Preoperative adjuvant chemotherapy of skeletal and soft tissue sarcomas

Preoperative adjuvant chemotherapy for skeletal and soft tissue sarcomas requires: (1) correct identification of the effective postoperative adjuvant chemotherapy, (2) eradication of any of the micrometastatic foci that may have already occurred in many of the patients with these sarcomas, (3) easier and safer limb-salvage procedure, being clearly defined, with shrinkage of the primary lesion. For this purpose, a preoperative adjuvant chemotherapy regimen making practical use of intra-arterial CDDP (cis-dichlorodiammineplatinum II) infusion is desired in multi-drug combined chemotherapeutic treatment, including HDMTX (high-dose methotrexate), ADR (adriamycin) and CDDP. In this paper, the clinical application of preoperative adjuvant chemotherapy to skeletal and soft tissue sarcomas with combination of HDMTX and CDDP is presented in the light of the observations of tumor response to these anticancer agents, and the possibility of to establishing a new preoperative adjuvant protocol is discussed.     

Adjuvant chemotherapy for soft tissue sarcomas

Soft tissue sarcomas are rare mesenchymal neoplasms with considerable heterogeneity in biologic behavior and response to systemic therapy. Most patients present with localized disease and are potentially curable with multidisciplinary treatment. In patients with a high risk of developing metastatic disease, optimal use of neoadjuvant/adjuvant therapy has a definite role in improving patient outcomes by decreasing local and distant recurrences. Histology-specific clinical trials enrolling a homogenous high-risk population have been more successful in demonstrating benefit than larger trials with unselected heterogeneous patient populations. In specific histologic subtypes responsive to chemotherapy, neoadjuvant chemotherapy with close monitoring of response is recommended.     

Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities

Sixty-five patients with high-grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high-dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow-up of 653 days revealed an advantage in continuous disease-free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one-sided Mantel-Haenszel test). The continuous disease-free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty-eight percent of patients had limb-sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease-free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four-year follow-up, reveals an improvement in disease-free and overall survival due to chemotherapy (P less than 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment adult patients with soft tissue sarcomas of the extremities.     

Role of chemotherapy in patients with soft tissue sarcomas

The management of soft tissue sarcomas has been highlighted in the last few years by the responsiveness of gastrointestinal stromal tumors to imatinib (Gleevec, Novartis). In this article, the use of chemotherapeutic agents in the management of this and some of the 50 or more subtypes of sarcomas are discussed, and a brief review of the use of chemotherapy in the adjuvant or neoadjuvant setting for people with large extremity sarcomas is provided. Doxorubicin and ifosfamide (Mitoxana, Bristol-Myers Squibb) remain the best individual drugs for sarcomas overall, although dacarbazine and gemcitabine (Gemzar, Eli Lilly) with or without a taxane has activity in at least a subset of sarcomas. The data regarding adjuvant chemotherapy for extremity soft tissue sarcomas is still quite mixed, with little if any overall survival advantage found to support its incorporation into disease management. The finding of tyrosine kinase inhibitors such as imatinib with demonstrated activity in gastrointestinal stromal tumors and dermatofibrosarcoma protuberans, as well as the finding of new agents such as ecteinascidin-743 (Yondelis, PharmaMar) with at least some activity against soft tissue sarcomas, reinforces the idea that we should target individual subtypes of sarcoma, just as treatment varies by subtype for the hematological malignancies.     

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).     

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.     

Advances in neoadjuvant chemotherapy in soft tissue sarcomas

Opinion statement The use of adjuvant chemotherapy in soft tissue sarcomas (STS) continues to be an area of controversy; however, the group of investigators favoring the use of an anthracycline- and ifosfamide-based regimen for high-risk (American Joint Committee on Cancer stage III) extremity STS is steadily increasing. The historic 5-year survival rate of approximately 50% in this high-risk group treated with local therapy alone represents a poor standard of care, thus there is a need to incorporate systemic therapy early in the management of these patients. Published data from the meta-analysis of doxorubicin-based adjuvant chemotherapy trials and the prospective randomized data with epirubicin and ifosfamide from the Italian Sarcoma Group are frequently used as rationale for this approach. In a rare and heterogenous group of diseases, such as STS, physicians run into negative studies for various reasons that have little to do with the efficacy of the treatment being tested. The wisdom may be in capitalizing further on a positive lead as opposed to nihilism. It is appropriate to acknowledge that the chemotherapeutic agents have limited efficacy and are toxic, especially when used at full therapeutic doses. Selecting patients in whom there is some evidence of benefit, justifying the poor quality of life from receiving chemotherapy, becomes very important. This rationale, with the lessons learned from osteosarcoma research, forms the basis for neoadjuvant chemotherapy for STS. Until we reach the day when we have identified critical tumorigenic targets and their effective inhibitors for most of these tumors, we are obligated to use the available therapeutic armamentarium in the best possible sequence.     

