Therapy For Soft Tissue Sarcoma Research Articles

Zoledronic Acid Prevents Loss of Trabecular Bone after Focal Irradiation in Mice

Radiation therapy for soft tissue sarcomas and metastatic disease can adversely affect bone, leading to late-onset fragility fractures. Adjunct administration of bisphosphonates has been postulated as means of minimizing these adverse effects. Using a murine model of focal hindlimb irradiation, we examined the potential for zoledronic acid treatment to minimize the deleterious effects of localized radiotherapy (RTx) on bone. Mice received a single, unilateral hindlimb exposure of 20 Gy. Beginning 4 days prior to irradiation, and at 1, 2 and 3 weeks post-irradiation, animals were treated with zoledronic acid or saline/vehicle injections. Areal bone mineral density was assessed at 4 days, and 2, 4 and 12 weeks post-irradiation by dual-energy X-ray absorptiometry (DXA). Micro-computed tomography and axial compression testing were used to quantify changes in morphological and mechanical properties of femurs at 4 and 12 weeks post-irradiation. Radiation had differential effects on cortical and trabecular bone, increasing cortical bone mineral content (BMC), cortical bone volume (BV) and trabecular separation (Tb.Sp) while decreasing trabecular number (Tb.N) by 12 weeks after localized radiotherapy. Administration of zoledronic acid increased hindlimb areal bone mineral density in both the presence and absence of radiotherapy, increased cortical bone mineral content and bone volume, increased trabecular bone volume (BV/TV), increased trabecular number, increased trabecular thickness (Tb.Th), and decreased trabecular separation compared to irradiated and vehicle control femurs. Despite these improvements in morphology with zoledronic acid, no biomechanical advantage was observed. Further work is needed to define the role of bisphosphonates in prevention of post-irradiation fragility fractures.

ERRATUM: Oncological outcome and prognostic factors in the therapy of soft tissue sarcoma of the extremities

Due to a technical error, authors’ names and surnames were reversed in the original published version of this paper [Orthop Rev (Pavia) 2012;4:e34 doi: 10.4081/or.2012.e34].<br />The correct authors’ details appear above.<p> </p>

Hypofractionated adjuvant radiation therapy of soft-tissue sarcoma achieves excellent results in elderly patients

Adjuvant radiation therapy (RT) is an essential part of combined limb-sparing treatment of soft-tissue sarcoma (STS). Elderly or medically unfit patients often have difficulty in completing 6-7 weeks of standard fractionated daily treatment. Our aim was to evaluate the efficacy of a hypofractionated adjuvant approach with RT for STS in elderly and debilitated patients. 21 elderly patients were treated with a short course of adjuvant RT (39-48 Gy, 3 Gy per fraction) for STS. The medical records of the patients were retrospectively reviewed for local or distant recurrence and side effects of RT. At a mean 26 months of follow-up, three local recurrences (14%) were detected. Eight patients (38%) had lung metastases during the observed period. Three of them died from metastatic disease. The hypofractionated radiation was well tolerated with minimum long-term side effects. Hypofractionated adjuvant radiation appears to be an effective treatment in terms of local control in elderly and debilitated patients. The results of this study might provide an alternative to commonly used standard fractionation of radiotherapy in sarcoma patients.

Hypofractionated adjuvant radiation therapy of soft tissue sarcoma in elderly patients.

