Role of isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan in locally advanced extremity soft tissue sarcoma

The management of locally advanced extremity soft tissue sarcoma of the limbs is challenging, particularly for recurrent tumors and those adjacent to neurovascular bundles and joints. Typically, the tumors are large, below the fascia, and high‐grade (T2b or stage III according to the American Joint Committee on Cancer) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics. Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF‐ILP) adds a therapeutic option to radiation therapy (RT) and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method and has been used now for almost 2 decades at more than 50 centers worldwide. TNF‐ILP yields a high rate of complete or nearly complete pathologic tumor remission. In combination with surgical resection of the tumor remnant after isolated limb perfusion, the limb salvage rate is close to 90%. Often, patients can be spared adjuvant RT without long‐term local tumor control rates being compromised. Nevertheless, TNF‐ILP has never been compared with another treatment regimen in a randomized trial. This review summarizes the mode of action and standard application of TNF‐ILP and focuses on a critical discussion of the role of TNF‐ILP in the multimodal treatment of locally advanced primary and recurrent extremity sarcoma. Cancer 2016 . © 2016 American Cancer Society. Cancer 2016;122:2624–2632. © 2016 American Cancer Society.     

Conditional survival of extremity soft-tissue sarcoma: results beyond the staging system

BACKGROUND:

With increasing interest in adult cancer survivorship, currently available prognostic estimates for long‐term survivors of extremity soft‐tissue sarcoma (ESTS) are limited. We assessed determinants of survival in adults surgically treated for nonmetastatic ESTS, conditional on specific survival periods.

Methods:

We identified 6215 persons aged >18 in the Surveillance Epidemiology and End Results program who were surgically treated for nonmetastatic ESTS from 1991 to 2006. We used Cox proportional hazards regression to assess demographic, tumor, and treatment factors associated with 10‐year sarcoma‐specific survival (SSS) at diagnosis and conditional on surviving 3 and 5 years postdiagnosis.

RESULTS:

At the time of diagnosis, age, tumor, and treatment factors predicted SSS. Although older age significantly predicted worse SSS for all age groups at diagnosis (HR 3.78 for age >81 vs 18‐35; P < .05 for all), the effect of age became nonsignificant as survival time increased, except for the oldest group (>80 years). Tumor size, grade, and histologic subtypes continued to be important predictors of SSS for all periods of conditional survival. Persons who underwent limb amputation were at 3 times the risk of mortality for all conditional survival periods.

CONCLUSIONS:

In this large population‐based experience of ESTS survivors, age >80, tumor, and treatment factors continued to affect long‐term survival, whereas the effect of age dampened over time. These estimates provide important counseling information for changing risk factors as survival time increases, help to streamline future surveillance programs, and provide insights into the design of adult survivorship care. Cancer 2011. © 2010 American Cancer Society.     

Isolated limb perfusion of soft tissue sarcomas: A comprehensive review of literature

Patients with primary irresectable, locally advanced soft tissue sarcomas of the limbs form a challenging group for the treating physician. Multimodality treatment is necessary to guarantee optimal limb salvage and survival rates. Since the introduction of isolated limb perfusion in the late fifties, several treatment regimens have been proposed. Isolated perfusion with melphalan and TNF-α, as part of a multimodality treatment, is regarded as the current best treatment option today. Ongoing studies are investigating potential benefit of other doses, new chemotherapeutic agents and new techniques in perfusion and radiotherapy. This article provides a historical overview of published literature and insight in upcoming treatment techniques.     

Histological response assessment following neoadjuvant isolated limb perfusion in patients with primary,localised, high-grade soft tissue sarcoma

Purpose: Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis. Patients and methods: This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. Results: The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P?=?0.227) or event-free (EFS) (P?=?0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P?<?0.001), EFS (P?=?0.002) and post-relapse survival probability (P?=?0.030) compared to patients with an intermediate or high mitotic count. Conclusions: The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP.     

