Two-year outcome of concurrent chemoradiation with carboplatin with or without adjuvant carboplatin/fluorouracil in nasopharyngeal cancer: A multicenter randomized trial

BackgroundAccording to the noninferiority result of chemoradiation with carboplatin in our previous nasopharyngeal carcinoma (NPC) study along with the inconclusive data on the efficacy of adjuvant chemotherapy (AC) following concurrent chemoradiotherapy (CCRT), we designed to assess the role of adjuvant carboplatin/fluorouracil following CCRT with carboplatin in locoregionally advanced NPC.Materials and MethodsA multicenter randomized trial was conducted at 5 cancer centers in Thailand. We enrolled in stage T2N0M0-T4N2M0 (American Joint Cancer Committee 7th edition) WHO Type 2 NPC patients. N3 or metastatic disease patients were excluded. Participants were randomized into 2 groups: CCRT plus AC group vs the CCRT alone group. Patients in both groups received weekly carboplatin 100 mg/m² for 6 cycles concurrently with radiotherapy 69.96-70 Gy. Patients in the AC group subsequently received 3 cycles of carboplatin area under curve-5 plus 1000 mg/m²/day of fluorouracil infusion within 96 hours every 3 weeks. We report the 2-year overall survival (OS), disease-free survival (DFS), loco-regional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Treatment-related toxicities and compliance were also explored.ResultsOf 175 patients, 82 (46.9%) were assigned to the AC group, and 93 (53.1%) to the CCRT group. The compliance rate during CCRT was 90% and 86% in the AC and CCRT group, whereas 81.7% during adjuvant treatment in the AC group. With a median follow-up time of 24.4 months (interquartile range 17.9-24.4), the 2-year OS rate was 89.6% in the AC group and 81.8% in the CCRT group (P= 0.167). The 2-year DFS rate was 86.8% in the AC group and 74.6% in the CCRT group (P = 0.042). The 2-year LRFS rate was 91.5% in the AC group and 88.2% in the CCRT group (P = 0.443). The 2-year DMFS rate was 85.4% in the AC group and 79.6% in the CCRT group (P = 0.294). The most frequent serious (grade 3/4) nonhematologic toxicity was acute mucositis, which occurred 5% in the AC group vs 4% in the CCRT group (P = 0.498). For hematologic toxicity, grade 3-4 leukopenia were found 10% and 5% in the adjuvant and CCRT groups, respectively (P = 0.003). Multivariate analyses determined stage N2 disease was an adverse prognostic factor associated with shorter OS, DFS, and DMFS. And the adjuvant treatment was a significant protective factor for only DFS.ConclusionsThe addition of adjuvant carboplatin/fluorouracil following CCRT with carboplatin significantly improved 2-year DFS in stage T2N0M0-T4N2M0 NPC albeit there was a nonsignificant trend in favor of a higher 2-year OS, LRFS, and DMFS. Long-term efficacy and late toxicities of AC still require exploration.     

A dosimetric comparison of two-phase adaptive intensity-modulated radiotherapy for locally advanced nasopharyngeal cancer

The purpose of this investigation was to evaluate the potential dosimetric benefits of a two-phase adaptive intensity-modulated radiotherapy (IMRT) protocol for patients with locally advanced nasopharyngeal cancer (NPC). A total of 17 patients with locally advanced NPC treated with IMRT had a second computed tomography (CT) scan after 17 fractions in order to apply and continue the treatment with an adapted plan after 20 fractions. To simulate the situation without adaptation, a hybrid plan was generated by applying the optimization parameters of the original treatment plan to the anatomy of the second CT scan. The dose–volume histograms (DVHs) and dose statistics of the hybrid plan and the adapted plan were compared. The mean volume of the ipsilateral and contralateral parotid gland decreased by 6.1 cm³ (30.5%) and 5.4 cm³ (24.3%), respectively. Compared with the hybrid plan, the adapted plan provided a higher dose to the target volumes with better homogeneity, and a lower dose to the organs at risk (OARs). The Dmin of all planning target volumes (PTVs) increased. The Dmax of the spinal cord and brainstem were lower in 94% of the patients (1.6–5.9 Gy, P < 0.001 and 2.1–9.9 Gy, P < 0.001, respectively). The D_mean of the contralateral parotid decreased in 70% of the patients (range, 0.2–4.4 Gy). We could not find a relationship between dose variability and weight loss. Our two-phase adaptive IMRT protocol improves dosimetric results in terms of target volumes and OARs in patients with locally advanced NPC.     

Growth of human immunodeficiency virus-uninfected children exposed to perinatal zidovudine for the prevention of mother-to-child human immunodeficiency virus transmission

BACKGROUND: Perinatal human immunodeficiency virus (HIV) prevention programs have been implemented in several countries, and many children have been or will be exposed to antiretrovirals in utero and during their first weeks of life. Although reducing substantially the number of infected children, the potential adverse consequences of these treatments on the health of HIV-uninfected children need to be assessed. OBJECTIVE: To investigate the impact of in utero and postnatal zidovudine exposure on the growth of HIV-uninfected children born to HIV-infected women. METHODS: We used data prospectively collected in 1408 live born children participating in a clinical trial comparing zidovudine regimens of different durations to prevent perinatal transmission in Thailand (PHPT-1). We used a linear mixed model to analyze the anthropometric measurements (weight for age, height for age and weight for height Z-scores) until 18 months of age according to zidovudine treatment duration (mothers, <7.5 weeks versus more; infants, 3 days versus >4 weeks). RESULTS: Children exposed in utero for >7.5 weeks had a slightly lower birth weight (Z-score difference, 0.08; P = 0.003). However, zidovudine exposure had no effect on the evolution of Z-scores from 6 weeks to 18 months of age. CONCLUSIONS: Although a longer in utero zidovudine exposure may have had a negative impact on birth weight, the magnitude of this effect was small and faded over time. Neither the total nor the postnatal duration of exposure was associated with changes in infant Z-scores from 6 weeks to 18 months of age.     

