Neoadjuvant cisplatin for head and neck cancer: Simulation of a novel schedule for improved therapeutic ratio

Current clinical studies support the role of neoadjuvant cisplatin administration prior to curative radiotherapy or radio-chemotherapy for advanced head and neck cancer. Nevertheless, based on locoregional control rates the studies indicate that there is need to redesign cisplatin-based schedules for induction chemotherapy, thus the ideal treatment regimen is yet to be established. While the pharmacokinetics/dynamics of daily cisplatin regimens correspond better with the cell cycle properties of head and neck cancers, weekly regimens are more commonly employed in clinics due to lower complications. Yet, the high rates of adverse events induced by current cisplatin schedules often represent a limiting factor in the overall success of the treatment.The aim of the present paper was to model the pharmacodynamic properties of cisplatin and to simulate and compare various neoadjuvant treatment regimens in regards to their effect on tumour control. Treatment simulation was undertaken on a virtual squamous cell carcinoma of the head and neck, previously grown by computer-based probabilistic methods.The model suggests that a novel cisplatin treatment, given every three days is comparable, in regards to tumour control, with the daily administration and more effective than the weekly regimen in neoadjuvant settings. Endpoints were assessed in terms of cell population regrowth after treatment cessation followed by two weeks of unperturbed growth. Simulation of two weeks low-dose daily cisplatin followed by two weeks ‘free growth’ lead to 15% population regrowth, while weekly high-dose cisplatin over three weeks, followed by two weeks unperturbed growth resulted in 52% tumour cell regrowth. The proposed novel schedule of low-dose third-daily cisplatin gives closer tumour regrowth to daily administration (27% versus 15%) than to the weekly regimen (52%) and also similar cell distribution along the cell cycle as the daily one, suggesting therefore comparable response to subsequent treatment.The advantage of using a third-daily drug regimen would be a decrease in normal tissue complication rates compared to daily administration and possibly an increase in tumour control when compared to the ‘conventional’ weekly cisplatin delivery.     

Species differences in tumour responses to cancer chemotherapy

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.     

Optimal control of treatment in a mathematical model of chronic myelogenous leukemia

We consider a mathematical model of drug therapy for chronic myelogenous leukemia for an individual patient over a fixed time horizon. The disease dynamics are given by a system of ordinary differential equations that describe the interaction between naive T cells, effector T cells and leukemic cancer cells in a hypothetical patient. We introduce two drug therapies into this model, one a targeted therapy, and the other a broad cytotoxic therapy. Our goal is to find treatment regimens that minimize the cancer cell count and the deleterious effects of the drugs for a given patient. We examine the control setting analytically, and include numerical solutions to illustrate the optimal regimens under various assumptions.     

Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model

Background

Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens.

Methods and Findings

Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log₁₀ colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice.

Conclusions

Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.     

Association between Regimen Composition and Treatment Response in Patients with Multidrug-Resistant Tuberculosis: A Prospective Cohort Study

Background

For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen.

Methods and Findings

We analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph.In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen).The main limitation of this analysis is that it is based on observational data, not a randomized trial, and drug regimens varied across sites. However, PETTS was a uniquely large and rigorous observational study in terms of both the number of patients enrolled and the standardization of laboratory testing. Other limitations include the assumption of equivalent efficacy across drugs in a category, incomplete data on adherence, and the fact that the analysis considers only initial sputum culture conversion, not reversion or long-term relapse.

Conclusions

MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. Rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens.     

Reinforcement learning strategies for clinical trials in nonsmall cell lung cancer

Typical regimens for advanced metastatic stage IIIB/IV nonsmall cell lung cancer (NSCLC) consist of multiple lines of treatment. We present an adaptive reinforcement learning approach to discover optimal individualized treatment regimens from a specially designed clinical trial (a "clinical reinforcement trial") of an experimental treatment for patients with advanced NSCLC who have not been treated previously with systemic therapy. In addition to the complexity of the problem of selecting optimal compounds for first- and second-line treatments based on prognostic factors, another primary goal is to determine the optimal time to initiate second-line therapy, either immediately or delayed after induction therapy, yielding the longest overall survival time. A reinforcement learning method called Q-learning is utilized, which involves learning an optimal regimen from patient data generated from the clinical reinforcement trial. Approximating the Q-function with time-indexed parameters can be achieved by using a modification of support vector regression that can utilize censored data. Within this framework, a simulation study shows that the procedure can extract optimal regimens for two lines of treatment directly from clinical data without prior knowledge of the treatment effect mechanism. In addition, we demonstrate that the design reliably selects the best initial time for second-line therapy while taking into account the heterogeneity of NSCLC across patients.     