Isolated limb perfusion for extremity sarcoma

Isolated limb perfusion has been used in patients with extremity sarcomas for over 40 years. In the majority of patients this approach has been employed as a limb-sparing alternative for patients with amputation as their only treatment option. Despite this long history of use in the treatment of patients with extremity sarcomas, many questions remain with respect to the appropriate drug or combination of drugs to be used in the perfusion circuit, the role of hyperthermia in isolated perfusion, and the use of hyperthermic perfusion in the neoadjuvant or adjuvant setting. Although many non-randomized studies have been performed, they suffer from a variety of problems, including small patient numbers, variety of chemotherapeutic agents employed, multiple levels of hyperthermia, and subjective evaluation of what constitutes amputation as a potential treatment option.     

A new limb salvage surgery in cases of high-grade soft tissue sarcoma using photodynamic surgery, followed by photo- and radiodynamic therapy with acridine orange

BACKGROUND: To maintain excellent limb function after tumor resection in patients with high-grade malignant sarcomas, we developed and established a new surgical adjuvant therapy using acridine orange (AO) after intra-lesional or marginal resection while sparing normal tissues of major nerves, vessels or bones adjacent to the tumor. METHOD: Our AO therapy procedure was combined with photodynamic surgery (PDS), photodynamic therapy (PDT) and radiodynamic therapy (RDT). In this study, 26 patients with primary high-grade soft tissue sarcomas were treated with AO therapy. RESULT: Results showed a low local recurrence rate (7.7%) and good local recurrence-free rate (88%) after AO therapy. Limb function of all patients was maintained at 100% of ISOLS criteria. CONCLUSION: Based on these results, we concluded that AO therapy is useful for local control after margin-positive tumor resection and for preserving excellent limb function in patients with high-grade soft tissue sarcomas.     

The prognostic significance of margin width for extremity and trunk sarcoma

BACKGROUND AND OBJECTIVES: To evaluate the significance of resection margin for soft tissue sarcoma (STS), we determined local recurrence-free interval (LRFI), distant metastases-free interval (DMFI), and overall survival (OS) for primary extremity and truncal STS with clear margins (> or =10 mm), close margins (1-9 mm), and positive margins (0 mm). METHODS: Patients were evaluated via review of charts and tumor specimens. RESULTS: Among 111 patients, tumors were predominantly high grade (86%), > or =5 cm (76%), and deep (81%). A minority of patients received adjuvant radiation (38%) and/or adjuvant chemotherapy (34%). Margin width was > or =10 mm (48%), 1-9 mm (40%), or 0 mm (12%). Margins > or =10 mm were less common for large (P = 0.009) or deep (P = 0.02) tumors. By multivariate analysis, independent factors for LRFI were tumor size (P = 0.04) and margin width (P = 0.03). Independent factors related to DMFI were tumor grade (P = 0.002), size (P = 0.007), and patient age (P = 0.02). Independent factors relating to OS were tumor grade (P = 0.001), size (P = 0.004), and depth (P = 0.03). CONCLUSIONS: Margins > or =10 mm independently predicted longer LRFI and are optimal for extremity STS resection. Adjuvant radiotherapy should be considered for all STS resected with margins <10 mm, and margin width should be considered when reporting and interpreting LR outcomes for these patients.     

Efficacy of high vs low dose TNF-isolated limb perfusion for locally advanced soft tissue sarcoma

Aims

The administration of a high dose of rTNF-α (3–4 mg) and Melphalan via isolated limb perfusion (ILP) for patients with locally advanced limb STS was shown to be effective. Reports that a low dose of TNF (1 mg) is as effective, led to the adoption of the low dose regimen as the treatment of choice. The purpose of this study was to compare two groups of patients with locally advanced limb STS, that was treated with high and low dose TNF-ILP, in terms of limb preservation.

Methods

Retrospective study of 41 patients who underwent ILP, with “high dose” (HD) and “low dose” (LD) TNF. ILP/TNF was performed on candidates to either amputation or significantly mutilating surgery without this treatment. In both groups, all patients, with the exception of three in each group, underwent resection of the residual tumor or tumor bed or limb 8–12 weeks after the procedure.

