Ifosfamide,vincristine, doxorubicin and dacarbazine in adult patients with advanced soft-tissue sarcoma

Summary A total of 37 adult patients with locally advanced or metastatic soft-tissue sarcoma (STS) entered a pilot study of combination chemotherapy based on the CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) regimen, in which cyclophosphamide was replaced by ifosfamide and mesna (1 g/m² ifosfamide given daily on days 1–5 as 2-h infusions, 1.5 mg/m² vincristine given on day 1 as a bolus injection, 50 mg/m² doxorubicin given on day 1 as a 5-min infusion, and 250 mg/m² dacarbazine given daily on days 1–5 as 30-min infusions). The overall response rate in 24 patients who were evaluable for response was 46% [95% confidence interval (CI), 25%–67%] and that in subjects who had not undergone prior chemotherapy was 50% (CI, 27%–73%). In all, 4 patients achieved a complete response (17%; CI, 5%–37%) and 2 remain in remission; 3 additional subjects were surgically rendered disease-free after they had shown a partial response. Overall, 31 patients were evaluable for toxicity. Toxicity was mainly hematological; in 3 patients the nadir WBC was <0.5×10⁹/l, and in 2 cases the nadir platelet count was <50×10⁹/l. During neutropenia, infections requiring intravenous antibiotics occurred in 8 patients (26%) and in 14 of 190 cycles (7.5%); 1 of these was fatal. We conclude that this new regimen offers promise for the treatment of advanced STS, producing acceptable toxicity.This study was supported in part by grants from Finska Läkaresällskapet (Finnish Medical Society)     

A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: The TRUSTS trial

PurposeTo evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression-free survival (PFS), compared to doxorubicin and, in the phase IIb part here, to select the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy.Patients and methodsIn this randomised multicentre prospective dose-selection phase IIb superiority trial, 133 patients were randomised between doxorubicin (n = 43), trabectedin (3-hour infusion, T3h) (n = 47) and trabectedin (24-hour infusion, T24h) (n = 43). PFS was defined as time from random assignment until objective progression by response evaluation criteria in solid tumours (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause.ResultsThe study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm. Median PFS was 2.8 months in the T3h arm, 3.1 months in the T24h arm and 5.5 months in the doxorubicin arm. No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.67–1.90, P = .675; T3h versus doxorubicin: HR 1.50, 95% CI 0.91–2.48, P = .944). Only one toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2%) (T3h), 8 (19.5%) (T24h) and 1 (2.5%) doxorubicin patients.ConclusionDoxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS). Trabectedin 1.5 mg/m²/24-hour infusion is the overall proven approach to delivering this agent in the second-line setting for patients with advanced or metastatic STS.     

Cisplatin. A phase II evaluation in previously untreated patients with soft tissue sarcomas

A Phase II trial of moderately high-dose cisplatin (120 mg/m2 with mannitol diuresis) was conducted in 26 previously untreated patients with soft tissue sarcomas. One partial response (major response rate, 4%) and two minor responses were seen. Severe nausea and vomiting and transient increases in the serum creatinine level were the most common side effects of treatment. Cisplatin has minimal activity as a single agent in patients with soft tissue sarcoma.     

High dose ifosfamide, doxorubicin, dacarbazine and G-CSF for patients with metastatic or locally advanced soft tissue sarcoma

SOFTTISSUESARCOMAS(STS)accountforapproximatelyl%ofadultmalignanciesandl5%ofpediatricmalignancies.Theuseofradicalsurgeryisthem0steffectivemethodfortreatmentofearystageSTS.Unfortunately,manypatientsarediagnosedlate0rreceiveinadequateprimarysurgerysothatmetastasesultimatelyoccULAlthoughsalvagetreatthentbyexcisionofthemetastasesissuccessfulforsomepatients,themajoritywilldiefromprogressivedisease.Doxorubicin(Adriamycin,ADR)isthemostactivesingleagentinsofttissuesarcomas,witharesponserate…     

沙利度胺治疗晚期软组织肉瘤的临床观察

目的 评价沙利度胺单药治疗晚期软组织肉瘤的疗效、不良反应及对患者生活质量的影响。方法 22例二线方案化疗失败的晚期软组织肉瘤患者口服沙利度胺,每日100mg晚睡前顿服,1周后加量至每日200mg,维持治疗至疾病进展,同时每日口服阿斯匹林75mg。每2个月评价疗效、毒副反应,参照Karnofsky评分评价患者生活质量（QOL）。结果 2例获得PR（9.1％）,4例SD（18.2％）,疾病控制率（DCR）为27.3％;中位无进展生存期为1个月,中位总生存期为5个月;3例（13.6%）生活质量改善,5例（22.7%）稳定。主要不良反应为便秘、疲乏、嗜睡,多为1～2级,其他不良反应少见。结论 单药沙利度胺治疗软组织肉瘤具有一定疗效,可提高部分患者的生活质量。     

