Cabazitaxel in the treatment of metastatic castration-resistant prostate cancer: patient selection and special considerations.

Cabazitaxel is an effective chemotherapeutic agent used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel. With the advent of new antiandrogen therapies, immune-based treatments, and radioactive-targeted therapy, there are now multiple effective and approved agents for this disease state. The optimal sequencing of these agents is unclear as there are no large-scale head-to-head comparisons. Clinicians must familiarize themselves with the most recent studies as well as drug toxicities to determine the best treatment option for their patients. In this review, we focus on the development of cabazitaxel for mCRPC, evaluate its efficacy, and highlight key strategies for toxicity management. Additionally, we summarize the studies that address cabazitaxel treatment sequencing and optimal dosing schedule

A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108368/1/cncr28767.pd

"Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions"-Treatment of ALL.

The outcome of adult acute lymphoblastic leukemia (ALL) has substantially improved by adopting pediatric-inspired regimens, and approximately half of the patients are nowadays cured. The evaluation of minimal residual disease currently represents the most important prognostic indicator, which drives treatment algorithms, which include allogeneic stem cell transplantation (allo-SCT) allocation. Indeed, for high-risk patients, allo-SCT should be pursued as soon as possible, whereas in standard-risk patients this procedure should be avoided also in light of related toxicity and because there are no significant benefits. Furthermore, better characterization of the molecular genetic events can drive therapeutic decisions: a historical example in this respect is represented by the use of tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive ALL; in the upcoming future, TKIs might be used also in other subgroups, such as breakpoint cluster region/Abelson 1-like cases and others with deregulated tyrosine kinases. Finally, the greatest progress is currently achieved with new immunotherapies targeting frequently expressed surface antigens in ALL. It is also a new chance for elderly ALL patients, so far spared from intensive chemotherapy and allo-SCT. These targeted therapies will substantially change this treatment algorithm and the great challenge is to find optimal sequence of the extended therapy options in an individual patient

Interventions for the treatment of oral cavity and oropharyngeal cancer:chemotherapy

<b>Background:</b> Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients.<p></p> <b>Objectives:</b> To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer results in improved survival, disease free survival, progression free survival, locoregional control and reduced recurrence of disease. To determine which regimen and time of administration (induction, concomitant or adjuvant) is associated with better outcomes.<p></p> <b>Search strategy:</b> Electronic searches of the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, AMED were undertaken on 28th July 2010. Reference lists of recent reviews and included studies were also searched to identify further trials.<p></p> <b>Selection criteria:</b> Randomised controlled trials where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and which compared the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration, were included.<p></p> <b>Data collection and analysis:</b> Trials which met the inclusion criteria were assessed for risk of bias using six domains: sequence generation, allocation concealment, blinding, completeness of outcome data, selective reporting and other possible sources of bias. Data were extracted using a specially designed form and entered into the characteristics of included studies table and the analysis sections of the review. The proportion of participants in each trial with oral cavity and oropharyngeal cancers are recorded in Additional Table 1.<p></p> <b>Main results:</b> There was no statistically significant improvement in overall survival associated with induction chemotherapy compared to locoregional treatment alone in 25 trials (hazard ratio (HR) of mortality 0.92, 95% confidence interval (CI) 0.84 to 1.00). Post-surgery adjuvant chemotherapy was associated with improved overall survival compared to surgery +/- radiotherapy alone in 10 trials (HR of mortality 0.88, 95% CI 0.79 to 0.99), and there was an additional benefit of adjuvant concomitant chemoradiotherapy compared to radiotherapy in 4 of these trials (HR of mortality 0.84, 95% CI 0.72 to 0.98). Concomitant chemoradiotherapy resulted in improved survival compared to radiotherapy alone in patients whose tumours were considered unresectable in 25 trials (HR of mortality 0.79, 95% CI 0.74 to 0.84). However, the additional toxicity attributable to chemotherapy in the combined regimens remains unquantified.<p></p> <b>Authors' conclusions:</b> Chemotherapy, in addition to radiotherapy and surgery, is associated with improved overall survival in patients with oral cavity and oropharyngeal cancers. Induction chemotherapy is associated with a 9% increase in survival and adjuvant concomitant chemoradiotherapy is associated with a 16% increase in overall survival following surgery. In patients with unresectable tumours, concomitant chemoradiotherapy showed a 22% benefit in overall survival compared with radiotherapy alone.<p></p&gt

Repurposing metformin for cancer treatment: current clinical studies.