High-dose chemotherapy in soft tissue sarcomas of adults

Few cytotoxic agents are active for the treatment of soft tissue sarcomas of adults: drugs active in monotherapy are doxorubicin, ifosfamide, dacarbazine and ET743. In patients with advanced stage soft tissue sarcomas (ASTS), a dose-response relationship has been established for doxorubicin and ifosfamide. Intensive combination chemotherapy regimens at conventional doses (MAID, or AI) yield higher objective response rates than monochemotherapy regimens, ranging between 25% and 44%, but failed improve survival rates as comparted to less intensive regimens. Recently, several phase I or II studies have investigated the use of high dose chemotherapy regimens as consolidation therapy in ASTS in response to conventional regimens. HDCT regimens have been reported to yield response rates ranging between 18% and 66%. Some of these patients with ASTS achieved long term complete remission, in particular in the subgroup of patients in complete remission after conventional chemotherapy in advanced phase. Phase III studies are required to confirm that survival may be improved by HDCT in subgroups of patients with ASTS.     

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas.     

Prognostic variables for the selection of patients with operable soft tissue sarcomas to be considered in adjuvant chemotherapy trials.

From 1975 to 1988, 144 patients naive of treatment, with non-metastatic soft tissue sarcoma were treated at Fondation Bergonié by surgery, followed by radiotherapy and without chemotherapy. An analysis of prognostic variables was done on this population to determine patients for whom an adjuvant chemotherapy would be relevant. Prognostic variables in overall survival (OS), metastasis-free survival (MFS), disease-free and local free recurrence survivals were analysed by univariate and multivariate analysis. In multivariate analysis using Cox's model, only tumour depth and tumour grade were significant with the MFS end point, while tumour depth, tumour grade and tumour site were significant when considering OS. A predictive stratification for patients is proposed: a favourable prognostic group with grade 1 tumour or superficial, grade 2 tumour (5-year OS: 97.8%; 5-year MFS: 100%); an intermediate prognostic group with deep, grade 2 tumour or superficial, grade 3 tumour (5-year OS: 58.8%; 5-year MFS: 48.1%); and finally a poor prognostic group with deep, grade 3 tumour (5-year OS: 31.7%; 5-year MFS: 34.1%). Patients in the intermediate and poor prognostic groups who present a high metastatic risk are to be considered for adjuvant chemotherapy trials.     

Alternating combination chemotherapy of advanced soft tissue sarcomas in adults

The possibility of improving treatment results using an alternating combination chemotherapy was explored in 40 evaluable patients with advanced soft tissue sarcomas. Treatment regimen consisted of adriamycin and DTIC alternating with vincristine, actinomycin D, and cyclophosphamide. Four patients achieved a complete response and eight achieved a partial response, with an overall response rate of 30%. The median duration of response was 14 months. The median survival time was 28 months for responders compared with 7 months for nonresponders (p = 0.001). Toxicity was predominantly limited to nausea, vomiting, and myelosuppression. Although this alternating regimen failed to improve response rates over other combinations, survival times observed in the present study should provide impetus to evaluate further the concept of sequential noncross-resistant combinations.     

软组织肉瘤化疗的临床研究

随着化疗的不断进步,以及传统辅助化疗、新辅助化疗、化疗联合骨髓或干细胞移植、局部热化疗等方案的采用,进展期软组织肉瘤(STS)的治疗效果有了一定程度的提高.为进一步提高疗效、改善预后,近期一些新型的药物开始应用于该领域.现就近年来进展期软组织肉瘤化疗的进展综述如下.     

Pediatric soft tissue sarcomas

Many of the soft tissue sarcomas that occur in children are of the same histology as those in adults; however, the relative prevalence of these sarcomas is different between children and adults. In some cases, the biologic behavior of pediatric sarcomas is more benign than that in adults. Treatment for sarcomas in children is also different. Pediatric sarcomas are more commonly responsive to chemotherapy. Furthermore, in children who are still growing, surgery and radiation are associated with higher morbidity than in adults. This article discusses the diagnosis and treatment of rhabdomyosarcoma and undifferentiated sarcomas, with an emphasis on surgical considerations, and the diagnosis and treatment of nonrhabdomyosarcomatous soft tissue sarcomas in children.     