改良MAID方案治疗54例晚期软组织肉瘤的疗效分析

背景与目的:临床研究表明MAID方案连续静脉输注72h治疗晚期软组织肉瘤的近期疗效较以阿霉素(ADR)为主的二药联合方案疗效高,肿瘤无进展时间长,但是对患者长期生存无明显改善,严重的Ⅲ/Ⅳ度血液学毒性和治疗相关死亡影响了其在临床广泛使用。本研究通过用四氢吡喃阿霉素(THP-ADR)替代MAID方案中的ADR和改良异环磷酰胺(IFO)用法治疗晚期软组织肉瘤,观察改良方案的疗效和不良反应。方法:通过多中心协作筛选符合标准的患者接受IFO2000mg/m2静脉滴注4hd1～3,美斯钠1200mg/m2在IFO治疗的0、4和8h静脉滴注d1～3,THP-ADR20mg/m2和达卡巴嗪(DTIC)333.3mg/m2持续静脉滴注d1～3,THP-ADR和DTIC溶于同一液体瓶或泵中通过中心静脉导管输注,每3周重复,至少2周期,评定近期疗效和毒性反应。对所有完成2周期治疗的患者每2月随访1次,直至随访截止。利用寿命表法计算长期生存率和肿瘤进展时间。结果:可评价的54例患者全部完成至少2周期改良MAID方案化疗,总有效率42.59%。不良反应较轻,Ⅲ Ⅳ度中性粒细胞减少发生率25.93%,粒细胞减少性发热11.11%,Ⅲ Ⅳ度血小板减少发生率16.67%,其它毒性少见,无明显的肝肾毒性、无治疗相关性死亡和中枢神经系统毒性反应。随访2年,至肿瘤进展时间为7个月,1年和2年生存率分别为61.11%和36.36%。结论:改良MAID方案简化了原方案中三种药物均需要同时连续输注的过程,有比较好的有效率和长期生存,未见严重毒性反应,耐受性良好,值得进一步前瞻性随机对照研究。     

Isolated limb perfusion with cisplatin and doxorubicin for locally advanced soft tissue sarcoma of an extremity.

AIMS: To identify independent adverse clinico-pathological factors for disease-free and overall survival in patients undergoing isolated limb perfusion (ILP) with cisplatin and doxorubicin for locally advanced soft tissue sarcoma (STS) of an extremity. METHODS: A retrospective analysis was carried out, using a univariate method and a multivariate analysis, to look at the patient, tumour and treatment associated with prognostic factors in 37 patients with locally advanced STSs of the limbs who underwent ILP with cisplatin and doxorubicin. Patient's age, gender, presenting status, tumour location, tumour grade, tumour stage according to TNM classification, tumour size and radiotherapy (RT) were analysed. Survival curves were calculated according to the Kaplan-Meier method. A Cox proportional hazard model was used to indicate which factors related to overall survival and the recurrence-free interval after ILP. RESULTS: No major systemic toxicity was seen. Regional toxicity was limited. Limb salvage was achieved in 94.6% of the patients. The estimated 5-year overall and disease-free survival rates were 62% and 54%, respectively. It was found that tumour stage, tumour grade, presenting status, RT and tumour size were associated with cumulative overall survival when the Kaplan-Meier method was applied (P<0.05). By Cox proportional hazards model, only tumour grade (P=0. 0254) was found to have significant influence on overall survival; however, tumour stage (P=0.0157) and RT (P=0.0014) were related to disease-free survival. CONCLUSIONS: ILP and delayed excision followed by RT achieves good limb salvage rates and may improve survival.     

Dose-intensive chemotherapy in advanced adult soft tissue sarcoma

The treatment of metastatic soft tissue sarcomas in adults is one of the most challenging areas in oncology. While multidisciplinary management of early-stage, localized disease has led to a number of improved outcomes, therapy of unresectable or advanced disease remains problematic. Virtually every conventional cytotoxic agent has been systematically assessed in this malignancy, yet only a handful have demonstrated significant activity. Adriamycin and ifosfamide are the only chemotherapeutic drugs to have consistently produced response rates of over 20% when given as single agents and these two drugs have been exhaustively studied alone or in combination. Recent efforts to improve response rates and by inference, disease-free survival and overall survival, have involved exploration of high-dose regime incorporating growth factors and/or autologous cellular support. In this article, the status of dose-intensive chemotherapy in advanced adult soft tissue sarcomas (excluding pediatric histologies, such as Ewing’s sarcoma and rhabdomyosarcoma) will be discussed. Emphasis will be placed on data from randomized Phase III trials but information from Phase I/II studies will also be reviewed and recommendations will be made on a systematic analysis of the data.     

