Targeting the VEGF pathway in metastatic bladder cancer

Introduction: Bladder cancer represents 7% of all new cancers diagnosed in the USA in 2015. Furthermore, the mortality of metastatic bladder cancer has not decreased substantially in the last four decades. Angiogenesis is known to play a major role in the pathogenesis of bladder cancer.

Areas covered: The following article provides an overview of the first results of agents targeting the VEGF pathway in the treatment of metastatic bladder cancer.

Expert opinion: Despite a few clinical trials providing preliminary encouraging results, the overall outcomes of the first published trials have been rather disappointing. In some instances, especially the case of trials which have investigated the use of new targeted agents as a single agent, no significant improvement in outcomes was seen, or was not sustained. In other cases, such as with combination trials, intolerable adverse effects have compromised the trials, due to overlapping toxicity between the targeted agent and chemotherapeutic agent(s). Further trials are warranted possibly combining different targeted agents or the use of sequential therapy. A better selection of the patient population may also be a key factor to improve patient outcomes, as many predictive factors of response seem to have already been identified.     

Emerging drugs in metastatic breast cancer

Background: Breast cancer is the most common cancer among women and comprises 26% of all cancers diagnosed in women in the United States. Among presenting patients, 3 – 6% already have metastatic disease, and 50 – 70% of the remaining patients develop systemic relapse. Recently many new drugs, particularly molecular targeted therapies, have been developed in the field. Objective: To review the current and emerging data on the treatment of metastatic breast cancer, with emphasis on novel therapies that show promise. Methods: PubMed and ASCO annual meeting abstracts were used for a literature search. Results/conclusions: Despite improved response rates, conventional treatments still result only in transient remission in most cases. New therapeutic alternatives and new strategies to overcome drug resistance are needed to improve these results.     

A review on the treatment of relapsed/metastatic head and neck cancer

The efficacy of traditional chemotherapy in inducing objective responses and prolonging survival in recurrent or metastatic head and neck cancer has been disappointing. More recent drugs have not proven superior to the classic regimen of cisplatin and 5-fluorouracil. Anti-EGFR monoclonal antibodies, either as single agents or associated to chemotherapy, have been shown to be active and little toxic. Among them, cetuximab has proven to be the most promising. Indeed the Extreme study, which compared the classic couple cisplatin (CDDP) + 5-fluorouracil with the same regimen plus cetuximab, has constituted a remarkable innovation. The results of that trial seem to indicate a third agent added to CDDP and 5-fluorouracil improved both progression-free survival and overall survival in the recurrent or metastatic setting. Unfortunately, the results obtained with the tyrosine kinase inhibitors are less impressive, and additional studies are needed to explore the potentiality of this class of drug. As far as antiangiogenetics are concerned, the research is insufficient for any conclusion to be drawn in terms of efficacy. It is hoped that, in the near future, the most active combination between biological agents and traditional chemotherapy will be found, so that the path successfully taken in other neoplastic diseases may be retraced.     

Therapeutic options for metastatic breast cancer

Metastatic breast cancer (MBC) remains an incurable disease despite ongoing therapeutic advances. Recently there has been progress extending the range of available cytotoxic chemotherapy drugs and optimizing their scheduling. In addition, a greater understanding of tumor biology has led to the development of a number of targeted therapies. Several of these newer agents, such as trastuzumab, lapatinib and bevacizumab, have demonstrated activity in combination with chemotherapy and have improved the prognosis of patients with MBC. We hope that further progress elucidating the pathophysiology and biology of MBC will continue to lead to corresponding advances in treatment.     

Opportunities to improve clinical trial design in urothelial bladder cancer

Abstract

Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR pathway, or immunotherapy are potential new directions in UC. The importance of quality-of-life as an end-point in clinical trials in UC should also not be overlooked. Ultimately, multidisciplinary large-scale collaborations will be the key to move this field forwards.     

Erdafitinib for the treatment of metastatic bladder cancer

ABSTRACT

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15–20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.

Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.

Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.     

