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出境医 / 临床实验 / PEARL PET-based Adaptive Radiotherapy Clinical Trial (PEARL)

PEARL PET-based Adaptive Radiotherapy Clinical Trial (PEARL)

Study Description
Brief Summary:
The PEARL study will recruit approximately 50 patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) who are about to undergo primary treatment with concurrent chemo-radiation from South Wales (Velindre Cancer Centre and Singleton Hospital, Swansea) and Bristol. The main aim is to see whether it is feasible to preform a positron emission tomography-computed tomography (PET-CT) scan after 2 weeks of radiotherapy and re-plan the radiotherapy based on this PET-CT scan, to re-distribute the dose of radiotherapy being delivered, so that a smaller area of normal tissues in the mouth and throat are treated to a high dose of radiotherapy.

Condition or disease Intervention/treatment Phase
Oropharyngeal Cancer Procedure: PET-CT scans Procedure: Outlining the biological GTVs (bGTV_P and bGTV_iP) Procedure: Blood samples for cell-free DNA analysis Procedure: Salivary samples for cell-free DNA analysis Not Applicable

Detailed Description:

PEARL is a prospective, interventional, non-randomised, phase II feasibility study for patients with good prognosis Human Papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) who are suitable for treatment with concurrent chemo-radiotherapy (CCRT).

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by Human Papillomavirus (HPV) infection (HPV-positive OPSCC) is increasing in the United Kingdom. It tends to affect younger patients and has a better outcome than most other head and neck cancers.

A large proportion of patients diagnosed with HPV-positive OPSCC will undergo non-surgical treatment. This usually involves 6 to 7 weeks of chemo-radiotherapy, with chemotherapy being given weekly or during the first and fourth week of the radiotherapy course (CCRT). Many patients with HPV-positive OPSCC are cured of their disease but often have to live for several decades with the side effects of their treatment. Side effects from radiotherapy are usually caused because normal tissues surrounding the cancer receive radiation whilst the cancer itself is being treated.

Positron emission tomography-computed tomography (PET-CT) scans are able to look at the metabolic (or biological) activity of cells and are currently recommended in the UK for response assessment after a patient has completed radiotherapy for a head and neck cancer but, as far as we know, have not yet been used routinely to adapt radiotherapy according to the individual patient's response during radiotherapy.

PEARL will explore the feasibility of individually adapting the radiotherapy plan for each patient after 2 weeks of radical CCRT, based on biological changes in tumour activity seen on an interim FDG-PET-CT scan, carried out early on during a course of treatment. The aim is to reduce the dose of radiotherapy received by surrounding normal tissues to ultimately reduce toxicity.

The study will establish the progression free survival rate (PFS) in patients who receive biologically adapted radiotherapy. Furthermore, it will also explore whether changes seen on PET-CT scan during treatment correlate with outcome and with changes in potential blood-based biomarkers of response. Toxicity rates will be assessed, particularly the effect of treatment on swallowing function.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: PEARL is a prospective, interventional, non-randomised, phase II feasibility study for patients with good prognosis Human Papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) who are suitable for treatment with concurrent chemo-radiotherapy (CCRT).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PEARL: PET-based Adaptive Radiotherapy Clinical Trial
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2023
Arms and Interventions
Arm Intervention/treatment
All trial participants

Baseline plasma and saliva tests for future translational analysis

Baseline planning FDG PET CT scan

Patients will start their 6 weeks of CCRT within two to three weeks following the planning scans. Cisplatin chemotherapy will be administered. 33 daily fractions of radiotherapy will be delivered over 6 weeks.

A second FDG-PET-CT scan (iPET) and repeat plasma and saliva tests will be carried out after 2 weeks of CCRT (on RT days 9 - 12) and the iPET assessed for residual FDG-avid disease. The biological GTV will be re-outlined based on the residual avid region of the tumour on the second PET-CT (bGTV_iP)

At the end of treatment, plasma and saliva tests will be carried out at 4 weeks post treatment and again at the 3 month post-treatment PET-CT

Swallowing and QoL assessments will be repeated 4 weeks (+/- 2 weeks) after treatment and will be repeated at 6, 12 and 24 months post-treatment. The plasma and saliva samples will be repeated at 12 and 24 months

 Procedure: PET-CT scans

Patients will have three scans during the trial.

