Limb salvage for skeletal and soft tissue sarcomas. Multidisciplinary preoperative therapy

One hundred eighty-three patients with malignant skeletal (83) or soft tissue sarcoma (100) were entered into the multimodality preoperative limb salvage protocol. Local recurrences were observed in 5 of 183 (2.7%). Six patients required amputation because of complications, and 13 patients died within 1 year from metastatic disease. There was no statistical difference in survival rates between a series of patients who had amputation and adjuvant therapy and patients treated by limb salvage and adjuvant therapy. Overall survival rates for patients with soft tissue sarcoma were 76%. Although the exact reason for the improved local control is not known, it is our belief that it is the result of the multidisciplinary therapy that destroys microscopic disease at the periphery of the primary tumor.     

Limb salvage in soft tissue sarcomas with selective combination of modalities

One hundred and seventy-one consecutive patients with soft tissue sarcomas were treated in the period 1977-1986. Of 144 patients with extremity sarcomas, only eight (6%) were managed with amputation. The overall estimated 5-year survival rate is 64%, and that for patients with extremity tumors is 71%. The 5-year local recurrence rate in extremity sarcomas was 6% for patients with minimum surgical margins 2 cm or greater and no further local therapy, and 6% for those with narrower surgical margins and adjuvant postoperative radiation; 80 patients (56%) were in the former group and 64 (44%) in the latter. With a selective combination of modalities, limb salvage can now be practiced in 94% of the patients with acceptable local control and survival rates.     

Limb salvage surgery in combination with brachytherapy and external beam radiation for high-grade soft tissue sarcomas

While combined treatment of high-grade soft tissue sarcoma with resection and radiotherapy has become an accepted standard, outlines of treatment algorithms remain a matter of debate. Our institutional practice foresees wide surgical resection with adjuvant brachytherapy and external beam radiation. It was the purpose of this study to determine long-term outcome, prognostic factors for local and systemic recurrence and morbidity in patients with high-grade soft tissue sarcomas of the extremities, who were subjected to this regimen.     

Limb salvage in soft tissue sarcomas involving neurovascular structures using combined surgical resection and brachytherapy

While there is debate in the literature concerning the tolerance of neurovascular structures to external beam radiation, the tolerance of these tissues to interstitial radiation has never been established. To evaluate the dose of radiation and its effect on early and late toxicity of neurovascular structures, a retrospective review of our experience was undertaken. Between 1975 and 1987, 299 patients with extremity sarcomas underwent limb-sparing surgery and tumor bed Iridium-192 interstitial implantation at Memorial Sloan-Kettering Cancer Center. Forty-five patients (15%) of this group were found to have locally advanced tumors involving major neurovascular structures. Of these patients, 64% had high grade lesions. Eleven percent had evidence of gross residual disease on these structures, and an additional 58% had microscopic residual disease at or close to the margins of resection. After loading catheters were placed directly upon the neurovascular structures in the exposed tumor bed and a median dose of 4400 cGy was delivered to the target volume. Eight patients had previous radiation to the treated field and 13 patients received postoperative radiation. With a median follow-up of 4 years, the 5-year actuarial disease-free survival was 69% and the 5-year actuarial freedom from in-field failure was 79%. The 5-year actuarial incidence of distant metastases was 30%. Eighty-four percent of the patients maintained long-term preservation of limb function without the need for amputation. Four patients (9%) ultimately developed evidence of radiation neuritis 6-20 months post therapy. All four patients had received additional radiation with cumulative doses exceeding 9000 cGy to the neurovascular bundle. We conclude that combined surgical resection and interstitial radiation for locally advanced sarcomas with neurovascular involvement can provide excellent local control with preservation of limb and neurovascular function without significant toxicity.     

