Approaches to local salvage of soft tissue sarcoma after primary site failure

Improvements in pretreatment evaluation and the wider application of specialized multidisciplinary care have substantially reduced the risk of local recurrence for patients with soft tissue sarcomas arising at any site, and the recurrences that are still seen are often those that are most difficult to manage effectively. The management strategy for an isolated local recurrence of soft tissue sarcoma is usually similar to that used for primary disease. With appropriate pretreatment evaluation and salvage therapy that includes a multidisciplinary approach, most patients with local recurrence can expect local disease control and a good functional outcome. The development of effective management of a local recurrence is often a complex problem. The necessary decisions are influenced by the tumor location, disease extent, and previous local therapy. The need for specialized care is stressed. Patient evaluation, management strategies, and expected outcome for various clinical scenarios are discussed.     

Prognostic factors for survival in soft tissue sarcoma

Between 1975 and 1984, 125 cases of histologically confirmed soft tissue sarcomata (STS) were registered in the Department of Clinical Oncology in Edinburgh. Of these, 100 were eligible for analysis of prognostic factors. The overall 5-year survival rate was 21.5%. Univariate analysis demonstrated that extent of surgery, radical versus palliative or no radiotherapy, mass as a presenting symptom, metastases at presentation, site, histological type, mitotic activity, grade and UICC stage all had a statistically significant effect on survival. Analysis using the proportional hazard regression model was performed on the 87 patients for whom all variables were recorded. When all histological and clinical features and treatment modalities were included in the model then radiotherapy, surgery, necrosis, sex and mitoses were identified as independent prognostic variables. When symptoms and treatment were excluded then the multivariate analysis identified sex and mitotic activity as independent parameters. For the 33 superficial STS with tumour size recorded multivariate analysis revealed size, necrosis and cellularity as independent prognostic variables. For the 31 deep STS histological type, sex, surgery and radiotherapy were identified as independent prognostic parameters.     

Prognostic significance of mast cells in soft tissue sarcoma

We counted the number of toluidine blue positive mast cells within and around the tumor in 44 patients with soft tissue sarcomas (STS). Irrespective of their histologic types, these cases were broadly divided into the following two groups: (1) low count (less than 20 mast cells/10 high-power fields [HPF]) and (2) high count (greater than or equal to 20 mast cells/10 HPF). The patients with a high mast cell count showed a significantly better 5-year survival rate than those with a low count (85.9% versus 30.5%; P less than 0.01). Five patients with distant metastases at first admission all belonged to the low count group. These results suggest that the number of mast cells within and around the tumor is a useful prognostic factor for STS.     

Failure patterns and survival in pediatric soft tissue sarcoma

We retrospectively analyzed 44 patients with localized soft tissue sarcomas who were seen and treated at the JCRT, DFCI, and TCH between 1970-1984. Patients with rhabdomyosarcoma were excluded. Primary tumors were located in the following sites: extremities 19 (43%), head and neck 9 (20%), and trunk 16 (37%). Median follow-up for survivors was 7.7 years (range 24 mo-16 years). Surgery was the initial aspect of treatment for all patients. All patients also received post-operative irradiation, 43 at presentation and one at local relapse, and 26 received adjuvant chemotherapy. Radiation was delivered to a dose of 4000 cGy (median) followed by a boost to a median dose of 5760 cGy (range 4500-7000 cGy). Actuarial 5- and 10-year disease-free survivals (DFS) were 70% and 59% while the actuarial 5- and 10-year overall survivals (OS) were both 75%. All parameters were assessed for significance by univariate analysis. OS was significantly affected by presenting stage when analyzed according to both the Intergroup Rhabdomyosarcoma Staging System (IRS) and the American Joint Committee on Cancer system (AJCC). For the IRS, OS at 10 years was 100% for Stage I, 72% for Stage II, and 54% for Stage III (p = 0.04). For the AJCC, OS at 10 years was 100% for Stage I and 65% for Stage II and III (p = 0.05). Primary site, histology, and use of adjuvant chemotherapy did not influence OS or DFS. Fourteen patients failed: 8 local, 1 distant, and 5 combined local and distant. There was no LF among the 9 pts. with primary lesions less than 5 cm compared to 11/29 (39%) whose tumor was greater than 5 cm (p = 0.04). Pts. with gross residual disease had a local DFS of 42%, but those with no residual or microscopic residual had a local DFS of 71% (p = 0.02). In conclusion, childhood STS has an excellent OS (75% at 10 years). Tumor size and residual tumor after surgery strongly predicted for local failure. Of interest, the pattern of failure is predominantly local in our series. This suggests that more aggressive local treatment is indicated in management of children with STS. Higher doses of irradiation as used for adult STS are probably indicated for patients with gross residual disease.     