Pelvic soft tissue sarcomas

Pelvic soft tissue sarcomas (PSTS) are a rare, heterogeneous group of tumors. They have been usually analyzed with retroperitoneal sarcomas (RPS), but actually have key differences. Due to their unique anatomic location, symptomatic presentation of PSTS may be more common than RPS. Adequate imaging approach is paramount for guiding differential diagnosis, while preoperative biopsy is mandatory, especially when preoperative treatment may be considered as initial approach. The most frequent histologic subtype is leiomyosarcoma, which is different as expected in the retroperitoneum where liposarcoma is the commonest histology. Also solitary fibrous tumor is commonly diagnosed in the pelvis. Surgical approach for PSTS differs from that for RPS mainly due to anatomic relations. Similarly, in the lack of definite evidence from specific trials about neoadjuvant and adjuvant treatments, the anatomic constraints to obtain wide margins in the pelvis as well as the expected functional outcome in case of organ resections should be factored into decision for individualized treatment offer. Vascular and genitourinary involvement are frequent, as well as herniation through pelvic foramina. For these reasons a multidisciplinary surgical team should always be considered. Early referral of these patients to high-volume centers is critical and may impact on survival, given that optimal initial resection is a major predictor of curative treatment. International consensus on PSTS treatment is advocated, similarly to the recent efforts realized for RPS.     

The treatment of soft tissue sarcomas with focus on chemotherapy: a review

Radical surgery remains the most effective treatment of soft tissue sarcomas. The postoperative addition of radiotherapy appears to reduce local recurrence in extremity lesions. To date, there are still only two drugs with major activity as a single agent in the treatment of soft tissue sarcomas: doxorubicin (DX) and ifosfamide (IFX). Doxorubicin should be administered preferably as 3-weekly bolus injections at doses higher than 60 mg/m2 because of its dose-response relationship. In combination chemotherapy ADIC and CYVADIC are probably the best choice. Although there are no definite data on increased activity with the addition of cyclophosphamide (CTX) and vincristine (VCR) to ADIC, we prefer CYVADIC because of the higher reported complete response rate. A limited number of patients with soft tissue sarcomas achieving a complete response with chemotherapy, will probably be cured, and for this reason it is important to aim at achieving a complete response. Preoperative intraarterial chemotherapy in locally advanced soft tissue sarcomas may further improve survival results, but before definite conclusions can be drawn, this technique should be investigated in randomized studies. Postoperative adjuvant chemotherapy should still be considered investigational, as no advantage has been observed in head, neck and trunk lesions, while data on extremity lesions are still conflicting.     

Current strategy of chemotherapy for reflactory bone and soft tissue sarcomas

Pulmonary metastases have been curative in some patients of osteosarcoma with aggressive surgical excision and intensive chemotherapy. But several retrospective studies and randomized II studies did not prove survival advantages of advanced cases with bone and soft tissue sarcoma. In treatment for refractory and advanced osteosarcoma after conventional treatments, clinical phase II trials showed 20-30% response ratio of high-dose ifosfamide and etoposide combination or carboplatin combination. In soft tissue sarcomas, high-dose ifosfamide and doxorubicin have over 50% response rate to advanced soft tissue sarcoma and total surgical excision of residual lung metastases prolong the survival. But new drugs active to refractory sarcoma had not reported in a recent decade.     

The role of chemotherapy as an adjuvant to surgery in the initial treatment of primary soft tissue sarcomas in adults

A prospective study was carried out to determine the results of chemotherapy as an adjuvant to surgery in the initial treatment of adult primary soft tissue sarcomas. The results were compared with those in a group of patients with similar histologic types of primary sarcoma treated by surgery alone. The chemotherapy regimen consisted of adriamycin, 60 mg/m2 intravenously on Day 1, and DTIC, 250 mg/m2 on Days 1 through 5. The cycle was repeated every 22 days. The total dose of adriamycin was 500 mg/m2; the DTIC was continued for 1 year. The adjuvant chemotherapy group consisted of 113 patients (group one) and the concurrent surgical resection group consisted of 144 patients (group two). In group one, 53 tumors were T1 and 60 tumors were T2; 67 of the tumors were grade 3 and 46 were grade 4. In group two, 65 had T1 and 79 had T2 tumors; 82 tumors were grade 3 and 62 were grade 4. The anatomic location and histologic types were similar in both groups. Seventy-seven (77%) of the 113 patients in group one lived disease free for 2 years, compared with 59% of the 144 patients treated by resection alone. Of the patients eligible for 5-year survival analysis, 74% were disease free in the adjuvant chemotherapy group, compared to 50% in the surgical group. The incidence of local recurrence was about the same in both groups. From a histologic standpoint, malignant fibrous histiocytomas and myogenic sarcomas appeared to benefit most with use of the use of the two-drug regimen used here, and the least favorable response was in liposarcomas and fibrosarcomas. In other histologic types, the role of adjuvant chemotherapy needs further clarification.