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Study oversight | The study was designed by the authors in conjunction with the sponsor and conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Guidelines for Good Clinical Practice. The study protocol and amendments were approved by the institutional review boards at participating sites. The study used an external data monitoring committee, which was responsible for ongoing safety monitoring during the study conduct as well as the prespecified interim futility and efficacy analyses. All patients provided written informed consent. | PMC10504075 | ||
Treatment | toxicity | DISEASE PROGRESSION | All patients received subcutaneous elranatamab 76 mg QW on a 28-d cycle with a two step-up priming dose regimen of 12 mg on day 1 and 32 mg on day 4 during the first week, with the exception of the first four patients enrolled in the study who received a single priming dose of 44 mg on day 1 before receiving the full dose of 76 mg starting on day 8. These first four patients were enrolled before the protocol was amended to include the 12/32 mg step-up regimen. Hospitalization was required for 48 h following the first step-up dose and for 24 h after the second step-up dose. Premedication with acetaminophen (650 mg or equivalent), diphenhydramine (25 mg or equivalent) and dexamethasone (20 mg or equivalent) was required before each step-up dose and before the first full dose of elranatamab. Patients who received QW dosing for at least six cycles and achieved a PR or better (≥PR) persisting for at least 2 months had their dosing interval changed to Q2W. Dose reductions and interruptions were permitted for toxicity. Elranatamab treatment was to be continued until disease progression, unacceptable toxicity or withdrawal of consent. | PMC10504075 |
Efficacy and safety assessments | CRS | The primary endpoint was confirmed ORR, defined as PR or better (≥PR) according to IMWG criteriaAEs were graded according to the NCI CTCAE (version 5.0), except for CRS and ICANS, which were graded according to the criteria of the American Society for Transplantation and Cellular TherapyAll analyses were performed in the 123 patients who received at least one dose of elranatamab, with the exception of CRS and ICANS analyses, which were performed on the 119 patients who received the 12/32 mg step-up regimen. | PMC10504075 | |
Statistical analysis | CRS | SECONDARY, EMD | Efficacy and safety were evaluated in all patients enrolled who received at least one dose of elranatamab (safety analysis set). A sample size of 120 patients was estimated to give a power of at least 98% to establish an ORR of more than 30% at a one-sided significance level of 0.025, assuming an ORR of at least 48%. As specified in the protocol and statistical analysis plan, if the null hypothesis for ORR by BICR (defined as ≤30% by IMWG) was rejected for cohort A, the key secondary endpoint of ORR by BICR for those without EMD at baseline was tested in a hierarchical fashion using the gatekeeping procedure that the ORR is ≤38% with a one-sided significance level of 0.025. If the null hypothesis for ORR by BICR for those without EMD at baseline was rejected for cohort A, the key secondary endpoint of ORR by BICR for those with EMD at baseline was tested in a hierarchical fashion using the gatekeeping procedure that the ORR is ≤12% with a one-sided significance level of 0.025. No other adjustments for multiple comparisons were made. Descriptive statistics were used for efficacy and safety outcomes unless otherwise stated. Exact two-sided 95% CIs were included for response endpoints. Time-to-event endpoints—except TTR—were summarized using the Kaplan–Meier method. Medians, rates at 15 months and their two-sided 95% CIs were included. The CIs for the median were calculated according to Brookmeyer and Crowley, and the CIs for the survival function estimates at particular time points were derived using the log(−log) method. Data cutoff for efficacy and safety was March 14, 2023, except for CRS and ICANS data, which was based on January 12, 2023. | PMC10504075 |
Reporting summary | Further information on research design is available in the | PMC10504075 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02528-9. | PMC10504075 | ||
Supplementary information |
Supplementary Tables 1 and 2.Reporting Summary | PMC10504075 | ||
Extended data | PMC10504075 | |||
Extended data | is available for this paper at 10.1038/s41591-023-02528-9. | PMC10504075 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02528-9. | PMC10504075 | ||
Acknowledgements | This study was funded by Pfizer. The authors would like to thank the patients who participated in the trial and the medical staff of participating centers. The medical writing support was provided by G. Shay-Lowell, Ph.D., CMPP, of Engage Scientific Solutions and was funded by Pfizer. | PMC10504075 | ||
Author contributions | All authors were involved in the trial conception/design, or the acquisition, analysis, or interpretation of data. All authors contributed to the drafting of the manuscript and approved the final version. | PMC10504075 | ||
Peer review | PMC10504075 | |||
Data availability | Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified patient data. See | PMC10504075 | ||
Competing interests | ONCOLOGY | A.M.L. reports consulting or advisory roles for Pfizer, Trillium Therapeutics and Arcellx; personal fees from ITeos Therapeutics, Janssen, Legend Biotech, Pfizer, Sanofi and Trillium Therapeutics; institutional research support from Bristol-Myers Squibb, Genentech, Janssen Oncology, Pfizer, Sanofi, Trillium Therapeutics and patents, royalties and/or other intellectual property interests with Serametrix. M.H.T. reports consulting or advisory roles for Janssen. G.K., Y.J., A.E.G. and D.A.S. have no competing interests to report. B.A. reports consulting or advisory roles for Amgen, Celgene, Janssen-Cilag and Sanofi; personal fees from Celgene, Janssen-Cilag, Sanofi and Takeda; research support from Janssen-Cilag and travel and accommodations expenses paid for by Amgen, Celgene, Janssen-Cilag and Takeda. N.J.B. reports consulting or advisory roles for Amgen, Celgene, Janssen, Karyopharm Therapeutics, Pfizer, Sanofi and Takeda; personal fees from AbbVie, Amgen, Celgene, Genentech/Roche, GSK, Janssen, Karyopharm Therapeutics, Sanofi and Takeda and patents, royalties, and/or other intellectual property interests with Celgene and Janssen. H.M.P. reports consulting or advisory roles for Bristo-Myers Squibb, GSK, Janssen, Takeda and Sanofi and research support from AbbVie and Bristol-Myers Squibb. R.N. reports consulting or advisory roles for Bristol-Myers Squibb, GSK, Janssen, Karyopharm Therapeutics and Takeda and research support from Bristol-Myers Squibb, GSK, Janssen, Karyopharm Therapeutics and Takeda. P.R.O. reports consulting or advisory roles for AbbVie, Bristol-Myers