Centralised treatment of soft tissue sarcomas in adults

The clinical research developed in specialised centres and oncologic cooperative groups has permitted various scientific societies to collect recommendations used in the treatment of soft tissue sarcomas (STS) and incorporate them into clinical practice guidelines (CPG). Some studies have been conducted in diverse healthcare ambits to assess the influence of CPG. This revision of the medical literature analyses the impact that healthcare management -centralised or otherwise- and clinical practice in conformity with CPG have on the clinical outcome variables of STS. Eight CPG have been identified, as well as 12 conformity studies or audits. These conformity studies and audits demonstrate that the grade of adaptation of medical interventions with CPG, medical healthcare in reference centres and procedures of referrals to these centres, as well as the process of organising healthcare teams into Sarcoma Committees, have a significant influence on clinical outcome. We can conclude that excellent healthcare of STS implies the adaptation of healthcare practice to CPG, the existence of Reference Centres guided by Sarcoma Committees, and the observance of strict referral procedures within the Healthcare Area.     

Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas

Purpose: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. Methods: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m² infused over 180 min followed by DTIC 500 mg/m² (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2′,2′-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. Results: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1–18). Grade 3–4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or γ-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0–24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. Conclusions: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.J. Fra and R. Losa contributed equally to this work.     

Radiotherapy as an integrated part of the treatment of soft tissue sarcomas

A considerable improvement in the prognosis of soft tissue sarcomas in the adult has been obtained with a treatment schedule combining surgery and routine radiation therapy (possibly preoperative and certainly postoperative); local recurrences, the predominant element in the natural history of the disease, have become very rare and limb function is generally maintained. Metastatic risk presents the major problem, and in our series spread of the disease remained uncontrolled in 25% of cases. Further research is required in this area, and a better definition of the risk factors, especially with regard to histology, is needed. We suggest that the possibility of reinforcing treatment of those histological forms at high metastatic risk by the introduction of multidrug therapy after local treatment be investigated. Such studies can only be effectively conducted within the framework of a multicenter collaborative controlled clinical trial.     

Intraarterial adriamycin in the treatment of soft tissue sarcomas

Ten patients with extremity sarcomas adriamycin 60 mg/M² into the artery supp supplying the area of tumor. There were minimal local side effects consisting of occasional local erythema or slight transitory pain. Nine of these patients had subsequent surgery, and an average 32.86% histologic tumor necrosis was recorded in the peripherally viable areas of seven patients with residual tumor, compared to a 5.71 % necrosis recorded in the biopsy sections (P value < 0.01).     

原发性256例软组织肉瘤手术治疗的临床分析

目的：探讨软组织肉瘤的诊断、手术治疗方法及其疗效。方法：对256例原发性软组织肉瘤患者的治疗情况进行回顾性分析。行局部广泛切除及根治切除术,对侵犯骨组织的软组织肉瘤则按微波原位灭活保肢手术处理。切除肿瘤后,行血管修复重建、带血管蒂游离皮瓣转移、局部皮瓣转移、肌腱移位、肌皮瓣移位。结果：发病年龄为20-70岁,占62.11%（159/256）,常见的病理类型为滑膜肉瘤、恶性纤维组织细胞瘤、脂肪肉瘤、横纹肌肉瘤、纤维肉瘤,占65.23%（167/256）。Kaplan-Meier法计算5年生存率为63.28%。结论：诊断采用CT、MRI为主的影像学,治疗以手术为主,辅助放疗和化疗。     