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment

Interventions for preventing oral mucositis for patients with cancer receiving treatment

Interventions for preventing oral mucositis for patients with cancer receiving treatmentTreatment for cancer (including bone marrow transplant) can cause oral mucositis (severe ulcers in the mouth). This painful condition can cause difficulties in eating, drinking and swallowing, and may also be associated with infections which may require the patient to stay longer in hospital. Different strategies are used to try and prevent this condition, and the review of trials found that some of these are effective. Two interventions, cryotherapy (ice chips) and keratinocyte growth factor (palifermin®) showed some benefit in preventing mucositis. Sucralfate is effective in reducing the severity of mucositis, and a further seven interventions, aloe vera, amifostine, intravenous glutamine, granulocyte‐colony stimulating factor (G‐CSF), honey, laser and antibiotic lozenges containing polymixin/tobramycin/amphotericin (PTA) showed weaker evidence of benefit. These were evaluated in patients with different types of cancer, undergoing different types of cancer treatment. Benefits may be restricted to the disease and treatment combinations evaluated

Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer

Objectives: To quantify and compare the treatment effects on three surrogate end points, progression-free survival (PFS), time to progression (TTP), and tumor response rate (TR) vs. overall survival (OS) based on a meta-analysis of randomized controlled trials (RCTs) of drug interventions in advanced colorectal cancer (aCRC). Study Design and Setting: We systematically searched for RCTs of pharmacologic therapies in aCRC between 2003 and 2013. Trial characteristics, risk of bias, and outcomes were recorded based on a predefined form. Univariate and multivariate random-effects meta-analyses were used to estimate pooled summary treatment effects. The ratio of hazard ratios (HRs)/odds ratios (ORs) and difference in medians were used to quantify the degree of difference in treatment effects on the surrogate end points and OS. Spearman ρ, surrogate threshold effect (STE), and R2 were also estimated across predefined trial-level covariates. Results: We included 101 RCTs. In univariate and multivariate meta-analyses, we found larger treatment effects for the surrogates than for OS. Compared with OS, treatment effects were on average 13% higher when HRs were measured and 3% to 45% higher when ORs were considered; differences in median PFS/TTP were higher than on OS by an average of 0.5 month. Spearman ρ ranged from 0.39 to 0.80, mean R2 from 0.06 to 0.65, and STE was 0.8 for HRPFS, 0.64 for HRTTP, or 0.28 for ORTR. The stratified analyses revealed high variability across all strata. Conclusion: None of the end points in this study were found to achieve the level of evidence (ie, mean R2trial > 0.60) that has been set to select high or excellent correlation levels by common surrogate evaluation tools. Previous surrogacy relationships observed between PFS and TTP vs. OS in selected settings may not apply across other classes or lines of therapy

Biomarker Development for Advanced Prostate Cancer

Patients diagnosed with advanced prostate cancer starting long term ADT follow a highly variable clinical course. Treatment intensification improves outcome overall, but without biomarkers we overtreat some subgroups and we are unable to direct the most effective treatment strategy to others. I developed a protocol for biomarker discovery and evaluation, leveraging the STAMPEDE trial, in which donated clinical samples are associated with prospective clinical data. Genomic copy number alterations commonly occur in prostate cancer, however the clinical implication of copy number change in advanced HSPC is unknown. I generated low coverage WGS data from FFPE tissue from participants in the control group of STAMPEDE and copy number profiled 688 tumour regions from 300 participants to describe the association between the burden of copy number alteration and outcome. The burden of copy number alteration positively associated with radiologically-evident distant metastases at diagnosis (P value=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P value=0.003) and death (P value=0.045) for each unit increase, stabilising into more modest increases with higher burdens. This association between copy number burden and outcome was similar in each of the metastatic states. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1X10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC, occurred more frequently in cases with higher copy number alteration. Intra-patient burden of copy number alteration variance associated with increased risk of distant metastases (Kruskal-Wallis test P value=0.037). In conclusion, copy number alteration at diagnosis in advanced prostate cancer associates with increased risk of metastases and accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death

Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer

Comparative StudyMeta-AnalysisReviewValidation StudiesThis is the final version of the article. Available from Elsevier via the DOI in this record.OBJECTIVES: To quantify and compare the treatment effects on three surrogate end points, progression-free survival (PFS), time to progression (TTP), and tumor response rate (TR) vs. overall survival (OS) based on a meta-analysis of randomized controlled trials (RCTs) of drug interventions in advanced colorectal cancer (aCRC). STUDY DESIGN AND SETTING: We systematically searched for RCTs of pharmacologic therapies in aCRC between 2003 and 2013. Trial characteristics, risk of bias, and outcomes were recorded based on a predefined form. Univariate and multivariate random-effects meta-analyses were used to estimate pooled summary treatment effects. The ratio of hazard ratios (HRs)/odds ratios (ORs) and difference in medians were used to quantify the degree of difference in treatment effects on the surrogate end points and OS. Spearman ρ, surrogate threshold effect (STE), and R(2) were also estimated across predefined trial-level covariates. RESULTS: We included 101 RCTs. In univariate and multivariate meta-analyses, we found larger treatment effects for the surrogates than for OS. Compared with OS, treatment effects were on average 13% higher when HRs were measured and 3% to 45% higher when ORs were considered; differences in median PFS/TTP were higher than on OS by an average of 0.5 month. Spearman ρ ranged from 0.39 to 0.80, mean R(2) from 0.06 to 0.65, and STE was 0.8 for HRPFS, 0.64 for HRTTP, or 0.28 for ORTR. The stratified analyses revealed high variability across all strata. CONCLUSION: None of the end points in this study were found to achieve the level of evidence (ie, mean R(2)trial > 0.60) that has been set to select high or excellent correlation levels by common surrogate evaluation tools. Previous surrogacy relationships observed between PFS and TTP vs. OS in selected settings may not apply across other classes or lines of therapy