Surgery and Reducing Ionizing Radiation of the Unknown Primary
NCT ID: NCT06578871
Last Updated: 2024-09-03
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
NOT_YET_RECRUITING
Clinical Phase
PHASE2
Total Enrollment
90 participants
Study Classification
INTERVENTIONAL
Study Start Date
2025-01-01
Study Completion Date
2027-05-30
Brief Summary
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About 3% of people with head and neck cancer have cancer in their lymph nodes, but doctors are unable to find the primary tumour. This situation has become more common due to human papillomavirus (HPV), a virus linked to certain cancers. Generally, patients with HPV-related cancers have a good outlook, with around 90% surviving for at least five years.
Recent advancements in medical technology, such as advanced imaging and specialized surgeries, have significantly improved doctors' ability to find these hidden tumours. These techniques can locate the primary tumour in 70-80% of cases. If the tumour remains undetected, it could be very small or potentially eliminated by the body's immune system.
The best way to treat this type of cancer is still debated. Current treatment options include surgery to remove lymph nodes or radiation therapy. There is no clear agreement on which areas should receive radiation. Often, surgery is performed on one side of the throat to try and locate the tumour's origin.
Researchers are exploring ways to minimize the harmful side effects of treatment. Some studies suggest that surgery alone might be sufficient for patients with small tumours in their neck, but more research is needed. Another important question is whether radiation needs to cover the entire throat area. Recent findings suggest that omitting radiation from some areas might reduce side effects such as difficulty swallowing and dry mouth.
The SUPERIOR trial aims to investigate whether reducing the amount of radiation can still be effective and improve patients' quality of life. The study also examines whether surgery alone is adequate for certain patients with HPV-related cancers.
Recent advancements in medical technology, such as advanced imaging and specialized surgeries, have significantly improved doctors' ability to find these hidden tumours. These techniques can locate the primary tumour in 70-80% of cases. If the tumour remains undetected, it could be very small or potentially eliminated by the body's immune system.
The best way to treat this type of cancer is still debated. Current treatment options include surgery to remove lymph nodes or radiation therapy. There is no clear agreement on which areas should receive radiation. Often, surgery is performed on one side of the throat to try and locate the tumour's origin.
Researchers are exploring ways to minimize the harmful side effects of treatment. Some studies suggest that surgery alone might be sufficient for patients with small tumours in their neck, but more research is needed. Another important question is whether radiation needs to cover the entire throat area. Recent findings suggest that omitting radiation from some areas might reduce side effects such as difficulty swallowing and dry mouth.
The SUPERIOR trial aims to investigate whether reducing the amount of radiation can still be effective and improve patients' quality of life. The study also examines whether surgery alone is adequate for certain patients with HPV-related cancers.
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Detailed Description
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Approximately 3% of all head and neck squamous cell carcinoma (SCC) patients present with nodal disease from an unknown primary (PUK). The incidence of PUK has increased in tandem with the rise of human papillomavirus (HPV)-mediated oropharyngeal SCC (OPSCC). HPV-mediated PUK now represents at least half of the head and neck PUK population, with an excellent prognosis and approximately 90% 5-year overall survival (OS).
The work-up for PUK has significantly improved with the introduction of positron emission tomography (PET) imaging and transoral robotic surgery (TORS). PET identifies at least 40% of primaries in PUK patients when clinical and radiological work-up is negative, and TORS has a higher primary identification rate (70%-80%). Current guidelines recommend tonsillectomy and tongue base mucosectomy in the work-up of PUK patients.
Definitive management of HPV-mediated PUK remains controversial, with curative options including primary neck dissection ± adjuvant therapy or primary radiotherapy ± concurrent chemotherapy. Treatment morbidity is significant, despite the excellent outcomes (90% 5-year OS). Key issues include the choice of initial treatment modality and whether to treat mucosal surfaces with radiation prophylactically.
Current guidelines recommend single-modality surgery (neck dissection) for low-volume neck disease. This recommendation is based on studies suggesting low primary emergence rates (1.5%-7%) and outcomes comparable to non-surgical treatment paradigms. Evidence from early-stage OPSCC supports surgery alone as a safe option for HPV-mediated PUK.
A critical question is whether to irradiate mucosal surfaces when using radiotherapy for HPV-mediated PUK. Emerging data suggest that omitting mucosal radiation has a very low risk (\<5%) of primary tumour emergence, potentially improving long-term quality of life and reducing toxicities like dysphagia and xerostomia. Several retrospective studies support the safety and reduced toxicity of involved neck radiotherapy without mucosal irradiation.