原发性256例软组织肉瘤手术治疗的临床分析

目的:探讨软组织肉瘤的诊断、手术治疗方法及其疗效。方法:对256例原发性软组织肉瘤患者的治疗情况进行回顾性分析。行局部广泛切除及根治切除术,对侵犯骨组织的软组织肉瘤则按微波原位灭活保肢手术处理。切除肿瘤后,行血管修复重建、带血管蒂游离皮瓣转移、局部皮瓣转移、肌腱移位、肌皮瓣移位。结果:发病年龄为20-70岁,占62.11%(159/256),常见的病理类型为滑膜肉瘤、恶性纤维组织细胞瘤、脂肪肉瘤、横纹肌肉瘤、纤维肉瘤,占65.23%(167/256)。Kaplan-Meier法计算5年生存率为63.28%。结论:诊断采用CT、MRI为主的影像学,治疗以手术为主,辅助放疗和化疗。     

腺泡状软组织肉瘤的临床治疗分析

目的探讨腺泡状软组织肉瘤手术切除及辅助放、化疗的临床治疗效果。方法对1993～2006年间收治的腺泡状软组织肉瘤12例回顾性分析。男5例,女7例。年龄11～37岁。肿瘤直径平均5.5cm。结果12例手术后切除缘评价中,达到广泛切除缘者10例,边缘切除缘者2例,术后辅助放疗2例,全组均予辅助化疗。12例手术后复发3例,占25%。有7例发生转移,首诊时转移2例,其中肺转移瘤5例,脑转移瘤2例。转移率58.3%。转移瘤单纯化疗5例中PR3例,NC1例,PD1例,3例PR患者均采用MAI方案。随访时间10个月～10年6个月,12例中7例生存,5例死亡,经过Kaolan-Meire生存率计算,3年生存率81.2%,5年生存率52.8%。结论腺泡状软组织肉瘤外科治疗应以广泛切除术为基本原则,术后辅助放疗可以减少复发,辅助化疗是转移瘤的主要治疗方法。     

野中野照射加大剂量顺铂水化防治软组织肉瘤术后复发的临床研究

目的评价野中野照射加大剂量顺铂（HD-PDD）水化技术在软组织肉瘤综合治疗中的地位及其疗效。方法127例软组织肉瘤术后患者随机分为研究组67例（野中野照射加HD-PDD水化）和对照组60例（常规照射、化疗）。研究组放射治疗：大野40～50 Gy,4～5周,小野20～30 Gy,3～4周,每天2野照射,间隔6 h;化疗：PDD 80～100 mg/m^2,每3周1次,共2～3次。对照组放射治疗：40～50 Gy,4～5周,后缩野加量20～30 Gy,2～3周。结果研究组和对照组1,3,5年生存率分别为95.5%和78.3%（P〈0.05）,82.1%和60.0%（P〈0.05）,70.2%和53.3%（P〉0.05）。研究组和对照组1,3,5年局部复发率分别为4.5%和10.0%（P〉0.05）,9.0%和31.7%（P〈0.05）,25.5%和41.7%（P〉0.05）。结论野中野照射加HD-PDD水化技术可在短时间内使肿瘤区接受较高剂量及获得放射治疗增敏,且明显提高了生存率,降低了局部复发率,作为术后综合治疗技术在软组织肉瘤治疗中具有重要价值。     

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.     

Preserving quality of life as a key treatment goal in advanced soft tissue sarcomas

Introduction: Health-related quality of life (HRQoL) is a patient-reported outcome that addresses patients’ perceptions of symptoms across physical, emotional, cognitive and social domains. As HRQoL is currently rarely measured outside clinical trials in oncology, it must be inferred from patients’ everyday performance during treatment. To gain insight into the HRQoL of advanced STS patients receiving palliative treatment in clinical practice, three case studies of patients treated with trabectedin are examined.

Areas covered: The patient in Case 1 has maintained complete remission for more than 8 years after receiving nine cycles of second-line trabectedin followed by secondary surgery for recurrent myxoid liposarcoma, and was able to resume normal activities during trabectedin treatment. Case 2 describes 10 years’ follow-up of a patient with myxoid liposarcoma who remains well after many lines of chemotherapy including extended use of trabectedin in the second line. The third case illustrates the feasibility of extending survival time in an elderly patient with metastatic leiomyosarcoma who was able to maintain a busy and active lifestyle while receiving second-line trabectedin.