Squibb, GSK, Janssen, Pfizer and Sanofi; personal fees from AbbVie, Celgene, GSK, H3 Biomedicine, Janssen, Pfizer and Sanofi; travel and accommodations expenses paid for by Pfizer and speaker’s bureau roles with Bristol-Myers Squibb, GSK, Janssen and Sanofi. J.M.L. reports consulting or advisory roles for Bristol-Myers Squibb, Janssen Oncology and Novartis; institutional research support from Astellas Pharma and Bristol-Myers Squibb and speaker’s bureau roles with Bristol-Myers Squibb, Janssen-Cilag and Roche. C.T. reports consulting or advisory roles for AbbVie, Amgen, Celgene, GSK, Janssen, Novartis and Takeda; personal fees from AbbVie, Amgen, Celgene, GSK, Janssen, Novartis, Sanofi and Takeda; research support from AbbVie, GSK and Sanofi and travel and accommodations expenses paid for by Pfizer and Janssen. H.Q. reports consulting or advisory roles for Amgen, Antengene, Bristol-Myers Squibb/Celgene, Celgene, CSL Behring, GSK, Janssen-Cilag, Karyopharm Therapeutics, Pfizer, Roche and Sanofi and research support from Amgen, Bristol-Myers Squibb/Celgene, Celgene, GSK, Karyopharm Therapeutics and Sanofi. J.D. reports a consulting or advisory role for Novartis and travel and accommodations expenses paid for by AstraZeneca Spain. H.Y. reports research support from Astellas Pharma. A.K.N. reports consulting or advisory roles for Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb, Cellectar, Genzyme, GSK, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Secura Bio and Takeda; personal fees from Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Cellectar, Genzyme, GSK, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Secura Bio and Takeda; institutional research support from Amgen, Arch Oncology, Bristol-Myers Squibb/Celgene, Cellectar, GSK, Janssen Oncology, Pfizer and Takeda and travel and accommodations expenses paid for by GSK. S.M. reports consulting or advisory roles for AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb/Celgene, GSK, Janssen, Regeneron, Roche, Sanofi and Takeda. N.R. reports consulting or advisory roles for Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, Merck and Takeda; personal fees from Medscape and Research To Practice and research support from 2Seventy Bio. S.I. reports consulting or advisory roles for Janssen, Sanofi, Takeda, Pfizer, Novartis, Bristol-Myers Squibb and AbbVie; personal fees from Bristol-Myers Squibb, Celgene, Janssen, Ono Pharmaceutical, Pfizer, Sanofi, and Takeda and research support from AbbVie, Amgen, Bristol-Myers Squibb, Caelum Biosciences, Celgene, Daiichi Sankyo Pharmaceutical, Janssen, Ono Pharmaceutical, Otsuka, Sanofi, Shionogi and Takeda. M.S.R. reports consulting or advisory roles for Amgen, Bristol-Myers Squibb, GSK, Janssen, Oncopeptides, Pfizer and Sanofi; personal fees from AbbVie, Bristol-Myers Squibb, GSK and Takeda and research support from Bristol-Myers Squibb, Janssen, Novartis and Sanofi. E.S. reports consulting or advisory roles for Shattuck Labs and Sanofi; personal fees from AbbVie, Janssen and travel and accommodations expenses paid for by Janssen. E.L., S.T.S., U.C., M.E., A.C. and A.V. report employment and stock ownership at Pfizer. M.M. reports consulting or advisory roles for Adaptive Biotechnologies, GSK, Jazz Pharmaceuticals, MaaT Pharma, Novartis, Sanofi and Xenikos; personal fees from Amgen, Astellas, Bristol-Myers Squibb, Celgene, Pfizer, Stemline-Menarini and Takeda and speaker’s bureau roles with Janssen, Jazz Pharmaceuticals and Sanofi. | PMC10504075 | |
References | PMC10504075 | |||
Background | coronavirus disease 2019 | CORONAVIRUS DISEASE 2019 | In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. | PMC10685492 |
Objectives | To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. | PMC10685492 | ||
Methods | We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. | PMC10685492 | ||
Results | sore throat, myalgia, cough, tiredness, headache, shivering, chills, shortness of breath | SORE THROAT, ADVERSE EVENTS | The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. | PMC10685492 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12985-023-02144-6. | PMC10685492 | ||
Keywords | PMC10685492 | |||
Introduction | coronavirus disease 2019 | CORONAVIRUS, CRITICAL ILLNESS, SEVERE ACUTE RESPIRATORY SYNDROME, CORONAVIRUS DISEASE 2019 | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the culprit of coronavirus disease 2019 (COVID-19), is continuously evolving globally [Several therapeutic approaches have been developed to reduce the symptom burden and the probability of progression into severe or critical illness. These mainly include antivirals (e.g. nirmatrelvir-ritonavir, monulpiravir, VV116) [Several traditional Chinese medicine formulae have been marketed and endorsed for clinical application by the We conducted the randomized, double-blind, international, multicenter, investigator-initiated clinical trial to investigate the efficacy and safety of Lianhuaqingwen capsules compared to placebo and combined with standard-of-care in adult patients with mild-to-moderate COVID-19 (FLOSAN study). We hypothesized that LHQW capsules would accelerate symptom recovery among adults with mild-to-moderate COVID-19. | PMC10685492 |
Methods | PMC10685492 | |||
Study design and patients | The FLOSAN trial recruited patients with mild-to-moderate COVID-19 from 12 hospitals in China, 3 hospitals in Thailand, and one hospital each in Vietnam and the Philippines between February and December 2022 (Additional file Baseline demographic and clinical characteristics of the full-analysis set | PMC10685492 | ||
Randomization and masking | RECRUITMENT | We randomly assigned patients (1:1) to receive treatment with LHQW or matching placebo (manufactured by Shijiazhuang Yiling Pharmaceutical Co. Ltd., Shijiazhuang, China) based on the randomization numbers generated with the SAS package (SAS Inc., Cary, USA). The block size was 4 with no stratification. With competitive recruitment scheme, the sub-site investigators allocated patients in an ascending order. The study medications had an identical color, odor and appearance, except that the placebo did not contain any active ingredient of LHQW. Patients, the study investigators and other staff were masked to treatment allocation until database lock. | PMC10685492 | |
Procedures | fever | RECRUITMENT | After randomization, patients took LHQW (4 capsules [0.35g/capsule], thrice daily) or matching placebo for 14 consecutive days following hospitalization in designated hospitals (in mainland China) and out-patient recruitment (in the Phillipines, Thailand and Viet Nam). Both groups received standard-of-care consisting of antipyretics, analgesic drugs, nutrition supplementation and fluid replacement. Acetaminophen, the non-steroidal anti-inflammatory drug, could be applied for ameliorating fever if the temperature reached 38.5 degrees or higher. Antivirals or medications with core components of LHQW were prohibited. Sites could follow local guidelines and protocols in their countries and regions. Patients attended four in-hospital (in mainland China) or out-patient (in Thailand, Vietnam and the Philippines) visits (days 3, 7, 10 and an end-of-study visit, typically scheduled at day 14). Patients who prematurely discontinued treatment due to accelerated symptom recovery or other reasons could attend all planned visits. During the study, patients were requested to fill out the diary card twice daily to evaluate the changes in symptoms. | PMC10685492 |
