma

Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.

A Nomogram for Local Recurrence Risk in Extremity Soft Tissue Sarcomas after Limb-sparing Surgery without Adjuvant Radiation

Two prospective randomized trials have shown local control benefit for adjuvant radiation (RT) in patients with primary extremity soft tissue sarcomas (STS). Nevertheless, whether adjuvant RT can be safely omitted in select patients with extremity STS continues to be widely debated. The purpose of this study is to develop a nomogram based on clinicopathologic factors to quantify the risk of local recurrence after limb-sparing surgery without adjuvant RT.

Acquisition of biologically relevant gene expression data by Affymetrix microarray analysis of archival formalin-fixed paraffin-embedded tumours

Robust protocols for microarray gene expression profiling of archival formalin-fixed paraffin-embedded tissue (FFPET) are needed to facilitate research when availability of fresh-frozen tissue is limited. Recent reports attest to the feasibility of this approach, but the clinical value of these data is poorly understood. We employed state-of-the-art RNA extraction and Affymetrix microarray technology to examine 34 archival FFPET primary extremity soft tissue sarcomas. Nineteen arrays met stringent QC criteria and were used to model prognostic signatures for metastatic recurrence. Arrays from two paired frozen and FFPET samples were compared: although FFPET sensitivity was low (∼50%), high specificity (95%) and positive predictive value (92%) suggest that transcript detection is reliable. Good agreement between arrays and real time (RT)–PCR was confirmed, especially for abundant transcripts, and RT–PCR validated the regulation pattern for 19 of 24 candidate genes (overall R2=0.4662). RT–PCR and immunohistochemistry on independent cases validated prognostic significance for several genes including RECQL4, FRRS1, CFH and MET – whose combined expression carried greater prognostic value than tumour grade – and cmet and TRKB proteins. These molecules warrant further evaluation in larger series. Reliable clinically relevant data can be obtained from archival FFPET, but protocol amendments are needed to improve the sensitivity and broad application of this approach.

High incidence of metastatic disease in primary high grade and large extremity soft tissue sarcomas treated without chemotherapy

BackgroundThe risk of metastasis and the survival in patients with primary extremity soft tissue sarcomas is worse when tumour size is large and the grade of malignancy is high. Such tumours may receive chemotherapy and/or radiation therapy (RTX) for optimising local control. Irradiation can either be applied preoperatively or after tumour resection. The question arises if the kind of RTX in the absence of chemotherapy influences the outcome concerning local control, metastatic disease, survival and complications.MethodsWe retrospectively reviewed the clinical outcome of 233 patients with a primary extremity soft tissue sarcoma treated between 1990 – 2000 with a mean follow-up of 35.8 (4–120) months in our institute. 41 patients had high grade, deep and large tumours (>8 cm), an AJCC stage III (no evidence of metastasis prior to treatment) and were treated with limb salvage surgery and irradiation but stayed without additional chemotherapy. Two groups of patients were compared: the first group received postoperative RTX after tumour resection (n = 33); the second group was treated with preoperative RTX (n = 8). Both groups did not differ concerning clinical parameters. We analysed primary and secondary outcomes.Results56% (23/41) of the population developed metastatic disease, 24% (10/41) local recurrence. The risk of metastasis was higher in the group with preoperative irradiation (p = 0.046). The overall (p = 0.0248) and relapse free survival (p = 0.104) were worse in this group. The delay to tumour resection amounted 8 weeks on average in the preoperative group. Local control was not different (p = 0.38) in both study groups. Wound infections and other combined therapy related complications were equally distributed (p = 0.22).ConclusionWithout chemotherapy there remains a high risk of metastasis in AJCC grade 3 patients. In high risk patients treated without chemotherapy the elapsed time to tumour resection after preoperative radiation might contribute to the development of metastasis. This outcome may support the thesis that a combination of RTX and offensive multimodal treatment protocols is advantageous in such a subset of patients