综合治疗在难治性软组织肉瘤的运用

目的：对软组织肉瘤特别是对于难治性病例施行综合治疗的合理性进行探讨。材料与方法：以我院１９９３年６月～１９９７年１２月间所收治的难治性病例为研究对象，对多模式的综合治疗方式进行分析。结果：疗效是肯定的，更重要的是保存了患者的肢体，提高了治疗后的生存质量，但远期效果有待进一步观察。结论：综合治疗有其理论依据，并为临床实践所证实。为进一步提高疗效及降低截肢率，我们初步制定了软组织恶性肿瘤的治疗规范。     

Radiation therapy for unresectable soft tissue sarcomas

Between 1954 and 1981, 72 patients with unresectable soft tissue sarcomas were treated with radiotherapy at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, 57 with photons alone and 15 with neutrons for at least part of the treatment. Twenty-three patients received systemic chemotherapy in addition to radiation therapy. The absolute 2-year and actuarial 5-year tumor control rates were 39 and 29%, respectively. In this heterogeneous series, the malignancy group (based on pathologic diagnosis) was the only factor significantly affecting tumor control probability, which at 5 years was 58% for 12 patients with group I tumors, 32% for 10 patients with group II tumors, and 17% for 50 patients with group III tumors. No relationship between total dose and tumor control probability was found in this group of patients, though the duration of tumor control was longer in those receiving 65 Gy or more. No apparent improvement in tumor control was observed in the subsets of patients receiving fast neutron therapy or combined modality treatment with chemotherapy, but because of the many unmatched variables between the groups, no meaningful comparison of treatment modalities can be made. Distant metastasis were seen more frequently in higher malignancy groups, whereas size or site of tumors did not significantly influence the incidence of distant metastasis. Six patients sustained major complications of radiotherapy, of whom five received total doses in excess of 70 Gy or its estimated biologic equivalent.     

Targeted therapy of soft tissue sarcomas

Soft tissue sarcomas (STS) are rare mesenchymal cancers with a heterogeneous histology. In terms of oncogenesis, sarcomas may be differentiated into diseases with defined molecular events and sarcomas presenting with complex karyotypes lacking identifiable specific genetic changes or expression profile signatures. The former subtype is amenable to therapy with targeted drugs, especially if the tumor carries a consistent causal mutation occurring early in the disease development. While targeted therapy based on tyrosine kinase inhibition such as imatinib and second generation tyrosine kinase inhibitors plays an important role in the treatment of gastrointestinal stromal tumors (GIST), some progress was also achieved in non-GIST sarcomas. Targeting the PI3 kinase/Akt pathway has been shown to be clinically promising in a diversity of different sarcoma subtypes, and inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor pathway is of special interest in vascular sarcoma subtypes. MDM2 and p53 seem to be interesting targets for STS, but their role has yet to be defined in further clinical trials. Modification of epigenetic mechanisms, especially deacetylation, might be crucial in other STS subtypes such as translocation-associated entities, but its role has yet to be clinically confirmed. Inclusion of patients in controlled clinical trials combined with a translational research platform is critical for further progress.     

肢体恶性软组织肿瘤的保肢治疗

目的 探讨四肢恶性软组织肿瘤保肢治疗的可行性。方法 22例肢体恶性软组织肿瘤患者中,滑膜肉瘤9例,横纹肌肉瘤及恶性纤维组织细胞瘤各5例。透明细胞肉瘤2例,恶性黄色肉芽肿1例。其中股部9例,臀部4例,膝部、足跟部各3例,小腿外侧、腕部、足背部各1例。16例行肿瘤扩大切除术,6例行肿瘤扩大切除皮瓣修复术。术后采用CVADIC方案行化疗,16例行放疗。结果 19例获得平均4年2个月的随访,2例复发,2例死亡(1例为复发后再次手术患者)。结论 肿瘤切除彻底是四肢恶性软组织肿瘤保肢治疗的前提;放疗可以改善局部控制率;CVADIC方案是治疗恶性软组织肿瘤的可行方案;肿瘤切除后软组织缺损修复,应选择操作简单、就近取材、效果良好的方法。     

