Liquid biopsy posttreatment surveillance in endemic nasopharyngeal carcinoma: a cost-effective strategy to integrate circulating cell-free Epstein-Barr virus DNA.

BACKGROUND: The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. METHODS: For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. RESULTS: For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. CONCLUSIONS: The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Combining tumor response and personalized risk assessment: Potential for adaptation of concurrent chemotherapy in locoregionally advanced nasopharyngeal carcinoma in the intensity-modulated radiotherapy era.

BACKGROUND AND PURPOSE: In the intensity-modulated radiotherapy (IMRT) era, the role of concurrent chemoradiotherapy (CCRT) after induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is undetermined, while concerns exist about CCRT-associated excessive toxicity. We aimed to combine tumor response and risk assessment to guide decisions about concurrent chemotherapy. MATERIALS AND METHODS: From April 2009 to December 2015, 744 LANPC patients treated with CCRT/IMRT after IC were included. Matching techniques were performed for treatment effect evaluation. Tumor response to IC was used for patient stratification. A nomogram was built based on multivariable Cox regression analysis to predict overall survival (OS). RESULTS: After IC, 508 patients (68.3%) had favorable tumor response (complete or partial response), among whom IC + CCRT achieved significantly superior 5-year disease-free survival and OS than IC + IMRT (82.2% vs. 72.5%, P = 0.025; 89.2% vs. 79.9%, P = 0.025). However, no significant difference was found in patients with unfavorable response (both P > 0.05). For favorable responders, a nomogram was built integrating age, smoking, T category, N category, pretreatment Epstein-Barr virus DNA and treatment modality. The concordance index was 0.713 and calibration was good. The nomogram determined three risk groups with distinct OS. High-risk patients benefited from CCRT after IC regarding disease-free survival, OS and distant metastasis-free survival, whereas low- and intermediate-risk patients did not. CONCLUSIONS: For LANPC patients with unfavorable response to IC, subsequent CCRT seems inadequate, rendering intensification necessary. For favorable responders with low risk, IC + IMRT represents a reasonable de-intensification approach, although confirmation by prospective data is needed.

Evidence Underlying Recommendations and Payments from Industry to Authors of the National Comprehensive Cancer Network Guidelines.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines are among the most widely used guidance in oncology. It is critical to understand the extent to which the recommendations in these guidelines are supported by evidence and to investigate whether these recommendations have been influenced by payments from industry to authors. MATERIALS AND METHODS: We examined the quality and consistency of evidence, as scored by guidelines authors, for systemic treatment incorporated in the NCCN guidelines. Payments data in 2015 were manually abstracted using the Open Payments database, which discloses all payments between the industry and American physicians. Correlations between the percentage of authors who received payments and the proportion of recommendations developed from low-level evidence per guideline were calculated using Spearman rank correlation. RESULTS: In total, 1,782 recommendations were identified in 29 guidelines, of which 1,282 (71.9%) were based on low-quality or low-consistency evidence (low-level evidence), including "case reports or clinical experience only" (18.9%). A substantial proportion (31/143, 21.7%) of category 1 (the highest level) recommendations were based on low-level evidence. The majority of authors (87.1%) received payments from industry. However, no association was found between the prevalence of payments among authors and the percentage of recommendations developed from low-level evidence per guideline. CONCLUSION: The majority of systemic treatment recommendations in the NCCN guidelines are based on low-level evidence, including more than one in five category 1 recommendations. Payments from industry were prevalent among authors. However, industrial payments among authors were not associated with inclusion of regimen/agent for which there is no conclusive evidence in the guidelines. IMPLICATIONS FOR PRACTICE: The authors found that the majority (71.9%) of systemic treatment recommendations issued in the current National Comprehensive Cancer Network guidelines were based on low-level evidence. Physicians should remain cautious when using current guidelines as the sole source guiding patient care decisions.

Comprehensive insights into the key components of bacterial assemblages in pharmaceutical wastewater treatment plants.