A mathematical model of cancer chemotherapy with an optimal selection of parameters

An optimal parameter selection model of cancer chemotherapy is presented which describes the treatment of a tumor over a fixed period of time by the repeated administration of a single drug. The drug is delivered at evenly spaced intervals over the treatment period at doses to be selected by the model. The model constructs a regimen that both minimizes the tumor population at the end of the treatment and satisfies constraints on the drug toxicity and intermediate tumor size. Numerical solutions show that an optimal regimen withholds the bulk of the doses until the end of the treatment period. When a drug used is of either moderate or low effectiveness, an optimal regimen is superior to a schedule that delivers all of the drug at the beginning of the treatment. This study questions whether the current method for the administration of chemotherapy is optimal and suggests that alternative regimens should be considered.     

Optimal timing and duration of induction therapy for HIV-1 infection

The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction–maintenance therapies might be optimized. Our model suggests that under a variety of biologically plausible conditions, 6–10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen. For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal. The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated. These observations have implications for both the timing and the kinds of drugs selected for induction–maintenance and therapy-intensification strategies.     

Comparison of the efficacy and safety of Consupren solution and Sandimmun Neoral solution, 50 ml in stable heart transplant patients

Cyclosporine A (CyA) is a standard component of immunosuppressive regimen after heart transplantation in most centres. The widespread clinical use of cyclosporine-based immunosuppressive regimens since 1983 has led to significant improvements in the survival of cardiac allograft recipients due to decreased mortality from infections and rejections. (1-3) CyA has been shown to be safe and effective. Owing to its success when used after the heart transplantation the number of patients has also risen. This caused growing financial demands on health insurance companies in the Czech Republic where the immunosuppressive drugs are fully reimbursed. A prospective randomized study in 11 stable heart transplant patients was performed to compare the efficacy and safety of Consupren (IVAX-CR) a Sandimmun Neoral (Novartis) solution based immunosuppressive regimen. The results suggest that Consupren solution can be used as an alternative treatment to Sandimmun Neoral in CyA based regimen.     

Optimal drug treatment regimens for HIV depend on adherence

Drug therapies aimed at suppressing the human immunodeficiency virus (HIV) are highly effective, often reducing the viral load to below the limits of detection for years. Adherence to such antiviral regimens, however, is typically far from ideal. We have previously developed a model that predicts optimal treatment regimens by weighing drug toxicity against CD4+ T-cell counts, including the probability that drug resistance will emerge. We use this model to investigate the influence of adherence on therapy benefit. For a drug with a given half-life, we compare the effects of varying the dose amount and dose interval for different rates of adherence, and compute the optimal dose regimen for adherence between 65% and 95%. Our results suggest that for optimal treatment benefit, drug regimens should be adjusted for poor adherence, usually by increasing the dose amount and leaving the dose interval fixed. We also find that the benefit of therapy can be surprisingly robust to poor adherence, as long as the dose interval and dose amount are chosen accordingly.     

Comparison of intravenous and oral high-dose methotrexate in treatment of solid tumours.

An outpatient regimen of oral high-dose methotrexate was studied in 14 patients with solid tumours over 12 months. Detailed pharmacokinetic analysis in five patients showed high oral bioavailability (mean +/- SE of mean 87.6 +/- 1.5%), indicating that with this regimen oral methotrexate was well absorbed and the first-pass effect low. Oral administration resulted in peak plasma methotrexate concentrations of 8.4 +/- 0.5 mumol/l (382 +/- 23 microgram/100 ml) and was almost as effective as intravenous administration, which achieved peak concentrations of 9.9 +/- 0.4 mumol/l (450 +/- 18 microgram/100 ml). In all 14 patients the clinical response to oral treatment was comparable to that reported to intravenous administration of high-dose methotrexate used in combination with other cytotoxic drugs. The disease-free interval in cases of adult sarcoma was 7.4 +/- 1.3 months and the relapse rate 29%. Out of four patients with small-cell carcinoma, two showed an objective response to oral treatment. We suggest that oral high-dose methotrexate given in divided doses is a rational alternative to expensive intravenous high-dose methotrexate regimens, but further clinical evaluation is necessary.     

Predicting differential responses to structured treatment interruptions during HAART

Highly active antiretroviral therapy (HAART) has been used clinically in various administration schemes for several years. However, due to the development of drug resistance, evolution of viral strains, serious side effects, and poor patient compliance, the combination of drugs used in HAART fails to effectively contain virus long term in a high proportion of patients. Our group and others have suggested a change to the usual regimen of continuous HAART through structured treatment interruptions (STIs). STIs may provide similar clinical benefits as continuous treatment such as reduced viral loads and reestablishment of CD4⁺ T cells while allowing patients drug holidays. We explore the use of STIs using a previously published model that accurately represents CD4⁺ T-cell counts and viral loads during both untreated HIV-1 infection and HAART therapy. We simulate the effects of different STI regimens including weekly and monthly interruptions together with variations in treatment initiation time. We predict that differential responses to STIs as observed in conflicting clinical trial data are impacted by the duration of the interruption, stage of infection at initiation of treatment, strength of the immune system in suppressing virus, or pre-therapy CD4⁺ T-cell count or virus load. Our results indicate that dynamics occurring below the limit of detection (LOD) are influenced by these factors, and contribute to reemergence or suppression of virus during interruptions. Simulations predict that short-term viral suppression with varying interruptions strategies does not guarantee long-term clinical benefit.     

预激方案HAG及CAG治疗老年初治急性髓性白血病的对比研究

目的:评价含粒细胞集落刺激因子(granulocyte colony-stimulating-factor,G-CSF)的预激HAG及CAG方案治疗老年初治急性髓性白血病(AML)的疗效及不良反应,并对两个方案的疗效及不良反应进行比较。方法:65例老年初治AML分为HAG预激治疗组及CAG预激方案治疗组,31例患者予以HAG预激方案治疗,34例患者予以预激方案CAG方案治疗,所有患者在第1疗程后间歇14d左右进行第2个疗程。结果:HAG预激方案治疗组的完全缓解率为74.2%,总有效率为83.8%;CAG预激治疗组完全缓解(CR)率为67.6%,总有效率达为82.4%。两治疗组的血液系统不良反应及非血液系统毒性不良反应比较无显著性差异。结论:HAG预激方案化疗强度温和、敏感性好、CR率及有效率高、毒副作用小;与CAG预激治疗比较,HAG预激方案可以取的相似的疗效及较少的不良反应,在老年初治AML患者值得推荐应用。     

Drug-Sparing Regimens for HIV Combination Therapy: Benefits Predicted for “Drug Coasting”

Structured Treatment Interruptions (STI) during HIV drug therapy were thought to potentially reduce side effects and toxicity, boost immune involvement, and possibly lower the viral set-point. Clinical trials of STI regimens, however, have had mixed results. We use an established mathematical model of HAART to estimate possible therapeutic outcomes for STI and for other, similar patterns in HIV combination therapy. We perform an exhaustive search of patterns of up to 60 days, for triple-drug combinations involving accurate pharmacokinetics for 12 specific antiviral drugs. The results of this analysis are consistent with recent clinical trials which have demonstrated that STI-type patterns, involving therapy interruption of weeks or months, are rarely optimal. Our analysis predicts, however, that the benefit of treatment can often be improved by including very short drug-free periods, during which the patient effectively “coasts” for a day or two on adequate drug concentrations due to the long half-life of some pharmaceuticals. Our analysis predicts many cases in which this may be achieved without increasing the risk of drug-resistance. This suggests that “drug coasting” patterns, significantly shorter than STI patterns, may merit further clinical investigation in efforts to find drug-sparing regimens for HIV. Electronic Supplementary Material The online version of this article () contains supplementary material, which is available to authorized users.     