Outcomes | gastrointestinal symptoms, COVID-19-related severe/critical disease, ground-glass opacity, ageusia, anosmia | SECONDARY, INFILTRATION, ADVERSE EVENT | The primary endpoint was evaluated at day 14 - the median time to sustained clinical improvement or resolution of the nine above-mentioned major symptoms, rated as being less than or equal to mild (scored 1 or 0) and remained stable for >24 hours (see Supplementary File for the symptom diary cards).Pre-specified secondary endpoints included the proportion of patients with sustained improvement or resolution of nine major symptoms at day 14, the median time to sustained improvement or resolution of each of these individual symptoms, the median time to onset of antipyretic effect and return to normal temperature (axillary temperature ≤ 37.0°C or oral temperature ≤ 37.3°C for >24 hours), the median time to sustained improvement or resolution of gastrointestinal symptoms, anosmia and ageusia, the proportion of patients with sustained improvement or resolution of all symptoms, the time to negative conversion of NAAT findings, and the rate of NAAT negative conversion (days 0, 7, 10, 14), the proportion of patients with major improvement in chest imaging, the incidence of COVID-19-related severe/critical disease, COVID-19-related and all-cause mortality within day 14. A designated experienced radiologist (blinded to study allocation) reviewed chest X-ray or computed tomography (CT) images and rated the outcomes. An improvement in chest radiology denoted a decreased area of infiltration, a decreased area of any radiologic abnormality, or decreased density of ground-glass opacity or nodules [Safety endpoints were evaluated from the first dosing to the end of follow-up, including vital signs, physical examination, major changes in laboratory test, abnormal twelve-lead electrocardiogram findings, and the adverse event (AE) and serious adverse event (SAE). See | PMC10685492 |
Statistical analysis | anosmia, death, ageusia, fever | EVENTS, RECRUITMENT, DISEASES, VIRAL SHEDDING | Assuming that the median time to sustained improvement or resolution was 12 days in control group and 9 days in LHQW group, 652 patients would be randomized to LHQW or placebo group (1:1) with a 95% power with a two-sided significance of 0.05 according to PASS software. In practice, patients were enrolled while taking into account RAT findings, and 344 patients per group would be needed when assuming that 95% of patients with positive RAT findings would yield positive NAAT findings. Recruitment of 860 patients would be needed while considering a 20% dropout rate.We conducted statistical analyses with SAS 9.4 software (SAS Institute, Cary, North Carolina). All patients who had been randomized and taken at least one dose of study medication and had a confirmed diagnosis of COVID-19 based on NAAT were included in the full-analysis set. Patients who fully complied with the protocol (adherence: 80% or greater) were included in per-protocol set. We prioritized data presentation of the full-analysis set. The primary endpoint was analyzed by using the Log-rank test and displayed with Kaplan-Meier curve. The time to events was presented as the median duration and 95% confidence interval (95%CI). The hazards ratio (HR) of clinical events was demonstrated. We analyzed the following endpoints with chi-square test or Fisher’s exact probability model, including the proportion of patients with alleviation of symptoms, reduction in viral shedding (censored at day 14), major improvement in radiology, severe and critical diseases, death and all-cause death. We also analyzed the median time to sustained alleviation of single symptom, the alleviation of fever, digestive symptoms, ageusia or anosmia and all clinical symptoms, and the duration of viral shedding with the same analytical strategy with the primary endpoint. We conducted The FLOSAN trial was registered with Chinese Clinical Trial Registry (No.: ChiCTR2200056727). The CONSORT checklist can be found in the supplemental file. | PMC10685492 |
Role of funding source | The sponsor participated in the study design along with the principal investigators, study medication provision and data collection. An independent third party participated in data analysis. The first and corresponding authors had full access to the data and the corresponding author had the final decision to submit the manuscript for publication. | PMC10685492 | ||
Discussion | DISEASE, CRITICAL ILLNESS | The FLOSAN study is the first international multicenter randomized controlled trial that evaluates the safety and efficacy of LHQW capsules among patients with mild-to-moderate COVID-19 in the western Pacific region. Treatment with LHQW for 14 days significantly shortened the time to sustained improvement or resolution of most cardinal symptoms and all symptoms combined. LHQW did not markedly accelerate the negative conversion of NAAT findings. No patient progressed into severe or critical illness or died. LHQW was well tolerated (Additional files With greater scientific rigor in the study design, findings of the FLOSAN study echoed the principal results of our previously published multicenter randomized study [Our findings were consistent with other published studies pertinent to Chinese herbs for treatment of COVID-19. Several meta-analyses, each with different sample sizes and studies with different design, have concluded the therapeutic benefits of LHQW capsules for mild-to-moderate COVID-19 [LHQW capsules were safe among patients with COVID-19, evidenced by the similar safety profile as compared with placebo group, which echoed with our [The main strengths included the international multicenter trial which has recruited a large sample size of patients from four countries of the western Pacific region, with no major differences in the therapeutic responses and safety profiles across the countries. Therefore, the findings were likely generalizable to patients from Asia. The double-blind study design with matching placebo has provided more solid evidence pertaining to the efficacy of LHQW capsules. Few clinical trials of the existing marketed drugs have been conducted during the Omicron outbreak, when the current trial was initiated.Our findings have further validated the efficacy of LHQW capsules for Omicron, the prevailing variant of SARS-CoV-2 