Therapeutic cancer vaccines: current status and moving forward

Concurrent with U.S. Food and Drug Administration (FDA) approval of the first therapeutic cancer vaccine, a wide spectrum of other cancer vaccine platforms that target a diverse range of tumor-associated antigens is currently being evaluated in randomized phase II and phase III trials. The profound influence of the tumor microenvironment and other immunosuppressive entities, however, can limit the effectiveness of these vaccines. Numerous strategies are currently being evaluated both preclinically and clinically to counteract these immunosuppressive entities, including the combined use of vaccines with immune checkpoint inhibitors, certain chemotherapeutics, small-molecule targeted therapies, and radiation. The potential influence of the appropriate patient population and clinical trial endpoint in vaccine therapy studies is discussed, as well as the potential importance of biomarkers in future directions of this field.     

肿瘤治疗性疫苗的研发现状与展望

近年来,随着对肿瘤抗原和抗肿瘤免疫反应机制的深入认识,肿瘤治疗性疫苗发展迅速,有望成为临床肿瘤治疗的重要手段。同时,随着新抗原的筛选、疫苗设计、疫苗递送系统、佐剂等关键技术的突破,进一步加速了这一领域的发展。在产品研发方面,众多国际大型的医药企业和新兴的生物科技公司正在布局不同的肿瘤治疗性疫苗项目,多个肿瘤治疗性疫苗获批上市,但临床效果欠佳。尽管目前肿瘤治疗性疫苗大多处于临床前和临床试验阶段,但展现出了良好的临床应用前景和市场价值。本文论述了国内外肿瘤治疗性疫苗的研发现状（主要聚焦当前发展迅速的个性化新抗原疫苗、DC疫苗和mRNA疫苗）,总结了目前所面临的挑战并展望了其发展前景,为未来肿瘤治疗性疫苗的研究和产品研发提供了新思路。     

Capecitabine in breast cancer: current status

Anthracyclines, together with taxanes, are at present the most active agents in metastatic breast cancer, while single-agent, bolus 5-fluorouracil (5-FU) is not very active in this setting. In view of encouraging results and tolerable toxicity of continuous infusion of 5-FU in gastrointestinal cancer, innovative oral 5-FU agents such as capecitabine have been developed. Capecitabine is a prodrug that is converted into the active compound 5-FU preferentially at the tumor site. An intermittent dosing schedule of capecitabine twice daily at a dose of 2510 mg/m2/day on days 1-14 in a 3-week cycle appeared to be feasible and resulted in a high dose intensity. A large phase II study investigating capecitabine in 135 advanced breast cancer patients, pretreated with anthracyclines and taxanes, observed three complete and 24 partial responses (response rate, 20%), with a mean duration of 8.0 months. Preliminary results of a study comparing capecitabine with paclitaxel in 42 breast cancer patients failing anthracyclines indicate that the efficacy of capecitabine is comparable to that of paclitaxel, with response rates of 36% and 21%, respectively. Another study reported a response rate of 25% for capecitabine as first-line therapy for advanced breast cancer in women aged > or = 55 years, which tended to be better than combination chemotherapy with cyclophosphamide/methotrexate/5-FU. In all studies, capecitabine side effects were mainly mild, and treatment-related grade 3/4 toxicity consisted of diarrhea (8%-11%), nausea (4%-11%), hand-foot syndrome (10%-18%), neutropenia (3%-20%), and bilirubin elevation (6%). Capecitabine is clearly an active agent for the treatment of breast cancer. It is currently registered in various countries for use in third-line treatment of metastatic disease. Its further role will have to be defined from data of randomized phase III studies.     