Results

In the HD group, marked tumor softening occurred within 48 h, and in tumors protruding through the skin, hemorrhagic necrosis was evident within 24 h. The overall response rate was 65.2%. Five patients achieved a CR and 10 had a PR; in five of these patients >90% necrosis of the tumor occurred. In eight patients, only minimal regression was observed (stabilization of disease). The rate of limb sparing was 69.5%. In the LD group, the overall response rate was 30.7%. CR was achieved in one patient. PR was observed in two. Two patients were lost to follow up. Of the remaining 15 patients, limb preservation was achieved in 53.3%.

Conclusion

Despite the retrospective comparison and possible selection bias, it is possible to raise the concern that at least some patients may benefit from a higher TNF dose perfusion in ILP for advanced limb STS.     

Clinical outcomes for patients with soft tissue sarcoma of the hand

BACKGROUND:

In an earlier report from the current study center regarding surgical treatment for patients with soft tissue sarcoma (STS) of the hand, it was concluded that repeat resection or amputation improves outcomes. Since then, the authors have aggressively sought to achieve negative resection margins, using standard or modified amputations when needed, and performing repeat resections to negative surgical margins when they were not achieved at the time of initial surgery. The current review was conducted to determine whether this approach resulted in better outcomes.

METHODS:

A retrospective review of 53 patients with STS of the hand who were treated between 1996 and 2005 was performed. Recurrence‐free survival (RFS) and functional outcome of hand‐preserving procedures were assessed according to the Musculoskeletal Tumor Society (MSTS) system.

RESULTS:

The median RFS was not reached at the time of last follow‐up. Of 53 patients, 6 (11%) had positive microscopic resection margins. Three patients underwent repeat resection to negative surgical margins, whereas another 3 patients did not. All 3 patients with positive microscopic surgical margins that were not re‐excised developed local disease recurrence; 2 patients also developed distant metastases. Two of the 50 patients with negative resection margins developed distant metastases. All 5 patients who developed local and/or distant disease recurrence had deep tumors. The median MSTS score was 29 (interquartile range, 27‐30). Patients who underwent more extensive resections, such as double ray amputations, had lower MSTS scores.

CONCLUSIONS:

Suboptimal biopsies and positive resection margins are associated with local and distant disease recurrence in patients with STS. The results of the current study suggest that aggressive surgical treatment can result in better clinical outcomes, and underscore that care must be taken when planning biopsies of hand tumors. Cancer 2011. © 2010 American Cancer Society.     

间室切除在四肢软组织肿瘤治疗中的应用

目的：探讨间室切除术在四肢软组织肿瘤治疗中方法及临床价值。方法：12例四肢软组织肿瘤，上肢2例，下肢lO例，首次治疗者8例，复发者4例。行股前间室切除术3例，股后间室切除术7例，前臂外侧间室切除l例，三角肌全切除l例。伴神经部分切除术2例。功能重建包括肌腱替代和皮瓣转位等。结果：本组均保留患肢，随访10～60个月，无瘤生存10例，复发和死亡各1例。结论：对于四肢软组织肿瘤，以控制肿瘤和保存肢体为治疗核心，间室切除术系目前较理想的方法。     

Preoperative chemoradiation and flap reconstruction provide high local control and low wound complication rates for patients undergoing limb salvage surgery for upper extremity tumors

BACKGROUND AND OBJECTIVES: Neoadjuvant protocols in the management of upper extremity sarcoma have improved local control rates but have been associated with high complication rates. We present a refinement of the Eilber protocol using judicious preoperative chemoradiation, limb salvage surgery, and flap coverage to achieve high local control rates with acceptable wound healing complications. METHODS: Patients presenting with upper extremity neoplasms from 1986 to 2002 were treated with a modified Eilber protocol, consisting of 3 days of adriamycin (30 mg/day) and sequential radiotherapy (300 cGy/day for 10 days). Limb salvage surgery with flap coverage where needed was performed 4-8 weeks later. Patients were followed prospectively for recurrence. RESULTS: Fifty-three consecutive patients with upper extremity tumors were treated and followed for a mean of 6.1 years. This cohort included 44 sarcomas and nine non-metastasizing, locally aggressive tumors. There were two local recurrences (3.8%). Limb salvage was achieved in all patients. Flaps were required in 43.4% of patients. Major complications occurred in 11%, were all flap related (partial flap loss, venous congestion), and went on to heal promptly with treatment. CONCLUSION: This modified Eilber protocol achieved 96% local control for upper extremity tumors with a wound complication rate of 11%. The liberal use of flaps of resulted in healed, stable wounds in all patients.     