e21521 Background: Adjuvant radiation therapy is an essential part of combined limb sparing treatment of STS. The recommended dose of radiation lies in the range of 60 Gy in standard fractionation of 1.8-2 Gy. Elderly or medically unfit patients often have difficulty in completing 6-7w of daily treatment. A prolonged course of radiation may be interrupted by acute side effects, which sometimes demands further extension of the overall course or even discontinuation of treatment. We intended to evaluate the efficacy of a hypofractionated adjuvant approach with radiation therapy for STS in the elderly and debilitated patients. Methods: 21 elderly patients were treated with a short course of adjuvant RT (39 to 48 Gy, 3 Gy per fraction) for STS. The medical records of the patients were retrospectively reviewed for the local or distant recurrence and side effects of RT. Results: Overall, the hypofractionated irradiation regimen of 39-48 Gy in 13-16 fractions was well tolerated with only 3 patients developing Grade 2-3 acute toxicity (mainly dermatitis). Three patients suffered from delayed Grade 2-3 toxicity (chronic pain, skin atrophy, teleangiectasiae) scaled according to CTSC. The mean time from the surgery until the initiation of RT was 65 days (SD 21.6). Mean RT time was 18.4 (SD 3) days. No delay of treatment due to acute toxicity was registered. All patients except for one were able to receive RT in the ambulatory setting. With a mean follow-up of 532 days (SD: 325), three local recurrences (14%) were detected. Three of eight patients with distant metastases died of sarcoma (graph 1). One patient with metastatic disease in the lung received salvage stereo tactic radiation therapy and was still alive 6 month after completion of SBRT with no evidence of disease. At a mean 532 days of follow up three local recurrences (14%) were detected .Eight patients (38%) had lung metastases during the observed period. Three of them died from metastatic disease. The hypofractionated radiation was well tolerated with minimum long term side effects. Conclusions: Hypofractionated adjuvant radiation appears to be an effective treatment in terms of local control in elderly and debilitated patients.

The Past, Present, and Future of Cytotoxic Chemotherapy and Pathway-Directed Targeted Agents for Soft Tissue Sarcoma

The individual rarity of the many subtypes of soft tissue sarcomas has historically mandated an empiric approach to systemic therapy. Doxorubicin, first reported to have activity in sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other drug or combination having shown an overall-survival advantage. Other cytotoxic agents, such as paclitaxel for angiosarcoma or gemcitabine with docetaxel for leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies. Trabectedin, particularly active against leiomyosarcoma and myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer cytotoxic agents, including ifosfamide derivatives, are in current phase III testing. Although advances is systemic therapy of soft-tissue sarcomas have been hampered by their biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule therapies for gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma and anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic tumor. Molecular therapies that have shown activity in diverse sarcoma populations include mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF-R) inhibitors. Among the latter, pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced sarcoma, and is now approved for use in the sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular tumor continue towards a goal of individualized sarcoma therapy.

Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression.

Agreement Among RTOG Sarcoma Radiation Oncologists in Contouring Suspicious Peritumoral Edema for Preoperative Radiation Therapy of Soft Tissue Sarcoma of the Extremity

Peritumoral edema may harbor sarcoma cells. The extent of suspicious edema (SE) included in the treatment volume is subject to clinical judgment, balancing the risk of missing tumor cells with excess toxicity. Our goal was to determine variability in SE delineation by sarcoma radiation oncologists (RO). Twelve expert ROs were provided with T1 gadolinium and T2-weighted MR images of 10 patients with high-grade extremity soft-tissue sarcoma. Gross tumor volume, clinical target volume (CTV)3cm (3 cm longitudinal and 1.5 cm radial margin), and CTV2cm (2 cm longitudinal and 1 cm radial margin) were contoured by a single observer. Suspicious peritumoral edema, defined as abnormal signal on T2 images, was independently delineated by all 12 ROs. Contouring agreement was analyzed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. The mean volumes of GTV, CTV2cm, and CTV3cm were, respectively, 130 cm(3) (7-413 cm(3)), 280 cm(3) and 360 cm(3). The mean consensus volume computed using the STAPLE algorithm at 95% confidence interval was 188 cm(3) (24-565 cm(3)) with a substantial overall agreement corrected for chance (mean kappa = 0.71; range: 0.32-0.87). The minimum, maximum, and mean volume of SE (excluding the GTV) were 4, 182, and 58 cm(3) (representing a median of 29% of the GTV volume). The median volume of SE not included in the CTV2cm and in the CTV3cm was 5 and 0.3 cm(3), respectively. There were 3 large tumors with >30 cm(3) of SE not included in the CTV3cm volume. Despite the fact that SE would empirically seem to be a more subjective volume, a substantial or near-perfect interobserver agreement was observed in SE delineation in most cases with high-grade soft-tissue sarcomas of the extremity. A median of 97% of the consensus SE is within the CTV2cm (99.8% within the CTV3cm). In a minority of cases, however, significant expansion of the CTVs is required to cover SE.

Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma

Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and anti-proliferative in vitro effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy.

The Past, Present, and Future of Cytotoxic Chemotherapy and Pathway-Directed Targeted Agents for Soft Tissue Sarcoma

The individual rarity of the many subtypes of soft tissue sarcomas has historically mandated an empiric approach to systemic therapy. Doxorubicin, first reported to have activity in sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other drug or combination having shown an overall-survival advantage. Other cytotoxic agents, such as paclitaxel for angiosarcoma or gemcitabine with docetaxel for leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies. Trabectedin, particularly active against leiomyosarcoma and myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer cytotoxic agents, including ifosfamide derivatives, are in current phase III testing. Although advances is systemic therapy of soft-tissue sarcomas have been hampered by their biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule therapies for gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma and anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic tumor. Molecular therapies that have shown activity in diverse sarcoma populations include mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF-R) inhibitors. Among the latter, pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced sarcoma, and is now approved for use in the sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular tumor continue towards a goal of individualized sarcoma therapy.

Oncological outcome and prognostic factors in the therapy of soft tissue sarcoma of the extremities

Uniform conclusions about therapeutic concepts and survival time of bone and soft tissue sarcoma patients are difficult due to the heterogeneity of histological subtypes as well as the different responses to neoadjuvant therapy. The subject of this retrospective study was the analysis of tumour free survival, risk and prognostic factors of sarcoma patients treated by limb sparing techniques or amputation. We included 118 patients with soft tissue sarcoma of the extremities treated primarily or secondarily at our institution between 1990 and 2008 with a minimum follow-up of 12 months. Data about the tumour free survival time, operative techniques and potential prognostic factors were analysed. The tumour-specific and overall survival were significantly influenced by two factors: the grading and distant metastases present at time of diagnosis. Optimal multimodal therapeutic concepts at a specialized Cancer Center decreased the risk of local recurrence. The importance of optimal preoperative and surgical course concerning the oncological long term outcome was investigated. The decrease in local recurrence as a result of multimodal therapeutic concepts at a specialized Cancer Center was confirmed. To evaluate the individual prognosis of a patient, multiple factors have to be considered. Factors for a poor prognosis are primary metastasis, high-grade tumours and several histological entities (e.g. synovial sarcoma, not other specified).

Interobserver Variation in Suspicious Edema Definition for Preoperative Radiation Therapy in Soft-tissue Sarcoma of the Extremity

Interobserver Variation in Suspicious Edema Definition for Preoperative Radiation Therapy in Soft-tissue Sarcoma of the Extremity

Predictive Factors for Chronic Lower Extremity Edema After Multimodality Limb-sparing Therapy of Soft-tissue Sarcoma of the Proximal Lower Extremity

Predictive Factors for Chronic Lower Extremity Edema After Multimodality Limb-sparing Therapy of Soft-tissue Sarcoma of the Proximal Lower Extremity

Indications of Microsurgery in Soft Tissue Sarcomas

Sarcomas are uncommon tumors and free-margin surgical resection remains the single most important treatment in the curative therapy of soft tissue sarcomas. Refinements in surgical techniques have led to increased function preservation and limb salvage. The records of patients (n = 41) who underwent microsurgical soft tissue reconstruction subsequent to resection of soft tissue sarcoma during the period 1998 to 2010 were reviewed and compared with a general nonmicrosurgery group (n = 188) in relation to clinicopathological characteristics, surgical procedures, postoperative complications, time until start of adjuvant radiation, functional outcome (Toronto Extremity Salvage Score, TESS), local recurrence, free survival, and disease-specific survival. Forty-one patients (age range: 23 to 95 years) received a total of 42 free flaps. When compared with the general nonmicrosurgery group, these patients presented significant differences with regard to location, histological grade, and neoadjuvant treatments. Complications were encountered in 10 cases, including 3 patients with complete flap loss and 1 patient with partial flap loss; other complications were cervical fistulae, knee arthritis, nonconsolidation, and wound infection. Extremity salvage was achieved in 90% (19/21) of limb sarcomas, with these patients showing adequate postoperative ambulation (TESS 77 ± 16) and adequate use of the upper extremity (TESS 66 ± 26). Two patients underwent amputation after recurrence. Disease-specific survival rates at 5 and 10 years were 79.49% and 76.93%, respectively. The microsurgical repair of sarcoma defects is a reliable option that, though not free of complications, is necessary in selected cases such as patients receiving neoadjuvant treatments and those with head and neck location and high-grade tumors. The procedure enables both adequate oncosurgical resection and function preservation. Our microsurgical sarcoma reconstruction data, based on an observation period of 12 years and presenting the results of 42 free tissue transfers in 41 patients, adds further evidence to the previously published smaller series.

Clinical trial end points for assessing efficacy of novel therapies for soft-tissue sarcomas

Soft-tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. Although outcome varies by histology, adults with disseminated metastatic STS have a poor prognosis despite current treatment options. The authors reviewed commonly used clinical end points for STS and discussed which end points may be appropriate for evaluating the clinical benefit of novel targeted therapies. In sarcoma, surrogates for both overall survival, the gold standard end point, and the objective response rate, measured by Response Evaluation Criteria in Solid Tumors, are commonly used. More appropriate end points for evaluating newly targeted agents include progression-free survival and clinical benefit rate. Results from recently completed Phase III trials of two targeted therapies in advanced STS, the mTOR inhibitor ridaforolimus and the multikinase inhibitor pazopanib, should shed light on whether progression-free survival and clinical benefit rate are appropriate end points in advanced STS.

Wound Complications in Preoperatively Irradiated Soft-Tissue Sarcomas of the Extremities

To determine whether the involvement of plastic surgery and the use of vascularized tissue flaps reduces the frequency of major wound complications after radiation therapy for soft-tissue sarcomas (STS) of the extremities. This retrospective study evaluated patients with STS of the extremities who underwent radiation therapy before surgery. Major complications were defined as secondary operations with anesthesia, seroma/hematoma aspirations, readmission for wound complications, or persistent deep packing. Between 1996 and 2010, 73 patients with extremity STS were preoperatively irradiated. Major wound complications occurred in 32% and secondary operations in 16% of patients. Plastic surgery closed 63% of the wounds, and vascularized tissue flaps were used in 22% of closures. When plastic surgery performed closure the frequency of secondary operations trended lower (11% vs 26%; P=.093), but the frequency of major wound complications was not different (28% vs 38%; P=.43). The use of a vascularized tissue flap seemed to have no effect on the frequency of complications. The occurrence of a major wound complication did not affect disease recurrence or survival. For all patients, 3-year local control was 94%, and overall survival was 72%. The rates of wound complications and secondary operations in this study were very similar to previously published results. We were not able to demonstrate a significant relationship between the involvement of plastic surgery and the rate of wound complications, although there was a trend toward reduced secondary operations when plastic surgery was involved in the initial operation. Wound complications were manageable and did not compromise outcomes.

Moving Beyond Response Criteria: New Measures of Success in the Treatment of Sarcomas

There is an urgent need to develop new therapies for soft tissue sarcomas. Traditional cytotoxic therapies, such as doxorubicin and ifosfamide, have been the standard approach to this disease. However, newer paradigms are emerging that are less toxic while targeting dysregulated pathways, tumor hypoxia, and genetic translocations. These newer therapies require different measures of activity as standard response criteria may inaccurately measure their effectiveness. Serious consideration of select endpoints and measures of tumor response are crucial to make significant strides in the treatment of sarcomas. Current studies on soft tissue sarcomas are slowly abandoning response rates while employing progression-free survival and time to progression as improved endpoints. With time and data, our understanding of the relative activity of these agents will grow and lead to improved benefits for our patients.

