可切除胰腺癌的围手术期治疗与全程管理

胰腺癌是恶性程度和致死率极高的消化道恶性肿瘤.可切除胰腺癌是指可以通过手术达到根治性切除的胰腺癌,临床研究表明辅助化疗能延长可切除胰腺癌患者的生存期,但总体预后仍不乐观.目前国内缺乏一套规范的可切除胰腺癌患者全程管理模式.本文通过对可切除胰腺癌近20年来辅助治疗、新辅助治疗、分子靶向治疗、靶向肿瘤微环境的治疗如免疫治疗...     

SEOM clinical guidelines for treatment of prostate cancer

Prostate cancer (PC) is the most common cancer in men. Many patients have prolonged survival and die of other diseases, so treatment decisions are often influenced by age and coexisting comorbidities. The main procedure to diagnose PC is an ultrasound-guided core needle biopsy, which is indicated when a digital rectal examination (DRE) finds nodularity or when PSA is >10 ng/ml, but is also recommended with PSA between 4.0 and 10 ng/ml. Depending on age, PSA, Gleason score and characteristics of the tumour, treatment options for localised PC are active surveillance, radical prostatectomy and radiation therapy. Androgen deprivation treatment (ADT) should be added to radiotherapy for men with intermediate- or high-risk PC. ADT is the current standard first-line treatment for metastatic PC. Castration-resistant PC is a heterogeneous entity. Several treatments such as sipuleucel-T, docetaxel-based chemotherapy, radium 223, cabazitaxel or abiraterone plus prednisone, zoledronic and denosumab, are useful for this situation.     

Novel agents and targets in managing patients with metastatic prostate cancer.

BACKGROUND: Docetaxel has recently been found to improve survival in patients with metastatic androgen-independent prostate cancer (AIPC). Chemotherapy as a first-line option leaves room for improvement, while second-line options are multiple and somewhat controversial. METHODS: Clinically relevant articles focusing on chemotherapy drugs for metastatic prostate cancer and their mechanism of action and efficacy were reviewed from January 2004 through April 2006. RESULTS: Docetaxel is the standard of care for AIPC. However, for doublets with docetaxel or second-line chemotherapy, multiple studies have shown interesting and promising results with calcitriol, thalidomide, bevacizumab, satraplatin, vaccines, ixabepilone, and atrasentan. CONCLUSIONS: Docetaxel should be considered for first-line treatment of metastatic AIPC. Due to its progression-free survival of only 6 months, more effective drugs and drug combinations need to be developed to treat patients with AIPC. Combination treatments with docetaxel and other new agents are promising, but adequately powered phase III trials need to be conducted with survival as the principal endpoint for these promising drug combinations.     

First line therapy in the treatment of metastatic prostate cancer

Hormonal therapy has been the main treatment for advanced prostate cancer for the past six decades. Maximum androgen blockade (MAB), combination therapy with castration and antiandrogens, has been compared with castration monotherapy since the late 1980s. However, the results of the different trials have been conflicting. Recently published meta-analyses have revealed that MAB with non-steroidal antiandrogens is slightly superior to monotherapy (surgical or medical castration) in the treatment of advanced prostate cancer, and that MAB has more adverse effects. The question of whether the modest survival advantage of MAB balances with the increase in adverse effects should be investigated. Some studies indicated that the survival of metastatic prostate cancer patients treated with immediate therapy was similar to that of men in whom treatment was delayed. Hormonal therapy has side effects and is costly, and delayed treatment may be beneficial to elderly men with silent metastasis. Intermittent hormonal therapy is a controversial approach to management of advanced prostate cancer, although laboratory data suggest that intermittent androgen deprivation may prolong the duration of androgen dependence. Intermittent hormonal therapy for patients with metastatic prostate cancer needs to be assessed in a randomized trial to determine the effect on overall survival and quality of life. Our results in a randomized clinical trial of chemo-endocrine therapy versus endocrine therapy alone suggested that the addition of chemotherapy (cisplatin plus pirarubicin) to initial endocrine therapy might be beneficial to patients with advanced prostate cancer, especially an aggressive form of prostate cancer. However, chemo-endocrine therapy should be considered an experimental approach at present.     

Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs

Background  

The progression of all cancers is characterized by increased-cell proliferation and decreased-apoptosis. The androgen-independent prostate cancer (AIPC) is the terminal stage of the disease. Many chemokines and cytokines are suspects to cause this increased tumor cell survival that ultimately leads to resistance to therapy and demise of the host. The AIPC cells, but not androgen-responsive cells, constitutively express abundant amount of the pro-inflammatory chemokine, Interleukin-8 (IL-8). The mechanism of IL-8 mediated survival and therapeutic resistance in AIPC cells is unclear at present. The purpose of this report is to show the pervasive role of IL-8 in malignant progression of androgen-independent prostate cancer (AIPC) and to provide a potential new therapeutic avenue, using RNA interference.     

TTD consensus document on the diagnosis and management of exocrine pancreatic cancer

Exocrine pancreatic cancer (PC) is a very aggressive and heterogeneous tumor with several cellular signaling pathways implicated in its pathogenesis and maintenance. Several risk factors increase the risk of developing PC. Therapeutic strategies used are dictated by the extent of disease. Supportive treatment is critical because of the high frequency of symptoms. For localized disease, surgery followed by adjuvant gemcitabine is the standard. Neoadjuvant and new adjuvant chemotherapy regimens are being evaluated. Locally advanced disease should respond best guided by a multidisciplinary team. Various treatment options are appropriate such as chemotherapy alone or chemoradiotherapy with integration of rescue surgery if the tumor becomes resectable. In metastatic disease, chemotherapy should be reserved for patients with ECOG 0–1 using Folfirinox or gemcitabine plus nab-paclitaxel as the most recommended options. Several therapeutic strategies targeting unregulated pathways are under evaluation with an unmet need for biomarkers to guide management.     

胰腺癌微环境治疗策略的进展与思考

胰腺癌恶性程度较高，明显的间质纤维化及肿瘤异质性是胰腺癌的重要特征，也是胰腺癌患者对目前传统化疗应答欠佳、预后极差的重要原因。因此，寻找有效的治疗策略是提高胰腺癌患者生存率的关键问题。鉴于胰腺癌“间质化”及“异质性”的特性，国内外学者致力于阐明肿瘤微环境在胰腺癌发展过程中的作用机制及寻找有效的微环境靶向治疗策略，以提高胰腺癌患者治疗反应率，实现对于胰腺癌患者精准治疗的目的。本文通过对胰腺癌的微环境研究现状及在精准治疗理念下的靶向胰腺癌微环境的最新进展进行概述，为进一步提高胰腺癌患者的生存率提供新思路。      

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease.     

Insulin-like growth factor receptor-1 (IGF-IR) as a target for prostate cancer therapy

Prostate cancer is the most commonly diagnosed cancer in men and is the second leading cause of cancer-related deaths in men each year. Androgen deprivation therapy is and has been the gold standard of care for advanced or metastatic prostate cancer for decades. While this treatment strategy initially shows benefit, eventually tumors recur as castration-resistant prostate cancer for which there are limited treatment options with only modest survival benefit. Upregulation of the insulin-like growth factor receptor type I (IGF-IR) signaling axis has been shown to drive the survival of prostate cancer cells in many studies. As many IGF-IR blockades have been developed, few have been tested preclinically and even fewer have entered clinical trials for prostate cancer therapy. In this review, we will update the most recent preclinical and clinical studies of IGF-IR therapy for prostate cancer. We will also discuss the challenges for IGF-IR targeted therapies to achieve clinical benefit for prostate cancer.     