Novel therapeutics in metastatic colorectal cancer: molecular insights and pharmacogenomic implications

Although the survival of metastatic colorectal cancer (mCRC) patients has improved five-fold over the last century, CRC remains a significant global health burden. Impressive strides have been made in identifying new regimens, employing maintenance strategies to limit treatment toxicities, and combining multidisciplinary approaches to achieve cure in oligometastatic disease. Attempts at personalized integration of targeted agents have been limited by the ability to identify molecularly enriched patient populations most likely to benefit. In this review, we discuss novel therapeutics and regimens recently approved and in development for mCRC. In addition, we discuss using older agents in novel combination and maintenance strategies, and highlight evidence for implementing pharmacogenomic data and non-invasive monitoring into the personalized management of mCRC patients.     

FIVB plus GM-CSF in metastatic colorectal cancer

The response rate of patients with metastatic colorectal cancer to the 4-drug combination [5-Fluorouracil (5-FU), dacarbazine, vincristine and bis-chloronitrosourea given 5 weekly (FIVB)] was better than the response rate to 5-FU. The dose limiting toxicity of the FIVB was myelosuppression. The present study investigates the effect of FIVB given with GM-CSF so that drug cycles could be given every 4 weeks.Thirty-five ambulatory patients with measurable metastatic colorectal cancer were treated with FIVB plus GM-CSF 4 weekly. All patients were evaluable for toxicity. Among the 163 cycles given only 4 were delayed because of leucopenia and 8 cycles were delayed because of gastrointestinal (GI) toxicity. A 50% dose reduction was given to 10 patients who had Grade 2 and 3 GI toxicity. Four of the 35 patients developed thromboembolic complications, 2 of which were lethal. Two patients were not evaluable for response as they were removed from study early because of toxicity. There were 2 complete responses and 6 partial responses. The median time to treatment failure was 3.8 months and median survival time 9.9 months.The addition of GM-CSF to FIVB decreased the expected leucopenia allowing drug treatment to be given 4 weekly to most patients. GI toxicity was dose limiting. Despite the increased dose intensity that could be delivered (to two thirds of patients), response rates were not definitely increased, no survival benefit was seen and important thromboembolic complications occurred.     

Novel chemotherapeutic agents for the treatment of brain cancer

Brain cancer encompasses both primary and metastatic brain tumours and accounts for over 120,000 new patients each year. Despite aggressive therapy, the majority of patients with brain cancer have poor prognosis and have brief survival intervals. Current chemotherapy drugs, used alone or in combination, have minimal or only modest activity. Novel agents that have recently been applied to brain cancer include temozolomide, irinotecan and paclitaxel. Temozolomide is a DNA alkylating agent, irinotecan inhibits DNA topoisomerase I and paclitaxel binds to microtubules and induces polymerisation. Neoplastic angiogenesis and brain tumour invasion are also targets for therapeutic intervention with new agents such as thalidomide, suramin and marimastat. All of these agents have demonstrated activity against brain cancer in vitro. Several of the drugs, in particular temozolomide, paclitaxel and irinotecan, have entered preliminary clinical trials and have demonstrated some efficacy. However, chemotherapy for primary brain tumours remains rather non-specific and mostly ineffective. The use of chemotherapy may be more effective against selected metastatic brain tumours. Continued basic research is needed to further elucidate the genetic basis of transformation, tumour invasion and angiogenesis. It is hoped that this research will lead to new therapeutic targets for drug design and development. In addition, new strategies must be developed to overcome the problem of chemotherapy resistance.     

Intravesical therapy for bladder cancer

Introduction: Transurethral resection of bladder tumor (TURBT) is the gold standard initial diagnostic intervention for bladder cancer and provides diagnostic, therapeutic and prognostic benefit in non-muscle-invasive bladder cancer (NMIBC). However, TURBT alone is inadequate for optimal management of NMIBC, as patients will experience recurrence or progression depending on tumor characteristics. Adjuvant intravesical therapy with either immunotherapy or chemotherapy has been shown to reduce recurrence and/or progression in appropriately selected patients through immunostimulation or direct cell ablation.

Areas covered: This review will discuss risk stratification of patients with NMIBC and role of intravesical therapies in reducing recurrence and progression of disease in these patients. A Medline search was performed to identify the best available evidence available from various systematic reviews, meta-analyses, and clinical trials on various immunotherapy and chemotherapy agents. In addition, the main aspects of drug pharmacology (mechanism of action, dosing and administration) and side effects will be reviewed.