Randomized phase III, multicenter, open-label study comparing TH-302 in combination with doxorubicin versus doxorubicin alone in subjects with locally advanced unresectable or metastatic soft tissue sarcoma.

TPS10100 Background: A hypoxic microenvironment characterizes solid tumors including soft tissue sarcoma (STS) and is associated with chemotherapy resistance. TH-302, a prodrug of the alkylating agent bromo-isophosphoramide mustard (BR-IPM) is reduced in hypoxic environments, releasing Br-IPM. Combining D with TH-302 should effectively target both the normoxic and hypoxic regions of STS. TH-302 was investigated with full-dose D (75 mg/m2). The regimen was well tolerated, &gt;60% completed 6 cycles. DLTs at higher doses were infection with neutropenia and grade 4 thrombocytopenia. The efficacy was higher than generally reported with single agent D (Sleijfer, The Oncologist, 2005). At MTD (75 mg/m2 D and 300 mg/m2 TH-302) best response were 2 (2%) CR, 30 (34%) PR, 43 (48%) SD. Median PFS and OS were 6.7 and 17.5 months, respectively. Based upon these data, a study (NCT01440088) is ongoing to assess the benefit of adding TH-302 to the standard D as first-line therapy of STS. Methods: The randomized (1:1) phase III study of TH-302 (300 mg/m2) with D versus D alone was initiated September 2011. Target goal is 450 patients. TH-302 is administered IV over 30-60 minutes on Days 1 and 8 (21-day cycle). D (75 mg/m2, bolus or continuous) is administered Day 1 starting 2-4 hrs after TH-302 when used in combination. Patients receiving TH-302 plus D without progression after 6 cycles may continue on TH-302 alone. Key eligibility criteria: locally advanced unresectable or metastatic STS untreated with chemotherapy (adjuvant allowed), ECOG 0/1, measurable disease (RECIST 1.1) and adequate hematologic, hepatic, renal function. A FDA Special Protocol Agreement was reached on study design and analyses. Primary efficacy endpoint is overall survival (OS) comparison of the combination vs D. The study is designed to detect a 40% improvement in OS with 85% power and one-sided alpha of 2.5%. An interim futility PFS analysis is scheduled after 113 PFS events. Significant improvement in PFS (one-sided p &lt; 0.10) is required to continue. A further analysis for early efficacy stoppage is scheduled after 175 OS events. IDMC will monitor safety and efficacy.

Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

Systemic Therapy in Soft Tissue Sarcomas: Past, Present and Future

Soft tissue sarcomas (STS) comprise 1% of all cancers diagnosed worldwide with more than 40 different histological subtypes each with distinct underlying biology, natural history and response to treatment. Due to the differential chemosensitivity it is imperative to have a correct histological diagnosis for optimal treatment of these patients. Even though surgery remains the primary modality of treatment there is increasing specialization of chemotherapy with respect to histological subtype. In general there is no place for "one size fits all strategy". To correctly define the role of chemotherapy, an extensive search was carried out online and offline for all relevant articles concerning chemotherapy in soft tissue sarcoma. This review aims to discuss the evolution of chemotherapy, its present role in neoadjuvant, adjuvant, metastatic settings and exciting trends with the advent of targeted therapies.

Dose–Effect Relationships for Femoral Fractures After Multimodality Limb-Sparing Therapy of Soft-Tissue Sarcomas of the Proximal Lower Extremity

We investigated the clinical and dosimetric predictors for radiation-associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS). We examined 131 patients with proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (≥30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated. Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 ± 8.9 Gy, V30 of 14.5 ± 2.3 cc, V45 of 11.8 ± 1.1 cc, and V60 of 7.2 ± 2.2 cc at the femoral neck compared with 22.9 ± 20.8 Gy, 4.8 ± 5.6 cc, 2.5 ± 3.9 cc, and 0.8 ± 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients. These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients.