Is It Time for Noncontinuous Therapy for Gastroesophageal Reflux Disease?

Gastroesophageal reflux disease (GERD) is a chronic disorder characterized by the reflux of gastric contents into the esophagus, leading to symptoms and potential long-term complications such as Barrett esophagus and esophageal adenocarcinoma. Currently, there are various medical, endoscopic, and surgical therapeutic strategies for GERD. However, proton pump inhibitors (PPIs), which effectively suppress acid secretion but require daily administration, remain the mainstay of treatment. Noncontinuous therapy for GERD includes on-demand and different variations of intermittent administration of antireflux medication. Attributes that make an antireflux medication a good candidate for noncontinuous therapy for GERD include potent acid suppression, rapid effect, durability of antisecretory effect, and flexibility of administration. Noncontinuous therapy for GERD is appealing to patients because it is convenient, reduces cost, and alleviates concerns about complications of long-term PPI use. Patients with nonerosive esophageal reflux disease or low-grade erosive esophagitis who have episodic heartburn are probably best suited for such treatment. Although PPIs have been shown to be efficacious as on-demand or intermittent therapy for GERD, their usefulness as on-demand treatment for episodic heartburn has been limited by their slow maximal effect on intragastric acid secretion. In contrast, potassium-competitive acid blockers (P-CABs) demonstrate the pharmacokinetic and pharmacodynamic characteristics that make this class of drugs a good candidate for noncontinuous treatment of GERD. Early studies using P-CABs for noncontinuous treatment of GERD have demonstrated promising results. Future studies are needed to further establish the value of P-CABs for such a therapeutic approach. This article reviews the current evidence on the use of PPIs and P-CABs in noncontinuous therapy for GERD.

Addressing Drug Resistance in Cancer: A Team Medicine Approach.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a 'Team Medicine' approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or 'adaptive' therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers.

The Tumor Invasion Paradox in Cancer Stem Cell-Driven Solid Tumors.

Cancer stem cells (CSCs) are key in understanding tumor growth and tumor progression. A counterintuitive effect of CSCs is the so-called tumor growth paradox: the effect where a tumor with a higher death rate may grow larger than a tumor with a lower death rate. Here we extend the modeling of the tumor growth paradox by including spatial structure and considering cancer invasion. Using agent-based modeling and a corresponding partial differential equation model, we demonstrate and prove mathematically a tumor invasion paradox: a larger cell death rate can lead to a faster invasion speed. We test this result on a generic hypothetical cancer with typical growth rates and typical treatment sensitivities. We find that the tumor invasion paradox may play a role for continuous and intermittent treatments, while it does not seem to be essential in fractionated treatments. It should be noted that no attempt was made to fit the model to a specific cancer, thus, our results are generic and theoretical.

Treatment breaks in first line treatment of advanced colorectal cancer: An individual patient data meta-analysis.

BACKGROUND: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break. PATIENTS AND METHODS: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken. RESULTS: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy). CONCLUSION: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.

Intravenous isavuconazole can be administered 5 days-a-week. A possibility suggested by a real-life observation.

In this report it is shown that intravenous formulation of isavuconazole could be administered 5/7 days a week in patients who can not swallow capsules, once the steady state has been stably reached and maintained, thanks to its very long half-life. In this case TDM should be highly recommended.

Maintenance Versus Intermittent Strategies in the Treatment of Metastatic Colorectal Cancer: A Meta-Analysis from Another Angle.

INTRODUCTION: Considering the differences in overall survival (OS) and progression-free survival (PFS), treatment options for metastatic colorectal cancer (mCRC) are still inconclusive. We carried out a meta-analysis of maintenance and intermittent strategies for the treatment of mCRC aiming at providing an accurate estimation of different treatments in increasing the chance and duration of survival. METHODS: PubMed, Embase and CNKI were systematically searched. The pooled hazard ratio (HR) and 95% confidence interval (CI) were counted. We used STATA 12.0 and RevMan 5.2 for statistical analyses. RESULTS: A total of six publications with a population of 1975 mCRC patients were included in our meta-analysis. Analysis of OS revealed a statistically significant benefit associated with maintenance therapy (HR: 0.86, 95% CI 0.75-0.98, P = 0.02). Comparing maintenance therapy with an intermittent strategy, the first progression-free survival (PFS1) showed no significant difference (HR, 0.77; 95% CI 0.48-1.24, P = 0.29), but maintenance therapy improved the second progression-free survival (PFS2) significantly (HR, 0.66; 95% CI 0.54-0.81, P < 0.001). Sensitivity analysis was carried out to assess the stability of results. No publication bias was detected during analysis. CONCLUSION: Compared with the maintenance strategy, first-line chemotherapy that was completely stopped until disease progression did not benefit mCRC patients in terms of OS and PFS2. Therefore, a maintenance strategy is a good option for individualized mCRC patients.