Feasibility of limb salvage and survival in soft tissue sarcomas

One hundred nine consecutive patients with soft tissue sarcomas were treated in the period 1977 through 1983. Of 85 patients with extremity sarcomas, only 3 patients (4%) were managed with amputation, whereas in the previous decade, 40% of such patients were treated with amputation in our institute. The current 5-year survival rate is 63%; in the previous decade it was 45%. In the current series, for extremity locations, patients with minimum surgical margins of 2 cm or greater and no further local therapy had a 5-year local recurrence rate of 17%, whereas those with minimum surgical margins of less than 2 cm and who were treated with adjuvant postoperative radiation had a local recurrence rate of 7%. In the previous period, the local recurrence rate was 30% after wide resection and 66.6% after local excision. With a combination of modalities, limb salvage can be practiced currently in the majority of patients with extremity soft tissue sarcomas without any adverse effect on recurrence rates and survival.     

Radiation therapy of soft tissue sarcomas.

Recent advances in radiation therapy in the clinical management of patients with sarcoma of soft tissue are discussed. Radical dose radiation therapy combined with limited surgery has been shown to be highly effective as treatment of early to moderately advanced sarcomas of the extremities. Desmoid tumors which are nonresectable have been treated with moderate to high radiation doses with regular success. The multimodality treatment of rhadbomysarcoma of childhood has yielded a dramatic improvement in 2-year survival figures. This approach includes radiation therapy, multidrug and multicycle chemotherapy, and surgery. Finally, the dominant importance of the histologic grade of sarcoma to the prognosis is discussed in terms of a proposed clinical staging system.     

Radiation therapy of retroperitoneal soft tissue sarcomas

Between 1971 and 1982, 23 patients have been treated with radiation therapy at the Massachusetts General Hospital (MGH) for retroperitoneal soft tissue sarcomas. Seventeen patients were treated with curative intent and six with palliative intent. Of the patients treated with curative intent, the 5 year actuarial survival rate was 54% and the 5 year actuarial local control rate was also 54%. With a complete surgical resection local tumor control was obtained in 5 of 7 patients (71%), 4 of 7 (57%) with incomplete resection and 1/3 (33%) with no resection having local control. The radiation dose appeared to influence tumor control with 2 of 6 patients (33%) having local control with less than 5,000 cGy compared to 0 of 5 patients with doses of 5,000 to 6,000 cGy and 5 of 6 (83%) with doses greater than 6,000 cGy. An effect of tumor grade on either local control or on rate of metastasis formation could not be demonstrated in this series. Long-term local control and survival appears to be associated with maximal surgical resection and high dose radiation therapy.     

Surgical management of soft tissue sarcomas of the hand and foot

BACKGROUND: Soft tissue sarcomas of the hand and foot present unique management challenges. The purpose of the current study study was to determine oncologic outcome, particularly with respect to factors affecting local recurrence, distant recurrence, and disease-specific survival. METHODS: A retrospective study was performed on 115 patients with soft tissue sarcomas of the hand or foot who were evaluated, treated, and followed at the authors' institution between 1980 and 1998. The medical records and radiographs were reviewed. Kaplan-Meier analysis was used to assess patient survival. RESULTS: Most patients (95%) were referred after previous surgery. The majority of tumors (75%) were T1 lesions (less than 5 cm), and most tumors (81%) were high grade. Patients who were treated by definitive, wide re-excision (n = 43) had a 10 year local recurrence-free survival of 88%, which was significantly better than the corresponding rate of 58% for patients who did not have re-excision (n = 40, P = 0.05). Radiation improved local control in patients who did not undergo re-excision (n = 17, P = 0.02). However, radiation did not improve local control in patients who had definitive re-excision with negative margins (n = 13, P = 0.51). The disease-specific survival at 5 and 10 years was 76% and 65%, respectively, for patients who presented with localized disease. Disease-specific patient survival was significantly worse for patients who had regional or distant metastasis. Radical amputation as initial surgical treatment did not decrease the likelihood of regional metastasis and did not improve disease-specific patient survival. The presence of distant metastasis at presentation was an independent predictor of local recurrence. CONCLUSION: Limb sparing treatment is possible in many patients with soft tissue sarcomas of the hand and foot. Re-excision to achieve microscopically negative surgical margins is an effective method of achieving a high rate of local control in appropriately selected patients who present after unplanned excision of the primary tumor. There does not appear to be a survival benefit to immediate radical amputation, which should be reserved for cases where surgical excision or re-excision with adequate margins cannot be performed without sacrifice of functionally significant neurovascular or osseous structures.     

