New therapy strategies in the management of breast cancer

Breast cancer (BC), the second leading cause of cancer-related deaths after lung cancer, is the most common cancer type among women worldwide. BC comprises multiple subtypes based on molecular properties. Depending on the type of BC, hormone therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Several new molecular targets, miRNAs, and long non-coding RNAs (lncRNAs), have been discovered over the past few decades and are powerful potential therapeutic targets. Here, we review advanced therapeutics as new players in BC management.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4–6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4-6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

乳腺癌晚期的化疗药物研究

目的探讨乳腺癌晚期患者的化疗治疗方案。方法对乳腺癌晚期的常用化疗药物进行研究。结果目前乳腺癌晚期患者进行全面的医治效果不佳,应用诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌疗效较高。结论诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌晚期患者安全可靠,单用、并用均可。     

Conventional cytotoxic and novel therapeutic concepts in colorectal cancer

Colorectal cancer (CRC) is a major cause of death, particularly in the Western world, leading to 400,000 deaths each year [1]. Of the patients, 30% have advanced disease at presentation, either locally or at distant sites and chemotherapy in this setting has an established role in improving survival and palliating symptoms [2]. In addition, approximately 50% of those patients initially believed to be cured by surgery, subsequently relapse and die of their disease. Adjuvant chemotherapy administered for six months after surgery for Dukes C colon cancer improves absolute survival by 5 - 10% [3]. However, the role of adjuvant chemotherapy in Dukes B colon or Dukes B/C rectal tumours is still controversial and is only recommended within the scope of a randomised clinical trial. Cytotoxic drug development for colorectal cancer has traditionally followed the established pathway of Phase I, Phase II and then Phase III trials in advanced disease, with subsequent translation into the adjuvant setting. For the purpose of this review current conventional chemotherapy for advanced CRC is described, followed by an explanation of newer developments that are predicated upon our increasing understanding of the molecular processes underpinning malignant transformation, invasion and metastasis. Paradigm shifts in trial design necessitated by a mechanistic approach to drug development are also discussed.     

国产吉西他滨联合铂类进行非小细胞肺癌化疗的生存状况观察

目的:评价国产吉西他滨联合铂类治疗非小细胞肺癌患者的生存状况。方法:60例非小细胞肺癌患者根据是否进行根治性手术,将本组患者分为晚期化疗组和根治性手术治疗+化疗组。晚期化疗组22例,根治性手术治疗+化疗组38例。采用国产吉西他滨联合顺铂/卡铂方案,化疗方案采用常规剂量及用法,每3周为1周期,所有患者至少完成2周期化疗。对所有患者均进行随访,分别评估2组生存状况。结果:晚期化疗组中22例患者化疗2周期后疗效为:1例CR,8例PR,13例SD。治疗有效率(CR+PR)为40.9%。晚期化疗组患者1年生存率44.0%,中位生存期12.39个月。根治性手术治疗组1年生存率89.0%,3年生存率80.0%,中位生存期48.0个月。结论:国产吉西他滨与铂类联合方案治疗非小细胞肺癌用药安全有效,生存状况同国外文献同类药物报道相似。     

New directions in the management of advanced pancreatic cancer: a review

Complete surgical resection is the only potentially curative option for pancreatic cancer. However, most patients have advanced/metastatic disease at the time of diagnosis, or will relapse after surgery. Systemic chemotherapy is only palliative. Gemcitabine-based therapy is an acceptable standard for unresectable locally advanced/metastatic pancreatic cancer, but average median survival is only 6 months. The addition of other chemotherapies (including other antimetabolites, platinum, and topoisomerase I inhibitors) or targeted therapies (farnesyl transferase inhibitors, metalloproteinase inhibitors, cetuximab and bevacizumab) to gemcitabine has failed to improve outcome. The combination of gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor of the human epidermal growth factor receptor, was recently approved by the US/European authorities for use in advanced disease. In a phase III trial, the combination demonstrated a significant improvement in overall survival compared with gemcitabine monotherapy. Positive efficacy results have also been observed in a phase III trial, favoring the addition of capecitabine to gemcitabine compared with gemcitabine alone. This review focuses on the recent developments in systemic treatment, and discusses how novel agents might be incorporated into future treatment strategies for pancreatic cancer.     