Cellular phones and cancer: current status

Evaluation of the impact of new technologies on the human body is essential in order to impose regulations to limit health risks. The appearance and evolution of cellular phones have been one of the fastest in the history of innovation. Research reported worldwide has tried to evaluate any potential link between adverse health effects and the mobile phone and its broadcasting stations. This article gives an overview of current research knowledge on the impact of radiofrequency waves on health. Epidemiologic, cellular and animal studies have been carried out, but none of them have reached definitive conclusions. Although some biological effects on cell culture have been observed, their link with human cancer development is far from established. Most of the animal studies show negative results. Epidemiologic studies lack a sufficient perspective to be able to evaluate the effect of evolving technologies used today. High levels of concern by the public have urged mobile phone operators, manufacturers and governmental authorities to finance a number of scientific projects aimed at defining adapted and effective regulations.     

Prostate cancer screening: current trends and future implications.

Screening for prostate cancer represents a clinical dilemma with no clear evidence to suggest decreased mortality from any diagnostic test. We now possess new knowledge regarding optimal combinations of DRE, TRUS, and PSA. While DRE and TRUS may be too subjective and PSA too nonspecific, their combined predictive values identify not only men at high risk but also those for whom continued frequent screening may not be cost effective. A monoclonal PSA decision level of no more than 4.0 ng/ml should be used, since 40 percent of cancers detected from 4.0 to 10.0 ng/ml already have extracapsular extension. Assuming that DRE is performed by experienced examiners, the combination of PSA and DRE should produce cost-effective early detection and minimize missed cancers below 4.0 ng/ml. TRUS should be reserved for those patients with either PSA elevations and/or DRE abnormalities. The use of TRUS gland volume data to further modify PSA decision levels, such as the "predicted" PSA concept, may also improve TRUS biopsy criteria and predictive values. Prostate cancer detection can then be objectively limited to a small percentage of the population and better selected for earlier, more localized disease. The ultimate decrease in mortality from screening remains to be demonstrated in randomized trials or observed only after decades of increased public awareness about prompt early detection combined with effective, definitive therapy.     

GVAX肿瘤疫苗临床研究现状和进展

目的:总结国内外近几年对于GVAX瘤苗的临床研究现状。方法:应用PubMed数据库检索系统,以"GVAX瘤苗"和"肿瘤免疫治疗"等为关键词,检索1993-01-2010-05关于GVAX瘤苗的制备及治疗各种肿瘤的文献。资料选择:选择所有与GVAX瘤苗有关的文献,最后纳入17篇。结果:GVAX瘤苗作为单药治疗肿瘤的效果有限,但对于一些肿瘤,GVAX瘤苗可不同程度地延长疾病进展时间和总体生存期,改善患者生活质量。联合其他的治疗方法如化疗、放疗、微创治疗和其他的免疫治疗等可能是GVAX瘤苗以后研究的方向。结论:不同的GVAX瘤苗已在各类肿瘤开展了一系列相关临床试验研究,并显示出较好的安全性和有效性。     

Gastric cancer: current status of treatment.

While carcinomas of the stomach is decreasing in incidence in the Dnited States, it is still a major cause of cancer death. But gastric neoplasms are not decreasing in some other geographic areas. According to some studies, 30% of all cancer in the U.S.S.R. originates in the stomach. The rate of gastric neoplasms is greatest in Japan, and over 54% of all cancer in the male population arises in the stomach. The peak age for development of stomach cancer is between 70 and 80 years; over 60% of all stomach cancer is diagnosed in patients between the ages of 60 and 70, while more than 10% is found in those over 80. The main hope for cure at this time rests with surgical treatment. However, despite increased use of surgery, the 5-year survival rate of approximately 13% for patients diagnosed during 1955-59 has not improved to any degree since that time. The major drugs commonly used to treat gastric cancer are 5-fluorouracil (5-FU) and mitomycin C. Controversy still exists concerning the optimum method for administering 5-FU, the most frequently used drug in the United States. The standard loading-course method was attended by a high risk of severe toxicity and drug-related deaths. Several variations of the loading course have evolved. Currently, the Mayo Clinic group uses a 5-day course of 13.5 mg 5-FU/kg repeated every 5 weeks, with therapy interrupted if stomatitis or diarrhea develops; with this regimen the drug-related mortality rate was reported to be less than 1%. Studies have shown that 5-FU plus radiotherapy can enhance survival in patients with locally unresectable diseases. The overall objective with 5-FU is 20-25% with an average of 4-5 months' duration of response. Despite the many patients treated with 5-FU, rarely has a systematic analysis been done of factors such as age, sex, disease-free interval, histologic grade of the tumor, or sites or metastases, which might predispose to a favourable or unfavorable response. In Japan the most commonly used drug for treatment of gastric cancer is mitomycin C, the second most frequently used drug in the United States. The overall objective response rate with mitomycin C is between 20 and 30%, with the higher response rates being reported in the Japanese data. The average duration of response ranges from 1 to 3 months. The nitrosoureas [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1,3-cis(2-chloroethyl)-1-nitrosourea (CCNU), and methyl CCNU (MeCCNU)] have shown some evidence of activity against gastric cancer. BCNU has yielded an objective response rate of 18% (6/33) and an average duration of response of 4.5 months in gastric cancer patients, most of whom had no prior therapy. Adriamycin recently has been shown to have some antitumor activity, with an approximate response rate of 25%. Combination approaches have been more successful in stomach cancer than in any other gastrointestinal neoplasm. The Japanese have reported higher response rates with a combination of 5-FU, mitomycin C, and cytosine arabinoside...     

