Docetaxel as rescue medication in anthracycline- and ifosfamide-resistant locally advanced or metastatic soft tissue sarcoma: Results of a phase II trial

Background:Metastatic soft tissue sarcoma not amenable tocurative surgery has a dismal prognosis. Aggressive treatment withanthracyclines and ifosfamide represents the current therapeuticmainstay in these patients, most of whom succumb to relapses. Thus, theefficacy of subsequent therapeutic approaches has to be weighed againsttoxicity caused by palliative treatment. Patients and methods:Patients with locally advanced ormetastatic soft tissue sarcoma refractory to treatment withanthracyclines and ifosfamide were enrolled into the present phase IIstudy. Patients were assigned to receive docetaxel at 100mg/m² every three weeks. In case of severe toxicity, patientswere switched to a weekly schedule of docetaxel (40mg/m²). Results:A total of 106 cycles (80% at the scheduled100 mg/m² dose level) were administered in 27 patients.Partial response was observed in 4 (15%) patients and 4(15%) patients experienced disease stabilization. Medianprogression free survival and overall survival were 2.4 (range:0.9–23.9) and 7.7 (range: 1.0–44.3) months,respectively. Upon renewed progression, three patients initiallyresponsive to treatment with docetaxel were successfully reinduced bytreatment with docetaxel. The safety profile of docetaxel was tolerableand the administration mostly manageable on an outpatient basis. Conclusions:Our results suggest that docetaxel representsan efficacious and tolerable treatment in a minority of patientsrefractory to standard treatment. There is a need for betteridentification of patients most likely to benefit from salvage treatmentwith docetaxel.     

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…     

阴茎上皮样肉瘤1例报告并文献复习

目的:探讨阴茎上皮样肉瘤的临床、病理特征、诊断、治疗方法及预后。方法:回顾性分析1例阴茎上皮样肉瘤患者的临床资料及诊治流程并结合文献复习。结果:69岁男性患者,因发现阴茎根部进行性增大包块3月入院就诊。下腹部CT示阴茎根部大小5.9 cm×5.6 cm×6.5 cm软组织肿块,倾向恶性肿瘤,肉瘤可能性大。行阴茎根部肿瘤切除术,术后病理诊断:镜下见肿瘤细胞呈圆形或卵圆形,染色深浅不一,部分呈空泡状,核仁明显。免疫组化染色结果:CK广谱（-）,vimentin（部分+）,EMA(大部分+),CD34(血管+),CD31(血管+),CD99(+),S-100(-),Bcl-2(-),HMB45(-),SMA(-),AFP(-)。术后患者恢复可出院,未行进一步治疗。术后7月患者发现左侧腹股沟出现进行性增大包块,术后10月患者复查盆腔CT示阴茎根部上份盆壁、左侧睾丸及左侧腹股沟区见多发软组织肿块,最大者位于左侧腹股沟区,大小约7.6 cm×6.8 cm,考虑局部复发并左侧睾丸、腹股沟转移,患者自行放弃行进一步治疗,最后随访日期为2018年1月。结论:阴茎上皮样肉瘤是一种罕见的阴茎间质恶性肿瘤,确诊依赖于病理学及特异性免疫组化染色结果,手术切除是其主要治疗方法,术后是否行放化疗治疗尚存争议,其易局部复发及区域淋巴结转移,总体预后较差。     

Vinflunine in platinum‐pretreated patients with locally advanced or metastatic urothelial carcinoma

BACKGROUND:

The activity and safety of vinflunine was evaluated in patients with locally advanced or metastatic urothelial carcinoma (UC) who developed disease progression within 12 months of platinum‐containing chemotherapy.

METHODS:

Patients with UC were eligible if they received a prior platinum‐based regimen in the neoadjuvant/adjuvant setting or as first‐line treatment for advanced/metastatic disease and had developed disease progression within 12 months. Vinflunine was administered intravenously every 3 weeks. Patients with Karnofsky performance status of 80 or 90, impaired renal function, prior pelvic irradiation, or age ≥75 years received an initial dose of 280 mg/m², which was escalated to 320 mg/m² in Cycle 2 if well tolerated. All other patients received an initial dose of 320 mg/m². The primary endpoint was response rate defined by an independent response review committee (IRRC).