circulating globally. This is important because of the scarcity of marketed medications and the large number of vulnerable population within mainland China, where some of the repurposed herbs with notable therapeutic potentials have already been marketed. LHQW capsules might help reduce healthcare burden during the surge of Omicron wave among community-dwelling patients with mild-to-moderate COVID-19.Some limitations should also be considered. First, there existed an imbalance in the sample size within individual countries, although we have not identified the signals indicating differential therapeutic responses across the nations. However, our findings were not materially altered in the main study outcomes when stratified by the countries (China vs. The rest combined). Second, the relatively short duration of observation cannot provide further evidence of the longer-term efficacy of LHQW (e.g. at day 28 or beyond). Third, caution should be exercised when extrapolating our conclusions to other populations, such as those with multiple comorbidities or immunosuppression. Furthermore, our study cannot directly address the molecular mechanisms underlying the efficacy of LHQW for the treatment of COVID-19. Finally,we did not employ the stratified randomization scheme. However, randomization was well balanced across the different metrics that could have affected the study outcomes (e.g. sex, age, duration of symptoms, disease severity). In light of the difference in the study regions and study sites, we have adopted the central block randomization scheme, and the results demonstrated balanced distribution of the demographic and other baseline disease severity metrics. | PMC10685492 | |
Conclusion | LHQW capsules are effective and safe for mild-to-moderate COVID-19 via accelerating symptom resolution and clinical recovery for mild-to-moderate COVID-19. LHQW might be worthwhile for patients who could now be managed within the community. | PMC10685492 | ||
Acknowledgements | RECRUITMENT, INFECTIOUS DISEASE | We thank Jihan Huang, PhD. (Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine) for performing the independent statistical analysis. We thank Shijiazhuang Yiling Pharmaceutical Co., Ltd. (Shijiazhuang, People’s Republic of China) for provision of the study medications. We also thank Drs. Yi Mao (Public Health Clinical Center of Chengdu, China), Jing Yuan (The Third People's Hospital of Shenzhen, China), Xing-hua Tan (Guangzhou Eighth People’s Hospital, Guangzhou Medical University, China), Xing-qi Dong (Yunnan Provincial Infectious Disease Hospital) and Xiao-hong Chen (Fuzhou Pulmonary Hospital of Fujian, China) for their facilitation of patient recruitment, and the patients and other study staff for participating in this study. | PMC10685492 | |
Author contributions | P. | J. P. Z., Z. F. Y. and N. S. Z. participated in study design; Y. L., L. S. J., P. M., H. Z. L., M. C., L. X. Z., P. A., F. Y. H., T. T. N. L., R. A. P., X. G., H. M. S., J. J. J., R. J. L., Z. D. and Y. Q. Z. recruited patients and performed follow up; W. J. G., J. P. Z. and N. S. Z. drafted the manuscript; J. P. Z. and N. S. Z. were responsible for study conception and provided critical review of the manuscript. All authors read and approved the final manuscript. J. P. Z. and N. S. Z. were the guarantors of the study. | PMC10685492 | |
Funding | The study was funded by Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine [No: ZYYCXTD-D-202206], and the Science and Technology Program of Hebei 225A2503D. | PMC10685492 | ||
Availability of data and materials | Data could be shared after publication after consultation with the corresponding authors. | PMC10685492 | ||
Declarations | PMC10685492 | |||
Ethics approval and consent to participate | Ethics approval has been obtained the ethics committee of each participating site, based on | PMC10685492 | ||
Competing interests | None. | PMC10685492 | ||
References | PMC10685492 | |||
Key Points | PMC10690456 | |||
Question | What are the cardiometabolic effects of a healthy plant-based (vegan) vs a healthy omnivorous diet among identical twins during an 8-week intervention? | PMC10690456 | ||
Findings | weight loss | In this randomized clinical trial of 22 healthy, adult, identical twin pairs, those consuming a healthy vegan diet showed significantly improved low-density lipoprotein cholesterol concentration, fasting insulin level, and weight loss compared with twins consuming a healthy omnivorous diet. | PMC10690456 | |
Meaning | The findings from this trial suggest that a healthy plant-based diet offers a significant protective cardiometabolic advantage compared with a healthy omnivorous diet.This randomized clinical trial of identical twin pairs compares the cardiometabolic effects of a healthy vegan diet with a healthy omnivorous diet. | PMC10690456 | ||
Importance | Increasing evidence suggests that, compared with an omnivorous diet, a vegan diet confers potential cardiovascular benefits from improved diet quality (ie, higher consumption of vegetables, legumes, fruits, whole grains, nuts, and seeds). | PMC10690456 | ||
Objective | To compare the effects of a healthy vegan vs healthy omnivorous diet on cardiometabolic measures during an 8-week intervention. | PMC10690456 | ||
Design, Setting, and Participants | MAY | This single-center, population-based randomized clinical trial of 22 pairs of twins (N = 44) randomized participants to a vegan or omnivorous diet (1 twin per diet). Participant enrollment began March 28, 2022, and continued through May 5, 2022. The date of final follow-up data collection was July 20, 2022. This 8-week, open-label, parallel, dietary randomized clinical trial compared the health impact of a vegan diet vs an omnivorous diet in identical twins. Primary analysis included all available data. | PMC10690456 | |
Intervention | Twin pairs were randomized to follow a healthy vegan diet or a healthy omnivorous diet for 8 weeks. Diet-specific meals were provided via a meal delivery service from baseline through week 4, and from weeks 5 to 8 participants prepared their own diet-appropriate meals and snacks. | PMC10690456 | ||
Main Outcomes and Measures | The primary outcome was difference in low-density lipoprotein cholesterol concentration from baseline to end point (week 8). Secondary outcome measures were changes in cardiometabolic factors (plasma lipids, glucose, and insulin levels and serum trimethylamine | PMC10690456 | ||
Results | A total of 22 pairs (N = 44) of twins (34 [77.3%] female; mean [SD] age, 39.6 [12.7] years; mean [SD] body mass index, 25.9 [4.7]) were enrolled in the study. After 8 weeks, compared with twins randomized to an omnivorous diet, the twins randomized to the vegan diet experienced significant mean (SD) decreases in low-density lipoprotein cholesterol concentration (−13.9 [5.8] mg/dL; 95% CI, −25.3 to −2.4 mg/dL), fasting insulin level (−2.9 [1.3] μIU/mL; 95% CI, −5.3 to −0.4 μIU/mL), and body weight (−1.9 [0.7] kg; 95% CI, −3.3 to −0.6 kg). | PMC10690456 | ||