Gallbladder cancer: current status in clinical practice

A total series of 68 unselected patients with gallbladder cancer, diagnosed during 1972 to 1981, was studied retrospectively. In 61 cases (90%), the diagnosis was histologically verified. The cardinal symptoms were local pain (87%), loss of weight (53%), and jaundice (59%). The diagnosis was established after autopsy in 22 patients (32%), and exploratory laparotomy in 22 patients (32%). Palliative surgery was carried out in 26 patients of whom seven (27%) died postoperatively. Only one patient, with an incidentally detected cancer at routine cholecystectomy, was treated radically. Four out of nine patients died within one month after PTC-drainage. The mean survival time for the whole series was 2.9 months. The longest survival was 21 months. Considering the increasing incidence of gallbladder cancer in Sweden, as well as of other cancers of the biliary system, these findings emphasize the need for intensified research. An epidemiological approach studying the correlation of gallbladder cancer with the changing trend of gallstone disease and its treatment would perhaps be fruitful.     

Dietary fat and prostate cancer: current status

Efforts to elucidate the causes of prostate cancer have met with little success to date. All that is known with certainty is that the incidence increases exponentially with age, varies by geography and by race or ethnicity, and is higher among men whose father or brother had the disease. Because the incidence changes in migrants and their offspring, exogenous factors certainly contribute to the risk of prostate cancer. Early epidemiologic studies implicated dietary fat as a likely causal factor for this cancer. However, scientific support for such an association has diminished in recent years as more epidemiologic evidence has accrued. Accordingly, we reviewed the relevant English language literature on this topic, including epidemiologic and animal studies, as well as current concepts regarding the involvement of fat in carcinogenesis to re-examine the fat-prostate cancer hypothesis. We conclude that dietary fat may indeed be related to prostate cancer risk, although the specific fat components that are responsible are not yet clear. Given the diverse effects of fatty acids on cellular biology and chemistry, it seems likely that the relationship is complex, involving the interplay of fat with other dietary factors, such as antioxidant vitamins and minerals, or with genetic factors that influence susceptibility. Some suggestions for further research are offered.     