EPHB4 tyrosine‐kinase receptor expression and biological significance in soft tissue sarcoma

Soft tissue sarcomas (STS) are heterogeneous malignant tumors of mesenchymal origin. Due to low incidence and high number of different histological subtypes, their pathogenesis and thus potential targets for their therapy remain barely investigated. Several studies revealed significant higher EPHB4 expression in malignancies such as prostate and colorectal cancer showing survival advantages for these tumor cells. Therefore we studied the expression of EPHB4 in a total of 46 clinical human specimens of different STS and human fibroblasts. EPHB4 mRNA and protein expression were significantly increased in synovial sarcoma. After targeting EPHB4 in fibrosarcoma, synovial sarcoma, liposarcoma and MFH sarcoma cell lines by siRNA or by inhibition of autophosphorylation using the specific EPHB4 kinase inhibitor NVP‐BHG712 a decreased proliferation rate/vitality of synovial‐ and fibrosarcoma cells was observed. Silencing of EPHB4 significantly reduced the transmigration of synovial sarcoma cells towards fibroblasts and endothelial cells. In addition, we assessed the anti‐metastatic effect of EPHB4 inhibition in vivo by intraperitoneal administration of the EPHB4 inhibitor in an appropriate sarcoma lung metastasis xenograft model. As result 43% of NVP‐BHG712 treated mice (n = 3/7) developed pulmonary metastases whereas all control mice (n = 5) revealed lung metastases. The residual 57% of mice (n = 4/7) showed only small local tumor cell spots. Size measurements of the Vimentin positive area explained significant decrease in lung metastasis formation (p < 0.05) after EPHB4 kinase inhibition. In summary, these data provide first evidence of the importance of EPHB4 in the tumorigenesis of synovial sarcoma and present EPHB4 as a potential target in the therapy of this malignancy.     

Prognostic significance of CD100 expression in soft tissue sarcoma

BACKGROUND: CD100, a class IV semaphorin, promotes angiogenesis, invasive growth, proliferation, and antiapoptosis of cancer cells in vitro. The expression of CD100 in soft tissue sarcoma (STS) and its correlation with clinicopathologic factors and prognostic significance were evaluated. METHODS: Expression levels of CD100 in patients with localized STS were evaluated immunohistochemically on paraffin-embedded sections from 81 patients, including 47 men and 34 women with a median age of 54 years. Staining intensity was categorized into weaker than (level 1) or equal to that of lymphocytes with a rate of <10% stained tumor cells (level 2) or >10% stained tumor cells (level 3). Ki-67 staining was performed in parallel. RESULTS: Forty-two tumors (52%) had level 1 CD100 expression, 18 tumors (22%) had level 2 CD100 expression, and 21 tumors (26%) had level 3 CD100 expression. Tumors that had level 2 and 3 CD100 expression were correlated significantly with higher mitotic count, cellularity, ratio of necrosis, and Ki-67 labeling index (LI) compared with tumors that had level 1 CD100 expression. There was no correlation between CD100 expression and other characteristics. Among the 3 levels of CD100 expression, higher expression levels were correlated with poorer overall and disease-free survival. Multivariate analysis revealed that CD100 expression (levels 1 and 2 vs level 3) and tumor size (5 cm) were independent prognosticators for overall survival (P < .05 for both), and CD100 expression (levels 1 and 2 vs level 3) was an independent prognosticator for disease-free survival (P < .05). CONCLUSIONS: The results from this study indicated the demonstrated prognostic significance of CD100 expression in STS.     

The significance of size change of soft tissue sarcoma during preoperative radiotherapy

Aim

To assess the significance of change in tumour size during preoperative radiotherapy in patients with soft tissue sarcoma (STS).

Methods

A retrospective review of 91 cases with STS was performed. Inclusion criteria were localised extremity and truncal STS with measurable disease, older than 18 years, treated with preoperative radiotherapy and wide local excision, in the period between January 1966 and December 2005. Patients with head and neck STS, or who received neoadjuvant chemotherapy were excluded. A difference in excess of 10% of the greatest tumour diameter of the pre-radiotherapy and the post-radiotherapy MRI scans was considered as change in tumour size.