  • The 1st scan (prePET) is a baseline diagnostic scan. The patient is in a thermoplastic shell and PET CT will be used by to define a bGTV_P. bGTV_P will then be used as an adjunct to help us delineate the GTV_P.
  • The 2nd scan (iPET) takes place following 2 weeks (10 fractions) of chemo-radiotherapy. The patient is in a thermoplastic shell and the PET CT will be used to delineate the remaining avid disease (bGTV_iP).
  • The 3rd scan takes place 3 months following the last dose of radiotherapy. It will be used to ascertain whether any avid disease remains and may inform the need for further treatment.

Procedure: Outlining the biological GTVs (bGTV_P and bGTV_iP)
The biological GTVs (bGTV_P and bGTV_iP) will be automatically delineated by ATLAAS and verified manually by a nuclear medicine physician and a clinical oncologist. It will consist of the high FDG uptake volume based on visual assessment whilst using suitable windowing levels. Any differences in contouring will be settled either by the two doctors reaching a consensus or by a third doctor if differences between the first two cannot be resolved.

Procedure: Blood samples for cell-free DNA analysis
In order to contribute to our understanding of how disease processes may be monitored in a less invasive and less morbid manner, we will be collecting blood and saliva samples prior to, during, and after the radical treatment of OPSCC in PEARL, to see if there is correlation with disease status and FDG-PET-CT response.

Procedure: Salivary samples for cell-free DNA analysis
In order to contribute to our understanding of how disease processes may be monitored in a less invasive and less morbid manner, we will be collecting blood and saliva samples prior to, during, and after the radical treatment of OPSCC in PEARL, to see if there is correlation with disease status and FDG-PET-CT response.
Outcome Measures
Primary Outcome Measures :
  1. Progression free survival at 2 years [ Time Frame: 2 years following enrolment ]
    To maintain a high progression free survival rate with biologically adapted radiotherapy in patients with good prognosis HPV positive OPSCC. To be certain that we are not having a negative impact on PFS by adapting the RT plan we will ensure that PFS is at least as high as expected after treatment with chemo-radiotherapy in patients with similarly staged HPV-positive OPSCC.


Secondary Outcome Measures :
  1. Monthly recruitment rate [ Time Frame: End of 2 years recruitment period ]
    As this is a feasibility study, recruitment will be monitored and monthly recruitment rate over 2 years will be presented.

  2. To test if individualized, adaptive, biologically-based radiotherapy planning is feasible and results in a significant change in the radiotherapy plan. [ Time Frame: 2 weeks (10 fractions) of chemo-radiotherapy ]
    Percentage reduction in mean dose to OAR (superior pharyngeal constrictor muscles, contralateral parotids, contralateral submandibular gland, salivary glands) as a result of PET-CT during treatment. Percentage change to PTV will also be presented.

  3. To test if individualized, adaptive, biologically-based radiotherapy planning results in a significant change in the radiotherapy plan. [ Time Frame: 2 weeks (10 fractions) of chemo-radiotherapy ]
    Percentage reduction in mean dose to OAR (superior pharyngeal constrictor muscles, contralateral parotids, contralateral submandibular gland, salivary glands) as a result of PET-CT during treatment. Percentage change to PTV will also be presented.

  4. To maintain high complete response rates 3 months after treatment [ Time Frame: 3 months post treatment ]
    The proportion of patients who are complete metabolic responders at 3 months as per PERCIST criteria will be presented.

  5. Acute toxicity rates [ Time Frame: 3 months post treatment ]
    Cumulative acute CTCAE toxicity score percentages during and up to 3 months after treatment will be presented.

  6. Late toxicity rates [ Time Frame: 6, 12 and 24 months post treatment ]
    Water swallow test will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.

  7. Late toxicity rates [ Time Frame: 6, 12 and 24 months post treatment] ]
    MDADI will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.

  8. Late toxicity rates [ Time Frame: 6, 12 and 24 months post treatment] ]
    QoL scores will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.

  9. To assess the effect of treatment on swallowing function [ Time Frame: 3, 6, 12 and 24 months post treatment ]
    Water swallow test scores will be plotted over time.

  10. To assess the effect of treatment on swallowing function [ Time Frame: 3, 6, 12 and 24 months post treatment ]
    MDADI scores will be plotted over time.

