吉西他滨联合奥沙利铂或替吉奥对比吉西他滨单药治疗晚期胰腺癌临床观察

目的：在真实临床背景下,比较吉西他滨联合奥沙利铂或替吉奥对比吉西他滨单药治疗晚期胰腺癌的疗效和不良反应。方法87例晚期胰腺癌患者分为三组：吉西他滨单药组（ G组）23例,吉西他滨1000 mg · m－2,静滴30 min,第1、8天。吉西他滨联合奥沙利铂组（GM组）33例,在G组基础上联合奥沙利铂130 mg· m－2,第1天。吉西他滨联合替吉奥胶囊组（ GS组）31例,在G组基础上联合口服替吉奥胶囊80／100／120 mg· d－1,每天2次,第1～14天;三组均每21 d为一周期。每2～3个周期进行评价。结果三组比较,其有效率（RR）、疾病控制率（DCR）和临床受益率（CBR）均未取得统计学意义（P＞0．0167）;GM组和GS组的中位无进展生存（PFS）和中位总生存时间（OS）均明显高于G组,差异有统计学意义（P＜0．0167）;而GM组和GS组比较,虽后者略显优势,但差异无统计学意义（P＞0．0167）。三组患者的主要不良反应为血液学毒性和消化道反应,联合化疗组的末梢神经损害和皮疹发生率略高于单药组,但差异不显著（ P＞0．05）。结论在真实临床背景下,GM方案和GS方案较吉西他滨单药治疗晚期胰腺癌可获得更好的生存期,且不良反应可以耐受,二者均可作为首选治疗方案。     

Currently available first-line drug therapies for treating pancreatic cancer

ABSTRACT

Introduction: Pancreatic adenocarcinoma is the 9th most common cancer in the United States and the 4th most common cause of cancer-related death given its poor prognosis.

Areas covered: The authors have performed a literature search for pertinent published clinical trials, ongoing Phase 3 clinical trials, and current treatment guidelines using PubMed, Clinicaltrials.gov, and NCCN, ASCO, ESMO, and JPS websites. The review itself discusses landmark studies and ongoing research into the chemotherapy regimens recommended by each oncologic society. The authors also examine drugs that were promising but failed in Phase 3 trials and those currently being investigated. Finally, the authors provide their expert opinion on the subject and provide their future perspectives.

Expert opinion: While advances in chemotherapy for pancreatic cancer have been limited in comparison to other cancers, there have been improvements in survival. Combination therapy and a goal of R0 resection are key elements to extend life. Novel agents directed at the unique properties of pancreatic cancer are promising.     

Systemic therapy for advanced pancreatic cancer: individualising cytotoxic therapy

Introduction: Pancreatic cancer is an aggressive solid tumour associated with a high risk of local invasion and metastatic spread. In the absence of validated screening approaches, many patients present with advanced, incurable disease. Despite advances in treatment, the prognosis for patients with advanced pancreatic cancer remains poor. The benefits of surgical resection and radiation are unproven in this setting and, as patients generally present with distant metastases, systemic therapy forms the mainstay of treatment. The importance of selecting the optimal cytotoxic therapy remains to be critical to improving outcome and retaining quality of life. This review sets out to compare the current therapies available for advanced pancreatic cancer.

Areas covered: This review examines the evolution of the systemic management of advanced pancreatic cancer, with a particular focus on the landmark Phase III trials identified from an extensive PubMed and Google scholar literature search. The article summarises the cytotoxic agents in use and the results of two decades of clinical trials to culminate in an almost doubling of survival in clinical trials.

Expert opinion: In the concluding expert opinion, the challenges interpreting and translating trial results into clinical practice are discussed, where patients are often older and of worse performance status. In the future, novel biomarkers might be used to tailor therapy.     

Safety of palliative chemotherapy in advanced pancreatic cancer

ABSTRACT

Introduction: Pancreatic cancer is a major health burden. Currently, the majority of patients is diagnosed at advanced stages and thus qualifies for palliative chemotherapy. Gemcitabine monotherapy has been the gold standard for many years. Recently, more effective chemotherapeutic regimens have shown meaningful clinical activity in patients with metastatic pancreatic cancer.

Areas covered: In this review we have aimed to give an overview on the treatment options for patients diagnosed with metastatic pancreatic cancer with an emphasis on the safety and toxicity of the applied regimens. We have conducted a pubmed search using the terms ‘metastatic pancreatic cancer’, ‘palliative chemotherapy’, ‘safety’ and ‘toxicity’. Our special focus rested on randomized phase III trials to provide readers with the highest level of available evidence.

Expert opinion: The emergence of new and more effective chemotherapy regimens gives clinicians more freedom in the treatment of metastatic pancreatic cancer. While being more effective, these regiments have a considerable degree of toxicity. Choosing the right treatment for any individual will be the next major challenge treating patients with pancreatic cancer.     

Gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer: a prospective observational study

Pancreatic cancer has one of the worst prognosis of any malignant disease. Systemic therapy is often administered because the disease is usually detected at advanced stages. Gemcitabine (Gemzar?, Eli Lilly & Co.) has proven activity in the treatment of pancreatic cancer. Gemcitabine 1000 mg/m² was given on days 1, 8 and 15, every 4 weeks. A total of 100 chemonaive patients with locally advanced or metastatic pancreatic cancer were enrolled; 32 and 68% had stage III and IV disease, respectively. The average number of administered cycles was 3.5 (range: 1 – 12). The overall response rate was 13%, with 13 partial responders. The median time to progression was 13.5 weeks (range: 3 – 56; 95% CI = 12 – 14). The median survival was 32 weeks (range: 4 – 104; 95% CI = 27 – 36). Clinical benefit response was acheived for 26 patients (26%). Grade 3/4 haematological toxicities occurred infrequently (anaemia: 5%; neutropenia: 8% and thrombocytopenia: 3% of patients). Grade 3/4 non-haematological toxicities were not observed. There were no treatment-related deaths. Gemcitabine treatment of patients with locally advanced or metastatic pancreatic cancer is effective and well-tolerated.     

吉西他滨联合替吉奥治疗晚期胰腺癌的系统评价

目的 系统评价吉西他滨联合替吉奥治疗晚期胰腺癌的有效性和安全性,为临床用药治疗提供科学依据。方法 计算机检索Cochrane图书馆临床对照试验资料库、EMBASE、PubMed、中国生物医学文献数据库（CBM）、中国期刊全文数据库（CNKI）、维普数据库（VIP）、万方科技等数据库中关于吉西他滨联合替吉奥治疗晚期胰腺癌临床随机对照试验（RCT）,检索时间均从各数据库创建至2019年12月。由两名评价员独立评价文献质量、提取资料并交叉核对,并进行方法学质量评价,采用RevMan 5.2的软件进行Meta-分析。结果 共纳入23篇RCTs,共1 817例患者,其中治疗组920例、对照组897例。Meta-分析结果显示：应用吉西他滨联合替吉奥组总有效率[RR=1.76,95% CI（1.51,2.04）,P<0.000 01]和临床获益率[RR=1.40,95% CI（1.30,1.50）,P<0.000 01]与对照组相比有显著性差异;在安全性方面,治疗组不良反应发生危险度高于对照组。结论 基于现有临床证据,吉西他滨联合替吉奥在治疗晚期胰腺癌方面均较对照组疗效更为显著,是一种较为理想的用药方案。     

局部进展期/转移性胰腺癌一线含吉西他滨化疗进展后的临床分析

目的分析局部进展期/转移性胰腺癌患者一线含吉西他滨化疗进展后的后续治疗模式及一线化疗进展后的预后因素。方法回顾性分析局部进展期/转移性胰腺癌患者一线使用含吉西他滨化疗进展后的临床特征、后续治疗方法、方案、疗效及生存期,用卡方检验进行组间比较,用Kaplan-Meier法进行单因素生存分析,用COX比例风险回归模型进行多因素分析。结果共纳入91例患者,其中32例(35.16%)患者一线化疗进展后仅行最佳支持治疗,59例(64.84%)患者继续行后线化疗。一线化疗最佳疗效为稳定或中位无进展生存期在91~180 d的患者继续后线化疗的比例低。84例患者一线化疗进展后中位生存期是151 d;序贯化疗和序贯最佳支持治疗的患者一线化疗进展后中位生存期分别为182和83 d,差异有统计学意义(P <0.01)。多因素分析显示:一线化疗进展后有无腹腔转移、二线化疗疗效和化疗线数是后续化疗组患者一线化疗进展后中位生存期的独立预后因素。结论一线化疗的疗效影响局部进展期/转移性胰腺癌患者后续治疗的模式,一线化疗进展后继续后线化疗的患者生存期更长,继续化疗的患者中无腹腔转移、二线最佳疗效为部分缓解、接受≥三线化疗者预后更好。     

A Phase II study of celecoxib,gemcitabine, and cisplatin in advanced pancreatic cancer

Summary Background. Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m² over 100 minutes, cisplatin 35 mg/m² I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. Results. Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6–7.6 months). The probability of survival at 6 months was 46% (90% CI, 27–62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.     

Nab-paclitaxel in the treatment of metastatic breast cancer: a comprehensive review

The novel paclitaxel formulation (nanoparticle albumin-bound [nab] paclitaxel (Abraxane^®) has recently been approved by the US FDA for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months after adjuvant chemotherapy. Apart from its superior efficacy, as demonstrated in the pivotal Phase III study, less toxicity compared with the traditional solvent-containing paclitaxel (Taxol^®) seems to contribute to its favorable therapeutic index. While approved as a single agent, nab-paclitaxel may prove more effective in combination with either biologic agents and/or other cytotoxic chemotherapeutic agents, as summarized in this article.     

A Phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors

Purpose: Pharmacological studies of gemcitabine (2,2-difluorodeoxycytidine) have shown that increased levels of the active triphosphate metabolite are achieved by prolonging infusion time while holding the dose rate constant. The primary aim of this study was to determine the maximum tolerated dose (MTD) of gemcitabine administered as a fixed rate infusion (10 mg/m²/min) on a weekly schedule in patients with untreated non-hematologic malignancies.Patients and methods: Twenty-seven patients (21 pancreatic adenocarcinoma, 3 hepatoma, 1 neuroendocrine tumor, and 2 adenocarcinoma of unknown primary) were enrolled in this open-label, non-randomized study. Three different entry dose levels (1200 mg/m², 1500 mg/m² and 1800 mg/m²) were evaluated for gemcitabine administered on days 1, 8, and 15 of a 28-day cycle.Results: The MTD was defined as 1500 mg/m² with granulocytopenia and thrombocytopenia being dose-limiting. There were no non-hematological dose limiting toxicities. The maximum WHO grade 3 or 4 toxicities for hemoglobin, leukocytes, neutrophils, and platelets for all doses of gemcitabine administered were 11.5%, 30.8%, 57.7%, and 26.9%, respectively. Non-hematologic toxicities included nausea, vomiting and fever. Four patients were withdrawn from the study for non-hematological toxicities: pneumonitis, ascites, disabling fatigue, and an acute myocardial infarction. Two of these events were severe (pneumonitis and myocardial infarction) but these may not be related to drug administration.Conclusion: Gemcitabine administered at a rate of 10 mg/m²/min was tolerated up to 1500 mg/m² in patients with previously untreated non-hematologic malignancies. Myelosuppression seen in this study is more severe than anticipated based on previous reports of bolus administration of similar doses of gemcitabine. This supports earlier studies suggesting that prolonged duration of infusion increases the intracellular accumulation of active metabolites of gemcitabine.     

Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations

Objective: To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC).

Methods: This study used the Medicare 5% sample and MarketScan Commercial (2010–2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase.

Results: This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively.

Limitations: The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy.

Conclusion: The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate the total cost of care in mCPRC.     

Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer

Background and purpose:

Pancreatic cancer is a highly aggressive malignancy, and improvement in systemic therapy is necessary to treat this frequently encountered metastatic disease. The current targeted agents used in combination with gemcitabine improved objective response rates, but with little or no improvements in survival and also increased toxicities in pancreatic cancer patients. Recently, we showed that the triterpenoid cucurbitacin B inhibited tumour growth in pancreatic cancer cells by inhibition of the JAK/STAT pathway, and synergistically increased antiproliferative effects of gemcitabine in vitro.

Experimental approach:

The anti-tumour effects and toxicities of cucurbitacin B in combination with gemcitabine were tested against human pancreatic cancer cells in a murine xenograft model.

Key results:

Combined therapy with cucurbitacin B and gemcitabine at relatively low doses (0.5 mg·kg⁻¹ and 25 mg·kg⁻¹ respectively) resulted in highly significant tumour growth inhibition of pancreatic cancer xenografts (up to 79%). Remarkably, this therapy was well tolerated by the animals, as shown by histology of visceral organs, analysis of serum chemistry, full blood counts and bone marrow colony numbers. Western blot analysis of the tumour samples of mice who received both cucurbitacin B and gemcitabine, revealed stronger inhibition of Bcl-XL, Bcl-2 and c-myc, and higher activation of the caspase cascades, than mice treated with either agent alone.

Conclusions and implications:

Combination of cucurbitacin B and gemcitabine had profound anti-proliferative effects in vivo against xenografts of human pancreatic cancer cells, without any significant signs of toxicity. This promising combination should be examined in therapeutic trials of pancreatic cancer.     

Association of obesity with healthcare resource utilization and costs in a commercial population

Objective: To examine the association of obesity with healthcare resource utilization (HRU) and costs among commercially insured individuals.

Methods: This retrospective observational cohort study used administrative claims from 1 January 2007 to 1 December 2013. The ICD-9-CM status codes (V85 hierarchy) from 2008 to 2012 classified body mass index (BMI) into the World Health Organizations’ BMI categories. The date of first observed BMI code was defined as the index date and continuous eligibility for one year pre- and post- index date was ensured. Post-index claims determined individuals’ HRU and costs. Sampling weights developed using the entropy balance method and National Health and Nutrition Examination Survey data ensured representation of the US adult commercially insured population. Baseline characteristics were described across BMI classes and associations between BMI categories, and outcomes were examined using multivariable regression.