Expert opinion: The selection of the appropriate intravesical agent for NMIBC is complex and is dependent on risk stratification and intravesical agent toxicity. Intravesical induction and maintenance immunotherapy with Bacillus Calmette–Guerin (BCG) is the preferred and most effective agent for patients with high-risk NMIBC (carcinoma in situ and high-grade disease) and reduces both recurrence and progression.     

Strategies to improve drug delivery in bladder cancer therapy

Bladder cancer is the ninth most common malignancy in the world featuring very high gender variability in occurrence. Current options for bladder cancer therapy include surgery, immunotherapy, chemotherapy and radiotherapy with a trend towards multimodal treatments. However, successful management remains a challenge for urologists and oncologists because of the high risk for recurrence and progression. Particularly in the field of bladder cancer chemotherapy, efficacy of treatment might be improved by advanced drug delivery strategies aimed at prolonged residence time within the bladder cavity and increased permeability of the bladder wall during intravesical instillation. Moreover, a deeper understanding of the biology of bladder carcinogenesis and malignant progression stimulated the development of a new generation of anticancer drugs for targeted therapies that might result in increased treatment specificity together with lower toxic potential and higher therapeutic indices. This review discusses the available strategies for ‘targeted therapy’, focusing on molecular targets, and for ‘controlled delivery’, comprising all other approaches towards improved drug delivery.     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Docetaxel for the treatment of bladder cancer

Introduction: Docetaxel has had a significant impact on the management of urothelial carcinoma (UC). Multiple phase II trials have been conducted to evaluate the efficacy of docetaxel in the treatment of metastatic UC. Docetaxel is an accepted community standard for the therapy of platinum-treated patients with metastatic UC.

Areas covered: This review focuses on the data supporting a role for docetaxel in the therapy of advanced UC. It also explores the future development of docetaxel and describes the ongoing clinical trials in the treatment of UC.

Expert opinion: Docetaxel plays an important role as one of the standard agents used in the comparator arms of randomized trials evaluating new agents as salvage therapy for metastatic UC. Furthermore, biologic agents are being developed in chemo-biologic regimens using docetaxel as the platform. In the context of emerging novel agents such as T-cell checkpoint inhibitors, docetaxel may continue to play a role as a salvage therapy in select patients ineligible for immunotherapy or following checkpoint inhibitors.     

Emerging drugs in colorectal cancer

A raft of novel agents with different modes of action is finally challenging the position of 5-fluorouracil (5-FU) as the gold standard treatment for colorectal cancer. Oral fluoropyrimidines, topoisomerase I inhibitors and new generation platinum compounds are all currently being investigated. There is also increasing interest in the development and use of biological therapies, which may allow treatments to become tailored to individual patients and cause less toxicity than conventional cytotoxics. It is hoped that with the development of these new drugs, the response rates and survival for patients with colorectal cancer will improve from the poor prognosis that many face at present.     

转移性结直肠癌二线治疗的研究进展

结直肠癌在全球范围内都是威胁人们健康的重大疾病。内科治疗是进展期结直肠癌的最主要、也是最有效的治疗措施。近年来,转移性结直肠癌的内科治疗效果得到了很大提高。化疗及分子靶向药物治疗能显著改善转移性结直肠癌患者的二线治疗的预后,延长生存时间、提高生活质量。     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

Novel non-operative treatment and treatment strategies in pancreatic cancer

Patients with advanced pancreatic cancer have traditionally been treated with palliative care only. The last decade has seen significant improvements in the surgical treatment of this disease but until the late 1990s there was no effective non-surgical treatment for these tumours. The introduction of gemcitabine has given clinicians treating patients with pancreatic cancer a new option. The published randomised data of gemcitabine in patients with pancreatic cancer has shown both a small survival advantage and significant improvements in quality of life indicators in these patients. These data have stimulated a resurgence of interest in pancreatic tumours and several studies have been or are currently investigating novel treatments or treatment strategies. The explosion in the molecular knowledge of cancer has led to the development of several ‘molecular designer drugs’ that have been tested in pancreatic cancer. The furthest advanced of these is a matrix metalloproteinase (MMP) inhibitor called marimastat. The first randomised data using this new class of agents is increasing and suggests that marimastat may have a role in the future treatment of patients with pancreatic cancer. Other agents such as gastrimmune, are about to enter Phase III studies and several other molecular treatment strategies are progressing from the in vitro stage towards the clinical arena. Each of these treatments and treatment regimens are discussed along with their current progress.     

