Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study

To assess the efficacy of the combination of long-acting release (LAR) octreotide and tamoxifen (TMX) for the treatment of advanced hepatocellular carcinoma (HCC). A total of 109 patients with advanced HCC were randomised to receive octreotide LAR combined with TMX (n=56) (experimental treatment group) or TMX alone (n=53; control group). The clinical, biological and tumoural parameters were recorded every 3 months until death. Primary end point was patient survival; secondary end points were the impact of therapy on tumour response, quality of life and variceal bleeding episodes. Univariate and multivariate analyses were performed for assessment of specific prognostic factors. The median survival was 3 months (95% CI 1.4-4.6) for the experimental treatment group and 6 months (CI 95% 2-10) for the control group (P=0.609). There was no difference in terms of alpha-foetoprotein (alpha-FP) decrease, tumour regression, improvement of quality of life and prevention of variceal bleeding between the two groups. Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, alpha-FP level <400 ng ml(-1) and Okuda stage I. The combination of octreotide LAR and TMX does not influence survival, tumour progression or quality of life in patients with advanced HCC.     

The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: A clinical phase II study

Purpose:The aim of this phase II study was to evaluate the tumourresponse of neuroendocrine tumours to targeted irradiation with theradiolabelled somatostatin analogue ⁹⁰Y-DOTATOC. In addition, thepalliative effect of ⁹⁰Y-DOTATOC treatment on the malignantcarcinoid syndrome and tumour-associated pain was investigated. Patients and methods:Forty-one patients (mean age 53 years) withneuroendocrine gastroenteropancreatic and bronchial tumours were included.Eighty-two percent of the patients had therapy resistant and progressivedisease. The treatment consisted of four intravenous injections of a total of6000 MBq/m^{2 90}Y-DOTATOC, administered at intervals ofsix weeks. Results:The overall response rate was 24%. For endocrinepancreatic tumours it was 36%. Complete remissions (CR) were found in2% (1 of 41), partial remissions (PR) in 22% (9 of 41),minor response in 12% (5 of 41), stable disease (SD) in 49% (20of 41) and progressive disease (PD) in 15% (6 of 41). The median followup was 15 months (range 1 month to 36 months). The median duration of responsehas not been reached at 26 months. The two-year survival time was 76 ±16%. Eighty-three percent of the patients suffering from the malignantcarcinoid syndrome achieved a significant reduction of symptoms. The treatmentwas well tolerated. A reduction of pain score was observed in all patients (5of 41) with morphine dependent tumour-associated pain. Side effects includedgrade III (NCIGC) pancytopenia in 5%, and vomiting shortly afterinjection in 23%. No grade III–IV renal toxicity wasobserved. Conclusion:Targeted radiotherapy with ⁹⁰Y-DOTATOC isa novel, well-tolerated treatment for neuroendocrine tumours with a remarkableobjective response rate, survival time, and symptomatic response.     

Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up

BackgroundMonocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany.MethodsA total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan–Meier curves and uni-variate log rank test Cox models.FindingsMedian overall survival of all patients was 59 (95% confidence interval [CI] 49–68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83–5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79–5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41–12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18–0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9–46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71–4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2–1.5% of patients.InterpretationThese results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.     

Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses

Because women with advanced ovarian cancer have poor outcomes, it is imperative to continue exploring for novel therapies. The opportunity for intraperitoneal treatment, especially in the subgroup of patients with minimal residual disease, in which the intraperitoneal approach may have a biologic rationale for benefit over and above the standard intravenous route, needs to be explored to the fullest extent. The MEDLINE, EMBASE, and Cochrane Library databases were searched up to January 2006 for randomized trials that compared first-line intraperitoneal-containing chemotherapy with first-line intravenous chemotherapy in the treatment of women with stage III epithelial ovarian cancer. Seven randomized, controlled trials were identified, including 3 large Phase III trials and 4 smaller randomized trials. The 3 large Phase III trials detected statistically significant overall survival benefits with intraperitoneal cisplatin-containing chemotherapy compared with intravenous chemotherapy alone. The improvements in survival were 8 months, 11 months, and 16 months, respectively. Pooled analysis from 6 of the 7 randomized trials confirmed the survival effect with intraperitoneal chemotherapy compared with intravenous chemotherapy alone (relative risk, 0.88; 95% confidence interval, 0.81-0.95). Severe adverse events and catheter-related complications with intraperitoneal chemotherapy were significantly more common and often were dose-limiting. The results from this review indicated that cisplatin-containing intraperitoneal chemotherapy should be offered to patients on the basis of significant improvements in overall survival. The appropriate clinical and institutional multidisciplinary facilities are needed for the safe delivery of this treatment in optimally debulked patients. Further research is needed concerning specific aspects of the treatment, such as optimal agent, dose, and scheduling.     