Immunotherapy with low-dose interleukin-2 in association with melatonin as salvage therapy for metastatic soft tissue sarcomas

Polychemotherapy represents the only standard medical therapy of metastatic soft tissue sarcomas (STS), whereas the recent biotherapies with cytokines, such as interleukin-2 (IL-2), seem not to have a relevant therapeutic role. The pineal hormone melatonin (MLT), whose immunomodulating activity is well known, would seem to exert a direct cytostatic action on STS cell proliferation. Moreover, MLT has been proven to amplify IL-2 efficacy. On this basis, a pilot phase II study with low-dose IL-2 plus MLT has been performed in untreatable metastatic STS patients. The study included 13 evaluable metastatic STS patients with poor PS, who progressed on at least one previous polychemotherapeutic line. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks and MLT was given orally at 40 mg/day in the evening. A partial response was achieved in one patient with leiomyosarcoma. Eight other patients had a stable disease (SD) whereas the remaining 4 patients progressed. A survival longer than 1 year was achieved in 6/13 patients and the percent of 1-year survival was significantly higher in patients with response or SD than in the progressed ones (6/9 vs 0/4). Mean increases in lymphocyte and eosinophil numbers were significantly higher in patients with response or SD than in the progressed ones. These preliminary results would suggest that immunotherapy with low-dose IL-2 plus MLT may have some impact at least on the survival time of untreatable metastatic STS patients with poor clinical conditions.     

Isolated regional therapy for advanced extremity soft tissue sarcomas

Patients presenting with unresectable, large, primary or recurrent extremity soft tissue sarcoma or locally advanced extremity tumors may benefit from treatment options in the form of isolated regional perfusion therapy. Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) have proved to be efficacious with acceptable systemic and regional toxicity profiles. Both procedures are attractive as options for patients who might otherwise be facing amputation as limb salvage procedures. HILP and ILI can be offered as either definitive treatment or as neoadjuvant therapy followed by surgery and/or radiation treatment. Response rates are encouraging as are limb preservation rates after regional therapy. Ongoing multicenter collaborations and clinical trials are required to gain knowledge on HILP and ILI for unresectable extremity sarcoma and expand the indications for use in the management of advanced extremity soft tissue sarcoma.     

Neoadjuvant and adjuvant therapy for extremity soft tissue sarcomas

Despite the overall good prognosis in patients who have localized soft tissue sarcoma (STS) of the extremities, approximately half of those who have high-risk features ultimately will die from metastatic disease that was present as microscopic foci at the time of diagnosis. The principal role of adjuvant and neoadjuvant chemotherapy is to improve the "cure" rate through eradication of these microscopic foci. Over the last 30 years there have been numerous studies attempting to determine whether adjuvant or neoadjuvant systemic chemotherapy does lead to an improvement in disease-specific survival in patients who have localized STS. It is still unclear whether there may be a role for systemic chemotherapy in patients who have high-risk localized STS of the extremities. This article discusses some of the issues surrounding this most controversial area in the management of STS.     

软组织肉瘤分子靶向治疗研究进展

软组织肉瘤(soft tissue sarcoma,STS) 是一组起源于间叶组织的恶性肿瘤,约占成人恶性肿瘤的 1%,恶性程度较高和亚类繁多是其主要特点。目前主要治疗手段包括手术、放疗及化疗等。与胃肠间质瘤对伊马替尼的良好反应不同,其他 STS 的治疗面临着更多困难,不同亚型间遗传性和临床特点异质性强,生存时间差异较大。近年来,分子靶向药物的应用进展迅速,在个体化治疗和提高患者生存质量等方面优势明显,为不宜手术和不能接受常规化疗的患者提供了新的治疗手段。本文就近年来 STS 的靶向治疗药物和相关通路进行简要阐述。      