Results

Increase in tumour size was noted in 28 patients (31%) (Group 1). No change or decrease in size was observed in 63 patients (Group 2). There were no significance differences in local control or overall survival rates between the 2 groups. The estimated overall actuarial local recurrence free, event-free and overall survival rates were 90.5%, 64.4%, 62.9% in Group 1, and 85.7%, 60.8%, 68.9% in Group 2 respectively.

Conclusion

Increase in tumour size during preoperative radiotherapy for soft tissue sarcoma does not seem to associate with inferior local tumour control or compromise survival. Lack of reduction in tumour size is not necessarily a sign of lack of response to preoperative radiotherapy.     

Long-term prognosis of primary retroperitoneal soft tissue sarcoma.

AIMS: To evaluate the result of treatment and long-term outcome of a population-based cohort of patients with retroperitoneal soft tissue sarcoma (RSTS). METHODS: Between 1 January 1989 and 1 January 1994, 143 patients diagnosed as having primary RSTS were selected from a national pathology database (PALGA) in the Netherlands. In this population-based group of patients, the result of surgery, overall survival (OS) and disease-free survival (DFS) were analysed as well as factors affecting OS and DFS. Median follow-up was 10.2 years. RESULTS: Operative treatment resulted in a complete tumour resection in 55% of the patients (n=78), low- and intermediate-grade tumours were more often completely resected than high-grade tumours (P=0.016). Five- and 10-year cumulative OS was 39% and 21%, respectively, while DFS was 22% and 17%, respectively. In a multivariate analysis low malignancy grade (P=0.017) and a complete tumour resection (P<0.001) were associated with better OS. CONCLUSIONS: Complete tumour resection and low malignancy grade were independent favourable prognosticators. However, these factors were related too, since surgical success was influenced by malignancy grade.     

Screening populations at high risk for soft tissue sarcoma and surveillance following soft tissue sarcoma resection

Soft tissue sarcomas (STS) are a rare and diverse group of tumors that affect both adult and pediatric populations. This review discusses current screening recommendations for populations at increased risk for STS, including those with genetic predispositions. We also review surveillance guidelines for those at risk for recurrence following curative-intent surgery.     

Impact of improved local control on survival in patients with soft tissue sarcoma

An estimate has been made of the gain in survival if the local failure rate for sarcoma of soft tissue was reduced to zero by the application of new treatment methods. The assumption is that the loss, due to distant metastasis and intercurrent disease among patients who achieve local control by the current treatment, would be the same among new local controls. For patients with stage M0 disease at diagnosis (all sites, all histological types), the current local failure rate is approximately 30%. By eliminating these failures, the overall survival rate would be expected to increase by 10-20 percentage points.     

Outcome of primary soft tissue sarcoma of the knee and elbow

PURPOSE: Concern is frequently raised regarding the tolerance of irradiation over a joint space. The purpose of this study was to determine the outcome in terms of relapse and potential complications in patients with knee and elbow soft tissue sarcoma treated with limb-sparing surgery with or without adjuvant radiotherapy (RT). METHODS AND MATERIALS: A review of our prospective database between June 1982 and December 1999 identified 86 adult patients with primary soft tissue sarcoma arising from the knee (n = 65; 76%) or elbow (n = 21; 24%) treated with limb-sparing surgery. Tumors had high-grade histologic features in 72% and were >5 cm in 48% of patients. Adjuvant RT was given to 46 (54%) of 86 patients. The type of RT was postoperative external beam RT in 63% and brachytherapy in 37%. Of the 46 patients who received RT, 85% (n = 39) had deep, 78% (n = 36) high-grade, and 54% (n = 25) >5-cm tumors. Complications were assessed in terms of wound complications requiring repeated surgery, bone fracture, nerve damage, and joint stiffness. RESULTS: With a median follow-up of 48 months (range 4-175), the 5-year actuarial rate of local control, distant control, and overall survival was 75% (95% confidence interval [CI] 64-85%), 82% (95% CI 73-91%), and 81% (95% CI 71-91%), respectively. The 5-year local control rate for patients who received RT was 80% vs. 71% for those who did not (p = 0.3). The type of RT did not significantly influence the local control rate. Patients treated with external beam RT had a 5-year local control rate of 84% compared with 73% for those treated with brachytherapy (p = 0.4). On multivariate analysis, tumor size >5 cm retained its significance as an independent predictor of poor local control (p = 0.04; relative risk 3; 95% CI 1-6). In addition, high-grade histologic features emerged as an independent predictor of local recurrence (p = 0.02; relative risk 4; 95% CI 1-20). No statistically significant difference was found between the RT and no-RT group in terms of the 5-year actuarial rate of wound reoperation (10% vs. 3%, p = 0.1), bone fracture (3% vs. 5%, p = 0.5), or nerve damage (6% vs. 3%, p = 0.5). Joint stiffness was significantly higher in the RT group (24% vs. 0%, p = 0.001), but this stiffness was severe to moderate in only 2 patients. CONCLUSION: On the basis of the findings of this retrospective review, adjuvant RT seems to be relatively well tolerated despite the inclusion of part of the joint space in the irradiation portal. Joint stiffness was seen more frequently with adjuvant RT, but it was moderate to severe in only a small number of patients.     