Why i.p. therapy cannot yet be considered as a standard of care for the first-line treatment of ovarian cancer: a systematic review.

A National Cancer Institute (NCI) clinical announcement recommended i.p. therapy for women with optimally debulked ovarian cancer. Its basis was a summary of eight randomised controlled trials and two systematic reviews, which appear to indicate benefit of i.p. therapy. However, the systematic reviews that inform the recommendations have been inappropriately presented and interpreted. The systematic reviews inappropriately pooled results from 'confounded' trials in which different drugs and different doses of drugs were given in the control and i.p. treatment arms. Therefore, it is not possible to assess which component of treatment is responsible for improving outcome. In addition, none of the trials use a control arm of the internationally accepted standard of care. Using just the unconfounded trials, indirect comparisons show that the magnitude of benefit observed when i.p. regimens are compared with older i.v. regimens [hazard ratio (HR) for overall survival (OS) 0.75; 95% confidence interval (CI) 0.60-0.92, P = 0.006] is smaller than the magnitude of benefit achieved with modern day standard of i.v. treatment compared with the same i.v. regimen used as control in the unconfounded i.p. trials (HR for OS 0.68; 95% CI 0.58-0.80, P < 0.001). A further difficulty is that the reviews cannot recommend an i.p. regimen for standard use. Drug-related toxicity and catheter complications that occur with i.p. therapy are considerable. The NCI recommendations have major implications for the treatment of women with ovarian cancer and for the next generation of clinical trials. We do not believe that the body of evidence currently available supports the recommendation that i.p. therapy should form part of routine care. The choice of treatment of women with newly diagnosed, optimally debulked, ovarian cancer, where therapy has the best chance of influencing OS, is too important to be left with this uncertainty. A clinical trial that investigates a practical and acceptable regimen which gives some or all chemotherapy by the i.p. route and compares this with standard i.v. chemotherapy should be a priority for those who wish to promote its use.     

The effectiveness of treatment for depression/depressive symptoms in adults with cancer: a systematic review

Depression is common in cancer patients, and this often remains undetected and untreated. Depression has been associated with poorer quality of life, in addition to increased impairment of immune response and poorer survival in cancer patients. Previous systematic reviews and meta-analyses of the efficacy of interventions for cancer patients with depression have failed to distinguish between caseness for depression and depressive symptoms. The findings from this systematic review show that there is limited trial data on the efficacy of prescribed antidepressants in reducing the incidence of major depression and depressive symptoms in cancer patients. Contrary to previous reviews that failed to distinguish between depressive symptoms and depression, this review found very little data from clinical trials (without the possibility of confounding factors) to demonstrate that psychotherapeutic interventions are effective in reducing depression in cancer patients. A number of small-scale, single-centre trials indicated that psychotherapeutic interventions (especially cognitive behavioural therapy) can have effects on depressive symptoms in cancer patients. However, given the methodological limitations of studies to date, lack of evidence should not be interpreted as implying lack of efficacy. In conclusion, there is a need for adequately powered studies of pharmacological and psychotherapeutic studies, which are targeted at cancer patients with a diagnosis of depression and include monitoring of the use of other pharmacological/psychotherapeutic and complementary and alternative medicine interventions.     

腹腔化疗或联合其他方法综合治疗晚期原发性肝癌72例的疗效观察

Objective: To evaluate the effect of intraperitoneal chemotherapy or in combination with other therapies in patients with advanced primary liver cancer.Methods: 72 patients with advanced primary liver cancer with no indication for surgery received intraperitoneal chemotherapy in combination with other therapies including transcatheter arterial chemoembolization(TACE), radiofrequency catheter ablation(RFA), percutaneous ethanol injection therapy(PELT)and radiotherapy.Of them, 29 cases were complicated with hilar or retroperitoneal multiple lymph node metastases, 14 with portal vein embolus, 15 with intraperitoneal and diaphragmatic metastases, 6 with chylous ascites, one with cancerous ascites, and 7 with suspected cancerous ascites(referring to large amounts of ascites without hypoproteinemia while exfoliative cytology of the ascites was positive).The mean maximum tumor size was 8.2 cm in diameter.Liver function at the initial treatment was Child A in 53 cases, and Child B in 19 cases.Intraperitoneal chemotherapy was performed in all these patients.The intraperitoneal chemotherapy protocols included: 5-FU 0.5-0.75 g/d for 10-15 consecutive days, with a total dosage of 5-12.5g, and at the last day of chemotherapy 10 mg mitomycin(MMC)or 100 mg carboplatin was injected.For 7 cases of cholangiocarcinoma, Gemzar 800-1000 mg was administered additionally.A majority of all these patients received another one or two therapy methods followed by intraperitoneal chemotherapy.TACE was performed in the patients with multiple tumors or nodule more than 5 cm in diameter in the liver, RFA or PElT with nodule fewer than 4 in number and 5 cm or less than 5 cm in diameter and radiotherapy, only for metastases, with metastatic lymph nodes, localized metastasis within the abdominal cavity or portal vein embolus.Interval time between two methods was one month or so.Two months after the sequential therapy, repeated treatment would be given if general medical condition and liver function were perfect at that time.Results: The median survival time of the group was 13.97±6.27 months.The 1-and 2-year survival rates were 59.7% and 30.6% respectively.The mean survival time of the patients with liver function Child A was 15.91±5.49 months, and that of the patients with Child B was 8.55±5.09 months.The difference was statistically significant(P＜0.05).Conclusion: Intraperitoneal chemotherapy or in combination with other therapies in patients with advanced primary liver cancer with metastases to abdominal cavity is an effective method.It can prolong the survival time and improve life quality for a certain percentage of patients with advanced primary liver cancer.     

Lenvatinib for the treatment of radioiodine-refractory differentiated thyroid carcinoma: a systematic review and indirect comparison with sorafenib

Introduction: Thyroid carcinoma is the most prevalent endocrine malignancy, with an increasing incidence over the past decades. Treatment of differentiated thyroid cancer consists of surgery followed by radioactive iodine (RAI) ablation of the thyroid remnant, and TSH suppression. Among new therapeutic solutions for patients with advanced RR-DTC stage, the most promising seem to be sorafenib and lenvatinib, up to now considered to be orphan drugs.

Areas covered: We performed a systematic review of medical databases to collect all eligible clinical trials referring to the topic of our analysis. Due to the lack of direct clinical trials comparing the drugs we used an adjusted indirect comparison of efficacy and safety of tyrosine kinase inhibitors (TKIs) by Bucher method.

Expert commentary: Lenvatinib and sorafenib are drugs with strong evidence on efficacy in treatment of RR-DTC. Based on the currently available clinical data lenvatinib occurred more efficacious then sorafenib in RR-DTC therapy. Safety profile of the drugs was acceptable and comparative. Kinase inhibitors constitute a substantial progress in treatment of advanced thyroid cancer, have achieved long-lasting response and have improved survival without progress of the disease. In the near future we will deal with a range of therapeutic options for patients.     

Repeated cycles of peptide receptor radionuclide therapy (PRRT) - Results and side-effects of the radioisotope Y-DOTA TATE, Lu-DOTA TATE or Y/Lu-DOTA TATE therapy in patients with disseminated NET

Purpose

PRRT is a known tool in the management of patients with disseminated and inoperable NETs. The aim of study was to assess the effectiveness of the repeated cycles of PRRT in patients with disseminated and inoperable NETs.

Material and methods

Eighty nine patients were included in the PRRT. Among them 16 patients (18%) were qualified for a repeated PRRT cycle due to progression of the disease. In one of the patients qualified for the repeated cycle, PRRT was used as neoadjuvant therapy. The results and side-effects of the repeated cycles of PRRT were analyzed.

Results

Disease stabilization was observed in 10 patients 6 months after the repeated PRRT cycle and in 5 patients after 12 and 18 months. Ten of the patients who had received repeated PRRT cycles died. In the case of neoadjuvant therapy, further reduction of the tumor size was observed, enabling qualification for surgery. Clinically significant reduction in the mean values of morphological parameters was not observed. Only after 12 and 18 months the mean values of creatinine levels were higher than the normal range (only in 2 patients).

Conclusions

The repeated cycles of PRRT did not cause a clinically significant increase of the toxicity of PRRT. The changes in kidney and blood morphology parameters were transient. The repeated cycles of PRRT enabled stabilization of the disease.     

预防性颅脑照射在完全缓解的小细胞肺癌中应用的系统评价

目的 系统评价预防性颅脑照射(PCI)在完全缓解(CR)的小细胞肺癌(SCLC)中应用的临床价值及最佳治疗剂量.方法 计算机检索PubMed、EMBASE、Cochrane Library和中国生物医学文献数据库、中文科技期刊全文数据库、中国期刊全文数据库、万方数据库,同时从参考文献中追溯查找.收集国内外有关的随机对照实验(RCT),评价纳入文献的方法学质量,并利用RevMan5.0软件进行Meta分析.结果 共纳入15个研究(2233例),其中13个RCT为行PCI与不行PCI(no-PCI)的对照,2个RCT为标准剂量(25Gy)与较高剂量(36Gy)的对照.Meta分析结果显示:相对于no-PCI组,PCI 可提高SCLC患者的 1、3、5年生存率[OR=1.51,95%CI（1.14-2.01）、OR=1.77,95%CI(1.33-2.35)、OR=1.57,95%CI(1.09-2.25)）和无瘤生存率［OR=2.43,95%CI(1.76-3.34)］,降低脑转移率［OR=0.29,95%CI（0.19-0.46））和其他转移率［OR=0.59,95%CI(0.43-0.80)］,而在局部区域复发率［OR=0.89,95%CI（0.66-1.21））方面无差异;与较高剂量组相比,标准剂量组可提高SCLC患者的1年生存率［OR=1.43,95%CI(1.07-1.92)］和1年无瘤生存率［OR=1.43,95%CI(1.05-1.95)］,在改善SCLC患者的2年生存率［OR=1.23,95%CI(0.91-1.66)］、3年生存率［OR=1.29,95%CI(0.94-1.76)］、2年无瘤生存率［OR=1.22,95%CI(0.89-1.67)］、3年无瘤生存率［OR=1.22,95%CI(0.88-1.70)］[KG（*8）方面无差异,但在1年脑转移发生率［OR=[KG]]1.74,95%CI（1.16-2.60））方面要高于较高剂量组.〖HT5"H〗结论 在经化疗和放射治疗后完全缓解的SCLC患者中,PCI能提高总生存率和无瘤生存率,并能降低脑转移及其他远处转移率,可作为一种有效的预防治疗手段.较高剂量PCI组并不能显著降低脑转移总发生率和死亡率,故认为25Gy的PCI是标准治疗剂量.     

Efficacy and safety of liver transplantation in patients with cholangiocarcinoma: a systematic review and meta-analysis

The aim of our study was to evaluate the efficacy and safety of liver transplantation in patients with cholangiocarcinoma. According to the requirements of Cochrane systematic review, a thorough literature search was performed in PubMed/Medline, Embase and Cochrane electronic databases between 1995 and 2009 in terms of the key words "liver transplantation" and "cholangiocarcinoma," "cholangiocellular carcinoma" or "bile duct cancer," with restricted articles for the English language. Data were processed for a meta-analysis by Stata 10 software. Altogether 14 clinical trials containing 605 transplanted patients of bile duct cancers were finally enrolled in our study. The overall 1-, 3- and 5-year pooled survival rates were 0.73 [95% confidence interval (CI) = 0.65-0.80], 0.42 (95% CI = 0.33-0.51) and 0.39 (95% CI = 0.28-0.51), respectively. Of note, preoperative adjuvant therapies [orthotopic liver transplantation (OLT)-PAT group] rendered the transplanted individuals with comparably favorable outcomes with 1-, 3- and 5-year pooled survival rates of 0.83 (95% CI = 0.57-0.98), 0.57 (95% CI = 0.18-0.92) and 0.65 (95% CI = 0.40-0.87). In addition, the overall pooled incidence of complications was 0.62 (95% CI = 0.44-0.78), among which that of OLT-PAT group (0.58; 95% CI = 0.20-0.92) was relatively acceptable compared to those of liver transplantation alone (0.61; 95% CI = 0.33-0.85) and liver transplantation with extended bile duct resection (0.78; 95% CI = 0.55-0.94). In comparison to curative resection of cholangiocarcinoma with the 5-year survival rate reported from 20 to 40%, the role of liver transplantation alone is so limited. In the future, attention will be focused on liver transplantation following neoadjuvant radiochemotherapy, which requires a well-designed, prospective randomized controlled study.     