Future randomized trials for non small-cell lung cancer

Combination chemotherapy is the standard of care for management of previously untreated, good performance status patients with advanced non small-cell lung cancer. Most of the regimens in use worldwide are platinum-based doublets. Recent data from the Eastern Cooperative Oncology Group suggest that multiple different platinum-based regimens produce similar response rates and overall survival when used as first-line treatment. In upcoming randomized trials designed to explore possible improvements in therapy, three different strategies are being evaluated. One involves head-to-head comparisons of new, often non-platinum-based doublet combinations with standard platinum-based, two-drug regimens. A second emphasizes the possible benefits of combinations using three cytotoxic agents compared to a two-drug standard. The third is focused on adding a new molecular targeting agent, such as an anti growth factor, growth factor receptor antibody, or an intracellular signal transduction inhibitor, to a standard combination of two cytotoxic drugs. This paper reviews some of the randomized phase III trials exemplifying each of these approaches to therapy for patients with advanced non small-cell lung cancer.     

多西他赛联合沙利度胺治疗激素非依赖性晚期前列腺癌的临床观察

Objective:To evaluate the clinical effects and adverse reactions of Docetaxel and Thalidomide in treating ad-vanced androgen independent prostate cancer (AIPC). Methods:12 cases of advanced AIPC were given a combined treat-ment of Docataxel and Thalidomide, with Docetaxel 75 mg/m2 on day 1 and Thalidomide 100 mg per day as initial dose and 300 mg as terminal dose by an increase of 50 mg every week. Results:The post-treatment values of prostate specific antigen (PSA) were normal (< 4 ng/L) in 10 patients, less than 50% of pretreatment value in one patient, and no significant change in one patient. The median survival time was 14 months and period of the median symptoms reduction was 16.3 months. Com-mon adverse reactions were tolerable, including nausea, vomiting, leukopenia, anemia and thrombocytopenia. Conclusion:The regimen of Docetaxel combined with Thalidomide was effective and tolerable in the treatment of advanced AIPC.     

2021版CSCO胃癌诊疗指南转移性胃癌更新解读

对于晚期或转移性胃癌患者,目前公认采取以全身抗肿瘤药物治疗为主的多学科综合治疗和全程多方位管理以延长患者生存时间和改善患者生存质量。中国临床肿瘤学会（CSCO）胃癌诊疗指南每年更新,融合国内外最新的临床研究进展,关注中国人群研究数据和贴近本国临床实践。2021版CSCO转移性胃癌诊疗指南更新主要围绕免疫治疗、抗HER2靶向治疗和胃癌支持治疗等方面展开。基于2020年晚期胃癌在免疫治疗取得重大突破,更新重点聚焦免疫治疗,2021版CSCO指南从新的临床证据出发,针对免疫治疗从一线到三线,如何选择不同的程序性死亡受体-1（programmed cell death 1,PD-1）单抗药物,不同的适用人群均作出了详细推荐及注释,以期规范免疫治疗在晚期胃癌中的应用。本文就2021版CSCO指南对免疫治疗、抗HER2靶向治疗和胃癌支持治疗等方面的更新作总结性的解读,概括性阐明2021版CSCO中反映的晚期转移性胃癌治疗的新进展。      

Optimal hormonal therapy for advanced prostatic carcinoma

Although the clinical presentation of stage D2 (M+) prostate cancer is decreasing because of screening, we are witnessing a new spectrum of advanced disease. According to our concept of incurable or advanced prostate cancer, more than half of currently diagnosed prostate cancer patients are potential candidates for hormonal therapy. Hormonal therapy has been the mainstay of treatment for advanced phases of prostate cancer for more than 50 years. However, the optimal form of this therapy is still an enigma. The choice of hormonal therapy for carcinoma of the prostate depends not only on the desired progression-free and overall survival, but also on the patient's quality of life, treatment costs, and treatment toxicities. At present, several important questions have been raised over the optimal treatment modalities for advanced prostate cancer. This review discusses some of the current challenges in the hormonal management of advanced prostate cancer.     

Treatment of locally advanced prostate cancer: is chemotherapy the next step?