树突状细胞肿瘤疫苗：全球临床试验巡礼

自2011年度的诺贝尔生理学或医学奖获得者Ralph M.Steinman发现树突状细胞(dendritic cell,DC)及其在获得性免疫应答中的关键作用以来,全球范围的DC肿瘤疫苗研究持续进行了数十年,一系列临床试验正在进行或已经完成,目前已经有3种DC肿瘤疫苗获得了上市批准:Sipuleucel-T、CreaVax RCC和Hybricell,但基于DC的免疫治疗方法尚未成为肿瘤治疗的一种标准方法。为了让国内同行深入了解全球范围内开展DC肿瘤疫苗临床试验的现状,本文基于国际医学期刊编辑委员会认可的临床试验注册网站和PubMed网站数据库对全球DC肿瘤疫苗临床试验概况(地区和国家分布、涉及的肿瘤类型、开展年份和试验分期)作了介绍,重点对43项已经有论文发表的临床试验情况(受试者选择、DC培养方法、疫苗接种方案、疗效评估方法和试验结果)进行了总结,着重分析了当前DC肿瘤疫苗临床研究的发展趋势和存在问题,提出了加强DC肿瘤疫苗临床试验工作的若干建议:健全我国DC肿瘤疫苗临床试验相关的监管政策;密切关注国际"体内DC靶向"策略的新动向;抓紧建立DC培养方法、疫苗接种方案和疗效评估的标准;加强对DC肿瘤疫苗的质量监控;重视DC肿瘤疫苗的基础研究和临床试验注册;提高临床试验方案的质量;慎重选择受试患者和疗效评估时间点;治疗时应同步开展免疫监测等。抛砖引玉,以期引起国内同行的重视和讨论,并尽可能在将来的工作中加以研究和得到解决。     

Chemoradiotherapy for esophageal cancer: current status and perspectives

The optimal role of chemoradiotherapy in the multimodality treatment of esophageal cancer is still controversial. According to a series of clinical trials, definitive chemoradiotherapy is considered the standard of care for patients with medically inoperable or surgically unresectable esophageal cancer. This modality provides survivals comparable to those in Western series of surgery alone and is one of the standards of care even for resectable-stage disease. Recent reports of primary chemoradiotherapy from Japan suggest survival comparable to that of surgery in Japanese patients with stage I disease, but radical surgery is still the standard treatment for T2–3NanyM0 disease in Japan. However, it is clear that this approach has limitations in treatment outcomes. Trimodality therapy, i.e., preoperative chemoradiotherapy followed by surgery, is more favored than surgery alone in clinical practice, particularly in patients with adenocarcinoma, although current data from randomized trials are insufficient to support this approach. To improve the local control rate of chemoradiotherapy, intensification of the radiation dose has been attempted, but this has failed to demonstrate any superiority in terms of local control or survival. The addition of new agents, including molecular targeting agents, to the current standard chemoradiotherapy has shown more promising results and warrants further investigations in future studies. Salvage treatment for patients who do not achieve a complete response (CR) is necessary to improve the overall treatment results. Salvage surgery, as well as endoscopic resection, in selected patients, may provide an improvement in survival. Until high rates of local control can be consistently achieved with chemoradiotherapy alone, these salvage treatments will be an integral component of multimodality treatment for esophageal cancer, and should be active areas for clinical investigations.     

Chemoradiotherapy for uterine cancer: current status and perspectives

The conventional local treatment methods (surgery and radiation) for cervical cancer have reached a plateau in terms of survival benefit and, therefore, in this review, new treatment strategies (combined chemotherapy [CT] and local therapy) to overcome the poor prognosis were examined in high-risk groups. The effectiveness of neoadjuvant chemotherapy (NAC) administered prior to radiotherapy (RT) has not been confirmed for any disease stages. But NAC followed by surgery may improve survival in patients with stage Ib2 compared with surgery alone; and in patients with stage Ib2 to IIB compared with RT alone. Five large randomized clinical trials (RCTs) demonstrated a significant survival benefit for patients treated with concurrent chemoradiotherapy (CCRT), using a cisplatin (CDDP)-based regimen, with a 28%–50% relative reduction in the risk of death. In addition, the results of a metaanalysis of 19 RCTs of CCRT (1981–2000) involving 4580 patients showed that CCRT significantly improved overall survival (OS) hazard ratio ([HR] 0.71; P < 0.0001), as well as progression-free survival (PFS; HR 0.61; P < 0.0001). In line with these results, CCRT is currently recommended as standard therapy for advanced cancer (stage III/IVA) in the United States. However, there remains much controversy and uncertainty regarding the optimal therapeutic approaches, especially for patients with advanced cancer. Additional RCTs should be conducted to find the optimal CT regimen and RT for Japanese patients, considering acute and late complications, as well as differences in pelvic anatomy, total radiation dose, and RT procedures between Japan and other countries. Evidence obtained from such studies should establish the optimal CCRT treatment protocol and define the patient population (disease stage) that the protocol really benefits.     