Dose-intensive chemotherapy in advanced adult soft tissue sarcoma

The treatment of metastatic soft tissue sarcomas in adults is one of the most challenging areas in oncology. While multidisciplinary management of early-stage, localized disease has led to a number of improved outcomes, therapy of unresectable or advanced disease remains problematic. Virtually every conventional cytotoxic agent has been systematically assessed in this malignancy, yet only a handful have demonstrated significant activity. Adriamycin and ifosfamide are the only chemotherapeutic drugs to have consistently produced response rates of over 20% when given as single agents and these two drugs have been exhaustively studied alone or in combination. Recent efforts to improve response rates and, by inference, disease-free survival and overall survival, have involved exploration of high-dose regimen incorporating growth factors and/or autologous cellular support. In this article, the status of dose-intensive chemotherapy in advanced adult soft tissue sarcomas (excluding pediatric histologies, such as Ewing's sarcoma and rhabdomyosarcoma) will be discussed. Emphasis will be placed on data from randomized Phase III trials but information from Phase I/II studies will also be reviewed and recommendations will be made on a systematic analysis of the data.     

Phase II study of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma

Purpose  

The purpose of this prospective multicenter phase II study was to evaluate the efficacy and toxicity of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma.     

Phase II study of daily oral perifosine in patients with advanced soft tissue sarcoma

BACKGROUND: A multicenter Phase II study was performed to evaluate the clinical activity of an initial loading (150 mg every 6 hours x 4 doses) dose followed by continuous daily oral dosing (100 mg/day) of perifosine in patients with advanced soft tissue sarcomas (STSs). METHODS: Patients with measurable metastatic STS received perifosine as first-, second-, or third-line treatment and underwent disease assessment every 8 weeks until disease progression, excessive toxicity, or patient refusal. RESULTS: Twenty-three patients received 66 cycles (1 cycle = 4 weeks) of perifosine. One partial response of 9 months duration was observed. The overall 3 and 6 month progression-free survival was 22% and 9%. NCI CTC (v2.0) Grade 1 to 2 gastrointestinal toxicity or fatigue were the most common (>50% of subjects) toxicities observed. The steady-state plasma perifosine levels (Css) were similar to prior experience (mean 6 microg/mL). Patients with Css levels >6 microg/mL appeared more likely to remain on study past 2 months than those with levels <6 microg/mL. CONCLUSIONS: Despite not achieving the primary objective of > or =40% 6-month progression-free survival rate, optimism remains for this agent in STS patients. Prolonged responses in heavily pretreated STS patients continue to be observed with perifosine treatment. Continued assessment of perifosine in STS appears warranted, with special attention to specific histologies or tumor characteristics that might identify a more sensitive population and achieving perifosine Css levels >6 microg/mL.     

Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma.

PURPOSE: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma. EXPERIMENTAL DESIGN: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; < or =225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks. RESULTS: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months. CONCLUSION: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.     

Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcoma

Leiomyosarcomas (LMS) are rare tumors with poor prognosis owing to the high rate of recurrent and metastatic disease. The combination of doxorubicin (Adriamycin) plus ifosfamide and mesna (AIM) results in moderate response rates of 10%-30%. The aim of this study was to assess the efficacy of the AIM regimen along with multimodality treatment including surgery and radiotherapy in patients with LMS. The clinicopathologic characteristics and outcomes of 51 patients with recurrent or metastatic LMS diagnosed between 2000 and 2014 who received the AIM regimen were analyzed retrospectively. Treatment consisted of ifosfamide 2500 mg/m² on days 1-3 (with mesna 2500 mg/m² days 1-3, 4-hour i.v. infusion), and doxorubicin 60 mg/m² on day 1 (2-hour i.v. infusion), which was repeated every 21 days. The mean age of the patients at diagnosis was 48.9 ± 11.2 years. A total of 42 patients were females (82.4%). The primary tumor site was the uterus in 30 (58.8%) patients. The most common metastatic sites were lung and liver. The median follow-up was 27.9 months (min: 4.3 max: 164.8). The median progression-free survival was 6.7 months (95% CI: 4.1-9.2). The median overall survival (OS) was 24.6 months (95% CI: 16.2-33.0). The overall response rate was 12% (6/51 pts). Response rates were higher in patients with uterine LMS (17%) compared with those with nonuterine LMS (5%); however, the OS times were similar. Surgical intervention for local or distant recurrence was associated with improved median OS (41 vs 16.6 months, P < 0.001). Myelosuppression was the major toxicity of this combination. In our study, the AIM regimen was effective in patients with LMS. Resection of local or distant recurrence was found to improve survival in our study.     