PURPOSE: Management of locally advanced prostate cancer remains controversial. Various single and combination modality approaches have been advocated, but an accepted standard of care remains undefined. The purpose of this review is to define the current knowledge in managing locally advanced prostate cancer and to propose new treatment approaches based on current knowledge. MATERIALS AND METHODS: A MEDLINE search to detect all relevant articles on the management of locally advanced prostate cancer was performed. A review of the staging, natural history, and prognosis of this disease was also performed. RESULTS: The lack of a clearly defined treatment approach to patients with locally advanced prostate cancer stems from multiple factors, including ambiguities in clinical staging, inadequate knowledge of the natural history of the cancer, and a dearth of comparative randomized trials evaluating efficacy of different therapies. Single modality treatment, including radical prostatectomy (RP) or external-beam radiotherapy alone, is associated with high rates of failure. The use of adjuvant hormonal ablation therapy in combination with external-beam radiotherapy has shown improvement in progression-free and overall survival, although similar improvements have not been clearly demonstrated for surgical patients treated with hormonal therapy. New advances in chemotherapy for hormone-refractory prostate cancer suggest that response rates may be as high as 50% or more, and current trials are evaluating the addition of chemotherapy to hormonal ablation in either surgery or radiation therapy in locally advanced prostate cancer. CONCLUSION: Optimal management of locally advanced prostate cancer remains undefined. Standard treatment options include RP, external-beam radiotherapy, or hormonal ablation therapy, alone or in combination. New approaches being tested include improved methods for delivering radiation or combining hormonal ablation with surgery or radiation. It is possible that other forms of systemic therapy, including chemotherapy, may become important components of multimodality treatment. Clinical trials designed to test this hypothesis are ongoing.     

Broadening horizons in medical management of prostate cancer

HORMONAL THERAPY: Testosterone suppression achieved either medically or surgically is the standard initial treatment for men with advanced prostate cancer. Most men respond but the disease progresses after a median of 1-2 years. Clinical trials suggest that intermittent androgen deprivation therapy (ADT) provides equal or longer time to castration-independence than continuous ADT, and is preferred, especially since there are subtle long-term toxicities associated with ADT. Further hormonal manipulations (including addition and withdrawal of peripheral antiandrogens, steroid synthesis inhibitors such as ketoconazole, and estrogens) can be transiently effective in selected patients with castration-resistant prostate cancer (CRPC). Androgen-dependent signalling pathways remain active in most men with CRPC and are associated with mutation, changes in expression or modulation of the androgen receptor (AR); abiraterone acetate and MDV3100 are promising drugs being evaluated in clinical trials that may lead to further hormonal response. CHEMOTHERAPY: Eventually men who progress rapidly, are symptomatic, and/or develop metastasis to visceral organs require chemotherapy. Three-weekly docetaxel with prednisone has been shown to improve survival and relieve symptoms but eventually men develop progressive disease or become intolerant to docetaxel. Multiple trials are evaluating new drugs (mainly molecular targeted agents) either given first line with docetaxel chemotherapy, or to men who have progressive disease after receiving docetaxel. Cabazitaxel was shown recently to improve survival as compared to mitoxantrone when used second line and has been approved by the United States Food and Drug Administration (FDA). CONCLUSION: Despite major advances, treatment of men with advanced CRPC remains a challenge both for the seeker and giver of care.     

An antibody against DR4 (TRAIL-R1) in combination with doxorubicin selectively kills malignant but not normal prostate cells

Prostate cancer is a major health problem among American men and new treatment approaches are needed. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL/Apo2L) is a death ligand that can induce apoptosis in some but not all cancer cells. Resistance to TRAIL-mediated apoptosis can be overcome by radiation or chemotherapy. The effect of doxorubicin/TRAIL combination therapy was compared among PC3, normal prostate epithelial (PrEC) and stromal (PrSC) cells and cell viability measured by MTS assay. Combination of doxorubicin and TRAIL caused cytotoxicity in all cells tested, although PrSC were more resistant. There was no correlation between TRAIL phenotype and expression of c-FLIP, caspases or TRAIL decoy receptors, although PrSC failed to express DR4. A DR4-specific antibody, which behaved as an agonist in combination with doxorubicin, selectively induced cell death in malignant but not normal prostate cells. Although normal PrEC expressed DR4 as determined by western blot, flow cytometry revealed that only maligant prostate cancer cells (PC3, JCA-1) and not PrEC's exhibited DR4 surface expression. Therefore, combination of doxorubicin and an antibody to DR4 might have therapeutic potential for the treatment of prostate cancer by selectively targeting malignant prostate cells.     

