Management of advanced and/or metastatic carcinoid tumors: historical perspectives and emerging therapies

Introduction: Carcinoid tumors are uncommon neoplasms that offer unique therapeutic challenges to practicing physicians. Several chemotherapy combinations and IFN-α have been used for the treatment of unresectable carcinoid tumors over the last decades, but they have shown variable clinical results. Given the heterogeneity of these tumors, there is no clear therapeutic agent or combination that confers a significant advantage over others.

Areas covered: The authors provide a comprehensive evaluation of the existing therapies for advanced carcinoid tumors such as traditional agents, combination therapies and newer drugs.

Expert opinion: Somatostatin analogs are known to provide symptomatic relief in patients with carcinoid syndrome, but their antiproliferative effect has not been proven beyond the reasonable doubt. Traditional streptozocin-based regimens may offer a survival benefit in patients with advanced carcinoids, yet their toxicity is not negligible. Temozolomide has shown efficacy alone and in combination with other agents, and its further testing in advanced carcinoid tumors appears warranted. Efficacy of various tyrosine kinase inhibitors, VEGF inhibitors and mTOR inhibitors appears promising, and should be explored in patients with metastatic carcinoid tumors. In addition, use of these agents in combination with traditional chemotherapeutic agents should also be investigated.     

Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006

Standard treatment for glioblastoma multiforme (GBM) changed in 2005 when addition of temozolomide (TMZ) to maximal surgical resection followed by radiation therapy (RT) was shown to prolong survival in a clinical trial. In this study, we assessed treatment patterns and survival of patients with GBM in community settings in the United States. Patients with newly diagnosed GBM who were aged ≥20 years in 2006 (n = 1202) were identified as part of the National Cancer Institute 's Patterns of Care Studies. We assessed treatment patterns, and in the subset of patients who received total or partial surgical resection, we used multivariable regression analysis to assess patient, clinical, and health system factors associated with receipt of adjuvant chemotherapy and RT and survival through 2008. Approximately 65% of patients with GBM received total or partial surgical resection, and approximately 70% of these patients received adjuvant TMZ and RT. Receipt of adjuvant therapy was associated with patient age, marital status, health insurance, and tumor location. Median survival in all patients was 10 months (95% confidence interval [CI], 9-11 months). Receipt of adjuvant therapy following resection was associated with a lower risk of dying in adjusted analyses for patients who received TMZ and RT (hazard ratio [HR], 0.25; 95% CI, 0.18-0.35) and other adjuvant therapies (HR, 0.55; 95% CI, 0.37-0.81), compared with no adjuvant therapy. We observed rapid diffusion of a new standard of treatment, adjuvant and concurrent TMZ with RT, among adult patients with newly diagnosed GBM in the community setting following publication of a pivotal clinical trial.     

Initial treatment patterns over time for anaplastic oligodendroglial tumors

Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981-2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980-1984 vs 5% in 2005-2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980-1984 vs 38% in 2005-2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005-2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005-2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.     

Successful treatment of metastatic alveolar rhabdomyosarcoma with MGMT gene promoter methylation by temozolomide‐based combination chemotherapy

A 3‐year‐old male presented with a large retroperitoneal mass and multiple metastases. Biopsy results suggested alveolar rhabdomyosarcoma bearing a methylated O6‐methylguanine‐DNA methyltransferase (MGMT) gene promoter. Serum microRNA‐206 levels were elevated and remained high after three cycles of vincristine, dactinomycin, and cyclophosphamide (VAC). Replacement of vincristine, irinotecan, and temozolomide (VIT) for VAC induced a marked tumor reduction and normalization of the miR‐206 levels. The patient completed 14 cycles of VIT with local radiotherapy and has been in remission for 31 months. Temozolomide could be effective for tumors with a methylated MGMT gene promoter. Individualized therapy is warranted for such patients.     

存活蛋白对胶质瘤细胞替莫唑胺敏感性的影响

目的 探讨存活蛋白(survivin)对人脑胶质瘤细胞替莫唑胺(TMZ)敏感性的影响及其可能机制.方法 构建过表达survivin的U87/sur胶质瘤细胞,以及抑制survivin表达的U87/sur si胶质瘤细胞,经100μmol/L TMZ处理后,采用MTT法检测细胞增殖情况,克隆形成实验检测细胞的克隆形成能力,异硫氰酸荧光素标记的膜联素V/碘化丙啶(annexin V-FITC/PI)双标记联合流式细胞术检测细胞凋亡情况,Western blotting检测活化caspase-3表达水平.结果 经TMZ处理后,与亲代细胞相比,U87/sur si细胞的增殖活性明显下降,克隆形成率明显降低,凋亡率明显增加,而U87/sur细胞的增殖活性明显增强,克隆形成率明显增高,凋亡率明显下降.经TMZ处理后,与亲代细胞相比,U87/sur si细胞中活化的caspase-3蛋白水平升高,而U87/sur细胞中活化的caspase-3蛋白水平下降.结论 抑制survivin可明显提高胶质瘤细胞对TMZ的敏感性,其机制可能与survivin促进细胞凋亡有关.     

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review

BackgroundThe DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.MethodsWe performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.ResultsMethylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.ConclusionsWe cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.     

Management of glioblastoma

Glioblastoma multiforme (GBM) are among the most devastating neoplasms claiming the lives of patients within a median of 1 year after diagnosis. Treatment of GBM requires a multidisciplinary approach. Treatments include surgery, radiotherapy, chemotherapy and so on. Temozolomide (TMZ) has emerged as an active agent against malignant gliomas. On the basis of the work by the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada, concurrent radiotherapy and the oral alkylating agent TMZ followed by adjuvant TMZ has become the standard of care for patients with newly diagnosed GBM, although the methylation status of the O⁶-mehylguanine-DNA methyltransferase promoter is predictive for survival of GBM patients. Gliadel is a biodegradable polymer wafer impregnated with carmustine. Gliadel has been one of the few treatment modalities to demonstrate a statistical benefit in patients with malignant glioma. These new FDA approved drugs advanced the treatment of malignant glioma, but more progress is needed. Patients require improvements in chemotherapy, surgery, radiotherapy, molecular targeted therapy, immunotoxin using the convection-enhanced delivery and more.     

替莫唑胺衍生物治疗人脑胶质瘤的实验研究

目的 观察替莫唑胺(TMZ)类水溶性衍生物2T-P400、2T-P600对人脑胶质瘤的抑制效应.方法 体外抑瘤实验:以MTT法测定2T-P400、2T-P600、PEG400、PEG600、TMZ相对于空白对照组对胶质瘤细胞SHG-44的抑制率.体内抑瘤实验:制备荷SHG44人脑胶质瘤裸小鼠模型,将荷瘤鼠随机分为TMZ组、2T-P400组、2T-P600组、聚乙二醇(PEG)组及生理盐水组,TMZ口服给药,其他药物均为鼠尾静脉注射给药,每4天测量肿瘤体积.结果 体外抑瘤效应:2T-P400和2T-P600对SHG44细胞的杀伤效果与TMZ相近,均明显优于PEG400和PEG600 (P ＜0.01).体内抑瘤效应:TMZ组、2T-P400组和2T-P600组抑瘤率亦明显高于PEG组及生理盐水组(P＜0.05),未见明显药物不良反应.结论 2T-P400、2T-P600保留TMZ的抑瘤活性,为胶质瘤病人在术后TMZ类药物化疗提供新的药物及用药途径选择.     

Nanotube x-ray for cancer therapy: a compact microbeam radiation therapy system for brain tumor treatment

Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation.