High-dose ifosfamide plus adriamycin in the treatment of adult advanced soft tissue sarcomas: Is it feasible?

Background: Adriamycin (ADM) and ifosfamide (IFO) are the two most active agents in the treatment of soft tissue sarcomas (STS) with a clear dose-response relationship. We evaluated the feasibility and toxicity of a high-dose IFO-plus-ADM combination.Patients and methods: Fourteen patients with advanced disease and nine patients in adjuvant setting received IFO 12.5 g/m² in 120-hour continuous infusion with Mesna uroprotection and ADM 20 mg/m² on days 1–3 and G-CSF every three weeks.Results: Twenty-three patients received 89 chemotherapy cycles (70 cycles at full dose). Seventeen patients received the planned treatment, and nine patients required dose reductions. We observed grade 3–4 neutropenia in 52 cycles (59%)/20 patients; grade 3–4 thrombocytopenia in 16 cycles (18%)/nine patients; grade 3–4 anaemia in 24 cycles (27%)/11 patients. Eight patients experienced febrile neutropenia and six patients required blood transfusions.Conclusions: While feasible, this regimen showed heavy toxicity. Nevertheless, 74% of the patients were able to complete the planned treatment. Adjustment of the schedule of IFO continuous infusion to improve this combination is currently under investigation.     

Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas

Background: Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS.Patients and methods: Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m²/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 µg/m²/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting.Results: A total of 159 cycles of therapy were given (median 4 per patient, range 3–6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5–21+ months), and the overall median survival ranged from 6–30+ months (median 13 months).Conclusions: High-dose ifosfamide is an active regimen in anthracycline- pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.     

Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: A study of the Spanish Group for Research on Sarcomas (GEIS)

Background: The agent Ifosfamide (IFOS) is active against soft tissue sarcomas (STS), and patients who progress to IFOS at doses 10 g/m² show remissions when exposed to high-dose ifosfamide (HDI) (i.e., doses >10 g/m²), which supports a dose-response relationship for this drug. Because of a lack of first-line studies in adult STS patients, we decided to test the activity and toxicity of HDI in a phase II trial.Patients and methods: Forty-eight patients were enrolled in the study. IFOS was administered at a dose of 14 g/m² by continuous infusion over six days every four weeks. Granulocyte-macrophage colony-stimulating factor (GM-CSF) at 5 µg/kg/day for 10 consecutive days was systematically administered after an episode of neutropenic fever or a delay in hematologic recovery. Patients were treated until progression or the occurrence of severe toxicity, and surgical rescue was attempted when possible.Results: Six pathology-established complete remissions and 11 partial remissions were observed in 45 assessable patients with a response rate of 37.7% (95% CI: 25.5%–50%). Grade 3–4 toxicity (% of cycles) was noted by hemoglobin (17%), leukocyte (75%), granulocyte (75%) and platelet (13%) counts in 158 evaluable cycles. GM-CSF was administered to 28 patients, and 25 suffered one or more episodes of neutropenic fever. Renal toxicity was mild and reversible with some degree of tubular and glomerular dysfunction detected in up to 60% of patients. Grade 3 CNS toxicity was observed in 32% of patients but only one required interruption of therapy. Sixty-four per cent of the patients had asthenia grade 2–3 and 20% were excluded from the study due to excessive toxicity. There was one treatment-related death.Conclusions: HDI is an active drug in first-line therapy against adult STS. Different administration schedules should be evaluated in an attempt to improve its therapeutic index.     

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.     

Phase I study of twelve-day prolonged infusion of high-dose ifosfamide and doxorubicin as first-line chemotherapy in adult patients with advanced soft tissue sarcomas.

PURPOSE: To determine whether a prolonged 12-day continuous infusion allows the administration of high-dose ifosfamide (IFO) with an acceptable toxicity profile when combined with full-dose doxorubicin (Adriamycin; ADM) as first-line chemotherapy in patients with advanced soft tissue sarcomas. PATIENTS AND METHODS: Escalating doses of continuous infusion IFO (8-15 g/m2) given on days 1 to 12 in combination with ADM 75 mg/m2 given on day 8 and prophylactic granulocyte colony-stimulating factor support were administered every 4 weeks to 35 chemona?ve patients with advanced soft tissue sarcomas. RESULTS: The maximum tolerated dose was IFO 15 g/m2. Hematological toxicity was the main dose-limiting toxicity and was dose dependent. Furthermore, thrombocytopenia was cumulative. Grade 4 (WHO) neutropenia and thrombocytopenia were recorded in 48% and 14% of courses, respectively. Eight patients experienced febrile neutropenia. A partial response was observed in 16 out of 30 assessable patients [53%, 95% confidence interval (CI) 25-63]; median time to progression was 25 weeks (range 4-91). CONCLUSIONS: This study proved that a prolonged 12-day continuous infusion allows an increase in the total IFO dose that can be safely combined with ADM. A multicentric phase II study by the Italian Sarcoma Group to assess its antitumor activity is currently ongoing in patients with advanced soft tissue sarcomas.     