nm23蛋白在软组织肉瘤中的表达及意义

目的探讨nm23蛋白在软组织肉瘤中的表达及与软组织肉瘤分级的关系。方法应用FNCLCC（法国癌症中心联盟）分级系统对108例软组织肉瘤进行组织病理学分级并应用免疫组织化学技术Evision二步法检测nm23蛋白在这些肿瘤中的表达情况。结果108例软组织肉瘤中1级、2级、3级分别为23例、28例和57例;免疫组织化学染色结果显示,在1级、2级、3级中nm23蛋白的阳性表达率分别为26．1％、32．1％、61．4％,经卡方检验P〈0．05,差异有显著性。结论nm23蛋白表达与软组织肉瘤组织学分级相关并且分级越高阳性表达率越高,因此nm23在软组织肉瘤中可能扮演着促进肿瘤浸润与转移的作用。     

术后放射治疗在原发肢体软组织肉瘤治疗中的作用

分析本院收治的原发于肢体的软组织肉瘤的治疗情况 ,评价术后放射治疗的作用。方法　本院共收治 15 1例 ,可供分析的 139例 ,分析影响生存和局控的因素及术后放射治疗的意义。生存率和局控率用Kaplan Meier方法计算 ,单因素分析用Logrank检验 ,多因素分析用Cox回归方法。结果　全组 5年生存率为 70 .2 % ,10年为 5 0 .4% ;5年无瘤生存率为 5 2 .9% ,10年为41.2 %。单因素分析对全组病例生存率有影响的因素 :肿瘤大小、年龄和治疗方式 (P值分别为0 .0 0 8,0 .0 0 7和 0 .0 40 )。多因素分析只有治疗方式对生存有影响 (P =0 .0 40 )。首次治疗方式对局控影响差异有极显著性 (P <0 .0 1)。手术方式对单纯手术组局控影响差异有极显著性 (P <0 .0 1) ;肿瘤 <5cm时 ,射野大小对术后放射治疗组局控影响差异有极显著性 (P <0 .0 1)。结论　术后放射治疗能提高局部控制率 ,初始射野应相对大 ,并采用缩野技术。对恶性度低、肿瘤 <5cm、手术切缘阴性患者第 1次术后可不做放射治疗。     

Effect of marital status on treatment and survival of extremity soft tissue sarcoma

BackgroundSpousal support has been hypothesized as providing important psychosocial support for patients and as such has been noted to provide a survival advantage in a number of chronic diseases and cancers. However, the specific effect of marital status on survival in soft tissue sarcomas (STSs) of the extremity has not been explored in detail.Patients and methodsA total of 7384 patients were evaluated for this study using a Surveillance, Epidemiology, and End Results (SEER) registry query for patients over 20 years old with extremity STS diagnosed between 2004 and 2009. Survival outcomes were analyzed using Gray's test after patients were stratified by marital status. The Fine and Gray model, a multivariable regression model, was used to assess whether marital status was an independent predictor of sarcoma specific death. Statistical significance was maintained at P < 0.05.ResultsAnalysis of the SEER database showed that single patients were more likely to die of their STS and at a faster rate than married patients. No differences were noted in tumor size and tumor site on presentation between married and single patients. However, single patients presented with higher grade tumors more frequently (P = 0.013), received less radiotherapy (P < 0.001), and had less surgery carried out (P < 0.001), compared with their married peers. Regression analysis showed that after accounting for tumor size, grade, site, histology, use of radiotherapy, age, gender, region where the patients were from, and income, being single continued to serve as an independent predictor of sarcoma-specific death; P < 0.0001.ConclusionOverall survival is worse for single patients, when compared with married patients, with STS. Single patients do not undergo surgical resection or receive radiation therapy as frequently as their married counterparts. Social support systems and barriers to care should be evaluated at time of diagnosis and addressed in single patients to potentially improve survival outcomes.     

