title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Patient characteristics | MAY | From May 2020 to September 2020, a total of 102 eligible patients were randomly assigned into the study. One patient in control intervention group withdrew consent and 1 patient failed to complete radiotherapy. One patient in Sanyrene group was excluded from final analysis due to incomplete radiotherapy. Ultimately, 99 patients were included in the final analysis (Fig. Patient characteristics were well balanced in both arms (Table
Baseline characteristics of patients [Median (range)/n (%)]BMI, body mass index; 3D-CRT, 3-dimensional conformal radiation therapy; VMAT, volumetric modulated arc radiation therapy; CCRT, concurrent chemotherapy | PMC10604398 | |
Efficacy | toxicity, dermatitis, skin toxicity, skin toxicities | BREAST CANCER, HEAD AND NECK CANCER, SKIN TOXICITIES, ONCOLOGY, DERMATITIS, SKIN TOXICITY | All patients completed their follow-up records at 4 weeks post-radiotherapy. Of all patients, 55 patients (55.5%) experienced grade 1 skin toxicity, 30 patients (30.3%) experienced grade 2 toxicity, and 14 patients (14.1%) experienced grade 3 skin toxicity during the whole treatment and follow-up period. None of patients in this study experienced grade 4 RD. The incidence rate of ≥ grade 2 RD was 22% (95% confidence interval (CI), 12–36.3%) in Sanyrene group, as compared with 67.3% (95% CI, 52.3–79.6%) in the control intervention group (
Incidence rate of ≥ grade 2 of radiation dermatitis in two treatment group
RTOG skin toxicities in both groups [n (%)]RTOG, Radiation Therapy Oncology Group
Incidence rate of time to ≥ grade 2 of radiation dermatitis between two groups
Univariate and multivariate analysis for grade 2 skin toxicityTreatment Group(Sanyrene vs. Control intervention)HNC, head and neck cancer; BC, breast cancer; 3D-CRT, 3-dimensional conformal radiation therapy; VMAT, volumetric modulated arc radiation therapy; CCRT, Concurrent chemotherapyMean score of SD-16 were much higher in control intervention group than Sanyrene group at end of RT (25 vs.8.3), 2 weeks after RT (22.9 vs. 0.5) and 4 weeks after RT (4.2 vs.0), with significantly statistical difference between two groups (Fig.
Mean score of SD-16 between two groups in whole treatment process | PMC10604398 |
Discussion | toxicity, pain, head and neck cancer, dermatitis, skin toxicity, cutaneous inflammation | DISEASE, HEAD AND NECK CANCER, BLIND, DERMATITIS, SKIN TOXICITY | To our knowledge, this is the first study to identify the prophylactic effect of Sanyrene- a liquid dressing with linoleic acid and linolenic acid mixture in radiotherapy induced dermatitis. In this study, we found Sanyrene significantly reduced the incidence rate of ≥ grade 2 RD when compared to control intervention. Moreover, patients in Sanyrene group had better Qol and more mild pain than those in control intervention group during the whole RT process up to 4 weeks after end of RT. As there is no consensus on the standard intervention, our study is an evidence to supplement the strategy of RD prophylaxis and management.Barrier films and dressings are kind of treatment methods for acute RD, but there is lack of consensus recommendation among guidelines for use of these methods. A single-blinded, randomized controlled study reported a silicone-based film dressing could reduce 41% and 49.4% risks of developing grade 2 and 3 skin toxicity compared to control arm in patients with head and neck cancer receiving radiotherapy, but skin related Qol was not improved by this dressing [Many studies reported linoleic acid and linolenic acid were benefit for skin by attenuating cutaneous inflammation through the competition with the inflammatory arachidonic acid and the inhibition of proinflammatory eicosanoid production [There were some limitations in this study. Firstly, it was difficult to blind physicians or patients in this trial because Sanyrene and control intervention (a cream containing Vitamin E and hyaluronic acid) had different properties. To reduce the confounding bias as much as possible, we chose two nurses who were not involved in the study to assess the grade of skin toxicity according to acute RTOG criteria. If consensus was not reached, the third nurse would assess the skin toxicity again and consensus meetings were conducted to resolve the disagreements. These nurses accepted training of toxicity assessing before beginning of the study. Therefore, we did blind the assessors of RD grade for trying to avoid bias. Secondly, subgroup analysis found Sanyrene effectively prevented incidence rate of ≥ grade 2 RD in patients with BC and HNC respectively, but bias was unavoidable due to small sample in each subgroup. Especially for head and neck cancer, concurrent chemoradiotherapy which could improve incidence of RD was not a rigorous inclusion criteria. Therefore, randomized controlled studies aiming to single disease should be conducted to confirm the efficacy of Sanyrene in preventing RD. | PMC10604398 |
Conclusion | head and neck cancer, breast cancer | HEAD AND NECK CANCER, BREAST CANCER | This trial suggests that Sanyrene is effective on preventing serious RD and improving skin related Qol in patients with breast cancer and head and neck cancer receiving radiotherapy. However, these results should be further validated by trials with rigorous design. | PMC10604398 |
Acknowledgements | Not applicable. | PMC10604398 | ||
Author contributions | X.L. and J.G. contributed to the preparation of manuscript and interpretation of the data. Y.Y. contributed to the the analysis and interpretation of the data. M.C., X.Z., J.Z. and P.W. contributed to the collection of data. J.Z. and L.Z. contributed to the design of the study and critical revision of the manuscript. All authors reviewed the manuscript. | PMC10604398 | ||
Funding | No funding was received for this study. | PMC10604398 | ||
Data Availability | All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author. | PMC10604398 | ||
Declarations | PMC10604398 | |||
Competing interests | The authors declare no competing interests. | PMC10604398 | ||
Ethics approval and consent to participate | This study was approved by the Ethics Committee of the First Affiliated Hospital of Air Force Medical University (ethical approval number: KY20202016-F-1). Written informed consent was obtained from participants to participate in the study. | PMC10604398 | ||
Consent for publication | Not applicable. | PMC10604398 | ||
References | PMC10604398 | |||
Abstract | PMC10448250 | |||
Objective | To determine the effects of salt reduction interventions designed for home cooks and family members. | PMC10448250 | ||
Design | Cluster randomised controlled trial. | PMC10448250 | ||
Setting | Six provinces in northern, central, and southern China from 15 October 2018 to 30 December 2019. | PMC10448250 | ||
Participants | 60 communities from six provinces (10 communities from each province) were randomised; each community comprised 26 people (two people from each of 13 families). | PMC10448250 | ||
Interventions | Participants in the intervention group received 12 month interventions, including supportive environment building for salt reduction, six education sessions on salt reduction, and salt intake monitoring by seven day weighed record of salt and salty condiments. The control group did not receive any of the interventions. | PMC10448250 | ||
Main outcome measure | Difference between the two groups in change in salt intake measured by 24 hour urinary sodium during the 12 month follow-up. | PMC10448250 | ||
Results | 1576 participants (775 (49.2%) men; mean age 55.8 (standard deviation 10.8) years) from 788 families (one home cook and one other adult in each family) completed the baseline assessment. After baseline assessment, 30 communities with 786 participants were allocated to the intervention group and 30 communities with 790 participants to the control group. During the trial, 157 (10%) participants were lost to follow-up, and the remaining 706 participants in the intervention group and 713 participants in the control group completed the follow-up assessment. During the 12 month follow-up, the urinary sodium excretion decreased from 4368.7 (standard deviation 1880.3) mg per 24 hours to 3977.0 (1688.8) mg per 24 hours in the intervention group and from 4418.7 (1973.7) mg per 24 hours to 4330.9 (1859.8) mg per 24 hours in the control group. Compared with the control group, adjusted mixed linear model analysis showed that the 24 hour urinary sodium excretion in the intervention group was reduced by 336.8 (95% confidence interval 127.9 to 545.7) mg per 24 hours (P=0.002); the systolic and diastolic blood pressures were reduced by 2.0 (0.4 to 3.5) (P=0.01) and 1.1 (0.1 to 2.0) mm Hg (P=0.03), respectively; and the knowledge, attitude, and behaviours in the intervention group improved significantly. | PMC10448250 | ||
Conclusions | The community based salt reduction package targeting home cooks and family members was effective in lowering salt intake and blood pressure. This intervention has the potential to be widely applied in China and other countries where home cooking remains a major source of salt intake. | PMC10448250 | ||
Trial registration | Chinese Clinical Trial Registry ChiCTR1800016804. | PMC10448250 | ||
Introduction | stroke | KIDNEY DISEASE, HEART DISEASE, STROKE, HYPERTENSION, GASTRIC CANCER | Excess dietary salt consumption is a major risk factor for hypertension, stroke, heart disease, kidney disease, and gastric cancer.Salt reduction has been adopted as one of the most cost effective public health policies worldwide. The World Health Organization and the United Nations Food and Agriculture Organization issued a joint report in 2003, calling for a reduction in population salt intake to less than 5 g per day (<2000 mg sodium).As salt used in home cooking is the major contributor to salt intake in Chinese families, and home cooks are the people responsible for purchasing food and preparing meals for family members, comprehensive interventions should be provided for home cooks, and the effectiveness should be critically evaluated. In addition, few randomised controlled trials have been conducted to examine the effect of salt reduction interventions focusing on health education and behaviour change in the community setting in China. | PMC10448250 |
Methods | PMC10448250 | |||
Study design | A parallel cluster randomised controlled trial was conducted between October 2018 and December 2019 in communities from six cities in six provinces—Qinghai, Hebei, Heilongjiang, Sichuan, Jiangxi, and Hunan. A detailed design has been published elsewhere. | PMC10448250 | ||
Participants | Twenty six adults from 13 families, two from each including the usual cook, were recruited from each community for outcome evaluation. Eligible people were aged between 18 and 75 years and were home cooks and family members who ate homemade meals at least four times every week. If more than one family member in a family agreed to participate in the outcome assessments, the spouse of the home cook or a family member of the opposite sex to the home cook would be selected first. Participants resided in the community for more than six months and had no relocation plans for the next 24 months. We excluded anyone who was pregnant or lactating or could not collect or refused to collect 24 hour urine. | PMC10448250 | ||
Interventions | DISEASE | The intervention included health education lectures, monitoring of salt intake, and establishment of a supportive environment. The intervention lasted for one year.The lectures comprised six sessions of education on salt reduction, disseminating knowledge on the harmful effects of high sodium intake on health, the source of salt in the daily diet, use of low sodium salt, skills for reducing salt intake during cooking (for example, using natural spices instead of salty condiments to improve the taste) and tips for purchasing pre-packaged food (for example, choosing low sodium products by reading nutrition labels). Each lesson lasted 40 minutes, and lessons were conducted once every two months by trained personnel from the local county Center for Disease Control and Prevention (CDC). From session two to session six, a quiz was used before the lecture to help participants to review the key points taught in the previous sessions. Home cooks were invited to participate in all the lectures (and family members were also encouraged to do so).Salt intake was monitored by using a seven day estimation method.A supportive environment containing health education information on salt reduction was established in the community through various media strategies, including posters, short videos, loudspeaker broadcasts, leaflets, and manuals. In addition, we provided salt restriction spoons to the families as practical tools to reduce salt intake. The intervention aimed to create an atmosphere of salt reduction all over the community, so as to help to promote individual behaviour change. A detailed description of the intervention activities is provided in supplementary table A. | PMC10448250 | |
Outcomes | SECONDARY | The primary outcome was the difference between the two groups in the change from baseline to follow-up in salt intake measured by 24 hour urinary sodium. The secondary outcomes were the differences in the change in blood pressure and in knowledge, attitude, and behaviours between the two groups.Data were collected by well trained field investigators through a specially designed mobile device based electronic data capture system (mEDC, Electronic Data Collection). The urine sample was excluded if the collection time was less than 20 hours or more than 28 hours. If the duration of urine collection was not 24 hours but within 20-28 hours, we calculated adjusted 24 hour urine volume as total volume divided by collection time and multiplied by 24. The calculations of 24 hour urinary sodium and potassium were as follows: sodium (mg/day)=23 (mg/mmol)×concentration (mmol/L)×adjusted 24 hour urine volume (L/day); potassium (mg/day)=39.1 (mg/mmol)×concentration (mmol/L)×adjusted 24 hour urine volume (L/day).The biochemists who made the measurements of urinary electrolytes were unaware of the group to which the participant was allocated. Urine samples were defined as incomplete and excluded from the analysis if the 24 hour urine volume was <500 mL or creatinine was <4.0 mmol for women or <6.0 mmol for men. | PMC10448250 | |
Sample size | We assumed a standard deviation for 24 hour urinary sodium excretion of 85 mmol/24 hours (1960 mg/day) and an intra-class correlation coefficient of 0.05. | PMC10448250 | ||
Randomisation and masking | RECRUITMENT | The 60 communities were assigned to the intervention group or the control group in a one to one ratio. Randomisation was computer generated centrally by the Chinese CDC, stratified by provinces. The randomisation procedure was carried out after the baseline survey, and the participants and local investigators who undertook recruitment and baseline data collection were unaware of the group allocation. | PMC10448250 | |