阿瑞匹坦预防软组织肉瘤脂质体多柔比星联合异环磷酰胺化疗恶心呕吐临床观察

目的 阿瑞匹坦(Aprepitant)是一种神经激肽1(Neurokinin 1,NK-1)受体阻滞剂,近年来在中国被批准用于化疗引起的恶心呕吐(chemotherapy induced nausea and vomiting,CINv),但此药物在软组织肉瘤(soft tissue sarcomas,STS)多日化疗中止吐效果的研究报道很少.本试验通过前瞻性队列研究观察阿瑞匹坦预防STS患者接受脂质体多柔比星(Liposome doxorubicin)和异环磷酰胺(Ifosfamide)联合化疗中CINv的效果.方法 选择2016-02-01-2016-06-30北京大学肿瘤医院骨与软组织肿瘤科收治的软组织肉瘤患者32例,均接受含脂质体多柔比星与异环磷酰胺的5 d化疗方案,由研究者根据化疗前的预防性止吐治疗方式非随机分为阿瑞匹坦组和对照组,进行前瞻性队列研究.阿瑞匹坦组止吐用药包括阿瑞匹坦、昂丹司琼和地塞米松磷酸钠,对照组止吐药物包括昂丹司琼和地塞米松磷酸钠.记录患者化疗后的恶心、呕吐反应,解救治疗及不良反应.主要观察呕吐方面包括急性期完全缓解率,化疗开始后24 h无呕吐发作且未进行解救治疗;延迟期完全缓解率,化疗开始后第2~10天无呕吐发作且未进行解救治疗;恶心方面包括急性期完全保护率,化疗开始后24 h无呕吐、无解救治疗且无明显恶心,视觉模拟评分(visual analogue scale,vAS)<25 mm;延迟期完全保护率,化疗开始后第2~10天无呕吐、无解救治疗且无明显恶心,vAS<25 mm.计数资料的比较使用Fisher精确检验,计量资料使用正态性检验,用x-±s表示计量资料组间差异,如为正态分布则采用t检验,如为非正态分布则采用两个独立样本的Mann-WhitneyU秩和检验.结果 阿瑞匹坦组15例,对照组17例,两组的患者临床特征差异无统计学意义.阿瑞匹坦组和对照组患者的每日平均呕吐次数的最高值出现在化疗开始后的第5天,分别为(0.5±1.4)和(1.7±1.9)次,差异有统计学意义,U=80,P=0.034;每日平均vAS的最高值也出现在化疗开始后的第5天,分别为(22±13.2)和(33.5±21.2)mm,差异无统计学意义,U=80.5,P=0.07.阿瑞匹坦组与对照组患者的急性期完全缓解率分别为100.0%(15/15)和88.2%(15/17),差异无统计学意义,P=0.486;延迟期完全缓解率分别为80.0%(12/15)和41.2%(7/17),差异有统计学意义,P=0.036.阿瑞匹坦组与对照组患者急性期完全保护率分别为13.3%(2/15)和23.5%(4/17),差异无统计学意义,P=0.659;延迟期完全保护率分别为33.3%(5/15)和11.8%(2/17),差异无统计学意义,P=0.209.阿瑞匹坦组患者中未观察到阿瑞匹坦相关的不良反应.结论 STS患者在接受包含脂质体多柔比星及异环磷酰胺化疗时,最严重的恶心呕吐常发生于化疗开始后的第5天,加用阿瑞匹坦能提高延迟期完全缓解率.     

Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients

Background: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide/mesna ± GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12–18 g/m² in adult patients with advanced sarcomas.Patients and methods: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m² total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed.Results: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m² total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m² total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%).Conclusion: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14–16 g/m² per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.     

Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study

The aim of the study was to determine the dose-limiting toxicity and maximum tolerated dose of a first-line combination of doxorubicin and gemcitabine in adult patients with advanced soft tissue sarcomas and to explore its activity and toxicity, and the presence of possible interactions between these agents. Patients with measurable disease were initially treated with doxorubicin 60 mg m(-2) by i.v. bolus on day 1 followed by gemcitabine at 800 mg m(-2) over 80 min on days 1 and 8, every 21 days. Concentrations of gemcitabine and 2',2'-difluorodeoxyuridine in plasma, and gemcitabine triphosphate levels in peripheral blood mononuclear cells were determined during 8 h after the start of gemcitabine infusion. Myelosuppression and stomatitis were limiting toxicities, and the initial dose level was applied for the Phase II trial, where grade 3-4 granulocytopenia occurred in 70% of patients, grade 3 stomatitis in 46% and febrile neutropenia in 20%. Objective activity in 36 patients was 22% (95% CI: 9-35%), and a 50% remission rate was noted in leiomyosarcomas. Administration of doxorubicin preceding gemcitabine significantly reduced the synthesis of gemcitabine triphosphate. Clinical activity, similar to that of single-agent doxorubicin, and the toxicity encountered do not justify further studies with this schedule of administration.     

Results of chemotherapy using ifosfamide with doxorubicin in advanced breast cancer

Summary Ifosfamide has single agent activity in advanced breast cancer and may potentiate the activity of doxorubicin. The combination of ifosfamide 5 g/m² and doxorubicin 40 mg/m² every 3 weeks for 4 cycles was used to treat 77 patients with advanced breast cancer. Fifty three patients had not received prior chemotherapy. All patients had one or more poor prognostic features, including tumor expression of epidermal growth factor receptor in 11/12 tested. The overall response rate was 74% (95% confidence intervals 62%-83%). The median survival was 9.4 months. The principal toxicities were febrile neutropenia and ifosfamide encephalopathy each in 6% of patients. A high percentage of the projected dose intensity was administered. This is a highly active combination with acceptable toxicity in advanced breast cancer, although the long term survival remains poor. Further exploration of ifosfamide in combination chemotherapy for advanced breast cancer is warranted.     

大剂量异环磷酰胺持续静滴联合阿霉素治疗进展期软组织肉瘤的临床观察

目的：评价大剂量异环磷酰胺持续７２ｈ静滴联合阿霉素治疗进展期软组织肉瘤的临床疗效和毒副反应。方法：２００８年３月～２００８年１０月收治进展期软组织肉瘤患者１５例,应用大剂量异环磷酰胺联合阿霉素治疗,异环磷酰胺总量１２ｇ／ｍ^２,持续静滴７２ｈ;阿霉素６０ｍｇ／ｍ^２第１天静滴。２１天为１周期。完成２～６周期,中位周期数为４。结果：全组患者ＣＲ１例（６.６７％）,ＰＲ１例（６.６７％）,ＳＤ１２例（８０.０％）,ＰＤ１例（６.６７％）,有效率１３.３％（２／１５）,疾病控制率９３.３％（１４／１５）。中位无疾病进展生存期６个月（３～１０个月）,中位总生存期７个月（３～１０个月）。主要毒副反应为粒细胞减少、胃肠道反应和脱发,其他毒副反应少见。结论：大剂量异环磷酰胺持续７２ｈ静脉滴注联合阿霉素方案治疗进展期软组织肉瘤可行,能够有效控制疾病进展,毒副反应可以耐受,值得进一步深入研究。     

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).     

Repetitive high-dose therapy with ifosfamide, thiotepa and paclitaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer: Results of a phase I study

Background: This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC).Patients and methods: The planned treatment was three cycles of high-dose ifosfamide, thiotepa and conventional-dose paclitaxel delivered every 28 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim.Results: Twenty-three patients were entered into this trial. Of the planned 69 treatment cycles, 59 were delivered and fifteen patients completed all three cycles. The dose-limiting toxicities were renal tubular acidosis, encephalopathy, mucositis and enterocolitis. There was one treatment-related hemorrhagic death.Conclusions: The recommended doses for phase II or III studies are ifosfamide (10 g/m2), thiotepa (350 mg/m2) and paclitaxel (175 mg/m2).     

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer

The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate anti-tumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m(2) intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m(2)/day to 2750 mg/m(2)/day as a continuous infusion from day 1-3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support dose-limiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m(2) on day 1 and ifosfamide 2750 mg/m(2)/day on days 1-3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m(2) on day 1 and ifosfamide 2500 mg/m(2)/day continuous infusion on days 1-3.     