Cox regression methods for two-stage randomization designs

Two-stage randomization designs (TSRD) are becoming increasingly common in oncology and AIDS clinical trials as they make more efficient use of study participants to examine therapeutic regimens. In these designs patients are initially randomized to an induction treatment, followed by randomization to a maintenance treatment conditional on their induction response and consent to further study treatment. Broader acceptance of TSRDs in drug development may hinge on the ability to make appropriate intent-to-treat type inference within this design framework as to whether an experimental induction regimen is better than a standard induction regimen when maintenance treatment is fixed. Recently Lunceford, Davidian, and Tsiatis (2002, Biometrics 58, 48-57) introduced an inverse probability weighting based analytical framework for estimating survival distributions and mean restricted survival times, as well as for comparing treatment policies at landmarks in the TSRD setting. In practice Cox regression is widely used and in this article we extend the analytical framework of Lunceford et al. (2002) to derive a consistent estimator for the log hazard in the Cox model and a robust score test to compare treatment policies. Large sample properties of these methods are derived, illustrated via a simulation study, and applied to a TSRD clinical trial.     

Melatonin in clinical oncology

The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).     

Population-Level Impact of Shorter-Course Regimens for Tuberculosis: A Model-Based Analysis

Despite current control efforts, global tuberculosis (TB) incidence is decreasing slowly. New regimens that can shorten treatment hold promise for improving treatment completion and success, but their impact on population-level transmission remains unclear. Earlier models projected that a four-month regimen could reduce TB incidence by 10% but assumed that an entire course of therapy must be completed to derive any benefit. We constructed a dynamic transmission model of TB disease calibrated to global estimates of incidence, prevalence, mortality, and treatment success. To account for the efficacy of partial treatment, we used data from clinical trials of early short-course regimens to estimate relapse rates among TB patients who completed one-third, one-half, two-thirds, and all of their first-line treatment regimens. We projected population-level incidence and mortality over 10 years, comparing standard six-month therapy to hypothetical shorter-course regimens with equivalent treatment success but fewer defaults. The impact of hypothetical four-month regimens on TB incidence after 10 years was smaller than estimated in previous modeling analyses (1.9% [95% uncertainty range 0.6–3.1%] vs. 10%). Impact on TB mortality was larger (3.5% at 10 years) but still modest. Transmission impact was most sensitive to the proportion of patients completing therapy: four-month therapy led to greater incidence reductions in settings where 25% of patients leave care (“default”) over six months. Our findings remained robust under one-way variation of model parameters. These findings suggest that novel regimens that shorten treatment duration may have only a modest effect on TB transmission except in settings of very low treatment completion.     

Chronic Granulocytic Leukaemia: Multiple-drug Chemotherapy for Acute Transformation

The response to 60 trials of therapy in 50 patients with chronic granulocytic leukaemia (C.G.L.) in acute transformation is reported. None of the 13 patients who received single-agent chemotherapy had a satisfactory response. The use of two drugs in combination produced only one satisfactory response in 30 patients. Various types of multiple-drug treatments in eight patients achieved one good response which lasted four months. In contrast when nine patients with rapidly progressive acute transformation of C.G.L. received a regimen—TRAMPCO(L)—incorporating seven or eight drugs (thioguanine, daunorubicin, cytarabine, methotrexate, prednisolone, cyclophosphamide, and vincristine, with or without L-asparaginase colaspase) five improved significantly. Four patients had a good clinical and haematological response with survival for over three, eight, over 12, and 14 and a half months; and one patient had a partial response. Toxicity was not extreme and maintenance therapy with the same regimen was given on an outpatient basis. TRAMPCO(L) seems superior to previously reported regimens and should be considered for rapidly progressive transformation of C.G.L. especially when simpler treatments have failed.