Statistical analysis | hypertension | SECONDARY, HYPERTENSION | We analysed the data according to the intention-to-treat principle. Participants who completed the baseline survey were analysed according to their randomly assigned group. We compared the difference in 24 hour urinary sodium excretion, as well as the secondary outcomes, between the two groups by using linear mixed models with participants nested within family units and families nested within community/village units. We included groups (intervention and control), time (baseline and end of the trial), (time×group) interactions, and potential confounding variables, including age, sex, body mass index, province, and education level, in the model, with the (time×group) interaction term indicating different changes by the group from baseline to the end of the trial. We did post hoc subgroup analyses considering age, sex, education level, family income, and hypertension status. To test the robustness of the primary findings, we did two sensitivity analyses: analysing the results without adjustment for the potential confounding variables and adding possibly incomplete 24 hour urine collections to the samples for analysis.We used SAS version 9.4 for the analyses and calculated all P values as two sided. We determined statistical significance by a false discovery rate of less than 0.05. | PMC10448250 |
Patient and public involvement | Provincial CDCs, county level CDCs, and primary healthcare centres were involved in the design and conduct of this study. At the protocol stage, we gained their opinions on the content of the intervention and the electronic data collection system. Personnel at the county level CDCs helped to translate the educational materials, which were produced by the research team, into language appropriate to the local people. | PMC10448250 | ||
Results | REGRESSION, POSITIVE | We recruited 60 communities (10 in each province) into the study in October 2018. A total of 1576 participants from 788 families completed the baseline survey. The mean age was 55.8 (standard deviation 10.8) years, and 775 (49.2%) were male. During the trial, 157 (10%) participants were lost to follow-up as they moved to another county or were unable to attend follow-up assessments (Flowchart of participantsBaseline characteristics. Values are numbers (percentages) unless stated otherwiseSD=standard deviation.The establishment of a supportive environment intervention covered all the people living in the intervention communities. Data collected during the intervention showed that 953 posters were put up, and 10 510 leaflets and 5265 manuals were distributed to people living in the intervention communities. Short videos were played in the health service stations of 25 communities in five provinces (not in Qinghai). Loudspeaker broadcasts were played in 25 communities in five provinces (not in Sichuan). Six lectures and six salt intake monitoring activities were organised in all communities in the intervention group as planned. The number of people who took part in the lectures was 4975 (on average, 28 for each lecture in each community).The mean baseline urinary sodium excretion was 4418.7 (standard deviation 1973.7) mg per 24 hours in the control group and 4368.7 (1880.3) mg per 24 hours in the intervention group. During the 12 month trial, we observed decreases in sodium excretion in the two groups after adjustment for confounders. After adjustment, the mean difference between the intervention group and the control group was −336.8 (95% confidence interval −545.7 to −127.9) mg per 24 hours, which is equivalent to a 0.9 g per 24 hours decrease in salt intake (Results for 24 h urinary sodium excretion, potassium excretion, sodium-to-potassium ratio, and blood pressureCI=confidence interval; SD=standard deviation.Results were obtained from mixed linear model with random intercept of participants nested within family and random intercept of family nested within communities; all values for urinary outcomes were adjusted for age, sex, body mass index at baseline and follow-up, province, and education level. All values for blood pressure were further adjusted for outdoor temperature at baseline and follow-up, physical activity, and alcohol drinking status.Comparison of means within each group. Positive values indicate increase from baseline to 12 month follow-up; negative values indicate decrease from baseline to 12 month follow-up.Comparison between intervention group and control group in changes from baseline to 12 month follow-up. Positive values indicate that intervention group had greater increase or smaller decrease from baseline to 12 month follow-up compared with control group; negative values indicate that intervention group had greater decrease or smaller increase from baseline to 12 month follow-up compared with control group.Results for 24 hour urinary sodium excretion by subgroup (mg/24 h)CI=confidence interval; SD=standard deviation.Results were obtained from mixed linear model with random intercept of participants nested within family and random intercept of family nested within communities; all values for urinary outcomes were adjusted for age, sex, body mass index at baseline and follow-up, city, and education level.Comparison of means within each group. Positive values indicate increase from baseline to 12 month follow-up; negative values indicate decrease from baseline to 12 month follow-up.Comparison between intervention group and control group in changes from baseline to 12 month follow-up. Positive values indicate that intervention group had greater increase or smaller decrease from baseline to 12 month follow-up compared with control group; negative values indicate that intervention group had greater decrease or smaller increase from baseline to 12 month follow-up compared with control group.Age was defined as natural cubic spline with internal knots at 25th, 50th, and 75th centiles.
Results for knowledge, attitude, and behavioursCI=confidence interval; OR=odds ratio.Results were obtained from mixed effect logistic regression model with random intercept of participants nested within family and random intercept of family nested within communities; all values were adjusted for age, sex, body mass at baseline and follow-up, city, and education level.Questionnaires about using low sodium salt substitutes were filled out by people who had heard about low sodium salt substitutes.Supplementary tables E and F show the results of the sensitivity analyses. The mean effects on urinary sodium (−318.4 (−527.0 to −109.7) mg per 24 hours) and blood pressure (systolic −1.3 (−2.8 to 0.2) mm Hg; diastolic −0.7 (−1.7 to 0.2 ) mm Hg) were smaller if not adjusted for the confounders (supplementary table E). The mean effect was similar to the main results when possibly incomplete 24 hour urine collections were included (supplementary table F). | PMC10448250 | |
Discussion | We developed a set of community based salt reduction interventions targeting home cooks and family members. This cluster randomised controlled trial showed that the intervention package not only effectively reduced the urinary sodium excretion by 336.8 mg/day (0.9 g/day salt reduction) but also lowered systolic blood pressure by 1.98 mm Hg and diastolic blood pressure by 1.05 mm Hg within one year. Salt related knowledge, attitude, and behaviours also improved significantly.Population level multicomponent salt reduction activities have the potential to reduce dietary salt intake. | PMC10448250 | ||
Comparison with other studies | Hg lower mean systolic blood pressure | Our results showed that the reduction in urinary sodium excretion was accompanied by a decrease in blood pressure, especially systolic blood pressure. A recent meta-analysis of randomised salt reduction trials found that every 100 mmol/day (2.3 g/day) reduction in urinary sodium excretion was associated with a 5.56 (95% confidence interval −4.52 to −6.59) mm Hg lower mean systolic blood pressure and a 2.33 (−1.66 to −3.00) mm Hg lower mean diastolic blood pressure. | PMC10448250 | |
Strengths and limitations of study | This was a large scale, community based salt reduction study targeting families in communities in eastern, central, and western regions of China. A stringent and standardised protocol was implemented at all study sites, with a high follow-up rate of 90%. An electronic data collection system was used to ensure high quality data collection. People who analysed the urine samples in the laboratory were blinded to whether the samples were from participants in the control or intervention group, which avoided potential bias in the sodium measurements.Our study also had some limitations. Firstly, we used 24 hour urine sodium excretion to evaluate the daily salt intake, which is acknowledged to be the most accurate method. However, single 24 hour urine collection provided limited information on dietary salt intake compared with multiple 24 hour urine collections. Secondly, the study outcomes (that is, 24 hour urinary sodium and blood pressure) were assessed at the start and at the end of the trial, so the change in the intervention effect over time could not be observed. Thirdly, the effect of the intervention measures was evaluated as a whole, which means that the independent effect of each measure could not be determined. | PMC10448250 | ||
Conclusions and public health implications | EVENTS, AIDS | This study showed that the comprehensive salt reduction interventions targeting home cooks and family members were effective in terms of both urinary sodium and blood pressure reduction. The reduction of 0.9 g/day in salt intake observed in our study seems modest; however, it has substantial public health significance in terms of preventing cardiovascular events and reducing medical costs.In 2016 the Chinese government issued its “Healthy China 2030” plan and set a goal of a 20% reduction of daily salt intake in adults by 2030. Our study was a positive action to help in achieving China’s salt reduction target, and the effect was evident during the one year trial. When implementing the interventions in the real world in the long term, strong policy support and continuing input of grassroots personnel are important guarantees for the sustainability of the community based salt reduction interventions. Village doctors and neighbourhood committees are involved in mobilising residents to participate in the activities. Grassroots professional staff are responsible for giving lectures and providing guidance on salt monitoring. Integration of the salt reduction interventions into health policy and introduction of a system of incentives and assessment for the local personnel would be useful aids to implementation. Furthermore, community based interventions should be accessible to older people, who may not be familiar with the use of a smartphone. This would make the generalisation of self-monitoring of salt intake using the WeChat app challenging.To evaluate the long term effect of the interventions, we have been collecting data on urine sodium and blood pressure of the participants one and two years after the trial. We hope that these data will provide more evidence on the effect of the community based interventions in the future.In conclusion, this study provides new scientific evidence on the involvement of home cooks in salt reduction interventions and has the potential to be widely applied in China and other countries where home cooking is a major source of salt intake. Feasible public health policy is needed to facilitate the sustainability of the community based salt reduction interventions. | PMC10448250 | |
What is already known on this topic | disease burdenSalt reduction | Salt intake in China is more than double the recommended limit, which causes a heavy disease burdenSalt reduction is a cost effective public health policyMost dietary salt in China is added during home cooking, but evidence from randomised controlled trials of interventions targeting home cooks has been lacking | PMC10448250 | |
What this study adds | cardiovascular diseasesWe | DISEASE, CARDIOVASCULAR DISEASES | A package of community based salt reduction interventions for home cooks and family members to gain knowledge of and develop skills in salt reduction has been developedThese interventions were feasible and effective in improving salt reduction behaviours and reducing urinary sodium excretion and blood pressureThis intervention package has the potential to be scaled up to larger areas so as to help in the prevention of cardiovascular diseasesWe thank all the participants who were involved in the research. We are grateful to the staff from local Centers for Disease Control and Prevention and the primary healthcare centres for contributing to the data collection. We extend our gratitude to Xiao Hu and Yibing Yang for their help with the quality control of baseline assessment.Extra material supplied by authorsWeb appendix: Supplementary materialsContributors: PZ, XZ, JW, YL, JM, FJH, and GAM designed the study, developed the protocol, and were involved in the interpretation of the results. WY, YG, DJ, YD, FG, SY, XZ, DS, and YL were responsible for the onsite field investigation and participated in monitoring and supervision of data collection. DS, XZ, and JS were involved in the statistical analysis of the study. XZ and DS drafted the manuscript, and all authors commented on and contributed to the final version. JW and PZ received the funding and are the guarantors. PZ is the co-corresponding author and can be reached at zpuhong@georgeinstitute.org.cn. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.Funding: This research was funded by the UK National Institute for Health Research (16/136/77) using UK aid from the UK government to support global health research. The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health Research or the UK Department of Health and Social Care. The funders had no role in considering the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication.Competing interests: All authors have completed the ICMJE uniform disclosure form at The lead authors (the manuscript’s guarantors) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.Dissemination to participants and related patient and public communities: Once the study has been published, provincial Centers for Disease Control and Prevention, county level Centers for Disease Control and Prevention, primary healthcare centres, and participants will be informed of the results via newsletters, WeChat, and website updates.Provenance and peer review: Not commissioned; externally peer reviewed. | PMC10448250 |
Ethics statements | PMC10448250 | |||
Ethical approval | DISEASE | The study protocol was approved by Queen Mary (University of London) Ethics of Research Committee (QMERC2018/13) and the Institutional Review Board of the Chinese Center for Disease Control and Prevention (No 201801). All participants who took part in the outcome assessments gave written informed consent. | PMC10448250 | |
Data availability statement | DISEASE | Relevant anonymised individual level data will be made available one year after publication of the primary manuscript on request from the corresponding authors. Request for data sharing will be handled in line with the relevant regulations for data access and sharing in China and will need the approval of the trial steering committee and the Institutional Review Board of the Chinese Center for Disease Control and Prevention. | PMC10448250 | |
Subject terms | While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.gov #NCT04470427). In the mAb trial, protective efficacy of 92% (95% confidence interval (CI): 84%, 98%) is associated with a nAb titer of 1000 IU50/ml, with lower efficacy at lower nAb titers. In the vaccine trial, protective efficacies of 93% [95% CI: 91%, 95%] and 97% (95% CI: 95%, 98%) are associated with nAb titers of 100 and 1000 IU50/ml, respectively. These data quantitate a nAb titer correlate of protection for mAbs benchmarked alongside vaccine induced nAb titers and support nAb titer as a surrogate endpoint for authorizing new mAbs.Here the authors assess neutralizing antibody (nAb) levels as correlate of protection in a monoclonal antibody prevention trial and a vaccine trial for COVID-19 and show that nAb titers correlate with clinical protection against COVID-19 supporting nAb titer as a surrogate endpoint for authorization of monoclonal antibodies. | PMC10276829 | ||