Conclusions and Relevance | In this randomized clinical trial of the cardiometabolic effects of omnivorous vs vegan diets in identical twins, the healthy vegan diet led to improved cardiometabolic outcomes compared with a healthy omnivorous diet. Clinicians can consider this dietary approach as a healthy alternative for their patients. | PMC10690456 | ||
Trial Registration | ClinicalTrials.gov Identifier: | PMC10690456 | ||
Introduction | Plant-based diets have gained recent popularity not only for their lower environmental impact compared with an omnivorous dietary pattern but also for their health benefits.A vegan dietary pattern is typically lower in energy density but higher in fiber, vitamins, minerals, and phytonutrients compared with other dietary patterns. | PMC10690456 | ||
Methods | This study followed the ethical standards of the Declaration of Helsinki | PMC10690456 | ||
Study Design | MAY | This single-site, parallel-group, dietary intervention randomized clinical trial randomized healthy, adult identical twins to a healthy vegan or omnivorous diet for 8 weeks. Participant enrollment began March 28, 2022, and continued through May 5, 2022. The date of final follow-up data collection was July 20, 2022.The primary outcome was the difference from baseline to 8 weeks in low-density lipoprotein cholesterol (LDL-C) levels between the diet groups. Secondary outcomes included differences from baseline to 8 weeks in body weight and levels of fasting triglycerides, high-density lipoprotein cholesterol, glucose, insulin, trimethylamine | PMC10690456 | |
Participants | We aimed to recruit 22 pairs of identical twins 18 years or older, a sample size determined by resource availability rather than a formal power calculation. Identical twins were recruited primarily from the Stanford Twin Registry and randomized using computerized random-number generation by a statistician (K.M.C.) blinded to the intervention, delivery, or data collection. Adult twins 18 years or older willing to consume a plant-based (vegan) or omnivore diet for 8 weeks were included. We excluded participants who weighed 45.36 kg (100 lb) or less, had a body mass index (calculated as weight in kilograms divided by height in meters squared) of 40 or higher, had an LDL-C level of 190 mg/dL or higher (to convert to millimoles per liter, multiply by 0.0259), had a systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher, or were pregnant. Individuals self-reported race and ethnicity for the purpose of demographic reporting. Inclusion and exclusion criteria have been previously published. | PMC10690456 | ||
Dietary Intervention | The study consisted of two 4-week phases: delivered meals and self-provided meals. Participants were provided all no-cost meals for the first 4 study weeks by a nationwide meal delivery company (Trifecta Nutrition). It was expected that after 4 weeks of food delivery and health educator counseling that participants would understand the amounts and types of foods they should purchase and prepare to achieve maximum adherence to the diets when self-providing meals.Research staff worked with Trifecta Nutrition to develop menu offerings to match a healthy vegan and omnivorous diet, which emphasized vegetables, fruits, and whole grains while limiting added sugars and refined grains. During the initial 4 weeks, meals were delivered once each week, with 7 days of breakfast, lunch, and dinner meals. Participants also purchased and consumed snacks to meet their energy requirements following guidance from health educators.Guiding principles were reinforced: (1) choose minimally processed foods; (2) build a balanced plate with vegetables, starch, protein, and healthy fats; (3) choose variety within each food group; and (4) individualize these guidelines to meet preferences and needs (eAppendix in | PMC10690456 | ||
Collection of Dietary Intake | SECONDARY | Two types of dietary data were collected. For the primary reporting data, 3 unannounced 24-hour dietary recalls—a structured interview intended to capture detailed information about food and drink intakes—were administered within a 1-week window (2 weekdays and 1 weekend day) of each time point (baseline, week 4, and week 8). Data were collected via telephone by a registered dietitian (L.R.D.) using Nutrition Data System for Research (Nutrition Coordinating Center). For the secondary reporting data, participants were encouraged to log their food intake using the Cronometer app (Cronometer Pro, Nutrition Tracking Software for Professionals; Cronometer); these data were used by health educators for real-time guidance of participants. | PMC10690456 | |
Anthropometric and Metabolic Data | BLOOD | At 3 time points, participants visited the Stanford Clinical and Translational Research Unit after an overnight fast of 10 to 12 hours: baseline, 4 weeks (phase 1), and 8 weeks (phase 2). Blood draw and clinical measures were assessed using standard methods (eMethods in | PMC10690456 | |
Statistical Analysis | Descriptive statistics, mean (SD) or number (percentage), were used for continuous and categorical variables, respectively. | PMC10690456 | ||
Baseline Characteristics of the Study Participants | Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.SI conversion factors: To convert HDL-C and LDL-C to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113; glucose to mmol/L, multiply by 0.0555; insulin to pmol/L, multiply by 6.945; vitamin BData are presented as number (percentage) of patients unless otherwise indicated.Analyses were completed using R Studio, version 2022.12.0 (Posit Software). A 2-sided | PMC10690456 | ||
Results | A total of 22 pairs of randomized twins (N = 44) were enrolled in the study. The CONSORT flow diagram of participants ( | PMC10690456 | ||
TwiNS CONSORT Flow Diagram | PMC10690456 | |||
Cardiovascular Health Outcomes at the End of 8 Weeks and Main Effect Model Estimates for Primary and Secondary Outcome Analyses | SECONDARY | Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TMAO, trimethylamine SI conversion factors: To convert HDL-C and LDL-C to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113; glucose to mmol/L, multiply by 0.0555; insulin to pmol/L, multiply by 6.945; vitamin BAll laboratory data are fasting values from plasma (lipids, glucose, insulin, and vitamin BMeans (SEMs) are unadjusted.Primary and secondary outcomes fixed effects for diet and time (baseline as reference) and an interaction effect for diet (omnivore as reference) by time, a random effect for twin pair to account for the correlation between identical twins (ie, random intercept allowed intercept to vary for each twin pair), and a random effect for participant to account for correlation of longitudinal data. | PMC10690456 | |
Diet and Nutrient Intake | Reported energy intake during each of the two 4-week phases (food delivery and self-provided) were lower compared with baseline for both groups (eFigures 1 to 5 and eTables 2 to 6 and 23 in | PMC10690456 | ||
Primary Outcome | Participants receiving the vegan diet showed a mean (SD) decrease of 13.9 (5.8) mg/dL (95% CI, −25.3 to −2.4 mg/dL) in the unadjusted mean LDL-C level at 8 weeks from baseline compared with participants receiving the omnivorous diet ( | PMC10690456 | ||
Median Change From Baseline to 8 Weeks in Primary and Secondary Outcomes Between Vegan and Omnivorous Diet Arms | SECONDARY | For primary and secondary outcomes, percent change and | PMC10690456 | |
Secondary Outcomes | Compared with participants receiving the omnivorous diet, participants receiving the vegan diet saw a significant mean (SD) decrease of 2.9 (1.3) μIU/mL in fasting insulin (95% CI, −5.3 to −0.4 μIU/mL) from baseline to 8 weeks ( | PMC10690456 | ||
Sensitivity Analysis | Three outlier TMAO levels greater than 15 μM were noted: 2 at baseline and 1 at 8 weeks. After the outliers were eliminated, the TMAO level was significantly different between diet groups at 8 weeks: in this analysis, participants on the vegan diet showed a mean (SD) decrease of −2.1 (0.7) μM (95% CI, −3.5 to −0.7 μM) in the difference of TMAO from baseline to 8 weeks compared with participants on the omnivorous diet (eFigure 13 in | PMC10690456 | ||
Exploratory Analysis | Paired and unpaired 2-tailed | PMC10690456 | ||
Discussion | eating a vegan diet | In this randomized clinical trial of healthy, adult identical twins, the 8-week change in LDL-C level—the primary outcome—was significantly lower for twins receiving the vegan diet compared with twins receiving the omnivorous diet. Insulin levels and weight were also significantly lower among the twins on the vegan diet from baseline to 8 weeks. Vegan-diet participants had total lower protein intake as a percentage of calories, lower dietary satisfaction, lower intake of dietary cholesterol, but higher intake of vegetable servings and intake of dietary iron. Vegans had lower intake of vitamin BTwo factors may have limited our opportunity to observe additional differences between the study groups. First, participants in both diet groups were assigned to eat a healthy diet, usually healthier compared with their prestudy dietary pattern demonstrated by increased vegetable intake and decreased refined grains intake. Even the omnivorous participants improved their diet quality during the 8-week intervention (eg, increased vegetables and whole grain intake and decreased added sugars and refined grains). Second, within both groups, potential differences in clinical end point changes may have been blunted because participants were healthy at baseline. For example, participants’ mean baseline LDL-C level was 114 mg/dL,Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health.Novel to this study was our population of identical twins, a valuable resource in scientific research that provided a unique opportunity to investigate the effects of a dietary intervention while controlling for genetic and environmental factors,We were surprised that TMAO concentrations did not significantly differ between diets at 8 weeks because of the higher meat content in the omnivorous diet and of the meat TMAO precursors choline and carnitine.A recent meta-epidemiologic study | PMC10690456 | |
Strengths and Limitations | Several aspects of our design and implementation were strengths. First, enrolling identical twins was beneficial because we were able to eliminate the confounding influences of age, sex, and genetic factors that may affect clinical outcomes. Identical twins often share a similar environment and lifestyle, reducing environmental factors on the study results. Second, the initial 4-week period of food delivery facilitated participants’ high adherence to the diet, whereas the latter 4 weeks of self-provided foods increased generalizability. Third, we used LDL-C, a well-established cardiometabolic clinical value, as the primary outcome.The study also has some limitations. First, the adult twin population was generally healthy and may not be generalizable to other populations. Second, we studied a small sample size (N = 44); however, the use of monozygotic twins may reduce issues of reproducibility because the twins acted as their own controls. Third, study duration was short (8 weeks); however, in this study as well as several previous trials, | PMC10690456 | ||
Conclusions | cardiometabolic | In this randomized clinical trial, we observed cardiometabolic advantages for the healthy vegan vs the healthy omnivorous diet among healthy, adult identical twins. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits. | PMC10690456 | |
Abstract | PMC9939110 | |||
Introduction | lung cancer, SCLC | LUNG CANCER, SCLC | Currently, only a few options are available for the treatment of patients with small‐cell lung cancer (SCLC) after the failure of first‐line platinum‐based chemotherapy. The present study aimed to evaluate the efficacy and safety of apatinib plus chemotherapy for second‐line treatment of advanced SCLC. | PMC9939110 |
Patients and Methods | toxicity | DISEASE, DISEASE PROGRESSION, SECONDARY | This prospective clinical trial recruited patients treated with apatinib plus second‐line chemotherapy until disease progression or intolerable toxicity. Logrank test power analysis was used for calculating samples. The primary endpoint was progression‐free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. | PMC9939110 |
Results | thrombocytopenia, proteinuria, neutropenia, leucopenia | ADVERSE EVENTS, THROMBOCYTOPENIA, NEUTROPENIA, LEUCOPENIA | A total of 29/31 enrolled patients were available for response evaluation until October 2019. The ORR and DCR were 27.59% (8/29) and 96.55% (28/29), respectively. The median PFS and OS were 7.36 months and 14.16 months, respectively, indicating better efficacy compared with the standard second‐line chemotherapies. The most common adverse events (AEs) were neutropenia (41.94%, 13/31), followed by leucopenia (35.48%, 11/31) and thrombocytopenia (25.81%, 8/31). The grade 3–4 AEs occurred in 12 (38.71%) patients, of which neutropenia (19.35%, 6/31), leucopenia (9.68%, 3/31), and proteinuria (6.45%, 2/31) were most common. Patients receiving an initial dose of apatinib 250 mg had a better tolerance. | PMC9939110 |
Conclusion | SCLC, toxicities | SCLC | Antiangiogenic therapy plus chemotherapy had encouraging efficacy in advanced SCLC patients, which provides an insight into the current status of second‐line therapy in SCLC.Antiangiogenic therapy (Apatinib) plus chemotherapy had better efficacy compared with standard second‐line chemotherapies for advanced SCLC patients. No more intolerable toxicities were observed for this new regimen, which should provide a highlight view on the current status of second‐line therapy in SCLC.