Intermittent vs continuous docetaxel therapy in patients with metastatic castration-resistant prostate cancer - a phase III study (PRINCE).

OBJECTIVE: To investigate non-inferiority of intermittent docetaxel compared to continuous docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENT AND METHODS: The investigator initiated randomised phase III study included 187 chemotherapy-naïve patients with mCRPC who were allocated to two treatment arms: intermittent docetaxel and continuous docetaxel. Docetaxel was applied in both arms as weekly (35 mg/m2 ) or 3-weekly (75 mg/m2 ). The primary endpoint was 1-year survival, which was tested for non-inferiority (margin δ = 0.125). The secondary endpoints were: overall survival (OS), progression-free survival (PFS), median time to treatment failure (TTF), and toxicity. RESULTS: Of 156 eligible patients, 78 were allocated to each arm. The intermittent treatment met the non-inferiority criteria for 1-year survival (two-sided 95% confidence interval, -0.12, 18, P = 0.022), but not for OS, according to the result of a post hoc analysis. The differences between the study arms in PFS and TTF were not significant. The median (range) treatment holiday in the intermittent arm was 110 (13-486) days, or 38% of the overall treatment duration. Safety profiles of both study arms were comparable. The main limitation of this study was that the planned number of patients could not be recruited. CONCLUSION: Intermittent docetaxel chemotherapy was non-inferior to continuous therapy for 1-year survival; non-inferiority in regard to OS was not reached.

The Genetic/Non-genetic Duality of Drug 'Resistance' in Cancer.

Drug resistance is a serious impediment to the treatment of cancer. However, the mechanisms involved remain poorly understood. While it is widely held that the phenomenon is genetic in nature, emerging evidence suggests that non-genetic mechanisms may also be important. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination and intermittent therapies, as opposed to sustained monotherapy, appear more effective in attenuating it. Here we iterate the confusion in understanding the phenomenon by which cancer cells evade drug response and underscore the need to recognize the genetic/non-genetic duality of drug resistance in cancer. We discuss how ecological and evolutionary principles may help to reconcile the duality and may even offer new treatment strategies.

Intermittent docetaxel chemotherapy is feasible for castration-resistant prostate cancer.

This study was conducted with the aim to investigate the feasibility of intermittent treatment with docetaxel chemotherapy for castration-resistant prostate cancer (CRPC). A total of 51 men with CRPC received docetaxel at 75 mg/m2 every 3 weeks combined with oral dexamethasone 1.0-2.0 mg/day between 2008 and 2013. The prostate-specific antigen (PSA) level was monitored every 3 weeks. Chemotherapy was suspended when the serum PSA level decreased to < 4 ng/ml, with a reduction rate of >50% from the baseline. Treatment was resumed when serum PSA increased to > 2 ng/ml, with an increase rate of >50% from the nadir. Of the 51 cases, 27 (52.9%) qualified for intermittent treatment; 17 patients received two courses of docetaxel chemotherapy and 10 received three courses. The median off-treatment interval was 266 days for the first drug holiday, 129.5 days for the second and 146.5 days for the third. The multivariate analysis indicated low baseline PSA (

Comparison of intermittent and continuous androgen deprivation and quality of life between patients with locally advanced and patients with metastatic prostate cancer: a post hoc analysis of the randomized FinnProstate Study VII.