Introduction | infection, death, illness | CORONAVIRUS, INFECTION, ADENOVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME | Adenovirus vector, mRNA, and protein subunit vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective in reducing the incidence of symptomatic infection, severe illness, hospitalization, and death due to COVID-19Antiviral mAbs are effective in the treatment and prevention of COVID-19Clinical efficacy data from a randomized prevention trial (COV-2069) of the mAb combination, casirivimab, and imdevimab, both highly potent neutralizing antibodies recognizing the spike protein of SARS-CoV-2 | PMC10276829 |
Results | PMC10276829 | |||
Neutralization titer kinetics | For participants in the monoclonal antibody COV-2069 trial, the median half-life of the neutralization titer was 26 days. For vaccinated individuals in the COVE trial, the estimated half-life was 70 days. The predicted nAb kinetics of 10 randomly selected COV-2069 and COVE participants over the course of their respective follow-up periods are given in Fig. | PMC10276829 | ||
Predicted pseudo-virus neutralization titer by days since full immunization (day 1 for mAbs, day 57 for vaccine) for ten randomly selected participants from the COVE immunogenicity subcohort (gold) and COV-2969 (green) trials. | EVENT, DECAY | The COVE lines use the measured Day 57 neutralization titer (red circle) with subsequent decay determined by a common slope estimated from independent data. Casirivimab + imdevimab mAb lines use concentration curves based on sex and weight and subsequently converted to neutralization titer. The curves start at day 8 days post full immunization (vaccine) or injection (mAb) and stop at the time of event or the end of follow-up. | PMC10276829 | |
Monoclonal antibody (casirivimab + imdevimab) preventive efficacy | The cumulative incidence of COVID-19 by randomization group is given in Supplementary Fig. | PMC10276829 | ||
Vaccine (mRNA-1273) efficacy | Starting 7 days after the day 57 visit through the end of the blinded phase, a total of 47 vaccine group participants and 659 placebo group participants acquired COVID-19 resulting in an estimated VE of 100% x (1–48/659) = 92.6%. The cumulative incidence of COVID-19 by arm is given in Supplementary Fig. | PMC10276829 | ||
Efficacy curves for the monoclonal antibody combination (casirivimab + imdevimab) and mRNA-1273 vaccine | The relationship between predicted log10 nAb titer at the time of exposure and protection against COVID-19 is shown in Fig. | PMC10276829 | ||
Protective efficacy (PE) of casirivimab + imdevimab mAbs (solid green curve) and vaccine efficacy (VE) of mRNA-1273 (dashed orange curve) against COVID-19 as a function of predicted pseudo-virus neutralization titer at the time of exposure. | Shaded area provides 95% pointwise confidence intervals with lighter green emphasizing greater uncertainty for lower titers. PE and VE curves cover the distribution of titers achieved during follow-up with no extrapolation. | PMC10276829 | ||
Quantifying the role of extant nAb titers in vaccine induced protection | We deconstructed the total vaccine effect as the product of an extant nAb titer effect times all other vaccinal effects beyond extant nAb titer. The analysis suggests that at a predicted neutralization titer of 1000 IU50/ml, the percent of total vaccine efficacy due to extant antibody was 72% (95% CI: 50%, 100%) and the probability that a person protected by the vaccine would have been protected by the mAb at the same titer level was 0.95 (95% CI: 0.86, 1.00) (Supplementary Sections | PMC10276829 | ||
In mRNA-1273 vaccine disease cases nAb titers rise in those with lower titers | DISEASE | To further investigate the effect of an anamnestic versus extant antibody response in protection, we evaluated the kinetics of antibody levels in vaccinated disease cases during the blinded phase of the COVE trial | PMC10276829 | |
Binding antibody concentration and neutralization titers at 28 days post second dose, the onset of COVID-19 symptoms, and 28 days later in vaccinated participants who acquired COVID-19 during the blinded phase of COVE. | Day 0 is the onset of symptoms. | PMC10276829 | ||
Discussion | SARS | Although the mRNA-1273 vaccine and casirivimab + imdevimab mAbs for COVID-19 prevention have high efficacy over the duration studied, the relative contribution of antibody at the time of exposure differs. For nAb titers greater than 1000 IU50/ml, the clinical efficacy of both mRNA-1273 and casirivimab + imdevimab to prevent COVID-19 is >90%, with extant antibody being responsible for approximately 72% of the total vaccine effect at a nAb titer of 1000 IU50/ml. At lower titers (e.g., <100 IU50/ml), mRNA-1273 efficacy persists, in contrast to the waning efficacy associated with the mAb combination casirivimab + imdevimab, where precise quantitation of protective efficacy at lower nAb titers was not possible due to the low number of COVID-19 cases at late timepoints in COV-2069.While the efficacy of casirivimab + imdevimab to prevent SARS CoV-2 is driven entirely by passive immunity with exogenous monoclonal antibodies | PMC10276829 | |
A schematic illustrating the role of extant circulating and possibly mucosal antibodies in vaccine induced protection. | infection, nAbs | INFECTION, DISEASE, EMERGENCY | Four identical exposure scenarios are depicted. At a higher neutralization titer e.g., 1000 IU50/ml, extant antibody alone results in protection with no need for engagement of B cells, T cells, or other vaccine induced elements. At a lower titer e.g., <100 IU50/ml, mAb antibody alone is not enough for high protection. Thus, vaccine induced protection for lower titers requires engagement of some combination of anamnestic B cell responses (e.g., nAbs antibodies that mediate FcR effector functions), CD8 + T cells, and other vaccine induced immune responses.Vaccine induced nAbs are highly correlated with the prevention of COVID-19 in multiple vaccine trialsThe European Medicines Agency recently recommended authorizing Sanofi’s monovalent B.1.351 protein vaccine as a booster based on clinical immunobridging with a BNT162b2 mRNA comparator vaccine using nAb titer as an endpoint.In contrast, authorization of mAbs appears to require clinical endpoint studies, even though the case for nAb titer as a surrogate of protection is mechanistically stronger as the mAb is the single component of the intervention. Furthermore, recent meta-analyses show similar relationship between nAb titer and protection for vaccines and the monoclonal antibody adintrevimabThe current approach to Food and Drug Administration (FDA) and Emergency Use Authorization (EUA) regulation of mAbs is challenging. While nAb titer alone is currently insufficient as a surrogate of protection to support EUA, nAb titers are monitored against VOCs and inform recommendations to discontinue the use of previously authorized mAbs if there is evidence of substantial reduction in nAb titers to emergent variants. For example, the combinations balmlanivimab + estesvimab, casirivimab + imdevimab and sotrovimab are no longer authorized for treatment of COVID-19 based on low neutralization activity against the Omicron-lineage VOC. EvusheldOur study has the following limitations: mRNA-1273 induced nAbs declined relatively little during follow-up and the correlate of protection curve was not estimated for low titers, therefore not allowing for a side-by-side comparison of mRNA-1273 