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m⁻², cisplatin 60 mg m⁻² on day 1 and capecitabine 1000 mg m⁻² daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43–82), disease stabilisation of 25% (95% CI: 11–47) and a disease control rate (CR+PR+SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.     

Efficacy and toxicity of gemcitabine plus docetaxel combination as a second line therapy for patients with advanced stage soft tissue sarcoma

Purpose: To assess the safety and efficacy of a gemcitabine plus docetaxel regimen as a second line therapy for patients with advanced soft tissue sarcoma (STS) resistant to doxorubicin and ifosfamide-based therapy. Patients and Methods: Medical records of 64 patients with advanced STS who received gemcitabine plus docetaxel regimen as a second line treatment between May 2006 and June 2011 were examined. All patients had been previously treated with doxorubicin plus ifosfamide-based regimen at first line setting. Patients received gemcitabine 900 mg/m2 on days one and eight intravenously over 90 minutes, followed by docetaxel 75 mg/m2 on day eight intravenously over one hour. Cycles were repeated every 3 weeks. Results: The male-to-female ratio was 37/27 and the median age was 44 years (range; 19-67 years). Objective responses were observed in 13 (20.3 %) patients (2 CR, 11 PR) and stable disease in 21 (32.8 %). Total clinical benefit (CR+PR+SD) was observed in 34 (53.1 %). Median overall survival (OS) was 18 months (95% confidence interval (CI):12.1-23.9) and Median time to progression (TTP) was 4.8 months (95% CI: 3.6-6). A total of 243 cycles of chemotherapy were administered. The median number of cycle was 3 (range;1-11). The most common grade 3-4 hematologic toxicity was neutropenia (35.9 %). The most common nonhematologic toxicities consisted of nausea/vomiting (37.5 %), mucositis (32.8 %), peripheral neuropathy (29.7%), and fatigue (26 %). There was no toxicity-related death. Conclusion: The combination of gemcitabine plus docetaxel is an active and tolerable regimen as a second line therapy for patients with advanced soft tissue sarcoma who have failed doxorubicin and ifosfamide-based therapy.     

Chemotherapy of advanced bone and soft tissue sarcoma

The primary site of metastasis of bone and soft tissue sarcoma is the lung. Control of these sarcomas depends upon the prevention and treatment of their pulmonary metastasis. The introduction of a chemotherapy consisting mainly of Adriamycin and high-dose methotrexate dramatically improved the prognosis of osteosarcoma. However the effectiveness of chemotherapy has not yet been duplicated in soft tissue sarcomas except some childhood sarcomas. We analyzed the clinical data for pulmonary metastasis of osteosarcomas and soft tissue sarcomas. Based on these analyses, we tried to clarify the nature of pulmonary metastasis of these sarcomas and to evaluate its response to treatment, that this would yield clues to future treatment of these sarcomas.     

High-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma

A chemotherapy regimen with epirubicin (60 mg/m2, days 1, 2 and 3) and cisplatin (30 mg/m2, days 2, 3, 4 and 5) was started for 35 patients with advanced soft tissue sarcoma (28 males and 7 females; median age, 50 years). All patients were chemotherapy-naive and with an expected survival of more than 2 months. All patients were evaluable for activity and toxicity. The intercycle interval was 4 weeks. Median number of cycles applied was 4 (range, 2-8). The overall response rate was 20/35 (57.1%). A complete response (CR) was achieved in 7/35 patients (20%), lasting for 26+, 26+, 13+, 13+, 9+, 9+ and 5 months; 13/35 patients (37.1%) entered a partial remission (PR), 9/35 patients (25.7%) had stable disease (SD), and 6/35 (17.1%) had progressive disease (PD). In non-responders (SD + PD), the median survival was 4 months; the median survival of responders (CR + PR) was 9+ months (the median has not yet been reached). Hematologic toxicity of grade 4 was present at least in one cycle for hemoglobin in 6/35 patients, for leukocytes in 22/35, and for platelets in 13/35. No hemorrhagic syndrome was observed. The leukopenia was usually of short duration (nadir on days 10-12). Febrile episodes were present in 18 patients during the nadir of leukopenia. No other significant toxicity was noted (apart from grade III alopecia in all patients), and specifically, there was neither acute nor cumulative cardiotoxicity.     

Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer

The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60 mg/m² and T at escalating doses from 600 to 800 μg/m², which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose - given to 18 patients in total - was 700 μg/m² T with 60 mg/m² D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.