Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer

Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.     

A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy

Chronotherapy is no longer a novel concept in cancer treatment after approximately 20 years of development. Many clinical trials have provided strong supporting evidence that chronomodulated treatment yields better results than a traditional dosage regimen. This study aimed to evaluate the adverse reactions, effect on immune functions, and therapeutic efficacy of chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) combined with intensity-modulated radiation therapy (IMRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 148 patients with biopsy-diagnosed untreated stage III-IVb NPC were randomly assigned to undergo two cycles of chronomodulated infusion (study group) or flat intermittent infusion (control group) of DDP (100 mg/m2 on day 1, 21 days/cycle) synchronized with radical radiotherapy. Patients in the study group received chronomodulated infusion, with peak delivery of DDP at 16:00 pm. Patients in the control group received a routine constant rate of infusion. Both groups were treated with the same radiotherapy techniques. Over a median follow-up of 20 months, the study group had better outcomes for adverse effects and immune functions compared with the control group. During the phase of concurrent chemoradiotherapy, the incidence of nausea, vomiting, and oral mucositis in the study and control groups was 66.7% and 79.5% (p < 0.05), 47.9% and 71.2% (p < 0.05), and 73.9% and 87.7% (p < 0.05), respectively. There was no significant difference in 2-year overall survival, progression-free survival, and distant metastasis-free survival between the two groups (p > 0.05). Chronochemotherapy significantly reduced the incidence of adverse reactions and enhanced the tolerance for treatment without affecting survival. It is worth mentioning that reduced destruction of immune function is a novel area of exploration in chronotherapy research.     

The Effects of Chronomodulated Therapy with 5-Fluorouracil (5-Fu) and Folinic Acid (Fa) on the Toxicity and Quality of Life in Patients with Advanced Gastric Cancer

This study was designed to assess the tolerability of chronomodulated infusion chemotherapy, individualized by the rhythm of peripheral blood cells. Twenty patients with metastatic gastric cancer were randomized to chronotherapy or day-time arms of 5-fluorouracil (FU) (600 mg/m², 8 h inf.d1-5) and folinic acid (FA) (20 mg/m², iv, d1-5) in the first cycle and crossed-over to the other arm in the following cycles. Ten of 18 evaluable patients were assigned to chronotherapy arm and eight to day-time in the first cycle. Although there was no significant difference between two arms on enrollment, chronotherapy arm yielded an improvement of 45% of QLQ-C30 scores (p = 0.021) and the day-time arm had 11% improvement (p = 0.575). After the crossing-over, chronotherapy arm, again, had a significant improvement in QLQ-C30 scores, compared to the day-time arm (14% vs. -18%, p = 0.001, respectively). Mucositis/diarrhea was significantly higher in the day-time arm compared to chronotherapy arm (p = 0.015). In conclusion, chronomodulated infusion of 5-FU might improve the quality of life.     

Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics

Even though 5-fluorouracil (FU) is one of the oldest anticancer drugs, its use in cancer chemotherapy continues to increase. Fluorouracil is a pro-drug that requires intracellular activation to exert its effects. This makes it difficult to associate blood drug concentration with cell toxicity directly, although data from the literature show the existence of such a relationship. The relationship between FU pharmacokinetics and patient response has been explored extensively and reports attest a link between systemic drug exposure and response and survival. This has led to the concept of maximal tolerated exposure, and strategies to achieve this rely on pharmacokinetic follow-up and individual dose adjustment. More than 80% of the administered FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme. Dihydropyrimidine dehydrogenase activity is found in most tissues but is highest in the liver. Peripheral blood mononuclear cells (PBMC) are used to monitor clinically DPD activity. A significant, but weak correlation between PBMC and liver DPD activity has been observed. The relationship between PBMC-DPD activity and FU systemic clearance is weak (r²=0.10); thus, simply determining PBMC-DPD is not sufficient to predict accurately FU clearance. Population pharmacokinetic analysis identified patient co-variables that influence FU clearance; drug kinetics is significantly reduced by increased age, high serum alkaline phosphatase, length of drug infusion, and low PBMC-DPD. Autoregulation of FU metabolism also is suggested; inhibition of DPD activity was observed after FU administration in both colorectal cancer patients and an animal model. Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC-DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2-5 d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery.     

Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics

Even though 5-fluorouracil (FU) is one of the oldest anticancer drugs, its use in cancer chemotherapy continues to increase. Fluorouracil is a pro-drug that requires intracellular activation to exert its effects. This makes it difficult to associate blood drug concentration with cell toxicity directly, although data from the literature show the existence of such a relationship. The relationship between FU pharmacokinetics and patient response has been explored extensively and reports attest a link between systemic drug exposure and response and survival. This has led to the concept of maximal tolerated exposure, and strategies to achieve this rely on pharmacokinetic follow-up and individual dose adjustment. More than 80% of the administered FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme. Dihydropyrimidine dehydrogenase activity is found in most tissues but is highest in the liver. Peripheral blood mononuclear cells (PBMC) are used to monitor clinically DPD activity. A significant, but weak correlation between PBMC and liver DPD activity has been observed. The relationship between PBMC–DPD activity and FU systemic clearance is weak (r²=0.10); thus, simply determining PBMC–DPD is not sufficient to predict accurately FU clearance. Population pharmacokinetic analysis identified patient co-variables that influence FU clearance; drug kinetics is significantly reduced by increased age, high serum alkaline phosphatase, length of drug infusion, and low PBMC–DPD. Autoregulation of FU metabolism also is suggested; inhibition of DPD activity was observed after FU administration in both colorectal cancer patients and an animal model. Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC–DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2–5 d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery.     

Optimal Sequence of Irinotecan and Oxaliplatin-Based Regimens in Metastatic Colorectal Cancer: A Population-Based Observational Study

The optimal sequence of irinotecan and oxaliplatin-based regimens for metastatic colorectal cancer remains unclear. We conducted a population-based observational study by retrospectively reviewing records from Taiwan’s National Health Insurance Research Database to explore this issue. Patients aged ≥20 years with metastatic colorectal cancer newly diagnosed between 2004 and 2008 (n = 9490) were enrolled in current study. Among these 9490 patients, 3895 patients (41.04%) did not receive any chemotherapy within the first three months after catastrophic illness registration. Patients who received best supportive care were older and had higher Charlson comorbidity indexes and incidences of comorbidities than those who received irinotecan-based regimens, oxaliplatin-based regimens, and 5-fluorouracil/capecitabine alone. Patients who received irinotecan followed by oxaliplatin-based regimens and those who received the reverse sequence were further stratified into arm A (n = 542) and arm B (n = 1156), respectively. The median first time to next treatment was not significantly different between arm A and arm B (210 days vs. 196 days; p = 0.17). However, the median second time to next treatment was longer in arm A than in arm B (155 days vs. 123 days; p = 0.006), which translated into a better overall survival (487 days vs. 454 days; p = 0.02). The crossover rate was higher in arm A than in arm B (47.84% vs. 41.61%; p<0.001). Multivariate Cox regression analyses showed that overall survival was comparable between the two chemotherapy sequences (p = 0.27). Our study suggested that irinotecan followed by oxaliplatin-based regimens might be a better chemotherapy treatment option for metastatic colorectal cancer than the reverse sequence given the higher crossover rate and potential overall survival benefit.     

Effects of aging and arm swing on the metabolic cost of stability in human walking

To gain insight into the mechanical determinants of walking energetics, we investigated the effects of aging and arm swing on the metabolic cost of stabilization. We tested two hypotheses: (1) elderly adults consume more metabolic energy during walking than young adults because they consume more metabolic energy for lateral stabilization, and (2) arm swing reduces the metabolic cost of stabilization during walking in young and elderly adults. To test these hypotheses, we provided external lateral stabilization by applying bilateral forces (10% body weight) to a waist belt via elastic cords while young and elderly subjects walked at 1.3m/s on a motorized treadmill with arm swing and with no arm swing. We found that the external stabilizer reduced the net rate of metabolic energy consumption to a similar extent in elderly and young subjects. This reduction was greater (6-7%) when subjects walked with no arm swing than when they walked normally (3-4%). When young or elderly subjects eliminated arm swing while walking with no external stabilization, net metabolic power increased by 5-6%. We conclude that the greater metabolic cost of walking in elderly adults is not caused by a greater cost of lateral stabilization. Moreover, arm swing reduces the metabolic cost of walking in both young and elderly adults likely by contributing to stability.     

Chronomodulated chemotherapy and irradiation: an idea whose time has come?