and casirivimab + imdevimab induced nAbs at low titers. Our studies were conducted in the pre-Omicron era limiting the generalizability of our results to additional variants. Ongoing work is assessing the impact of neutralization titer on Omicron disease and will be important to contrast with our results. While the COVE follow-up ended before the emergence of Delta, COV-2069 did extend into the Delta era. In deconstructing the role of extant antibody in vaccine induced protection, we used casirivimab and imdevimab which are both IgG1 antibodies and are an imperfect proxy for mRNA-1273 induced antibodies which are polyclonal and include other IgG isotypes, IgM and IgA, which may differ in their potential to penetrate the mucosa and in non-neutralizing functions. Our analyses are for a specific mAb combination and vaccine, similar analyses for other mAbs and vaccines would be informative. In the COV-2069 trial, testing for asymptomatic infection was participant driven after the first month resulting in relatively few asymptomatic cases later in the trial. We used predicted neutralization titer for each individual throughout follow-up; using actual titers from frequent sampling might sharpen our results but is not logistically feasible. Baseline characteristics of the participants in the two trials differ somewhat, ideally a randomized 3 arm trial of placebo, mAb, and vaccine would be analyzed. In the COV-2069 trial some vaccination occurred which might weaken our results. Finally, while the confidence of protective efficacy of casirivimab + imdevimab at titers >1000 IU50/ml is high, there is large uncertainty about the extent of protective efficacy at lower titers.Using clinical and drug concentration data from a randomized, controlled prevention trial with casirivimab and imdevimab (completed prior to the emergence of Omicron and Omicron lineage VOCs), alongside ex vivo data from a standardized neutralization assay using reference strain D614G, we identified a strong correlation between mAb neutralization titer and protective efficacy. This result coupled with evidence from other mAb trials, acceptance of neutralization titer against variants for established mAbs, and the extensive evidence from vaccine studies strongly supports the consideration of neutralization titer as a surrogate of clinical efficacy for the development of next generation mAbs for emerging SARS-CoV-2 variants. As SARS-CoV-2 evolution compromises the benefits of available mAbs, this issue has great urgency for millions of immunocompromised hosts who respond poorly to vaccines. | PMC10276829 |
Methods | PMC10276829 | |||
Study design and population: casirivimab + imdevimab mAb prevention trial | Details of the casirivimab + imdevimab COV-2069 clinical trial for the prevention of COVID-19 are described elsewhereThe analysis set of participants without SARS-CoV-2 through day 8, included 829 and 801 participants in the mAb, and placebo arms, respectively (Supplementary Table The mAb and placebo arm participants display similar characteristics with a mean age of 42 years, 47% male, 86% white, mean body mass index (BMI) of 29, and 11% health care worker or first responder. | PMC10276829 | ||
Study design and population: COVE mRNA-1273 vaccine trial | DISEASE | Details of the COVE trial through the end of the blinded phase are published elsewhereGilbert et alWe also used data from Follmann, Janes et al., who evaluated the kinetics of the antibody response to disease during the blinded phase of COVE, for supportive analysisA schematic of the two studies is given in Fig. | PMC10276829 | |
Schematic of the COV-2069 mAb prevention trial and mRNA-1273 vaccine trial (COVE) as analyzed in this report. | ASYMPTOMATIC COVID-19 | Both trials were conducted before the emergence of the Omicron VOC in trial participants, had similar populations, enrolled SARS-CoV-2 naïve individuals, and had similar definitions of symptomatic COVID-19 illness. | PMC10276829 | |
Neutralizing antibody data | For COV-2069 trial participants, pharmacokinetic (PK) antibody concentration curves of casirivimab and imdevimab in serum over 8-months were estimated using population PK models developed for casirivimab and imdevimab from three clinical studies. The population PK models were two compartment models with linear elimination and first-order absorption following subcutaneous dosing | PMC10276829 | ||
Statistical analyses | REGRESSION, DECAY | For each individual in each trial a predicted neutralization titer on each day throughout follow-up was constructed as follows. The relationship between log10 mAb concentration of casirivimab + imdevimab and log10 pseudovirus neutralization titer was estimated using linear regression. For each participant in the COV-2069 trial, the slope from a linear regression of predicted log10 neutralization titer on days since injection was estimated over 8-months of follow-up. For the COVE antibody kinetics analysis, a hierarchical Bayesian model was used to estimate the posterior distribution of the rate of decay of the log neutralization titer, denoted B, over days 57, 119, and 209. The log10 neutralization titer on any day | PMC10276829 | |
Reporting summary | Further information on research design is available in the | PMC10276829 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-39292-w. | PMC10276829 | ||
Acknowledgements | Cancer | INFECTIOUS DISEASES, ALLERGY, CANCER | We thank the volunteers who participated in the COV-2069 and COVE clinical trials. We thank Heather Angier for assistance with technical editing. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. These studies were supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. | PMC10276829 |
Author contributions | D.M., A.M. | Conceptualization: D.F., M.M., and M.F. Methodology: D.F., M.F., and J.F. Formal Analysis: D.F., M.F., J.F., and A.M. Writing – original draft: D.F., M.C., M.O.B., and M.M. Writing – review & editing: D.F., J.F., M.P.F., D.M., A.M., H.M.E.S., H.J., N.D.-R., D.B., Y.F., M.M., M.P.O., G.A.H., A.H., K.-C.C., E.F.-N., K.C.T., F.I., L.R.B., J.M., H.Z., W.D., P.G.B., and M.S.C. | PMC10276829 | |
Peer review | PMC10276829 | |||
Funding | Open Access funding provided by the National Institutes of Health (NIH). | PMC10276829 | ||
Data availability | For COV-2069Qualified researchers can request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymised participant data will be considered for sharing once the product and indication has been approved by major health authorities (e.g., US Food and Drug Administration, European Medicines Agency, Pharmaceuticals and Medical Devices Agency, and so on), if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification. Requests should be submitted to For COVEAs the trial is ongoing, access to participant-level data and supporting clinical documents with qualified external researchers may be available upon request and is subject to review once the trial is complete. Such requests can be made to Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. A materials transfer and/or data access agreement with the sponsor will be required for accessing of shared data. All other relevant data are presented in the paper. The protocol is available in the Supplementary Information: Clintrials.gov. NCT04470427. Data requests should have a response within 2 weeks. | PMC10276829 | ||
Code availability | Code to estimate the proportional hazards models used in the manuscript are available on github | PMC10276829 | ||