  11. To assess the effect of treatment on swallowing function [ Time Frame: 3, 6, 12 and 24 months post treatment ]
    QoL scores will be plotted over time.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed squamous cell carcinoma of the oropharynx
  2. Positive p16 Immunohistochemistry on local testing
  3. UICC TNM (8th edition) stage T1 - T3 N0 - N1 M0
  4. Multidisciplinary team (MDT) decision to treat with primary chemoradiotherapy
  5. Patients considered fit for radical treatment with primary chemoradiotherapy (including sufficient renal function (GFR>50ml/min)
  6. Aged 18 years or older
  7. Not smoked in the last 2 years
  8. Written informed consent provided
  9. Patients with reproductive potential (male or female), who are sexually active during the duration of the trial consent to using a highly effective method of contraception for at least six months after the last dose of chemoradiotherapy. Effective forms of contraception are described in section 15.5.

Exclusion Criteria:

  1. Known HPV negative squamous cell carcinoma of the head and neck
  2. T1 - T3 tumours where primary treatment with concomitant chemo-radiotherapy is not considered appropriate
  3. T4 disease
  4. N2 (TMN8) nodal disease
  5. Distant metastatic disease
  6. Current smokers or smokers who have stopped within the past 2 years
  7. Diabetes mellitus
  8. Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction prior to index oropharyngeal cancer
  9. Previous radiotherapy to the head and neck
  10. History of malignancy in the last 5 years, except basal cell carcinoma of the skin, or carcinoma in situ of the cervix
  11. Tumour non-avid on PET-CT or not visible on cross sectional imaging
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Martina Svobodova 02920687463 svobodovam@cardiff.ac.uk
Contact: Lisette Nixon 02920678458 pearl@cardiff.ac.uk

Locations
Layout table for location information
United Kingdom
Velindre Cancer Center at Velindre Hospital
Cardiff, Wales, United Kingdom, CF14 2TL
Singleton Hospital
Swansea, Wales, United Kingdom, SA2 8QA
University Hospitals Bristol NHS Foundation Trust
Bristol, United Kingdom, BS2 8ED
Sponsors and Collaborators
Velindre NHS Trust
Investigators
Layout table for investigator information
Principal Investigator: Mererid Evans Velindre Cancer Centre
Tracking Information
First Submitted Date  ICMJE October 3, 2018
First Posted Date  ICMJE May 2, 2019
Last Update Posted Date May 2, 2019
Estimated Study Start Date  ICMJE July 1, 2019
Estimated Primary Completion Date February 28, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2019) 		Progression free survival at 2 years [ Time Frame: 2 years following enrolment ]
To maintain a high progression free survival rate with biologically adapted radiotherapy in patients with good prognosis HPV positive OPSCC. To be certain that we are not having a negative impact on PFS by adapting the RT plan we will ensure that PFS is at least as high as expected after treatment with chemo-radiotherapy in patients with similarly staged HPV-positive OPSCC.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • Monthly recruitment rate [ Time Frame: End of 2 years recruitment period ]
    As this is a feasibility study, recruitment will be monitored and monthly recruitment rate over 2 years will be presented.
  • To test if individualized, adaptive, biologically-based radiotherapy planning is feasible and results in a significant change in the radiotherapy plan. [ Time Frame: 2 weeks (10 fractions) of chemo-radiotherapy ]
    Percentage reduction in mean dose to OAR (superior pharyngeal constrictor muscles, contralateral parotids, contralateral submandibular gland, salivary glands) as a result of PET-CT during treatment. Percentage change to PTV will also be presented.
  • To test if individualized, adaptive, biologically-based radiotherapy planning results in a significant change in the radiotherapy plan. [ Time Frame: 2 weeks (10 fractions) of chemo-radiotherapy ]
    Percentage reduction in mean dose to OAR (superior pharyngeal constrictor muscles, contralateral parotids, contralateral submandibular gland, salivary glands) as a result of PET-CT during treatment. Percentage change to PTV will also be presented.
  • To maintain high complete response rates 3 months after treatment [ Time Frame: 3 months post treatment ]
    The proportion of patients who are complete metabolic responders at 3 months as per PERCIST criteria will be presented.
  • Acute toxicity rates [ Time Frame: 3 months post treatment ]
    Cumulative acute CTCAE toxicity score percentages during and up to 3 months after treatment will be presented.
  • Late toxicity rates [ Time Frame: 6, 12 and 24 months post treatment ]
    Water swallow test will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.
  • Late toxicity rates [ Time Frame: 6, 12 and 24 months post treatment] ]
    MDADI will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.
  • Late toxicity rates [ Time Frame: 6, 12 and 24 months post treatment] ]
    QoL scores will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.
  • To assess the effect of treatment on swallowing function [ Time Frame: 3, 6, 12 and 24 months post treatment ]
    Water swallow test scores will be plotted over time.
  • To assess the effect of treatment on swallowing function [ Time Frame: 3, 6, 12 and 24 months post treatment ]
    MDADI scores will be plotted over time.
  • To assess the effect of treatment on swallowing function [ Time Frame: 3, 6, 12 and 24 months post treatment ]
    QoL scores will be plotted over time.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PEARL PET-based Adaptive Radiotherapy Clinical Trial
Official Title  ICMJE PEARL: PET-based Adaptive Radiotherapy Clinical Trial
Brief Summary The PEARL study will recruit approximately 50 patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) who are about to undergo primary treatment with concurrent chemo-radiation from South Wales (Velindre Cancer Centre and Singleton Hospital, Swansea) and Bristol. The main aim is to see whether it is feasible to preform a positron emission tomography-computed tomography (PET-CT) scan after 2 weeks of radiotherapy and re-plan the radiotherapy based on this PET-CT scan, to re-distribute the dose of radiotherapy being delivered, so that a smaller area of normal tissues in the mouth and throat are treated to a high dose of radiotherapy.
Detailed Description