Chemoradiotherapy for lung cancer: current status and perspectives

For many years, thoracic radiotherapy had been regarded as the standard treatment for patients with unresectable locally advanced non-small cell lung cancer. However, meta-analyses show that cisplatin-containing chemoradiotherapy is significantly superior to radiothe-rapy alone in terms of survival. Moreover, concurrent chemoradiotherapy yields a significantly increased response rate and enhanced survival duration when compared with the sequential approach. Cisplatin-based chemotherapy with concurrent thoracic radiotherapy yields a 5-year survival rate of approximately 15% for patients with unresectable locally advanced non-small cell lung cancer. The state-of-the-art treatment for limited-stage small cell lung cancer is considered to be four cycles of combination chemotherapy with cisplatin plus etoposide combined with early concurrent twice-daily thoracic irradiation (45Gy). If patients achieve complete remission, prophylactic cranial irradiation should be administered. A 5-year survival rate of approximately 25% is expected with the state-of-the-art treatment for limited-stage small cell lung cancer. Chemoradiotherapy is considered to be a standard treatment for both unresectable locally advanced non-small cell lung cancer and limited-stage small cell lung cancer. Several new strategies are currently being investigated to improve the survival of these patients. The incorporation of target-based drugs such as gefitinib is considered to be the most promising strategy for unresectable locally advanced non-small cell lung cancer. The incorporation of irinotecan is also a promising strategy to improve the survival of patients with limited-stage small cell lung cancer. The Japan Clinical Oncology Group is conducting clinical trials to develop new treatment strategies for both unresectable locally advanced non-small cell lung cancer and limited-stage small cell lung cancer.     

Platinum-based chemotherapy in metastatic breast cancer: current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently approximately 60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-na?ve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer.     

Breast cancer chemoprevention: current status and future directions

Cancer prevention is a relatively young concept. Perhaps the greatest strides in cancer research that have been made in the prevention arena have been in breast cancer. In this article we examine the meaning of "prevention" and discuss several of the trials under way or completed, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial. Semin Oncol 28:253-259.     

Trastuzumab and breast cancer: developments and current status

The emergence of trastuzumab has drastically changed therapy for breast cancer. Trastuzumab (Herceptin; Genentech) is a recombinant humanized monoclonal antibody that targets an epitope in the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. HER2 is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival, and differentiation via multiple signal transduction pathways. Overexpression of HER2 or amplification of the HER2 gene occurs in 20%–30% of human breast cancers. Preclinical models have demonstrated that this antibody has significant antitumor activity as a single agent, and it also has a synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancers that overexpress HER2 have shown trastuzumab to have clinical activity when used as monotherapy, while also improving survival when used as a first-line therapy in combination with chemotherapy. At present, clinical investigations are focusing attention on the efficacy of trastuzumab in both the adjuvant and neoadjuvant setting, as well as in the metastatic setting. In this review, we describe the developments and current status of trastuzumab-based treatment for breast cancer.     

Chemoradiotherapy for pancreatic cancer: current status and perspectives

The poor prognosis of pancreatic cancer is due to both its metastasis-prone and locally resistant nature. To improve therapeutic outcome, a multimodality approach is necessary. Chemoradiotherapy has been regarded as one of the standard treatment options, particularly for locally advanced pancreatic cancer. A number of clinical studies have been undertaken to establish the use of chemoradiotherapy, with or without surgical resection. This review systematically summarizes the current status, controversies, and prospects of postoperative, definitive, and preoperative chemoradiotherapy for pancreatic cancer.