Competing interests | D.M., A.M., A.H. owns stock | D.F., J.F., M.P.F., D.M., A.M., H.M.E.S., H.J., N.D.-R., D.B., Y.F., and M.M. have no competing interests to declare. M.P.O. is an employee, has stock options, a patent pending, and license and royalties with Regeneron Pharmaceuticals, Inc. G.A.H. is an employee and shareholder of Regeneron and is listed on pending patents for the REGEN-COV antibody cocktail. A.H. owns stock in Regeneron and Pfizer. K.-C.C. and E.F.-N. are employees and shareholders of Regeneron. K.C.T. and F.I. are employees and shareholders of Regeneron and are listed on a pending patent. L.R.B. is the Deputy Editor for the New England Journal of Medicine and has grants from the Bill and Melinda Gates Foundation, Harvard Medical School, the National Institutes of Health, and the Wellcome Trust. J.M. is an employee of and has stock options and stock grants from Moderna. H.Z. is an employee of and has stock options from Moderna. W.D. is an employee of Moderna. P.G.B. will be serving as an unpaid advisor on Moderna’s Zika Vaccine Advisory Board. M.S.C. serves on the scientific advisory boards of Aerium, ModexX, and Atea and has consulting roles with Astra Zenica and GSK. | PMC10276829 | |
Ethics approval | We have complied with all relevant ethical regulations in analyzing these data. For COV-2069 the central or local institutional review board or ethics committee at each study center oversaw trial conduct and documentation. The central IRB was WCG-IRB For COVE a central institutional review board, Advarra, approved the protocol and the consent forms. Informed consent was obtained for all subjects in the COV-2069 and COVE trials. The ClinicalTrials.gov numbers were NCT04470472 and NCT04452318 for COVE and COV-2069, respectively. | PMC10276829 | ||
References | PMC10276829 | |||
Purpose | ovarian cancer | ADVERSE EVENTS, OVARIAN CANCER | To determine the systemic exposure to cisplatin and paclitaxel after adjuvant intraperitoneal administration in patients with advanced ovarian cancer who underwent primary debulking surgery. This could provide an explanation for the high incidence of systemic adverse events associated with this treatment regimen. | PMC10033566 |
Methods | ovarian cancer | ADVERSE EVENTS, OVARIAN CANCER | This is a prospective pharmacokinetic study in patients with newly diagnosed advanced ovarian cancer who were treated with intraperitoneal administered cisplatin and paclitaxel. Plasma and peritoneal fluid samples were obtained during the first treatment cycle. The systemic exposure to cisplatin and paclitaxel was determined and compared to previously published exposure data after intravenous administration. An exploratory analysis was performed to investigate the relation between systemic exposure to cisplatin and the occurrence of adverse events. | PMC10033566 |
Results | Pharmacokinetics of ultrafiltered cisplatin were studied in eleven evaluable patients. The geometric mean [range] peak plasma concentration (C | PMC10033566 | ||
Conclusion | ADVERSE EVENTS | Systemic exposure to ultrafiltered cisplatin after intraperitoneal administration is high. In addition to a local effect, this provides a pharmacological explanation for high incidence of adverse events seen after intraperitoneal administration of high-dose cisplatin. The study was registered at ClinicalTrials.gov under registration number NCT02861872. | PMC10033566 | |
Supplementary Information | The online version contains supplementary material available at 10.1007/s00280-023-04512-z. | PMC10033566 | ||
Keywords | PMC10033566 | |||
Introduction | cancers, Ovarian cancer, cancer of the female reproductive system, gynaecological malignancies, deaths, hyperthermia | CANCERS, CATHETER COMPLICATIONS, ADVERSE EVENTS, ADVERSE EVENT, OVARIAN CANCER STAGE IIA, OVARIAN CANCER, EPITHELIAL OVARIAN CANCER, CAVITY, EVENTS | Ovarian cancer is a common type of cancer of the female reproductive system. Globally approximately 295,000 new diagnoses and 185,000 deaths were reported in the year 2018, which reflects a mortality-to-incidence ratio of approximately 0.6 which is the highest of all gynaecological cancers [Although first-line platinum-based chemotherapy is considered standard of care for advanced-stage epithelial ovarian cancer, a major controversy concerns the route of administration which can be intravenous or intraperitoneal. Intraperitoneal administration results in increased drug concentrations and exposure time at the target site, which is considered beneficial for the efficacy of these cytotoxic drugs. Despite the theoretical pharmacological advantage, the evidence for clinical benefit of intraperitoneal administration of chemotherapy after primary debulking surgery from phase III trials is inconclusive. Until now, four pivotal phase III trials have been performed investigating different agents, doses and schedules [Negative consequences of intraperitoneal, mainly cisplatin, administration of chemotherapy are higher incidence of adverse events, catheter complications and higher costs compared to intravenous treatment. Adverse events associated with intraperitoneal administration of platinum-based chemotherapy includes both local and systemic events [Intraperitoneal administration can be performed using different approaches. The first method is intraperitoneal administration using an indwelling catheter. The drug remains in the abdominal cavity after administration from where it will be absorbed. The second approach consists of perfusion of the drug immediately after cytoreductive surgery for several hours after which the chemotherapy is removed from the peritoneal cavity. This approach is often combined with hyperthermia, which is referred to as hyperthermic intraperitoneal chemotherapy (HIPEC). A recent developed intraperitoneal drug delivery technique is pressurized intraperitoneal aerosol chemotherapy (PIPAC) using a nebulizer. It can be expected that these different methods of intraperitoneal administration will impact the pharmacokinetics of the drugs. The majority of pharmacokinetic studies regarding intraperitoneal administration of chemotherapy in patients with gynaecological malignancies involve intraoperative administration. Although extensively studied in the past, the available full text articles in English regarding pharmacokinetics after intraperitoneal administration of cisplatin and paclitaxel using an indwelling catheter are considered sparse [The current study investigated the systemic exposure to both cisplatin and paclitaxel after intraperitoneal administration in patients with ovarian cancer stage III receiving intraperitoneal chemotherapy after primary debulking surgery to provide an explanation for the high incidence of systemic adverse events associated with this treatment regimen. Knowledge about the systemic uptake of drugs administered intraperitoneally can help to find the most optimal intraperitoneal chemotherapy schedule that balance efficacy and safety of the treatment. | PMC10033566 |
Materials and methods | PMC10033566 | |||
Patients and data collection | primary peritoneal cancer | FALLOPIAN TUBE, RESIDUAL DISEASE, ADVERSE EVENTS, EPITHELIAL OVARIAN CANCER | Eligible patients aged between 18 and 70 years, with newly diagnosed stage III epithelial ovarian cancer, including fallopian tube and primary peritoneal cancer, with optimal or complete primary debulking (residual disease ≤ 1 cm), a World Health Organisation (WHO) performance status of 0–2, normal blood counts and adequate renal and hepatic function, who were planned to receive adjuvant intraperitoneal chemotherapy were enrolled.Monitoring of haemoglobin, haematocrit, erythrocyte, thrombocyte and white blood cell (WBC) counts with differential classification of neutrophils, lymphocytes, monocytes, eosinophils and basophils, together with monitoring of liver panel, renal function and electrolytes took place as part of routine clinical care prior to the start and prior to day 8 of every treatment cycle. The occurrence of adverse events, other than laboratory abnormalities, that required a dose reduction or discontinuation of therapy were extracted from the medical record.The study protocol was approved by the institutional ethics committee Arnhem-Nijmegen (Nijmegen) and was compliant with the Declaration of Helsinki. All patients provided written informed consent before entering the study. The study was conducted at the Radboud University Medical Center in Nijmegen, the Netherlands. | PMC10033566 |