PEARL is a prospective, interventional, non-randomised, phase II feasibility study for patients with good prognosis Human Papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) who are suitable for treatment with concurrent chemo-radiotherapy (CCRT).

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by Human Papillomavirus (HPV) infection (HPV-positive OPSCC) is increasing in the United Kingdom. It tends to affect younger patients and has a better outcome than most other head and neck cancers.

A large proportion of patients diagnosed with HPV-positive OPSCC will undergo non-surgical treatment. This usually involves 6 to 7 weeks of chemo-radiotherapy, with chemotherapy being given weekly or during the first and fourth week of the radiotherapy course (CCRT). Many patients with HPV-positive OPSCC are cured of their disease but often have to live for several decades with the side effects of their treatment. Side effects from radiotherapy are usually caused because normal tissues surrounding the cancer receive radiation whilst the cancer itself is being treated.

Positron emission tomography-computed tomography (PET-CT) scans are able to look at the metabolic (or biological) activity of cells and are currently recommended in the UK for response assessment after a patient has completed radiotherapy for a head and neck cancer but, as far as we know, have not yet been used routinely to adapt radiotherapy according to the individual patient's response during radiotherapy.

PEARL will explore the feasibility of individually adapting the radiotherapy plan for each patient after 2 weeks of radical CCRT, based on biological changes in tumour activity seen on an interim FDG-PET-CT scan, carried out early on during a course of treatment. The aim is to reduce the dose of radiotherapy received by surrounding normal tissues to ultimately reduce toxicity.

The study will establish the progression free survival rate (PFS) in patients who receive biologically adapted radiotherapy. Furthermore, it will also explore whether changes seen on PET-CT scan during treatment correlate with outcome and with changes in potential blood-based biomarkers of response. Toxicity rates will be assessed, particularly the effect of treatment on swallowing function.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
PEARL is a prospective, interventional, non-randomised, phase II feasibility study for patients with good prognosis Human Papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) who are suitable for treatment with concurrent chemo-radiotherapy (CCRT).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Oropharyngeal Cancer
Intervention  ICMJE
  • Procedure: PET-CT scans

    Patients will have three scans during the trial.