肢体软组织肉瘤外科切缘的研究现状及进展

综合模式下的保肢手术是肢体软组织肉瘤治疗的发展趋势。切缘状态决定了外科治疗的质量,还将影响辅助治疗的决策。随着肿瘤治疗理念的改变和辅助治疗手段的发展,软组织肉瘤手术范围逐渐缩小。切缘阴性是软组织肉瘤外科治疗的基本目标,但对安全切缘并无统一的标准。若肿瘤邻近重要的血管、神经或骨骼,为保留肢体的功能,可以考虑边缘切除联合辅助治疗,尤其是术前放疗。在制定术前计划时,需要综合考虑肿瘤的病理学类型、肿瘤的部位、屏障结构的影响以及肿瘤对辅助治疗的反应。     

Racial and ethnic differences in treatment and survival among adults with primary extremity soft-tissue sarcoma

BACKGROUND: Limb preservation is preferred to amputation for patients with extremity soft tissue sarcoma (ESTS). Disparities in the treatment and outcomes of several malignancies have been reported, but not for ESTS. The authors assessed racial/ethnic differences in patient- and tumor-specific characteristics, treatment, and disease-specific survival in a population of adults with ESTS. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 6406 adult patients with ESTS who were diagnosed and treated between 1988 and 2003. Patients were categorized into 1 of 4 racial/ethnic groups: whites, blacks, Hispanics, and Asians. Comparisons of treatment and disease-specific survival were conducted with regression models that adjusted for patient age, sex, SEER geographic region, extent of disease, tumor grade, tumor size, and histology. RESULTS: Relative to whites, blacks received lower rates of adjuvant radiation with surgery (odds ratio [OR], 0.77; 95% confidence interval [95% CI], 0.66-0.90). Hispanics received significantly lower rates of limb-sparing surgery (OR, 0.76; 95% CI, 0.59-0.97). In a multivariate analysis controlling for patient age, sex, SEER geographic region, extent of disease, tumor grade, tumor size, and histology, blacks displayed a worse disease-specific survival (hazard ratio [HR] 1.39; 95% CI, 1.13-1.70), whereas Asians demonstrated superior disease-specific survival (HR, 0.67; 95% CI, 0.46-0.97). CONCLUSIONS: There were significant racial/ethnic differences in treatment and survival among adults with ESTS. Compared with whites, survival was poorer for blacks but better for Asians. These disparities were not explained by differences in patient or tumor characteristics.     

The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity

BACKGROUND:

Marginal excision of soft tissue sarcoma (STS), defined as resection through the tumor pseudocapsule or surrounding reactive tissue, increases the likelihood of local recurrence and necessitates re‐excision or postoperative radiation. However, its impact after preoperative radiation therapy (RT) remains unclear. This study therefore investigated the significance of marginal margins in patients treated with preoperative RT for extremity STS, reporting long‐term local control and limb preservation endpoints.

METHODS:

The records of 317 adults at the University of Florida with nonmetastatic extremity STS treated from 1980 to 2008 with preoperative RT as part of a limb conservation strategy were reviewed. The median follow‐up was 4.7 years (8.3 years for living patients). The median tumor size was 10 cm (range, 2‐36 cm), and 86% were high grade. The median RT dose was 50.4 Gy (range, 12.5‐57.6 Gy). Margins were classified as wide/radical (n = 105), marginal (n = 179), contaminated (n = 15), positive (n = 17), or unknown (n = 1). Endpoints were local control (LC), amputation‐free survival (AFS), cause‐specific survival (CSS), and overall survival (OS).