Yinghui Xu, Xu Wang, Chao Sun, and Zhiru Gao contributed equally. | PMC9939110 |
INTRODUCTION | toxicity, SCLC, Lung cancer | LUNG CANCER, SCLC, EVENT | Lung cancer regarded as one of the most common causes of cancer‐related mortality.Apatinib is an oral tyrosine kinase inhibitor (TKI) that specifically inhibits the vascular endothelial growth factor receptor‐2 (VEGFR‐2). As a new antiangiogenic drug, apatinib has shown promising clinical efficacy for SCLC patients. Dai et al. used apatinib as the maintenance treatment following the first‐line chemotherapy in SCLC patients, which showed promising efficacy and safety.However, the effect of apatinib plus chemotherapy in SCLC has not yet been defined. Apatinib might represent a new treatment for patients with SCLC, who have fewer options, especially in the event of relapse. In a retrospective analysis, the addition of apatinib to single‐agent chemotherapy showed a modest improvement in efficacy. Therefore, we designed a phase II, prospective, single‐center, single‐arm, clinical trial to study the clinical efficacy and toxicity of apatinib plus chemotherapy in pretreated patients with advanced SCLC. | PMC9939110 |
PATIENTS AND METHODS | PMC9939110 | |||
Patients | SCLC, allergic | BRAIN METASTASIS, SCLC, MALIGNANT TUMORS, ONCOLOGY, DISEASE PROGRESSION | In this single‐arm, phase II prospective study, pretreated patients with advanced SCLC were selected. The eligibility criteria were as follows: (1) 18–75‐years‐old; (2) Eastern Cooperative Oncology Group (ECOG) performance score ≤2; (3) Pathological examination confirmed SCLC; (4) Limited stage patients could receive thoracic radiation, surgery, or any other curative intent therapy as first‐line therapy; (5) Disease progression after first‐line chemotherapy; Platinum‐sensitive patients (relapse ≥6 months after first‐line chemotherapy) or platinum‐resistant patients (relapse <6 months after first‐line chemotherapy); (6) Absence of brain metastasis or asymptomatic brain metastasis was allowed; (7) Normal function of major organs (appropriate hematological, coagulation, hepatic, and renal function). The key exclusion criteria were as follows: (1) Previous treatment with apatinib or other antiangiogenetic agents; (2) Patients with other malignant tumors; (3) Patients allergic or intolerant to the study drugs.Generally, the first‐line therapy including surgery or radiotherapy refers to the initial treatment of patients with confirmed SCLC, we listed some conditions for the first‐line therapy including surgery or radiotherapy. (1) Some very early limited‐stage SCLC patients with clinical stage T1‐2N0M0 can undergo surgical treatment if the body can tolerate it, and then chemotherapy and radiotherapy should be further performed after the surgeryThis study was performed following the Declaration of Helsinki and the Principles of Good Clinical Practice. The protocol was reviewed and approved by the institutional review board of The First Hospital of Jilin University, Changchun, China and written informed consent was obtained from each participant. The | PMC9939110 |
Treatment schedule | death | DISEASE PROGRESSION, ADVERSE EFFECT | Initially, 18 patients were administered 500 mg apatinib once per day plus four cycles of chemotherapy, followed by single apatinib (500 mg) treatment until disease progression, death, intolerance, or consent withdrawal. Because of the intolerance to the dosage regimen at the primary stage, 13 patients were subsequently treated with 250 mg apatinib once daily plus four cycles of chemotherapy at the beginning of the treatment, followed by single apatinib (250 mg) treatment until disease progression, death, intolerance, or consent withdrawal. The dosage of apatinib was further adjusted to 250 mg every alternate day if a grade 3–4 adverse effect was observed. The chemotherapeutic agents were standard second‐line chemotherapy drugs, such as irinotecan (60 mg/m | PMC9939110 |
Efficacy and toxicity evaluation | death, Tumor, toxicity, Tumors, Toxicity, Cancer | TUMORS, DISEASE PROGRESSION, TUMOR, CANCER | All the patients were followed up until disease progression or death. Tumor response was evaluated by imaging every two cycles of treatment (every 6 weeks) according to the Response Evaluation Criteria in Solid Tumors guidelines version 1.1 (RECIST1.1). Any toxicity was observed and graded according to the National Cancer Institute Common Toxicity Criteria Version 4.0 (NCI CTCAE 4.0). All the recorded data were evaluated and checked by our clinicians. Other assessments, including physical examination, measurement of vital signs, complete blood count, biochemistry, and routine urine analysis, were also performed after every two cycles of treatment. | PMC9939110 |
Study endpoints | death | DISEASE, DISEASE PROGRESSION, SECONDARY | The primary endpoint of this study was PFS (the time from the start of treatment to the time of disease progression or death). The secondary endpoints included objective response rate (ORR) (proportion of patients achieving complete response or partial response), disease control rate (DCR) (proportion of patients with complete or partial response or stable disease), OS (the time from the start of treatment to the time of death, follow‐up failure, or follow‐up deadline), and safety. | PMC9939110 |
Statistical analysis | SCLC | SCLC | Previous large‐scale clinical studies indicated that the longest PFS of second‐line single‐agent chemotherapy for SCLC lasted about 4 months (Table | PMC9939110 |
RESULTS | PMC9939110 | |||
Patient characteristics | ONCOLOGY, MAY | A total of 31 patients were enrolled in this study from May 31, 2018 to October 25, 2019. The baseline characteristics of the subjects are listed in Table Clinical baseline characteristics of total patients (Abbreviations: ECOG, Eastern Cooperative Oncology Group. | PMC9939110 | |
Treatment outcomes | The detailed treatment outcomes of the 31 patients were depicted in the swimmers plot (Figure.Clinical outcomes and survival analysis of the patients. (A) Swimmers plot of survival outcomes of 31 patients. (B) Waterfall plot of best response among the evaluable 29 patients. Kaplan–Meier plots of (C) PFS and (D) OS.Subgroup analysis of PFS and OS of these enrolled patients. (A,B) Kaplan–Meier plots of PFS and OS in different initial dose. (C,D) Kaplan–Meier plots of PFS and OS in different age. (E,F) Kaplan–Meier plots of PFS and OS in different stage. (G,H) Kaplan–Meier plots of PFS and OS in different reaction to platimum. (I,J) Kaplan–Meier plots of PFS and OS in whether complete all chemotherapy. | PMC9939110 | ||
Treatment duration of apatinib and OS | DISEASE PROGRESSION | In the current study, the median treatment duration of apatinib was 7.36 months, and the median duration of single apatinib maintenance therapy was 4.93 months. In the cohort, 15 patients used apatinib for less than 6 months, and 16 patients used it for more than 6 months. The difference in OS between the two groups of patients during the entire treatment process was statistically significant (6.34 vs. 18.10 months, Subgroup analysis of the OS of patients with different treatment characteristics. (A) Survival of patients treated with apatinib for different durations. (B) Survival of patients receiving chemotherapy after disease progression. | PMC9939110 | |