RESULTS:

Per the IRRC, 22 patients achieved a partial response, with a response rate of 15% (95% confidence interval, 9%‐21%) with a median duration of response of 6.0 months. Sixty‐four (42%) patients had stable disease. The median progression‐free survival was 2.8 months, and the median overall survival was 8.2 months. Myelosuppression was the most frequent adverse event, with grade 3 of 4 (adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria [version 2.0] guidelines) neutropenia reported in 58% of the patients. Grade 3 of 4 febrile neutropenia occurred in 10 (7%) patients. Nonhematologic treatment‐related events (grade 3 of 4) were generally manageable and included constipation (17%), asthenia/fatigue (13%), ileus (5%), and abdominal pain (5%). No cumulative toxicity was observed.

CONCLUSIONS:

Vinflunine demonstrates moderate activity in patients with platinum‐pretreated UC. Toxicity is manageable and noncumulative. Cancer 2009. © 2009 American Cancer Society.     

局部晚期及转移性食管鳞癌免疫治疗现状分析

  目的  免疫治疗被批准用于晚期食管鳞癌（esophageal squamous cell carcinoma,ESCC）的二线治疗,但临床研究由于其严格的入排标准不能完全反映真实世界的情况。本研究旨在分析局部晚期和转移性ESCC免疫治疗现状,并探索可能影响预后的因素。  方法  纳入2018年1月至2020年11月在北京大学肿瘤肿瘤医院接受免疫治疗的局部晚期及转移性ESCC患者,分析临床病理资料、治疗情况、疗效、不良反应和无进展生存期（progression-free survival,PFS）。  结果  本研究纳入33例ESCC患者,其中1例合并强制性脊柱炎。患者均接受程序性细胞死亡抑制剂治疗,最常用的药物为信迪利单抗（17/33,52%）。25例（76%）接受免疫联合治疗,包括联合化疗或抗血管靶向治疗。接受一线、二线和三线及以上治疗的ESCC患者分别为19例（58%）、10例（30%）和4例（12%）。1~2级和3~4级治疗相关不良反应发生率分别为64%（21/33）和27%（9/33）。11例（33%）发生免疫相关性不良反应（immune-related adverse events,irAEs）,包括皮疹5例,甲状腺功能减退4例,免疫性肝炎2例,免疫性肠炎2例,反应性毛细血管增生症2例,免疫性肺炎1例。4例irAEs影响免疫治疗使用,其中3例采用类固醇激素治疗。总体客观缓解率为36%（12/33）。中位PFS为9.17个月（95%CI8.23~ 10.11）。多因素分析显示基线白细胞计数（P=0.010）、免疫治疗线数（P=0.004）、免疫治疗疗效（P=0.049）是PFS的独立影响因子。  结论  免疫治疗在晚期ESCC的临床实践中,药物选择和治疗模式更加多样,但是依然产生良好的疗效。早期应用免疫治疗有效患者可以获得更长的PFS,而白细胞计数升高可能为不良预后因素,未来需扩大人群进一步验证。      

Dose-intensive chemotherapy with growth factor or autologous bone marrow/stem cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a systematic review

A systematic review was performed to determine whether first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow/stem cell transplantation improves response rate, time-to-disease progression, or survival compared with standard-dose chemotherapy in patients with inoperable, locally advanced, or metastatic soft tissue sarcoma. The MEDLINE, EMBASE, and Cochrane Library databases were searched. Three randomized trials (2 phase 3, 1 phase 2), 12 phase 2, and 5 phase 1 dose-escalation trials were located. One randomized trial (N=314) did not detect significant differences in response rate (P=.65) or survival (log-rank P=.98) between high-dose doxorubicin plus ifosfamide with granulocyte macrophage colony-stimulating factor and doxorubicin plus ifosfamide at standard doses. Progression-free survival, however, was significantly longer in the high-dose arm (log-rank P=.03). Higher rates of thrombocytopenia, infection, grade 3 of 4 asthenia, and stomatitis were observed with high-dose compared with standard-dose chemotherapy. Preliminary results from a second randomized trial (N=162) indicated no benefit with respect to tumor response for an intensified mesna, doxorubicin (Adriamycin), ifosfamide, and dacarbazine regimen with granulocyte colony-stimulating factor support compared with standard doxorubicin, ifosfamide, and dacarbazine. Grade 4 thrombocytopenia was significantly higher with the high-dose regimen. Four phase 2 trials of high-dose regimens observed tumor response rates greater than 50%. Phase 1 trials reported dose-limiting toxicity for dose-intensive chemotherapy regimens. On the basis of the available evidence, high-dose chemotherapy with growth factor or autologous bone marrow/stem cell transplantation should not be used in the routine treatment of patients with inoperable, locally advanced, or metastatic soft tissue sarcoma.     