Novel approaches to target pancreatic cancer

Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.     

Capecitabine: an evidence-based review of its effectiveness in the treatment of carcinoma of the pancreas

Introduction:

More than 90% of patients with pancreatic cancer present either with incurable locally advanced or metastatic disease or relapse following surgery. For these patients systemic therapy offers the only prospect of salvage, but pancreatic cancer is one of the most chemoresistant of tumors; current chemotherapy can only delay progression in a limited proportion of patients and survival rates are poor. There is therefore a pressing need for more effective therapy. Capecitabine is a new oral prodrug of fluorouracil, which has shown activity in pancreatic cancer particularly when used in combination with gemcitabine.

Aims:

To review the emerging evidence for the clinical effectiveness of capecitabine in the management of carcinoma of the pancreas.

Evidence review:

There is evidence from phase II testing that capecitabine is active in pancreatic cancer. The Swiss Group for Clinical Cancer Research/Central European Cooperative Oncology Group (SAKK/CECOG) phase III trial found that the combination of gemcitabine and capecitabine did not improve overall median survival as compared with gemcitabine alone (8.4 vs 7.3 months, respectively; P=0.314) but subgroup analysis in patients with good performance score [Karnofsky Performance Scores (KPS) ≥90] revealed a significant survival improvement with the combination arm (10.1 months) compared with single-agent gemcitabine (7.5 months; P=0.033). Preliminary data from the GemCap phase III trial indicated significantly improved response rates and survival for the combination of gemcitabine with capecitabine (7.4 months) compared with gemcitabine alone (6 months; P=0.026) but analysis of the mature data with adequate follow-up awaits reporting.

Clinical potential:

The addition of capecitabine to gemcitabine may represent a small step forward in the management of advanced pancreatic cancer but further data are required in order to determine its full impact.     

Review of the use of topotecan in ovarian carcinoma

Ovarian cancer is the fifth leading cause of cancer deaths in women. The majority of patients present with advanced disease and relapse after first-line platinum-based chemotherapy; therefore, many proceed to treatment with salvage chemotherapy. Currently available treatment options are generally no longer curative in the relapse setting; hence, the emphasis of treatment is towards disease control and palliation of symptoms. There are several agents available for the treatment of relapsed ovarian carcinoma, of which topotecan is one of the most widely studied and characterised. This review aims to evaluate the role of topotecan in the management of this disease by considering the properties of the compound, the clinical efficacy in Phase II and III studies, its role in first- and second-line treatment and alternative dosing strategies to overcome toxicity.     

Review of the use of topotecan in ovarian carcinoma

Ovarian cancer is the fifth leading cause of cancer deaths in women. The majority of patients present with advanced disease and relapse after first-line platinum-based chemotherapy; therefore, many proceed to treatment with salvage chemotherapy. Currently available treatment options are generally no longer curative in the relapse setting; hence, the emphasis of treatment is towards disease control and palliation of symptoms. There are several agents available for the treatment of relapsed ovarian carcinoma, of which topotecan is one of the most widely studied and characterised. This review aims to evaluate the role of topotecan in the management of this disease by considering the properties of the compound, the clinical efficacy in Phase II and III studies, its role in first- and second-line treatment and alternative dosing strategies to overcome toxicity.     

Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer.     

Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer.     

Tirofiban: an investigational plateletglycoprotein IIb/IIIa receptor antagonist

Introduction: Fluoropyrimidines with oxaliplatin or irinotecan plus bevacizumab is the standard chemotherapy combination in patients with advanced colorectal cancer (CRC). Gemcitabine acts synergistically with fluoropyrimidines to enhance the binding of thymidylate synthase and increase inhibition of DNA synthesis. The objective of this review is to evaluate the literature for evidence of efficacy and safety of fluoropyrimidine plus gemcitabine (FG) in patients with advanced CRC. Methods: Relevant studies were identified in PubMed, Ovid, Cochrane database and the American Society of Clinical Oncology abstracts using the following search terms: gemcitabine, fluorouracil, capecitabine and colorectal cancer. Only studies using the FG combination were selected. Results: Forty-two advanced CRC patients were evaluated in two Phase I studies and the maximum tolerated dose of gemcitabine was 900 – 1,000 mg/m² weekly with either bolus 5-fluorouracil (5-FU) or capecitabine. A total of 216 advanced CRC patients were evaluated in six Phase II studies. Gemcitabine (750 – 1,250 mg/m²) with either 5-FU (continuous infusion or bolus) or capecitabine was administered as first-line therapy in two studies and as third-line therapy in three studies. The range reported for overall response rate was 30 – 38.3%, median time to progression was 4 – 8.3+ months and median survival was 9.8 – 18+ months. The most commonly reported grade 3 – 4 toxicities were neutropenia, thrombocytopenia and mucositis. Conclusions: Fluoropyrimidine plus gemcitabine is clinically active in patients with refractory CRC demonstrating prolonged median time to progression and acceptable toxicity only when bolus 5-FU was not used. Studies are underway to evaluate the combinations of FG with other chemotherapy or targeted agents. Meanwhile, FG may be considered for patients with advanced CRC who are refractory to primary treatment without other options or who are not eligible for clinical studies.     