Dose escalation in locally advanced carcinoma of the prostate

Radiotherapeutic management of advanced prostate cancer is challenging. Several retrospective analyses showed a dose response for local tumor control before the availability of conformal radiation therapy. Attempts to escalate dose without the benefit of modern treatment planning was commonly fraught with high rates of bowel or bladder complications. The advent of image-guided or computed tomography-based treatment planning has allowed safe delivery of high-dose radiation therapy in men with prostate cancer with an acceptable rate of side effects and complications. Several prospective clinical trials have been conducted both at single institutions and in the cooperative group setting. Early evidence suggests that patients with high-risk factors such as advanced clinical stage, high initial prostate-specific antigen, or poorly differentiated tumors may benefit from high-dose 3-dimensional conformal radiation therapy with improved biochemical and local tumor control. A published randomized trial with conformal radiation therapy shows that a modest escalation of radiation dose leads to improved biochemical disease-free survival for a select group of patients. A confirmatory trial within the Radiation Therapy Oncology Group is underway to determine if dose escalation will improve overall survival in men without compromising quality of life. Copyright Elsevier Inc. All rights reserved.     

晚期肾癌分子靶向治疗新进展

肾癌是泌尿系最常见的恶性肿瘤,透明细胞癌是常见病理类型,约占全部肾癌的 85 %～90 %。既往主要以化疗、白介素及干扰素药物等治疗肾癌。近年来随着肿瘤诊治水平的提高,对肾癌的认识和诊治取得重要突破,特别是分子靶向治疗为患者提供了新的治疗手段。以索拉非尼、舒尼替尼、帕唑帕尼、贝伐珠单抗、替西罗莫司、依维莫司、阿西替尼和卡博替尼等分子靶向治疗多种药物已应用于临床,为患者带来明显生存获益且耐受性较好。本文主要对晚期肾癌分子靶向治疗方面的最新进展进行综述。      

A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer

When chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7-10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P=0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIPC.     

Paclitaxel-carboplatin combination chemotherapy in advanced breast cancer

Patients with metastatic breast cancer receive multiple lines of cytotoxic chemotherapy, with taxane and anthracycline-based regimens being the most active. Anthracyclines carry the risk of significant cardiotoxicity at high cumulative doses and when combined with trastuzumab, an anti-HER2 antibody. Carboplatin has shown promising single-agent activity in advanced breast cancer, is not a P-glycoprotein substrate, and is conveniently administered on an outpatient basis. Preclinical experiments demonstrated schedule-dependent synergistic cytotoxic effects of the paclitaxel first/carboplatin last (PC) combination. Pharmacokinetic parameters of paclitaxel and carboplatin were studied by Hellenic Cooperative Oncology Group (HECOG) and no significant interaction or correlation with clinical parameters were found. We assessed PC both as salvage as well as first-line treatment of advanced breast cancer patients in phase II studies which disclosed 40–60% response rates and median survival times of 12–20 mo with manageable toxicity. These results were confirmed by other groups and prompted us to the first randomized phase III trial comparing PC to the standard of epirubicin/paclitaxel (EP), a trial that showed equivalent efficacy and tolerable toxicity for PC. Registry retrospective analysis identified factors prognostic for improved outcome: good performance status, low tumor burden, lack of anthracycline exposure and of hormonal maintenance therapy. PC combinations with HER1 or HER2 modulators are being evaluated both by HECOG and by international groups. Paclitaxel coupled with carboplatin provides an alternative therapeutic option for anthracycline-exposed patients and warrants further clinical research in the direction of anthracycline-free management of metastatic breast cancer.