Haematological Safety of Perinatal Zidovudine in Pregnant HIV-1–Infected Women in Thailand: Secondary Analysis of a Randomized Trial

Objectives:     

Tuberculosis treatment with mobile-phone medication reminders in northern Thailand

Thailand's implementation of the Directly Observed Treatment, Short course (DOTS) strategy to increase tuberculosis (TB) control program efficacy has not achieved the World Health Organization (WHO) TB key targets. We defined two TB control models in the study. Patients in Model 1 were treated with a conventional DOTS strategy and in Model 2, patients were treated the same as Model method 1 but were given a phone call reminder to take their medication. Multi-drug resistant tuberculosis (MDR-TB) and non-MDR-TB patients were randomized into either Model 1 or 2. Treatment outcomes were given as cure rates, completion rates, failure rates or success rates at 18 months in the MDR-TB group and 6 months in the non-MDR-TB group. The sputum conversion rate at 1 month were evaluated for both groups. In the MDR-TB group, the sputum conversion rate was 20% (95% CI 8-45) in Model 1 and 90% (95% CI 73-98) in Model 2 (p < 0.001). In the non-MDR-TB group, the sputum conversion rate was 52% (95% CI 36-70) in Model 1 and 37% (95% CI 22-56) in Model 2 although the difference was not significant (p = 0.221). The Model 2 success rates were significantly higher (73.7%, 96.7%) in both the MDR-TB and non-MDR-TB groups (p < 0.001, p = 0.047). The MDR-TB rate in northern Thailand decreased from 4.1% during April-September 2008 to 1.8% during April-September 2009. Further study of the association between implementation of Model 2 and MDR-TB incidence reduction needs to be carried out.     

Gestational age determination and prevention of HIV perinatal transmission.

OBJECTIVE: To compare different methods of gestational age (GA) measurement for ensuring effective zidovudine (ZDV) prophylaxis to prevent mother-to-child transmission of HIV. METHODS: For 1398 HIV-infected women enrolled in a perinatal prevention trial, gestation durations were calculated based on GA estimated using ultrasound (US), date of last menstruation period (LMP), first fundal height (FH(1)), and a specific algorithm was developed to provide a "reference" GA. The performance of each GA estimate was evaluated by the percentage of women who would have received > or =8 weeks ZDV, if prophylaxis was initiated at 28 weeks. RESULTS: The performances of the algorithm, US, LMP, and FH(1) were 95.5%, 94.8%, 88.4%, and 83.7%, respectively. US and FH(1) were significantly better when estimated before and after 24 weeks, respectively. CONCLUSION: In situations where no US is available and LMP is not or imprecisely known, FH(1) can be used after 24 weeks to schedule ZDV initiation date.     

Relationship between exposure to zidovudine and decrease of P24 antigenemia in HIV-infected patients in monotherapy

The link between virological response and exposure to zidovudine was studied in 40 HIV-infected patients of the protocol ANRS 01. During this 45-day trial, the patients received only oral zidovudine in six treatment groups. Our objectives were: to analyze and model the pharmacokinetics of zidovudine and the decrease of P24 antigenemia; to study the links between exposure and efficacy. For the pharmacokinetic study, 12 blood samples were collected from 0.16 to 24 h after the first dose and a compartmental model was used. For the pharmacodynamic study of P24 antigenemia, blood samples were collected before treatment and every 3 days until day 45; an exponantial decay model was used. The pharmacokinetic and pharmacodynamic parameters were estimated for each patient by nonlinear regression. The correlations between efficacy parameters and exposure parameters, were then studied in the 40 patients. The mean (+/- SD) apparent volume of distribution and clearance were 151 L (+/- 94) and 184 L/h (+/- 72), respectively. The mean initial antigen level was 472 pg/mL (+/- 409), the coefficient of reduction of antigenemia was 0.27 (+/- 0.21) and the rate of decrease was 0.27/day (+/- 0.16). The coefficient of P24 reduction was found to be significantly correlated to the daily area under the curve (P < 0.0014). This relationship was adequately described by an Imax model and the daily area under the curve, leading to 50% of antigenemia decrease, was estimated to be 2.32 mg x h/L (+/- 0.33). In conclusion, a significant relationship between exposure to zidovudine at day 1, and decrease of P24 antigenemia was found. It was estimated that the average steady-state concentration, which corresponds to 70% of maximal efficacy, was 0.22 mg/L. Together with the large interpatient variability of zidovudine pharmacokinetics, these findings confirmed that zidovudine should be monitored and a clinical target concentration was defined.