Significance of local treatment in patients with metastatic soft tissue sarcoma

Metastatic soft tissue sarcomas (STS) represent enormous challenges to improve the low survival rate, which is almost the same as past 2 decades ago, although surgery, radiotherapy and radiofrequency ablation has been accepted in the treatment of metastatic STS. Moreover, STS varies between elderly and younger victims in the aspect of diagnoses, prognosis, and treatment strategies. In order to evaluate the role of local treatment in improving prognosis for patients with metastatic STS and select the proper candidates who will benefit from local therapy, a single-institution nearly 50-year experience were collected and reviewed. Finally, we found that local treatments could improve treatment response and survival, but overall survival advantage could not be seen in elderly patients. This conclusion from a single institution could serve as a basis for future prospective multi-institutional large-scale studies.     

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.     

Phase II trial of pazopanib in patients with metastatic or unresectable chemoresistant sarcomas: A Japanese Musculoskeletal Oncology Group study

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single‐arm, multicenter, investigator‐initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end‐point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow‐up period was 22.2 (range, 4.9‐24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors.     

聚乙二醇化脂质体多柔比星联合异环磷酰胺治疗晚期转移性软组织肉瘤

背景与目的：软组织肉瘤一旦出现远处转移,预后极差,中位生存时间不到1年。多柔比星联合异环磷酰胺(ifosfamide,IFO)(AI方案)是晚期软组织肉瘤常用的一线联合治疗方案。聚乙二醇脂质体多柔比星(pegylated liposomal doxorubicin,PLD)活性成分为盐酸多柔比星,药物包裹在脂质体中,可减少多柔比星的临床毒性反应。该研究探讨PLD联合IFO治疗晚期转移性软组织肉瘤的临床疗效和安全性。方法：选取晚期转移性软组织肉瘤患者25例,使用PLD联合IFO方案,PLD剂量30 mg/m²,静脉滴注,第1天;IFO剂量1.8 g/m²,静脉滴注,第1~5天;美司钠360 mg/m²,用IFO时0、4和8 h,21 d为1个周期。结果：所有患者化疗1~8个周期,中位周期数4。25例患者中部分缓解9例(36%),疾病稳定12例(48%),疾病进展4例(16%),疾病控制率(完全缓解+部分缓解+疾病稳定)为84%(21/25)。中位无进展生存时间为7.3个月(95%CI：4.6~10.0个月)。由于失访病例较多,中位总生存时间未随访到。化疗后3/4级不良反应包括白细胞下降(20%)、粒细胞下降(28%)、贫血(4%)和呕吐(4%)。只有1例患者治疗过程中予以减量。结论：临床应用PLD联合IFO方案治疗晚期转移性软组织肉瘤疗效确切,且毒性反应较轻,值得进一步深入研究。     

Real-world systemic therapy utilization in Medicare patients with locally advanced or metastatic urothelial carcinoma diagnosed between 2008 and 2012

PurposeTreatment of advanced urothelial carcinoma (UC) remains a challenging clinical entity occurring predominantly in older patients with limited treatment options. However, real-world treatment patterns, differential cancer center access, and association with outcomes is lacking in nationally representative clinical practice and will provide context for emerging therapies.Materials and MethodsWe used SEER-Medicare data to identify patients with locally advanced or metastatic UC of the bladder or upper urinary tract diagnosed between 2008 and 2012. We characterized utilization systemic therapy, including first- and second-line chemotherapy. Patients receiving neoadjuvant chemotherapy were excluded; results were stratified by academic versus non-academic setting.Results3569 patients met study criteria; 48% received some form of chemotherapy within 2 years of diagnosis. Of these, one-third subsequently received second-line chemotherapy. The majority received a regimen including ≥2 agents. Gemcitabine alone or in combination with platinum was the most common first- and second-line treatment. Similar patterns of first- and second-line chemotherapy were observed between patients treated in academic and non-academic centers. Sensitivity analyses of trial-similar patients demonstrated increased utilization (69%). Receipt of platinum doublet as 1st line therapy was less likely in older patients and those with renal disease, and more likely for grade IV disease.ConclusionsRoughly half of all Medicare patients with locally advanced/metastatic UC receive systemic therapy regardless of access to academic cancer centers and despite poor oncologic outcomes. Cytotoxic, gemcitabine-based doublet chemotherapy remains the most common treatment. A substantial population of older patients exists for whom alternative, non-cytotoxic, treatment options may be of benefit.     