Expert commentary: Owing to its relatively benign safety profile, trabectedin frequently permits prolonged therapy and is generally well tolerated, often allowing patients to carry on with normal daily activities.     

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.     

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.     

New concepts for the treatment of pediatric nonrhabdomyosarcoma soft tissue sarcomas

Nonrhabdomyosarcoma soft tissue sarcomas form a group of rare tumors with a different biology and clinical behavior. The recently established European Pediatric Soft Tissue Sarcoma Study Group is organizing a new study devoted specifically to these tumors that were formerly treated according to the principles derived from experience with rhabdomyosarcoma, which is a clearly distinct entity. The new study includes two prospective trials, one for synovial sarcoma and the other for adult-type nonrhabdomyosarcoma soft tissue sarcomas. While surgery remains the mainstay of treatment, the role of adjuvant therapy is not yet clear and our understanding of the biology and natural history of nonrhabdomyosarcoma soft tissue sarcomas is still incomplete. This review presents the latest data on nonrhabdomyosarcoma soft tissue sarcoma treatment and outcome, and the rationale behind a risk-adapted treatment program that investigates the role of full-dose ifosfamide–doxorubicin chemotherapy in improving the response rate of patients with unresectable disease, the chances of avoiding adjuvant chemotherapy in low-risk synovial sarcomas, and the possible role of chemotherapy in high-risk adult-type soft tissue sarcomas.     

吡柔比星联合顺铂二线治疗进展期软组织肉瘤的临床观察

目的　观察吡柔比星联合顺铂二线治疗进展期软组织肉瘤的临床疗效和不良反应。方法　阿霉素和异环磷酰胺一线化疗失败的进展期软组织肉瘤患者９例,吡柔比星５０ｍｇ／ｍ^２第１天静滴,顺铂２５ｍｇ／ｍ^２第１～３天静滴。２１天为１周期,完成２～６个周期,中位周期数为４。结果　全组患者ＣＲ０例,ＰＲ２例（２２.2％）,ＳＤ５例（５５.6%）,ＰＤ２例（２２.２％）,有效率（ＲＲ）为２２.２％（２／９）,疾病控制率（ＤＣＲ）７７.８％（７／９）。中位无进展生存时间（ＰＦＳ）为３个月（２～２１个月）,中位总生存时间（ＯＳ）为７个月（３～２７个月）。主要不良反应为粒细胞减少、胃肠道反应和脱发,其他不良反应少见。结论　进展期软组织肉瘤患者阿霉素和异环磷酰胺一线化疗失败后改用吡柔比星联合顺铂二线治疗,能够有效控制疾病进展,不良反应可以耐受,值得进一步深入研究。     

Philosophy of treatment and the role of chemotherapy in paediatric soft tissue sarcomas

Although overall survival rates for children with soft tissue sarcoma have improved, progress for some sub-groups of patients has been less encouraging than might be expected. Priorities for the future include the better identification of patients who can be cured with minimal therapy and better treatment for those who have a poor outcome with current therapy. Improved understanding of the biology of this group of tumours may provide opportunities to utilise some of the more recently designed novel forms of therapy aimed at molecular targets. Although considerable amounts of valuable clinical data have been acquired through clinical trials in patients with RMS, further efforts to systematically explore therapy in children with non-RMS soft tissue sarcoma are now required and there are opportunities for adult-paediatric collaboration in designing new approaches to therapy.     