    • The 1st scan (prePET) is a baseline diagnostic scan. The patient is in a thermoplastic shell and PET CT will be used by to define a bGTV_P. bGTV_P will then be used as an adjunct to help us delineate the GTV_P.
    • The 2nd scan (iPET) takes place following 2 weeks (10 fractions) of chemo-radiotherapy. The patient is in a thermoplastic shell and the PET CT will be used to delineate the remaining avid disease (bGTV_iP).
    • The 3rd scan takes place 3 months following the last dose of radiotherapy. It will be used to ascertain whether any avid disease remains and may inform the need for further treatment.
  • Procedure: Outlining the biological GTVs (bGTV_P and bGTV_iP)
    The biological GTVs (bGTV_P and bGTV_iP) will be automatically delineated by ATLAAS and verified manually by a nuclear medicine physician and a clinical oncologist. It will consist of the high FDG uptake volume based on visual assessment whilst using suitable windowing levels. Any differences in contouring will be settled either by the two doctors reaching a consensus or by a third doctor if differences between the first two cannot be resolved.
  • Procedure: Blood samples for cell-free DNA analysis
    In order to contribute to our understanding of how disease processes may be monitored in a less invasive and less morbid manner, we will be collecting blood and saliva samples prior to, during, and after the radical treatment of OPSCC in PEARL, to see if there is correlation with disease status and FDG-PET-CT response.
  • Procedure: Salivary samples for cell-free DNA analysis
    In order to contribute to our understanding of how disease processes may be monitored in a less invasive and less morbid manner, we will be collecting blood and saliva samples prior to, during, and after the radical treatment of OPSCC in PEARL, to see if there is correlation with disease status and FDG-PET-CT response.
Study Arms  ICMJE All trial participants

Baseline plasma and saliva tests for future translational analysis

Baseline planning FDG PET CT scan

Patients will start their 6 weeks of CCRT within two to three weeks following the planning scans. Cisplatin chemotherapy will be administered. 33 daily fractions of radiotherapy will be delivered over 6 weeks.

A second FDG-PET-CT scan (iPET) and repeat plasma and saliva tests will be carried out after 2 weeks of CCRT (on RT days 9 - 12) and the iPET assessed for residual FDG-avid disease. The biological GTV will be re-outlined based on the residual avid region of the tumour on the second PET-CT (bGTV_iP)

At the end of treatment, plasma and saliva tests will be carried out at 4 weeks post treatment and again at the 3 month post-treatment PET-CT

Swallowing and QoL assessments will be repeated 4 weeks (+/- 2 weeks) after treatment and will be repeated at 6, 12 and 24 months post-treatment. The plasma and saliva samples will be repeated at 12 and 24 months

Interventions:
  • Procedure: PET-CT scans
  • Procedure: Outlining the biological GTVs (bGTV_P and bGTV_iP)
  • Procedure: Blood samples for cell-free DNA analysis
  • Procedure: Salivary samples for cell-free DNA analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 30, 2019) 		50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2023
Estimated Primary Completion Date February 28, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologically confirmed squamous cell carcinoma of the oropharynx
  2. Positive p16 Immunohistochemistry on local testing
  3. UICC TNM (8th edition) stage T1 - T3 N0 - N1 M0
  4. Multidisciplinary team (MDT) decision to treat with primary chemoradiotherapy
  5. Patients considered fit for radical treatment with primary chemoradiotherapy (including sufficient renal function (GFR>50ml/min)
  6. Aged 18 years or older
  7. Not smoked in the last 2 years
  8. Written informed consent provided
  9. Patients with reproductive potential (male or female), who are sexually active during the duration of the trial consent to using a highly effective method of contraception for at least six months after the last dose of chemoradiotherapy. Effective forms of contraception are described in section 15.5.

Exclusion Criteria:

  1. Known HPV negative squamous cell carcinoma of the head and neck
  2. T1 - T3 tumours where primary treatment with concomitant chemo-radiotherapy is not considered appropriate
  3. T4 disease
  4. N2 (TMN8) nodal disease
  5. Distant metastatic disease
  6. Current smokers or smokers who have stopped within the past 2 years
  7. Diabetes mellitus
  8. Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction prior to index oropharyngeal cancer
  9. Previous radiotherapy to the head and neck
  10. History of malignancy in the last 5 years, except basal cell carcinoma of the skin, or carcinoma in situ of the cervix
  11. Tumour non-avid on PET-CT or not visible on cross sectional imaging
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Martina Svobodova 02920687463 svobodovam@cardiff.ac.uk
Contact: Lisette Nixon 02920678458 pearl@cardiff.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03935672
Other Study ID Numbers  ICMJE 2018/VCC/0029
242633 ( Other Identifier: IRAS number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Lisette Nixon, Velindre NHS Trust
Study Sponsor  ICMJE Velindre NHS Trust
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mererid Evans Velindre Cancer Centre
PRS Account Velindre NHS Trust
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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