Pegylated liposomal doxorubicin as second-line therapy in the treatment of patients with advanced classic Kaposi sarcoma: a retrospective study

BACKGROUND: Classic Kaposi sarcoma (CKS) is a rare neoplasm that predominantly occurs in elderly subjects and has a variable clinical evolution. The clinical course is usually indolent, but occasionally the neoplasm progresses rapidly and spreads to internal organs, necessitating systemic chemotherapy. Because of the rarity of CKS, the best treatment has not been determined to date. To the authors' knowledge, few data exist regarding the use of pegylated liposomal doxorubicin (PLD) as first-line and second-line treatment in advanced CKS. The current retrospective study investigated the activity and toxicity of PLD in pretreated patients with aggressive, nonvisceral CKS. METHODS: Patients were treated with PLD at a dose of 20 mg/m(2) intravenously every 3 weeks until disease progression or the occurrence of intolerable side effects. Objective responses were determined after 3 and 6 cycles; toxicity was assessed every cycle. Secondary endpoints were pain intensity, progression-free survival, and overall survival. RESULTS: Twenty men with pretreated CKS (median age, 67 years) were treated with PLD. All patients received at least 6 cycles of therapy. Complete and partial responses were observed in 2 patients (10%) and 14 patients (70%), respectively. Neutropenia was the most significant grade 3 hematologic toxicity observed (evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events [version 3.0]), occurring in 20% of patients. Only 1 patient (5%) demonstrated grade 4 neutropenia. Fourteen patients (70%) achieved remission of pain and/or edema after 6 cycles. The median progression-free survival was 9 months (95% confidence interval, 5-13 months). At a median follow-up of 36 months, 15 patients (75%) remained alive. CONCLUSIONS: PLD is associated with an improvement in objective response and pain intensity and is well tolerated as a second-line treatment for CKS.     

An open-label,phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours

BackgroundCixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours.MethodsIn this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10 mg/kg) for 1 h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon’s optimum 2-stage design was applied (PFR at 12 weeks P0 = 20%, P1 = 40%, α = 0.10, β = 0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2.ResultsA total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n = 17), 14% for leiomyosarcoma (n = 22), 32% for adipocytic sarcoma (n = 37), 18% for synovial sarcoma (n = 17) and 11% for Ewing family of tumours (n = 18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%).ConclusionsPatients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.     

Dose-intensive chemotherapy with growth factor or autologous bone marrow or stem-cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a clinical practice guideline

Questions

• In patients with inoperable locally advanced or metastatic soft tissue sarcoma, does first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem-cell transplantation improve response rate, time to disease progression, or survival as compared with standard-dose chemotherapy?
• What are the effects of first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem-cell transplantation on toxicity and quality of life?

Perspectives

Because therapeutic options for adult patients with advanced or metastatic soft tissue sarcoma are scarce and the possibility of cure for these patients is extremely limited, the Sarcoma Disease Site Group (dsg) felt that a review of the available literature on dose-intensive chemotherapy for adult patients with locally advanced or metastatic soft tissue sarcoma and subsequent development of a clinical practice guideline based on the evidence were important.

Methodology

A systematic review was developed and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, a pathologist, a methodologist, and community representatives. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the Report Approval Panel.

Practice Guideline

Based on the systematic review, consensus, and external review, the Sarcoma dsg makes these recommendations:

• Dose-intensive chemotherapy with growth factor support is not recommended in the first-line treatment of patients with inoperable locally advanced or metastatic soft tissue sarcoma.
• The data are insufficient to support the use of high-dose chemotherapy with autologous bone marrow or stem-cell transplantation as first-line treatment in this group of patients.
• Eligible patients should be encouraged to enter clinical trials assessing novel approaches or compounds.

Qualifying Statements

High-dose chemotherapy with growth factor or autologous bone marrow or stem-cell transplantation has adverse effects similar to those seen with standard-dose chemotherapy. With high-dose regimens, the incidence of grades 3 and 4 thrombocytopenia is significantly higher, and neutropenic fever and febrile neutropenia occur more frequently. Compared with standard treatment, the rate of treatment-related death is also higher with high-dose regimens.     