Pancreatic cancer: the evolving role of systemic therapy

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the US. The outcome for patients with pancreatic cancer has not essentially altered over the past few decades. Several new drugs with activity against pancreatic cancer have recently been identified for use in palliative settings. Of these, gemcitabine is the most widely used agent against the disease, but its benefit is very modest. Pilot Phase II studies combining gemcitabine with 5-fluorouracil (5-FU), irinotecan, docetaxel or cisplatin show improved outcomes that need to be confirmed in randomised studies. Concurrent administration of gemcitabine and external beam radiation therapy (EBRT) for locally advanced pancreatic cancer is feasible and is currently undergoing efficacy evaluations. Current research in pancreatic cancer involves newer dosing schedules of gemcitabine, and combinations of gemcitabine with novel agents. Ultimately, better understanding of the molecular biology of pancreatic neoplasia will identify potential cellular targets for future development of new agents for pancreatic cancer.     

The role of gemcitabine alone and in combination in the treatment of pancreatic cancer

Pancreatic cancer, one of the most frequently reported gastrointestinal tumors, has a 5-year survival of less than 5%. Despite representing only 2-3% of the total cancer incidence, it is the fifth leading cause of cancer death. This is because it is commonly only diagnosed at an advanced stage. Until recently the traditional therapy for patients with advanced disease was palliative 5-fluorouracil (5-FU)-based chemotherapy. However, the novel antinucleoside gemcitabine (Gemzar) has demonstrated a survival benefit over 5-FU, and an improvement in disease-related symptoms and quality of life in patients with advanced disease. This review presents an overview of the clinical studies of gemcitabine, either alone or in combination, with other chemotherapeutic agents and/or radiation therapy, in the treatment of these patients. A comparison of these studies is made with those using alternative treatment regimens. The data suggest that gemcitabine in combination with biomodulated 5-FU should be considered the standard palliative treatment to which other new drug combinations or combined modality chemoradiation regimens should be compared.     

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.     

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.     

New therapies for castrate-resistant prostate cancer

INTRODUCTION: Prostate cancer is the second leading cause of cancer death in men in the USA, and most of these deaths will occur as a result of castrate-resistant prostate cancer (CRPC) that has progressed despite androgen deprivation therapy. There has been better understanding of castration resistance and molecular mechanisms of prostate cancer progression recently, leading to new treatment strategies. AREAS COVERED: This review focuses on emerging and new therapies for castrate-resistant prostate cancer, including hormonal therapy, immunotherapy and cytotoxic agents. EXPERT OPINION: New treatment strategies have been developed in recent years and, with improved understanding of advanced CRPC, additional targeted treatments are expected in the near future. Further cost effectiveness research of these treatments is warranted before dissemination of these promising agents.     

A cost–benefit analysis of chemotherapy for gastric cancer

Gastric cancer is the second most common cause of cancer-related deaths worldwide. Surgery remains the mainstay of any curative treatment; however, those patients who are considered not amenable of curative resection generally receive chemotherapy, in order to obtain palliation of symptoms and improved survival. Many drugs have been tested in several combination regimens yielding higher response rates. In spite of the fact that chemotherapy has been extensively used in advanced gastrointestinal cancer, there are few studies that focus on its economic costs. The aim of this paper is to review the results of the main studies regarding the relationship between the cost of chemotherapy and its effectiveness in advanced gastric and gastrointestinal cancer patients.