796例软组织肉瘤分析

目的:了解软组织肉瘤各病种发病情况及相对频率,并调查软组织肉瘤发病趋势。方法:对本院1993年1月至2003年12月所有收治的原发软组织肉瘤796例发病情况进行回顾性分析,从而初步得到各病种发病情况和相对频率,并推测其发病趋势。结果:依据病理分型发病率最高者为恶性纤维组织细胞瘤、滑膜肉瘤、脂肪肉瘤、横纹肌肉瘤等,分别占所收治例数的31.5%,16.8%,16.8%和16.2%。软组织肉瘤可见于各个年龄阶段,可发生于全身任何部位,但各亚型均有各自的特点。结论:软组织肉瘤发病率较低。恶性纤维组织细胞瘤在软组织肉瘤中发病率最高。软组织肉瘤的发病率呈逐年上升趋势。     

Limb-sparing treatment for soft tissue sarcomas: Influence of prognostic factors

At present, limb-sparing surgery is the most appropriate and acceptable treatment available for sarcomas of the extremities, although the right balance between conservative therapy and maximum efficacy has yet to be found. A better knowledge of prognostic factors may help in planning the appropriate strategy for each case. Eighty patients underwent limb-sparing surgery for limb sarcomas (17 had surgery alone; 19 had neo-adjuvant hyperthermic antiblastic perfusion combined or not with postoperative radiotherapy, and 44 had adjuvant radiotherapy). Univariate and multivariate analyses were made to detect statistically significant differences between subgroups and identify the more significant subset of prognostic factors. Only microscopically positive surgical margins were related to a greater risk of local recurrence, whereas overall survival was compromised by high grade and large tumor size. © 1996 Wiley-Liss, Inc.     

Multidisciplinary treatment of soft tissue sarcomas: An update

Standard treatment for soft tissue sarcoma, based on complete surgical resection with or without adjuvant radiotherapy and chemotherapy, has not substantially changed during the last several decades. Nevertheless, recent advances have contributed to considerable improvement in the management of these patients; for example, new magnetic resonance imaging sequences such as diffusion-weighted imaging and magnetic resonance imaging radiomics can better assess tumor extension and even estimate its grade. Detection of circulating genetic material (liquid biopsy) and next-generation sequencing are powerful techniques for genetic analysis, which will increase our understanding of the underlying molecular mechanisms and may reveal potential therapeutic targets. The role of chemotherapy in non-metastatic disease is still controversial, and there is a need to identify patients who really benefit from this treatment. Novel chemotherapeutic regimens have entered clinical praxis and can change the outcome of patients with metastatic disease. Advances in radiotherapy have helped decrease local adverse effects and sustain good local control of the disease. The following report provides an updated view of the diagnosis, treatment, and future perspectives on the management of patients with soft tissue sarcomas.     

Adjuvant chemotherapy in the treatment of primary soft tissue sarcomas, with special reference to intra-arterial infusion chemotherapy

Seventy-eight cases of adjuvant chemotherapy for primary soft tissue sarcoma including 51 cases of intra-arterial infusion chemotherapy were studied. The patients ranged in age from 1 to 92 years with a median age of 34 years. Thirty-nine patients were male and 39 were female. The seventy-eight cases were comprized of 17 rhabdomyosarcoma, 12 liposarcoma, 12 neurogenic sarcoma, 10 malignant fibrous histiocytoma, 8 leiomyosarcoma, 7 angiosarcoma, 8 others and 4 unclassified sarcomas. Fifty-one patients with soft tissue sarcoma of the extremities were treated by intra-arterial infusion chemotherapy with either VCQ (Vincristine and Carbazilquinone) or VCQ, A (Vincristine, Carbazilquinone and Adriamycin). Out of 42 patients with measurable lesions, 2 CR, 4 PR, 33 NC and 3 PD were obtained. Histological examinations demonstrated histological effect of GI 19, G IIa 11 and G IIb 7 by Ohboshi and Shimosato's criteria. Remarkable effects of treatment were noted in most rhabdomyosarcoma patients. After intra-arterial infusion chemotherapy, a variety of surgical procedures ranging from marginal resection and wide resection to radical amputation were employed in 44 patients. Local recurrence was 27% and distant metastasis developed in 47% of cases.     

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.