The local management of soft tissue sarcoma

Soft tissue sarcomas (STS) are rare tumors arising from the connective tissues. STS can arise at any anatomic site, can demonstrate varied behavior and prognosis, and therefore present a formidable challenge in management. The local treatment of STS demands technical complexity in the application of diagnostic tools, including pathology and imaging, as well as treatment approaches, including surgical ablation and reconstruction, radiotherapy, and, in defined cases, chemotherapy. The understanding of the management of these lesions is profoundly dependent on the multidisciplinary setting, where experience has been gained and skills are available to increase the likelihood of a successful result. Several proven options are available for optimal local management, and the choice of approach depends on the prevailing practice and resource profile of the treating center. With modern approaches, the local control rate can be expected to be at least 90% for extremity lesions, which constitute the most common STS. The experience in other anatomic sites is less favorable as a result of a combination of late diagnosis, technically difficult access sites, and possibly less familiarity with these less common presentations. The disappointing results make it all the more important for patients to be referred to a multidisciplinary setting with experience in sarcoma management to maximize the chance of successful local outcome.     

Hyperthermia in soft tissue sarcoma

Patients with high-risk soft tissue sarcomas (STS)–FNCLCC grade 2–3, size >5 cm, deep to the fascia—are at risk for developing local recurrence and distant metastasis despite surgical tumor resection. Therefore, the management of high–risk STS requires a multidisciplinary approach. Besides surgery, radiotherapy, and chemotherapy, regional hyperthermia (RHT) has the potential to become the fourth standard treatment modality for the treatment of these patients. RHT means non-invasive selective heating of the tumor area to temperatures within the range of 40–43°C for 60 min by the use of an electromagnetic heating device. Thereby RHT is always applied in addition to radiotherapy or chemotherapy or both but is not effective as a single treatment. Beside direct cytotoxicity, RHT in combination with chemotherapy enhances the drug cytotoxicity mainly by increased chemical reaction and intratumoral drug accumulation. For the neoadjuvant setting, RHT in combination with a doxorubicin- and ifosfamide-based chemotherapy has been shown to dramatically improve the tumor response rate but also prevents from early disease progression as compared to chemotherapy alone. The addition of RHT to a multimodal treatment of high-risk STS consisting of surgery, radiotherapy, and chemotherapy either in the neoadjuvant setting but also after incomplete or marginal tumor resection has been shown to significantly improve local recurrence- and disease-free survival. Based on these results and in conjunction with the low RHT-related toxicity, RHT combined with preoperative or postoperative chemotherapy should be considered as an additional standard treatment option for the multidisciplinary treatment of locally advanced high-grade STS.     

Clinical significance of pretreatment serum C-reactive protein level in soft tissue sarcoma

BACKGROUND:

The aim of this study was to determine whether circulating C‐reactive protein (CRP) levels before treatment predict the overall survival and disease‐free survival in soft tissue sarcoma patients.

METHODS:

A total of 102 primary soft tissue sarcoma patients from 2003 to 2009 were retrospectively reviewed. The CRP levels were obtained before treatment for all patients. The patients who presented with metastases at diagnosis were excluded from this study.

RESULTS:

Elevated CRP levels were seen in 18 patients. The tumor histological grade and American Joint Committee on Cancer stage in the patients with elevated CRP levels were significantly higher than those in patients with normal CRP levels. Patients with elevated CRP levels before initial treatment had a poorer overall survival than patients with normal CRP levels (P = .01). The overall survival estimates at 3 and 5 years were 75.3% and 53.8%, respectively, versus 90.3% and 81.3%, respectively. Patients with elevated CRP levels before initial treatment had poorer event‐free survival after initial treatment than patients with normal CRP levels (P < .001). The event‐free survival estimates at 2 and 5 years were 53.2% and 33.2%, respectively, versus 83.2% and 81.3%, respectively. A multivariate analysis also showed the preoperative CRP level to be an independent predictor of events.

CONCLUSIONS:

The pretreatment serum CRP level may be a marker of aggressive tumor characteristics. Pretreatment elevated CRP levels were found to be a poor prognostic factor for overall survival in a univariate analysis, and for disease‐free survival in a multivariate analysis, for soft tissue sarcoma patients. Cancer 2012;. © 2011 American Cancer Society.     

Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma.

BACKGROUND: The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas. PATIENTS AND METHODS: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors. RESULTS: NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC. CONCLUSION: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.