Results: The cohort included 9651 individuals with BMI V85 codes. After weighting, the BMI distribution was: normal (31.1%), overweight (33.4%), obese class I (22.0%), obese class II (8.1%) and obese class III (5.4%). Increasing BMI was associated with greater prevalence of cardiometabolic conditions, including hypertension, type 2 diabetes and metabolic syndrome. The use of antihypertensives, antihyperlipidemics, antidiabetics, analgesics and antidepressants rose with increasing BMI. Greater BMI level was associated with increased inpatient, emergency department and outpatient utilization, and higher total healthcare, medical and pharmacy costs.

Conclusions: Increasing BMI was associated with higher prevalence of cardiometabolic conditions and higher HRU and costs. There is an urgent need to address the epidemic of obesity and its clinical and economic impacts.     

吉西他滨对胰腺癌外周血调节性T细胞影响的研究

目的 探讨吉西他滨对胰腺癌外周血调节性T细胞的影响,为进一步提高过继免疫治疗的疗效提供依据和参考。方法 本研究入选2012年1月至2014年10月收治的32例胰腺癌患者,分为吉西他滨组(吉西他滨+过继免疫治疗)和对照组(单纯过继免疫治疗),观察两组患者治疗前后外周血调节性T细胞水平、化疗不良反应,并对两组患者的生存时间进行分析比较。结果 吉西他滨组患者治疗后外周血调节性T细胞水平较治疗前显著降低,与对照组相比亦显著降低,两组比较有统计学差异(P<0.05),吉西他滨组中位生存时间较对照组延长1.3个月(10.0个月与8.7个月比较)。结论 吉西他滨化疗可以显著降低胰腺癌患者外周血调节性T细胞水平,有效调节患者的肿瘤免疫耐受,提高过继免疫治疗的疗效。     

吉西他滨联合卡培他滨治疗复发转移性乳腺癌的临床观察

目的观察吉西他滨联合卡培他滨治疗复发转移性乳腺癌的临床疗效及不良反应。方法 32例蒽环类及紫杉类药物治疗失败的复发转移性乳腺癌患者接受吉西他滨联合卡培他滨治疗：吉西他滨1 000 mg·m-2,静脉滴注第1,8天;卡培他滨1 250 mg·m-2,口服,2次/日,第1~14天,每21 d为1周期,每2个周期评价疗效,最终观察目的为PFS及药物毒副反应。结果 32例患者中完全缓解（CR）3例,部分缓解（PR）11例,ORR为43.75%;中位PFS达7.5个月。主要不良反应为血液系统毒性：Ⅲ~IV度粒细胞减少发生率为42.5%;手足综合征发生率38.2%,胃肠道反应28.3%,无化疗相关死亡病例。结论吉西他滨联合卡培他滨治疗复发转移性乳腺癌近期疗效肯定,耐受良好,远期疗效有待进一步观察。     

Contribution of equilibrative nucleoside transporters 1 and 2 to gemcitabine uptake in pancreatic cancer cells

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA‐PaCa2 and As‐PC1. Uridine uptake was inhibited by non‐labeled GEM and also by S‐(4‐nitrobenzyl)‐6‐thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration‐dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high‐ and low‐affinity components with K_m values of micromolar and millimolar orders, respectively. Uptake was inhibited in a concentration‐dependent manner by NBMPR and was sodium ion‐independent. Moreover, the concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low‐affinity site. These results indicated that the high‐ and low‐affinity sites correspond to hENT1 and hENT2, respectively. The results indicated that at clinically relevant hepatic concentrations of GEM in GEM‐HAI therapy, the metastatic tumor exposure of GEM is predominantly determined by hENT2 under unsaturated conditions, suggesting that hENT2 expression in metastatic tumor would be a candidate biomarker for indicating anticancer therapy with GEM‐HAI.     

Recent developments in the pharmacological treatment of advanced pancreatic cancer

Metastatic pancreatic cancer is one of the leading causes of cancer-related death in North America and Europe. The high mortality rate associated with pancreatic cancer is related to the fact that the vast majority of patients develop incurable, metastatic disease. Such patients have, in the past, had few treatment options. In recent years, however, the systemic administration of gemcitabine has been accepted as a standard first-line treatment for patients with advanced pancreatic cancer. While treatment with gemcitabine has been shown to result in both clinical benefit and in prolongation of survival, objective tumour responses following therapy with gemcitabine are relatively uncommon and median survival times remain short. Current efforts have, therefore, focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Several such combinations appear to be associated with higher objective response rates than single-agent gemcitabine and have been well-tolerated in early clinical trials. Ongoing, prospectively randomised clinical trials will help better define the efficacy of these new combinations and will determine if they result in a significant benefit when compared to gemcitabine monotherapy. A number of novel chemotherapeutic and biological agents also appear promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.