Due to complexity and variety of pharmaceutical wastewater composition, little is known as for functionally important microflora of pharmaceutical wastewater treatment plants (pWWTPs). We compared bacterial composition and diversity of pWWTPs (27 sludge samples collected from 12 full-scale pWWTPs) with those of other industrial (iWWTPs) (27 samples) and municipal wastewater treatment plants (mWWTPs) (27 samples) through meta-analysis based on 16S rRNA gene amplicon sequencing, and identified putatively important organisms and their ecological correlations. Non-metric multidimensional scaling indicated that the pWWTPs, iWWTPs and mWWTPs showed distinctive differences in bacterial community composition (P < 1e-04), and the pWWTPs had significantly lower bacterial diversity than the mWWTPs (P < 1e-06). Thermotogae and Synergistetes phyla only strictly dominated in the pWWTPs, and 26, 30 and 6 specific genera were identified in the pWWTPs, mWWTPs and iWWTPs, respectively. Totally, 15 and 1300 OTUs were identified as core and occasional groups, representing 23.2% and 66.2% of the total read abundance of the pWWTPs, respectively. Permutational multivariate analysis of variance revealed that the bacterial components were clearly clustered corresponding to the types of pharmaceutical wastewater, and a total of 129 local specific OTUs were identified in the pWWTPs, among which anticancer antibiotics pWWTPs had the highest number of specific OTUs (40 ones). Co-occurrence network revealed that the species dominating in the same type of pWWTPs tended to co-occur much more frequently than theoretical random expectation. The results may extend our knowledge regarding the ecological status and correlation of the key microflora in pWWTPs.

Cost-Effectiveness Analysis of Routine Magnetic Resonance Imaging in the Follow-Up of Patients With Nasopharyngeal Carcinoma After Intensity Modulated Radiation Therapy.

PURPOSE: To estimate the clinical benefit and cost-effectiveness of routine head and neck magnetic resonance imaging (MRI) in the follow-up of patients with nasopharyngeal carcinoma after definitive intensity modulated radiation therapy. PATIENTS AND METHODS: Two Markov models were developed to compare the cost and effectiveness of 3 strategies: routine clinical surveillance without serial imaging and routine annual and biannual MRI surveillance in the first 5 years. Two hypothetical cohorts of patients with primary stage T1-2 or T3-4 nasopharyngeal carcinoma who achieved complete remission after radical treatment and remained asymptomatic were analyzed. Baseline probabilities, transition probabilities, utilities, and costs were derived from published studies. Markov models were used to calculate life-time costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Model robustness was addressed via univariable and probabilistic sensitivity analyses. RESULTS: In T1-2 patients, surveillance strategies utilizing routine MRI provided few QALYs compared with non-MRI clinical follow-up (annual MRI, 0.022 QALYs; biannual MRI, 0.035 QALYs), whereas the costs associated with MRI surveillance were considerable. Compared with clinical follow-up, the ICERs for annual and biannual MRI strategies were $328,389 and $403,857 per QALY. In T3-4 patients, annual and biannual MRI surveillance provided 0.052 and 0.088 incremental QALYs, with ICERs of $156,204 and $169,772 per QALY, respectively. Model conclusions were robust and remained stable in 1-way and probabilistic sensitivity analyses. CONCLUSIONS: Routine MRI surveillance was not cost-effective owing to the high cost of MRI coupled with low rates of failure in T1-2 patients, whereas annual MRI surveillance was the dominant and possibly a cost-effective strategy for T3-4 patients, depending on the social willingness to pay.

Publication status of contemporary oncology randomised controlled trials worldwide.

BACKGROUND: Little is known about the extent of selective publication in contemporary oncology randomised controlled trials (RCTs) worldwide. This study aimed to evaluate the rates of publication and timely publication (within 24 months) for contemporary oncology RCTs from all over the world. We also investigated the trial characteristics associated with publication and timely publication. PATIENTS AND METHODS: We identified all phase III oncology RCTs registered on ClinicalTrials.gov with a primary completion date between January 2008 and December 2012. We searched PubMed and EMBASE to identify publications. The final search date was 31 December 2015. Our primary outcome measure was the time to publication from the primary completion date to the date of primary publication in a peer-reviewed journal. RESULTS: We identified 598 completed oncology RCTs; overall, 398 (66.6%) had been published. For published trials, the median time to publication was 25 months (interquartile range, 16-37 months). Only 192 trials (32.1%) were published within 24 months. Timely publication was independently associated with trials completed late in 2012. Trials conducted in Asia and other regions were less likely to have timely publication, but trials conducted in different locations were all equally likely to be published. Industry- and NIH-funded trials were equally likely to be published timely or at any time after trial completion. Among 391 published trials with clear primary outcomes, there was a trend for timely publication of positive trials compared with negative trials. CONCLUSIONS: Despite the ethical obligations and societal expectations of disclosing findings promptly, oncology RCTs performed poorly.