Subsequent therapy and OS | DISEASE PROGRESSION | Next, 22/31 patients discontinued treatment due to disease progression. Among them, 15 patients accepted subsequent chemotherapy, and seven patients did not accept any subsequent anti‐cancer therapies. In this study, we observed that patients who accepted subsequent chemotherapy had longer OS than those who refused the regimen (18.10 vs. 6.34 months, | PMC9939110 | |
Multiple metastases and survival | BRAIN METASTASIS, METASTASIS, BONE METASTASIS, LYMPH NODE METASTASIS, LIVER METASTASIS | Organ metastasis analyses revealed that 9/31 (29.03%) patients had brain metastasis, but no significant clinical symptoms, 4/21 (12.9%) patients had liver metastasis, 12/31 (38.71%) patients had lymph node metastasis, 5/31 (16.13%) had adrenal metastasis, and 2/31 (6.45%) had bone metastasis (Table | PMC9939110 | |
Safety | neutropenia, diarrhea, thrombocytopenia, proteinuria, leucopenia, deaths, hypertension, hand‐foot syndrome | NEUTROPENIA, ADVERSE EVENTS, ADVERSE EVENT, THROMBOCYTOPENIA, LEUCOPENIA, HYPERTENSION | The most common adverse events (AEs) were neutropenia (41.94%, 13/31), followed by leucopenia (35.48%, 11/31), and thrombocytopenia (25.81%, 8/31). The other common AEs were proteinuria (22.58%, 7/31), diarrhea (22.58%, 7/31), hypertension (22.58%, 7/31), and hand‐foot syndrome (22.58%, 7/31). Almost all the patients had different AEs, but most of the AEs were mild and tolerable. The incidence of grade 3–4 AEs was observed in 12 (38.71%) patients, of which neutropenia (19.35%, 6/31), leucopenia (9.68%, 3/31), and proteinuria (6.45%, 2/31) were most common. The apatinib‐related AEs, proteinuria, hypertension, and hand‐foot syndrome, were tolerable. No treatment‐related deaths were reported. The AEs are described in Table Adverse events during the treatment phase in 31 patientsAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. | PMC9939110 |
Dose adjustment of apatinib | toxicities, hypertension, neutropenia, diarrhea | HYPERTENSION, NEUTROPENIA | Compared with the patients using 500 mg apatinib as the initial dose, the occurrence of treatment‐related AEs in the subgroup of patients using 250 mg initial apatinib was more optimistic. Consequently, 7/31 (22.58%) cases of intermittent medication, including four patients in the 500 mg dose group and three in the 250 mg dose group, were detected. Among the 18 patients (18/31) receiving an initial dose of apatinib 500 mg, 15 patients required dose reduction once (apatinib 250 mg/day) because of grade 3 or 4 toxicities, and two patients required second dose reduction to apatinib 250 mg every other day due to severe hypertension or neutropenia. The average duration for using apatinib 500 mg was 1.115 months. Among the 13 patients with an initial dose of apatinib 250 mg, only two patients accepted dose reduction to apatinib 250 mg every other day because of severe diarrhea (Table | PMC9939110 |
DISCUSSION | NSCLC, SCLC, vascularized malignant tumors, tumor, toxicity, lung cancer, gastric cancer | COLORECTAL CANCER, TUMOR, SCLC, PROLIFERATION, DISEASE, LUNG CANCER, HEPATOCELLULAR CARCINOMA, NSCLC, GASTRIC CANCER | Over the past two decades, antiangiogenic therapy has gained increasing attention because of its success in resisting multiple vascularized malignant tumors, such as colorectal cancer, NSCLC, and hepatocellular carcinoma.Herein, we used an oral small molecular antiangiogenic TKI apatinib in combination with chemotherapy as second‐line therapy for the treatment of advanced pretreated SCLC. Regarding the potential mechanism of this combination therapy, firstly, since VEGF plays a key role in angiogenesis and apatinib could exert its antigenic effect by inhibiting its induced endothelial cell proliferation and migration by targeting VEGFR2 with high selectivity.In our study, the majority of the patients presented partial response or stable disease. This new regimen showed better efficacy and tolerable toxicity for second‐line treatment of SCLC patients compared with the standard second‐line chemotherapies. In our study, PFS (7.36 months) and OS (14.16 months) were significantly longer than other therapies, such as topotecan, amrubicin, irinotecan, etc. Moreover, no intolerable AEs were observed in our study compared with other standard second‐line regimens (Table A similar retrospective study investigated the efficacy of induction chemotherapy in combination with apatinib (250 mg/day) as maintenance therapy in extensive‐stage SCLC and found that the PFS was 8.3 months and the OS was 17 months.The recommended dose of apatinib for advanced gastric cancer is 850 mg/day.As a highly selective VEGFR2 inhibitor, apatinib shows multidrug resistance and is also resistance to angiogenesis. In addition, it acts on tumor cells directly and enhances the sensitivity of chemotherapeutics.In addition, we estimated that the proportion of patients with this limited stage ranged from 20% to 40% by reviewing previous studies on second‐line treatment of SCLC.Nevertheless, the present study has some limitations. In addition to the small sample size, this study did not have a control group. Thus, it could not be concluded that the combination regimen is superior to apatinib or chemotherapy alone in this study. However, the advantages of apatinib combined with chemotherapy have been proven in other lung cancer studies. | PMC9939110 |
CONCLUSION | toxicity, SCLC | SCLC | Antiangiogenic therapy (apatinib) plus chemotherapy had encouraging efficacy. Also, no intolerable toxicity was observed for this new regimen, which should provide an insight into the current status of second‐line therapy in SCLC. | PMC9939110 |
AUTHORS’ CONTRIBUTIONS | Kewei Ma had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: Kewei Ma and Yinghui Xu. Acquisition, analysis, or interpretation of data: Xu Wang, Chao Sun, Junya Song. Drafting of the manuscript: Yinghui Xu, Zhiru Gao. Statistical analysis: Hua He, Ye Guo, Shi Qiu, Xiaohui Ma. Critical revision of the manuscript for important intellectual content: All authors. | PMC9939110 | ||
FUNDING INFORMATION | ONCOLOGY | K. Ma was supported by Wu Jieping Medical Foundation. Dr Y. Xu was supported by Youth Foundation of Norman Bethune Health Science Center of Jilin University (Grant ID: 2018B28) and Xisike Clinical Oncology Research Foundation (CSCO‐Haosen) (Grant ID: Y‐HS2017062). | PMC9939110 | |
CONFLICT OF INTEREST | The authors declare that they have no conflicts of interest or competing interests. | PMC9939110 | ||
Supporting information |
Figure S1
Figure. S2
Figure. S3
Table S1
Table S2
Table S3
Table S4
Click here for additional data file. | PMC9939110 | ||
ACKNOWLEDGMENT | We would like to thank all the patients and their families for their important contribution in the whole process of this study. This study was funded by Jiangsu Hengrui Pharmaceuticals. We would also like to acknowledge Y. Yu and X. Su statistical analysis (funded by Hengrui). | PMC9939110 |
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