Isolated limb perfusion is an effective treatment modality for locally advanced Kaposi sarcoma of the extremities

IntroductionKaposi sarcoma (KS) is a rare soft tissue sarcoma. In case of locally advanced disease, mutilating surgery such as amputations or major reconstructive procedures are sometimes inevitable. The aim of this study was to evaluate the effectiveness of isolated limb perfusion (ILP) in patients with locally advanced KS of the extremities.Material and methodsAll patients who underwent ILP for KS between 1996 and 2018 at Erasmus MC, Rotterdam were identified. Clinical data was obtained from either a prospectively maintained database or retrospective assessment of patient files.ResultsA total of 14 primary ILP's were performed in 11 patients. Median follow-up from primary ILP was 30 months (range, 5–98). The overall response rate of primary ILP was 100%, with a complete response (CR) rate of 50%. Only minimal local toxicity (Wieberdink I-III) was observed. Local progressive disease occurred after eight primary ILP's (57%) with a median local progression free survival (PFS) of 18 months (95% confidence interval [CI]: 7.0–28.9). Subsequently, four (46%) patients received a total of 5 recurrent ILP's. After the recurrent ILP on the same leg, the overall response rate was 75% and a CR-rate of 50%. One patient needed amputation post-operatively resulting in a limb salvage rate of 91%. One (9%) patient developed metastases four months after ILP.ConclusionsILP is a highly effective treatment modality with very limited morbidity rates for patients with locally advanced KS of the extremity. ILP should be considered as a treatment modality for locally advanced KS of the extremities.     

Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer

PurposeGemcitabine (G) has been shown to sensitize pancreatic cancer to radiotherapy but requires lower doses of G and thus delays aggressive systemic treatment, potentially leading to distant failure. We initiated a phase I trial combining ultra-fractionated low-dose radiotherapy with full dose G and erlotinib in the treatment of patients with advanced pancreatic cancer.MethodsPatients with locally advanced or metastatic pancreatic cancer confined to the abdomen and an ECOG performance status (PS) of 0–1 who had received 0–1 prior regimens (without G or E) and no prior radiotherapy were eligible. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4 h on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).Results27 patients (median age 64 years and 15 male) were enrolled between 11/24/08 and 4/12/12. 1 patient withdrew consent prior to receiving any protocol therapy. 17 patients had a PS of 1. The majority of patients were stage IV. One DLT was noted out of 7 patients at dose level (DL) 1. Subsequently no DLTs were noted in 3 patients each enrolled at DL2-4 or 11 patients in the expansion cohort. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Best response in 24 evaluable patients: PR (8), stable (15), PD 1. Median survival for the entire group was 9.1 months.ConclusionThis phase I study combining low-dose ultra-fractionated RT as a sensitizer to full dose G plus E was well tolerated with encouraging efficacy. This represents a novel strategy worthy of further investigation in advanced pancreatic cancer patients.     

Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma

Background

The number of elderly people with soft tissue sarcoma (STS) is increasing. A sizeable population of elderly patients with STS is unfit for conventional doxorubicin- or ifosfamide-based chemotherapy. We assessed the feasibility of metronomic oral cyclophosphamide (CPM) in this population.

Patients and methods

Patients aged 65 years or older with unresectable STS received CPM 100 mg twice daily plus prednisolone 20 mg daily, the first week of a 2-week cycle in the outpatient setting. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and progression-free survival.

Results

Twenty-six patients (median age: 72, range 66-88) received a total of 330 cycles (median per patient: 10, range 2-41) as first (n = 19) or second-line chemotherapy (n = 7). The most frequent histological subtypes were poorly differenciated sarcoma (n = 8), leiomyosarcoma and liposarcoma (n = 5 each) and angiosarcoma (n = 3). Grade ?3 lymphopenia was observed in 81% of pts but no opportunist infection occurred. Grade 3 anaemia and thrombocytopenia occurred in 2 pts (8%) each. No other grade 3-4 toxicity was seen. The response rate was 26.9% (95%CI: 9.9-44.0) and the disease control rate (responses and stable disease >12 weeks) was 69.2% (95%CI: 51.5-87.0). One complete (hepatic epithelioid haemangio-endothelioma) and 6 partial responses (including 5 pts with radiation-induced sarcomas) were seen. Progression-free survival ranged from 0 to 20.6 months (median: 6.8 months) and was significantly longer in patients with radiation-induced sarcomas (median: 7.8 versus 5.2 months, p = 0.02).

Conclusion

Metronomic CPM showed good safety results for this frail population, with promising activity in patients with radiation-induced sarcoma. Toxicity profile was favourable, allowing prolonged home staying and rare treatment discontinuations. A larger prospective study is warranted to confirm these encouraging results in elderly with STS.