Developing therapies for advanced bladder cancer

Chemotherapy is an indispensable measure in the treatment of invasive or metastatic bladder cancer as even if metastases are not clinically apparent, the majority of cases of invasive bladder cancer are accompanied by micrometastases. At present, MVAC (methotrexate, vinblastine, adriamycin, cisplatin) is the gold standard for bladder cancer chemotherapy. There have consequently been many attempts at MVAC dose-intensification as well as many studies of the feasibility of neoadjuvant chemotherapy using MVAC. Unfortunately, the majority of results from these studies have been negative or contradictory. However, a recent large-scale randomised, controlled study yielded more promising results. Evidence has recently emerged which indicates that a useful chemotherapeutic strategy could possibly be devised by adjusting the dose and timing of MVAC. Increasing effort is also being put into the development of new gold standards for bladder cancer chemotherapy based on the use of newly developed antitumour drugs, and a number of candidates have emerged. It is hoped that the future we will see successful establishment of a number of useful regimens as a result of Phase III clinical studies using MVAC as their control regimen. For example, both gemcitabine and the taxanes, in combination with other drugs, are strong candidates for this purpose. The ultimate therapeutic strategy for bladder cancer will be a therapeutic approach which permits conservation of the bladder even when the malignancy is invasive and steady progress is already being made toward this goal, in limited cases, by means of multidisciplinary treatment.     

Novel investigational therapeutics for panic disorder

Introduction: Panic disorder (PD) is a common disabling anxiety disorder associated with relevant social costs. Effective anti-panic medications exist but have several drawbacks. From a clinical perspective, there is still a strong unmet need for more effective, faster acting and more tolerable therapeutic treatments.

Areas covered: The authors review the available results on novel mechanism-based anti-panic drugs that are under investigation in animal studies up to Phase II studies. The preclinical studies investigated include: the modulators of the glutamate/orexin/cannabinoid systems, corticotrophin-releasing factor 1 (CRF1)/arginine vasopressine V_1B/angiotensin II receptor antagonists and neuropeptide S. The Phase I/II studies investigated include: the modulators of the glutamate system, isoxazoline derivative, translocator protein (18 kDa) ligands and CRF1/neurokinin receptor antagonists.

Expert opinion: There has been little progress in recent times. However, glutamate- and orexin-related molecular targets may represent very promising opportunities for treating panic attacks. Very preliminary findings suggest that the antagonists of CRF1 and A-II receptors may have anti-panic properties. However, new medications for PD are far from being implemented in clinical use. The reasons are multiple, including: the heterogeneity of the disorder, the translational validity of animal models and the insufficient use of biomarkers in preclinical/clinical studies. Nevertheless, biomarker-based strategies, pharmacogenomics, ‘personalized psychiatry’ and the NIH’s Research Domain Criteria approach could help to remove those obstacles limiting drug development.     

Phase II study of a combination of elliptinium and vinblastine in metastatic breast cancer

Thirty nine patients with metastatic breast cancer, all previously treated with chemotherapy including anthracycline, were given Elliptinium acetate (80 mg/m²/day) and a continous infusion of Vinblastine (2 mg/m²day) for 3 consecutive days every 4 weeks. Twenty nine patients had measurable metastatic disease. Nine (31%) achieved a partial response. No complete response was observed. Median duration of response was 6 months. The response rate was dependent on the number of metastatic sites and independent of the number of previous chemotherapy regimes. Side effects were dry mouth (27 patients), vomiting (9), neutropenia (3 patients with grade IV, 2 with grade III), muscle cramps (5) and thrombosis (3). Xerostomia and vomiting contributed to weight loss and fatigue (8 patients). We conclude that Elliptinium-Vinblastine combination has moderate activity as second line treatment in metastatic breast cancer. This combination causes xerostomia and fatigue with moderate myelosuppression.