OBJECTIVE: The aim of the study was to compare intermittent (IAD) and continuous (CAD) androgen deprivation therapy (ADT) between locally advanced (M0) and metastatic (M1) prostate cancer, and the effect of ADT on the quality of life. MATERIAL AND METHODS: In total, 852 men with advanced prostate cancer were enrolled to receive goserelin acetate for 24 weeks. Of these, 554 patients whose prostate-specific antigen (PSA) decreased to less than 10 ng/ml or by at least 50% (<20 ng/ml at baseline) were randomized to IAD or CAD. In the IAD arm, ADT was resumed for at least 24 weeks whenever PSA increased to greater than 20 ng/ml or above baseline. RESULTS: Median follow-up time was 65 months. Median times from randomization to progression, death, prostate cancer death and treatment failure in M0 and M1 patients were 46.8 and 21.4, 57.6 and 40.3, 59.5 and 40.7, and 41.9 and 20.0 months, respectively (p < 0.001). No significant differences emerged between IAD and CAD. ADT showed a beneficial effect on pain, activity limitation and social functioning in M1 patients, and a deleterious effect on physical capacity in M0 patients and on sexual functioning in both groups. IAD offered extra benefit for activity limitation, social functioning and recovery of sexual functioning. CONCLUSIONS: IAD is as efficient as CAD in treatment of locally advanced and metastatic prostate cancer. ADT improves quality of life in M1 patients, with IAD offering extra benefit.

Is intermittent androgen-deprivation therapy beneficial for patients with advanced prostate cancer?

Use of intermittent androgen-deprivation therapy (IADT) in patients with prostate cancer has been evaluated in several studies, in an attempt to delay the development of castration resistance and reduce side-effects associated with ADT. However it is still not clear whether survival is adversely affected in patients treated with IADT. In this review, we explore the available data in an attempt to identify the most suitable candidate patients for IADT, and discuss factors that may inform appropriate patient stratification. ADT is first-line treatment for advanced/metastatic prostate cancer and is also recommended for use with definitive radiotherapy for high-risk localised prostate cancer. The changes in hormone levels induced by ADT can lead to short- and long-term side-effects which, although treatable in most cases, can significantly reduce the tolerability of ADT treatment. IADT has been investigated in several phase II and phase III studies in patients with locally advanced or metastatic prostate cancer, in an attempt to delay time to tumour progression and reduce the side-effect burden of ADT. In selected patient groups IADT is no less effective than continuous ADT, ameliorating the impact of ADT-related side-effects, and, to a degree, their impact on patient health-related quality of life (HRQL). Further comparative study is required, particularly in relation to HRQL and long-term complications associated with ADT.

Intermittent androgen-deprivation therapy in prostate cancer: a critical review focused on phase 3 trials.

CONTEXT: Intermittent androgen deprivation (IAD) in prostate cancer (PCa) patients has been proposed to delay development of castration resistance and to reduce the side effects and costs of androgen deprivation therapy (ADT). OBJECTIVE: This review analyzes (1) the oncologic and quality of life (QoL) results from randomized phase 3 trials comparing IAD and continuous ADT and (2) the prognostic parameters for IAD. EVIDENCE ACQUISITION: We searched the Medline and Cochrane Library databases (primary fields: prostate neoplasm and intermittent androgen deprivation; secondary fields: randomized trials, survival, quality of life, predictors) without language restriction. EVIDENCE SYNTHESIS: We found seven extensively described phase 3 trials randomizing 4675 patients to IAD versus continuous ADT. Other randomized trials investigating IAD have been performed, but available data are limited and have been published only in preliminary fashion. In all seven trials, patients spent most of their time on, rather than off, ADT. The induction periods ranged from 3 mo to 8 mo; in all but one trial, the PSA level designated for ADT discontinuation was <4 ng/ml. Mean follow-up ranged from 40-108 mo. Collectively, these trials support the concept that, mainly in metastatic cases, IAD can produce oncologic results similar to continuous ADT. In terms of overall survival, the hazard ratios for IAD and continuous ADT were very similar (range: 0.98-1.08). The QoL benefit of IAD appears to be modest at best. With IAD, QoL is likely influenced by the duration of the off-treatment periods and by the rate of testosterone recovery. CONCLUSIONS: The evidence indicates that IAD is not inferior to continuous ADT. Data are insufficient to determine whether IAD is able to prevent the long-term complications of ADT. More comparative analysis focused on QoL is warranted.