The role of mitomycin in the treatment of non-small cell lung cancer: a systematic review with meta-analysis of the literature

In order to clarify the role of mitomycin (MMC) in the treatment of NSCLC, we performed a systematic review of the literature and qualitatively assessed the selected studies using the ELCWP and Chalmers scales. 5 trials (202 patients) assessed the activity of MMC as single-agent chemotherapy in NSCLC. The overall response rate was 25% (95% Cl 19-31). In 10 randomized phase III trials (1769 patients), we studied the role of MMC in combination therapy. A meta-analysis, based on the available published data, failed to show any survival advantage of the MMC containing regimens (hazard ratio = 0.95; 95% Cl 0.83-1.10). Finally, 4 eligible trials (139 patients) assessed the activity of MMC regimens as salvage therapy, 3 in combination with vindesine and one with cisplatin and vinblastine. The overall response rate for the MMC-vindesine regimen was 10.5% (95% Cl 1.7-19.4). In conclusion, MMC is an active drug for NSCLC but does not improve survival when combined with other active drugs, particularly cisplatin. Its use for salvage therapy appears to be associated with marginal activity only.     

Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors

¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is now approved for patients with advanced gastroenteropancreatic neuroendocrine tumors (NET), and it is therefore important to understand the efficacy and safety of PRRT in this patient population. PRRT efficacy and safety outcomes have frequently been summarized for patient populations with gastroenteropancreatic NET, but not specifically in patients with pancreatic NET (panNET). The pivotal phase 3 trial of ¹⁷⁷Lu-DOTATATE PRRT in NET was restricted to patients with a midgut primary site. No phase 3 trial data on PRRT treatment outcomes are currently available for the panNET patient population. This review presents the available evidence for panNET treatment outcomes with PRRT and demonstrates that the available data favor PRRT as a modality for this NET primary site. However, several other therapies for advanced panNET are currently available, and the sequencing and combination of PRRT with these other therapies is set to become the big challenge for the future of panNET management. Patient, tumor, and logistical factors (tumor burden, expression of somatostatin receptors, availability of PRRT, patient preferences, and concerns over long-term toxicity) need to be taken into consideration when selecting therapy.     

The efficacy and safety of gemcitabine-based combination therapy vs. gemcitabine alone for the treatment of advanced pancreatic cancer: a systematic review and meta-analysis

BackgroundGemcitabine (GEM) is used as a standard first-line drug to effectively alleviate symptoms and prolong survival time for advanced pancreatic cancer. Most randomized controlled trials (RCTs) show that GEM-based combination therapy is better than GEM alone, while some RCTs have the opposite conclusion. This study aimed to investigate whether GEM-based combination therapy would be superior to GEM alone by a systematic review and meta-analysis.MethodsAccording to the PICOS principles, RCTs (S) focused on comparing GEM-based combination therapy (I) vs. GEM alone (C) for advanced pancreatic cancer (P) were collected from eight electronic databases, outcome variables mainly include survival status and adverse events (AEs) (O). Review Manager 5.4 was used to evaluate the pooled effects of the results among selected articles. Pooled estimate of hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were used as measures of effect sizes. Quality assessment for individual study was performed using the Cochrane tool for risk of bias.ResultsA total of 17 studies including 5,197 patients were selected in this analysis. The pooled results revealed that GEM-based combination therapy significantly improved the overall survival (OS; HR =0.84; 95% CI: 0.79 to 0.90; P<0.00001), progression-free survival (PFS; HR =0.78; 95% CI: 0.72 to 0.84; P<0.00001), overall response rate (ORR; OR =1.92; 95% CI: 1.61 to 2.30; P<0.00001), 1-year survival rate (OR =1.44; 95% CI: 1.02 to 2.03; P=0.04), respectively. Subgroup analysis showed that the efficacy of GEM plus capecitabine (CAP) and GEM plus S-1 was better than that of GEM alone, while GEM plus cisplatin (CIS) did not achieve an improved effect. GEM-based combination therapy can significantly increase the incidence of AEs, such as leukopenia (P<0.001), neutropenia (P<0.001), anemia (P<0.05), nausea (P<0.001), diarrhea (P<0.05), and stomatitis (P<0.001). No publication bias existed in our meta-analysis (P>0.10).DiscussionOur study supported that GEM-based combination therapy was more beneficial to improve patient’s survival than GEM alone, while there was no additional benefits in GEM plus CIS. We also found that GEM-based combination therapy increased the incidence of AEs. Clinicians need to choose the appropriate combination therapy according to the specific situation.     

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a long-acting release (LAR) formulation of pasireotide (SOM230) in patients with gastroenteropancreatic neuroendocrine tumors: results from a randomized, multicenter, open-label, phase I study

Purpose

Pasireotide (SOM230), a novel multireceptor ligand somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst_{1–3, 5}). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics profiles of pasireotide long-acting release (LAR) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor (GEP NET) refractory to other SSAs.