RESULTS:

Five‐year CSS and OS rates were 62% and 59%, respectively. Five‐year LC and AFS was 93% and 89%, respectively. AFS by margin status was 64%, 83%, 97%, and 92% for positive, contaminated, marginal, and wide/radical margins, respectively (P<.005). Marginal excision following preoperative RT resulted in equivalent LC and AFS compared with wide/radical margins.

CONCLUSIONS:

Marginal resection after preoperative RT does not compromise LC or AFS in extremity STS. This finding may be related to radiosterilization of tumor cells within the reactive zone following preoperative RT. Cancer 2012;118: 3199–207. © 2011 American Cancer Society.     

Lymphadenectomy for isolated lymph node metastasis from extremity soft-tissue sarcomas

BACKGROUND: Previous studies have suggested that the prognosis in patients with extremity soft-tissue sarcomas (ESTS) with isolated lymph node (LN) metastases (stage IV) is comparable to that of patients with high-risk ESTS without metastases (stage III). This study was performed to determine the outcomes of patients who underwent aggressive therapy, including lymphadenectomy in patients with LN metastasis from ESTS. METHODS: Demographic details, pathology of the primary disease, timing of LN metastasis, and details of the multimodality treatment were obtained from the medical records of 35 patients with nodal metastasis from ESTS who were treated between 1981 and 2003. Survival after the diagnosis of primary disease and LN metastasis was compared with established historical outcomes for patients with American Joint Commission on Cancer (AJCC) stages III and IV ESTS. RESULTS: Epithelioid sarcomas (23%) and malignant fibrous histiocytomas (23%) were the most common primary histologic types. Twenty (57%) patients presented with synchronous nodal metastasis. Median follow-up from the time of diagnosis of lymph node metastasis was 48.5 months. The 1-year, 2-year, and 5-year actuarial survival rates in patients with synchronous nodal metastasis after lymphadenectomy and additional therapy were 79%, 62%, and 52%, respectively. In comparison, the 1-year, 2-year, and 5-year actuarial survival rates in patients with metachronous nodal metastasis after lymphadenectomy and additional therapy were 100%, 95%, and 66%, respectively. CONCLUSIONS: Patients with isolated regional lymph node metastases who are treated with aggressive approaches, including regional LN dissection, may experience prolonged survival similar to that which more closely approximates the survival seen in patients with stage III disease (5-year survival rate, 50%) rather than the survival seen in patients with stage IV disease (5-year survival rate, 25%). These data lend support for reconsideration of the current AJCC staging system for ESTS.     

Soft tissue sarcomas of the popliteal fossa: a single-institution retrospective review

BACKGROUND:

Soft tissue sarcomas (STSs) arising from the popliteal fossa present a challenge with regard to local control of primary tumors. Due to concerns of functional morbidity and neurovascular compromise, there is debate about what represents the best therapy for these patients.

METHODS:

We conducted a retrospective medical record review of patients treated at The University of Texas M. D. Anderson Cancer Center for STS of the popliteal fossa from 1990 to 2008.

RESULTS:

There were 47 eligible patients, 28 of whom were male and 19 of whom were female. Synovial sarcoma was the most common diagnosis, with 12 cases. Most patients had T2b tumors (31 patients; 66%). The median duration of follow‐up was 3.8 years (range, 0.6‐17.9 years). The 5‐ and 10‐year overall survival rates were 63% and 51%, respectively. Metastasis at diagnosis was associated with poorer overall survival (5‐year overall survival, 74% versus 13%; P<.001) and poorer recurrence‐free survival (5‐year recurrence‐free survival, 51% versus 0%; P<.001) on univariate analysis. Radiation therapy improved local recurrence‐free survival (5‐year local recurrence‐free survival, 56% versus 17%; P = .004), whereas a trend was observed for surgical margin status (P = .07). Tumor size and neurovascular involvement did not influence outcome. Twenty‐two patients had recurrent disease, with 15 patients having local recurrence, and 16 patients died from progressive disease.

CONCLUSIONS:

Radiation therapy may play an important role in the treatment of popliteal fossa STS, but further study is needed to better define the best clinical application. Additional study is needed to re‐evaluate association of surgical margin status and outcome. Cancer 2011; © 2010 American Cancer Society.