Treatment plan | Patients were treated with adjuvant chemotherapy after primary debulking surgery according to GOG-172 [ | PMC10033566 | ||
Pharmacokinetic sampling and analytical assay | BLOOD | Samples for assessment of pharmacokinetics were taken during the first cycle only, on day 2 and day 8. Blood samples were obtained from an indwelling canula in EDTA tubes as follows: before infusion, 15, 30 min, 1, 2, 4, 8, 16, 24 h after the end of the intraperitoneal chemotherapy infusion. A peritoneal fluid sample was taken through the Porth-a-Cath system at the end of intraperitoneal drug administration. Immediately after collection both blood and peritoneal fluid samples were centrifuged to separate plasma and debris in peritoneal fluid. An aliquot of plasma and peritoneal fluid was saved and stored at − 40 °C until analysis. For all cisplatin samples, plasma and peritoneal fluid was immediately ultrafiltered through a Centrifree | PMC10033566 | |
Population pharmacokinetic model | Cisplatin data (i.e., ultrafiltered peritoneal and plasma concentrations, and plasma protein bound concentrations obtained by difference between total and ultrafiltered plasma concentrations) were analyzed simultaneously by non-linear mixed effects modeling with NONMEM version 7.4.1 (ICON Development Solutions, Ellicott City, MD, USA) using PiranaArea-under-the-curve of ultrafiltered cisplatin plasma concentrations versus time from 0 to 24 h (AUC | PMC10033566 | ||
Results | PMC10033566 | |||
Pharmacokinetics of ultrafiltered cisplatin | Plasma ultrafiltered and total cisplatin PK data were available from eleven patients. Intraperitoneal fluid samples were available from six patients at the end of cisplatin administration. A total of 147 samples (6 IP, 71 UF and 70 PB cisplatin concentrations) were used to estimate pharmacokinetics parameters. The final structural pharmacokinetic model included four compartment: three compartments with available concentrations (VThe PopPK plasma ultrafiltered cisplatin concentration vs. time curve including individual observations is shown in Fig. PK POP plasma ultrafiltered cisplatin concentration vs. time curve including individual observations (∙) and 5th, 50th, 95th percentiles of plasma ultrafiltered cisplatin individual prediction | PMC10033566 | ||
Discussion | toxicity, ototoxicity, tumour | ADVERSE EVENTS, CAVITY, TUMOUR, OTOTOXICITY, PERIPHERAL NEUROPATHY | This study demonstrates that intraperitoneal administration of 100 mg/mSystemic exposure to unbound cisplatin is closely correlated with tumour response [The high systemic exposure to ultrafiltered cisplatin after intraperitoneal administration might be caused by higher fraction of complexed cisplatin to low weight molecules in the ultrafiltered part. When absorbed from the peritoneal cavity to the systemic compartment, cisplatin crosses epithelial barriers. A fraction of diaquaplatin, the active intermediate formed from cisplatin, is likely to be complexed to low-molecular weight molecules such as glutathione, cysteine and methionine before it reaches the blood stream. This complexed cisplatin is considered as inactive drug, but still contribute to the total amount of ultrafiltered cisplatin measured in plasma. Therefore the AUCTaking into account the high systemic exposure to ultrafiltered cisplatin after intraperitoneal administration, it is remarkable that the phase III studies supporting the use of intraperitoneal cisplatin uses equal [High systemic exposure to ultrafiltered cisplatin is expected to cause increased incidence of systemic adverse events like peripheral neuropathy, haematological toxicity and ototoxicity [In contrast to cisplatin, a large water insoluble drug like paclitaxel is very slowly absorbed from the peritoneal compartment. It has been demonstrated that the pharmacological advantage, very slow peritoneal clearance and a high peritoneal-plasma AUC ratio of 996 [Soundness of this study are its prospective nature, rich cisplatin blood sampling and the accurate time information for the blood samples. This is essential to accurately determine the pharmacokinetic parameters. The comparison with systemic exposure data after intravenous administration is helpful to place the findings of the study in perspective. Although this study yielded new insights in intraperitoneal drug delivery, there are some shortcomings that need to be addressed. First, since patients were allowed to leave the hospital after administration of paclitaxel, few paclitaxel samples could be collected beyond 12 h. Since paclitaxel is very slowly absorbed from the peritoneal compartment sampling at later timepoints is recommended for an accurate estimation of the systemic exposure. Second, since only one intraperitoneal fluid sample was collected, it was not possible to determine total exposure in the peritoneal compartment. Also peritoneal sampling through the PAC turned out to be more challenging than expected. The tube was often blocked while drawing up intraperitoneal fluid making it impossible to collect an intraperitoneal sample for the majority of patients. However the high CThe results of this study together with earlier findings in literature shed a new light on intraperitoneal chemotherapy administration. The importance of systemic exposure of intraperitoneal administrated drugs is often underestimated. We showed that the assumption that systemic exposure after intraperitoneal therapy remains low does not apply for all cytotoxic drugs and in some circumstances can be very high, as is the case for intraperitoneal administered cisplatin. The chemotherapy schedule used in this study is the GOG-172 regimen that demonstrated a 16-month improvement in median overall survival [Intraperitoneal administration of 100 mg/m | PMC10033566 |
Acknowledgements | We thank all the patients for their participation and all the personnel at the clinical site for collecting and processing the pharmacokinetic samples. We specially thank Mark Rietveld, Floor Ploos van Amstel, Laura Dobbe, Sabrina Marsili and Thierry Laffont for their support. | PMC10033566 | ||
Author contributions | Study design: PBO and NPvE; data collection: LAWdJ and LdV; data analysis and interpretation: LAWdJ, ML and LdV; analysis: ML and EC; manuscript writing: LAWdJ, ML and LdV; manuscript review: NPvE, EC and PBO. All authors read and approved the final version of the manuscript. | PMC10033566 | ||
Funding | This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | PMC10033566 | ||
Availability of data and material | The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | PMC10033566 | ||
Code availability | Not applicable. | PMC10033566 | ||
Declarations | PMC10033566 | |||
Conflict of interest | Dr. Nielka van Erp declares the following financial activities outside the submitted work: received grants for investigator driven studies from Astellas and Janssen-Cilag and educational grants for lectures from Sanofi and Bayer. The other authors declare that they have no conflicts of interest. | PMC10033566 | ||
Ethics approval | This clinical trial was approved by the institutional ethics committee Arnhem-Nijmegen (Nijmegen) and was compliant with the Declaration of Helsinki. | PMC10033566 | ||
Consent to participate | All patients provided written informed consent before entering the study. | PMC10033566 | ||
Consent for publication | Not applicable. | PMC10033566 | ||
References | PMC10033566 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.