The chronomodulated delivery of systemic chemotherapy given with irradiation (chemoradiation) is driven by an understanding of: the chronobiology of normal tissue response to cytotoxic insult, chronopharmacology, and by technologic advances in vascular access and in the availability of portable programmable pumps. Since circadian variation exists in the proliferative activity of acute-reacting normal tissues like the gut and bone marrow, a potential therapeutic gain can be realized by the chronomodulated administration of S-phase chemotherapeutic agents at biological times when these normal tissues are in a different cell phase and thus relatively spared (chronotolerance). The reasons for this are complex and possibly include newly described time-keeping genes that may influence the cell cycle. Another important aspect of chronotolerance is based on chronopharmacologic behavior of S-phase chemotherapeutic radiation sensitizing agents, especially 5-fluorouracil (5-FU). In this review laboratory and clinical evidence is presented for using chronomodulated 5-FU or the topoisomerase-I inhibitor, camptothecin, when best tolerated biologically. Although the main body of this work has been accomplished with pure chemotherapy schedules, there is emerging clinical evidence this approach to treatment also applies to the application of chemoradiation. This knowledge has been exploited only recently in the clinic. These data should be viewed as a call for additional studies to investigate the precise timing of systemic chemotherapeutic radio sensitizers to ameliorate toxicity and maximize treatment effect, especially with newer and potentially more toxic chemoradiation programs.     

Cost Resulting from Anti-Tuberculosis Drug Shortages in the United States: A Hypothetical Cohort Study

BackgroundFrom 2012 through 2014, the United States experienced acute shortages and price escalations of several first-line anti-tuberculosis (TB) medications. Because secondary TB drug regimens are longer and adverse events occur more frequently with them, we sought to conservatively estimate the cost, to patients and the health care system, of TB treatment and medication adverse events from alternative regimens during drug shortages.MethodsWe assessed the cost of treatment for TB disease in the absence of isoniazid (INH), rifampin (RIF), or pyrazinamide (PZA), or both INH and RIF. We simulated adverse events based on published probabilities using a monthly discrete-time stochastic model. For total costs, we summed costs of medications, routine testing, and treatment of adverse events using procedural terminology codes. We report average cost ratios of TB treatment during drug shortages to standard TB treatment.ResultsThe cost ratio of TB treatment without INH, RIF, or PZA to standard treatment was 1.7 (Range: 1.2, 2.3), 4.9 (Range: 3.2, 7.3), and 1.1 (Range: 0.7, 1.7) times higher, respectively. Without both INH and RIF, the cost ratio was 18.6 (Range: 10.0, 39.0) times higher. When the prices for INH, RIF and PZA were increased, the cost for standard treatment increased by a factor of 2.7 (Range: 1.9, 3.0). The percentage of patients experiencing at least one adverse event while taking standard therapy was 3.9% (Range: 1.3%, 11.8%). This percentage increased to 51.5% (Range: 20.1%, 83.8%) when RIF was unavailable, and increased to 82.5% (Range: 41.2%, 98.5%) when both INH and RIF were unavailable.ConclusionsOur conservative model illustrates that an interruption in first-line anti-TB medications leads to appreciable additional costs and adverse events for patients. The availability of these drugs in the United States should be ensured. Models that incorporate the effectiveness of alternative regimens, delays in treatment initiation, and TB transmission can provide broader perspectives on the impact of drug shortages.     

PF化疗同步联合时辰放疗与常规放疗治疗局部晚期鼻咽癌的随机对照研究

目的:比较局部晚期鼻咽癌分别接受顺铂联合氟尿嘧啶方案(PF)化疗联合时辰放疗以及PF化疗联合常规放疗时的疗效和毒副反应。方法:将我科45例初治局部晚期鼻咽癌患者随机分为时辰放疗组和常规放疗组,分别为22例和23例。两组均采用相同放射治疗方法和治疗剂量,同步给予PF方案化疗。时辰放疗组放疗时间在20:00-22:00,而常规放疗组在8:00-10:00。结果:两组患者在放疗结束3个月和6个月进行时比较发现,时辰放疗组患者的鼻咽部及颈部的肿瘤完全消退率(CR率)均比常规放疗组高(P<0.05)。而时辰放疗组的各种急性副作用发生率较常规放疗组低,但无统计学差异。治疗后时辰组CD4/CD8升高,常规组CD4/CD8降低(P<0.05)。结论:时辰放疗联合PF同步化疗针对局部晚期鼻咽癌患者疗效好,毒副作用轻,同时可能有利于改善患者的免疫功能。