Methods

In this randomized, multicenter, open-label, phase II study, patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were randomly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20, 40, or 60 mg once every 28 days for 3 months.

Results

Forty-two patients received pasireotide LAR. Adverse events were reported by 34 (81 %) patients, with the most frequently reported including diarrhea, fatigue, abdominal pain, and nausea. Mean fasting glucose levels were increased compared with baseline at all points throughout the study. After the third injection of pasireotide LAR, the median trough plasma concentrations on day 84 were 4.82, 12.0, and 19.7 ng/mL in the 20-, 40-, and 60-mg treatment groups, respectively. Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections (accumulation ratios were approximately 1 from all dose levels).

Conclusions

This study demonstrated that a new, once-monthly, intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET. Steady state levels of plasma pasireotide were achieved after three injections.     

Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis

The role of the anti-apoptotic protein Bcl-2 in lung cancer remains controversial. In order to clarify its impact on survival in small and non-small cell lung cancer (NSCLC), we performed a systematic review of the literature. Trials were selected for further analysis if they provided an independent assessment of Bcl-2 in lung cancer and reported analysis of survival data according to Bcl-2 status. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a quality scale designed by the European Lung Cancer Working Party (including study design, laboratory methods and analysis). Of 28 studies, 11 identified Bcl-2 expression as a favourable prognostic factor and three linked it with poor prognosis; 14 trials were not significant. No differences in scoring measurement were detected between the studies, except that significantly higher scores were found in the trials with the largest sample sizes. Assessments of methodology and of laboratory technique were made independently of the conclusion of the trials. A total of 25 trials, comprising 3370 patients, provided sufficient information for the meta-analysis. The studies were categorised according to histology, disease stage and laboratory technique. The combined hazard ratio (HR) suggested that a positive Bcl-2 status has a favourable impact on survival: 0.70 (95% confidence interval 0.57-0.86) in seven studies on stages I-II NSCLC; 0.50 (0.39-0.65) in eight studies on surgically resected NSCLC; 0.91 (0.76-1.10) in six studies on any stage NSCLC; 0.57 (0.41-0.78) in five studies on squamous cell cancer; 0.75 (0.61-0.93) and 0.71 (0.61-0.83) respectively for five studies detecting Bcl-2 by immunohistochemistry with Ab clone 100 and for 13 studies assessing Bcl-2 with Ab clone 124; 0.92 (0.73-1.16) for four studies on small cell lung cancer; 1.26 (0.58-2.72) for three studies on neuroendocrine tumours. In NSCLC, Bcl-2 expression was associated with a better prognosis. The data on Bcl-2 expression in small cell lung cancer were insufficient to assess its prognostic value.     

The necessity of intrathecal chemotherapy for the treatment of breast cancer patients with leptomeningeal metastasis: A systematic review and pooled analysis

Leptomeningeal carcinomatosis is a devastating disease. Despite its numerous complications, intrathecal (IT) chemotherapy remains a longstanding treatment for leptomeningeal carcinomatosis. Using case studies with internationally reported results, we attempted to determine the necessity of IT chemotherapy in treating leptomeningeal carcinomatosis. We conducted a systematic review and pooled analysis to compare hormone therapy, chemotherapy, and IT therapy. We excluded articles on IT trastuzumab therapy. We performed our literature search without language restriction. We retrieved articles that were published by as late as July 19, 2016. The present study was performed in accordance with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The Cox proportional hazard regression model was performed to examine the effects of prognostic variables. A total of 34 patients from 32 studies were considered eligible. The median age of the patients in the hormone treatment, chemotherapy, and IT therapy groups was 46, 51.5, and 51 years, respectively. The median overall survival (OS) of the patients in the hormone treatment, chemotherapy, and IT therapy groups was 65, 52, and 41 weeks, respectively. One patient who received hormone therapy exhibited the longest survival of approximately 8.5 years. Only magnetic resonance imaging response was associated with OS (hazard ratio = 0.05, 95% confidence interval 0.00-0.74; p = 0.03). Hormone status, HER2 status, age, central nervous system radiation therapy, IT therapy, metastasis sites (central nervous system only vs. others), and cerebrospinal fluid responses were all not associated with OS. Given its obvious side effects and lack of evidence of effectiveness from prospective randomized clinical trials, IT chemotherapy should be used with caution in the treatment of leptomeningeal metastasis breast cancer patients.