Salvage surgical resection after high-dose ifosfamide (HDIF) based regimens in advanced soft tissue sarcoma (ASTS): a potential positive selection bias--a study of the Spanish group for research on sarcomas (GEIS)

PURPOSE: To assess the impact of different factors on response rate (RR), time to tumor progression (TTP), and overall survival time (OS) in patients with locally advanced or metastatic soft tissue sarcoma (ASTS), included in three protocols with high-dose ifosfamide (HDIF). PATIENTS AND METHODS: One hundred fifty six ASTS patients included in three consecutive phase II trials with HDIF (>10 g/m(2)), alone or in combination with doxorubicin (DX), were analyzed. Cofactors were institution, trial, gender, age, performance status, histologic type, grade of malignancy, prior radiotherapy, presence of locoregional disease, metastatic site, salvage surgery, number of organs involved, and disease-free interval. RESULTS: By multivariate analysis performance status >0 and lack of salvage surgery correlated with a poorer survival. A good-risk and a poor-risk group were identified, with median survival time (OS) of 29, 5, and 10 months, respectively (P = 0.00001). The 1-, 2-, and 3-year OS for 83 good-risk patients (either with PS = 0 or receiving salvage surgery) was 83, 44, and 29%, respectively, those figures being 37, 7, and 3% for 73 poor-risk patients. CONCLUSION: The design of randomized trials in ASTS including HDIF should consider those prognostic factors as stratification variables.     

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.     

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.     

A phase II study of Doxil (liposomal doxorubicin): Lack of activity in poor prognosis soft tissue sarcomas

Background: Liposomal doxorubicin (Caelyx, Doxil) delivers doxorubicin to a tumor, but has a vastly altered pharmacology and attenuated acute and chronic toxicities. Therefore, its efficacy in soft tissue sarcomas is worth exploring.Patients and methods: Sixteen patients with recurrent or metastatic soft tissue sarcomas who had not failed prior doxorubicin were accrued into this phase II study. Patients were treated with Doxil at a dose of 50 mg/m2 every four weeks.Results: No responses were seen but three patients were removed from study after only one cycle of treatment. Moreover, leiomyosarcoma was the most common histology and most patients had low grade, and bulky, disseminated tumors. Treatment was well tolerated with no episodes of grade 4 toxicity and only five episodes of grade 3 toxicities: two episodes of neutropenia and one each of stomatitis, dermatologic toxicity and nausea and vomiting.Conclusions: Doxil's lack of activity in this study of patients with adult soft tissue sarcoma may be related to the poor prognostic features of our population. We confirm its favorable toxicity profile and suggest that additional studies be done in patients with other characteristics.     

Long-term results of a multicenter SAKK trial on high-dose ifosfamide and doxorubicin in advanced or metastatic gynecologic sarcomas.

BACKGROUND: Dose intensive chemotherapy has not been tested prospectively for the treatment of gynecologic sarcomas. We investigated the antitumor activity and toxicity of high-dose ifosfamide and doxorubicin, in the context of a multidisciplinary strategy for the treatment of advanced and metastatic, not pretreated, gynecologic sarcomas. PATIENTS AND METHODS: Thirty-nine patients were enrolled onto a phase I-II multicenter trial of ifosfamide, 10 g/m2 as a continuous infusion over 5 days, plus doxorubicin intravenously, 25 mg/m2/day for 3 days with Mesna and granulocyte-colony-stimulating factor every 21 days. Salvage therapy was allowed after chemotherapy. RESULTS: Among the 37 evaluable patients, the tumor was locally advanced (n = 11), with concomitant distant metastases (n = 5) or with distant metastases only (n = 21). After a median of three (range 1-7) chemotherapy cycles, six patients experienced a complete response and 12 a partial response for an overall response rate of 49% (95% CI 32% to 66%). The response rate was higher in poorly differentiated tumors (62%) compared with moderately well differentiated ones (18%), but was not different according to histology subtypes. Eleven patients had salvage therapy, either immediately following chemotherapy (n = 7) or at time of progression (n = 4). With a median follow-up time of 5 years, the median overall survival was 30.5 months. Hematological toxicity was as expected neutropenia, thrombopenia and anemia > or = grade 3 at 50%, 34% and 33% of cycles respectively. No toxic death occurred. CONCLUSIONS: High-dose ifosfamide plus doxorubicin is an active regimen for all subtypes of gynecological sarcomas. Its toxicity was manageable in a multicentric setting. The prolonged survival might be due to the multidisciplinary strategy that was possible in one-third of the patients.     

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.