Ifosfamide in the adjuvant therapy of soft tissue sarcomas

Ifosfamide and anthracyclines are the only active agents in advanced soft tissue sarcomas. Doxorubicin was always used in sarcomas, whereas ifosfamide was reintroduced in the clinic after the discovery of mesna which prevents its typical dose-limiting toxicity: hemorrhagic cystitis. In the adjuvant setting, doxorubicin was used alone or in combination in the first-generation trials, whereas its parent compounds epirubicin and ifosfamide were employed in the second-generation adjuvant trials, which started in the early 90s. Other relevant aspects of the second-generation trials are the use of the hematopoietic growth factors and the increase of the dose intensity, the introduction of more restrictive selection criteria and the use of the two most active agents, ifosfamide and anthracyclines. Only the Italian cooperative trial has been concluded, and the results reported and updated. After a median follow-up of 89.6 months (range 56-119), the intention-to-treat analysis still reveals a difference in overall survival which, however, is not statistically significant. However, the 5-year overall survival estimate, which is a reasonable end point for the survival analysis of adjuvant treatment in soft tissue sarcomas, was 66.0 and 46.1% for the treatment and the control groups, respectively (p = 0.04).     

Multidisiciplinary “limb salvage” treatment of soft tissue and skeletal sarcomas

Sixty-five patients with soft tissue sarcomas and 40 patients with skeletal sarcomas were treated pre-operatively with infra-arterial Doxorubicin and radiation therapy (3500 rad in 10 fractions). The tumors were widely excised and in the case of skeletal sarcomas, the bone was replaced with a cadaver allograft or metal endoprosthesis in an attempt to achieve limb salvage. Chemotherapy consisting of Adriamycin and Methotrexate was administered post-operatively. These patients have been followed from 6 to 70 months with a median follow-up for soft tissue and skeletal tumors of 24 and 30 months respectively. In the soft tissue sarcoma group there have been 2 local recurrences; actuarial overall and disease-free survival at 3 years was 64 and 61%, respectively. In the skeletal sarcoma group there have been only 2 recurrences and the actuarial survival and disease-free survival of 75 and 55% at 2 years, respectively. In the soft tissue sarcoma group there have been 33 thigh lesions, 13 of which have required periosteal stripping. Five of the patients with thigh lesions have developed femoral fractures. All of these patients had post-operative chemotherapy and four of the five patients had periosteal stripping. In the skeletal sarcoma group, eleven of the twenty-one cadaver allografts have either fractured or become unstable requiring replacement with metallic endoprostheses that have been used exclusively for the past two years. Ninty-seven of the total group of 105 patients achieved limb salvage to the last follow-up or time of death with an acceptable complication rate. Longer follow-up is mandatory to determine the late effects of this combined modality regimen.     

Recent advances in systemic therapy of soft tissue sarcomas

Improvements in surgical techniques, for example reconstructive surgery; and radiation therapy techniques, such as intensity-modulated radiotherapy; have made some impact on the functional outcomes of sarcomas with a local biology. Effective local control can be achieved with effective function in the vast majority of patients. The problem of distant metastases, however, continues to plague a large group of patients with this disease. Recent advances in the systemic therapy of sarcomas is highlighted by the rapid development and approval of the molecularly targeted therapy imatinib (Gleevec) for advanced gastrointestinal stromal tumors. Several other agents have been, or are being studied with far less rewarding results. Among these, the more encouraging examples include the nucleoside analog gemcitabine (Gemzar) and gemticibine/docetaxel (Taxotere) in combination, which display some selective activity in sarcomas of gynecologic origin. The marine compound ecteinascidin (ET-743) has been studied in two different schedules (24 and 3 h infusions), demonstrating biological activity worthy of further investigation. Identification of new agents with activity in this diverse group of diseases is extremely important. Identification of specific targets responsible for tumorigenesis and effective inhibition of these targets holds the most promise for future improvement in cure rates. However, until such time, it is equally important to emphasize clinical research attempting to further optimize the use of the standard chemotherapeutic agents, with growth-factor support in appropriately selected patients.