This trial is specifically designed with an upfront neck dissection alongside tonsillectomy and tongue base mucosectomy. Combining an upfront therapeutic neck dissection with the final stage of the diagnostic work-up has several benefits. Surgically treating the neck in selected patients during tonsillectomy and tongue base mucosectomy accelerates treatment, avoids additional delays, reduces costs to healthcare institutions, and prevents the need for a second surgery if no primary is identified. The addition of neck dissection to tonsillectomy and tongue base mucosectomy also involves relatively minor additional surgical morbidity in the context of a patient already undergoing pharyngeal surgery. In some instances, upfront surgical treatment of the neck may complete definitive treatment at the earliest opportunity. Patients with intermediate-volume neck disease, who require dual-modality treatment, also benefit from no further surgical delay and can proceed to radiotherapy following a single surgical encounter. An upfront neck dissection is also the gold standard for lymph node evaluation and may down-stage patients into a unimodality approach, thereby avoiding additional toxicity. For example, if imaging suggests multiple involved ipsilateral nodes in an HPV-mediated PUK patient, conventional treatment would involve dual-modality therapy. Pathological staging may down-stage this patient into a unimodality paradigm, sparing them significant toxicity.
In this randomized phase II trial, the study team hypothesizes that omitting mucosal radiation will lead to improved quality of life, decreased toxicity, and low rates of primary tumour emergence. Further, the researchers hypothesize that neck dissection alone for low-volume HPV-mediated PUK will result in excellent oncologic and functional outcomes.
The main objective is to assess the impact of omitting mucosal radiation on oncologic outcomes, toxicity, functional outcomes, and quality of life (QOL) in patients with p16-positive PUK.
The primary endpoint is to determine the rate of primary emergence of a mucosal p16-positive SCC in the upper aerodigestive tract compared to historical controls.
The secondary endpoints include:
Quality of life (using MDADI, EORTC QLQ-C30 and H\&N35, EQ-5D-5L, NDII) Overall survival (OS) Disease-free survival Regional recurrence within the neck Distant recurrence outside the upper aerodigestive tract and neck levels Rate of salvage treatment for primary emergence Rate of unsalvageable primary emergence Rate of percutaneous feeding tube insertion and use at 1 year Swallowing function (DIGEST score, FOIS) Toxicity (CTCAE version 5) Patients will be randomized 1:2 between the standard of care (Arm 1) and omission of radiation to mucosal surfaces (Arm 2).
Combining neck dissection with tonsillectomy and tongue base mucosectomy accelerates treatment, reduces costs, and avoids additional surgery. This approach involves minor additional surgical morbidity and can complete definitive treatment at the earliest opportunity. Upfront neck dissection also allows for accurate lymph node evaluation and potential down-staging, thereby sparing patients from additional toxicity.
The SUPERIOR trial aims to determine whether omitting mucosal radiation improves quality of life and reduces toxicity in HPV-mediated PUK patients, while evaluating the efficacy of neck dissection alone for low-volume disease. The study seeks to establish evidence-based guidelines for the optimal management of HPV-mediated PUK.
The work-up for PUK has significantly improved with the introduction of positron emission tomography (PET) imaging and transoral robotic surgery (TORS). PET identifies at least 40% of primaries in PUK patients when clinical and radiological work-up is negative, and TORS has a higher primary identification rate (70%-80%). Current guidelines recommend tonsillectomy and tongue base mucosectomy in the work-up of PUK patients.
Definitive management of HPV-mediated PUK remains controversial, with curative options including primary neck dissection ± adjuvant therapy or primary radiotherapy ± concurrent chemotherapy. Treatment morbidity is significant, despite the excellent outcomes (90% 5-year OS). Key issues include the choice of initial treatment modality and whether to treat mucosal surfaces with radiation prophylactically.
Current guidelines recommend single-modality surgery (neck dissection) for low-volume neck disease. This recommendation is based on studies suggesting low primary emergence rates (1.5%-7%) and outcomes comparable to non-surgical treatment paradigms. Evidence from early-stage OPSCC supports surgery alone as a safe option for HPV-mediated PUK.
A critical question is whether to irradiate mucosal surfaces when using radiotherapy for HPV-mediated PUK. Emerging data suggest that omitting mucosal radiation has a very low risk (\<5%) of primary tumour emergence, potentially improving long-term quality of life and reducing toxicities like dysphagia and xerostomia. Several retrospective studies support the safety and reduced toxicity of involved neck radiotherapy without mucosal irradiation.
This trial is specifically designed with an upfront neck dissection alongside tonsillectomy and tongue base mucosectomy. Combining an upfront therapeutic neck dissection with the final stage of the diagnostic work-up has several benefits. Surgically treating the neck in selected patients during tonsillectomy and tongue base mucosectomy accelerates treatment, avoids additional delays, reduces costs to healthcare institutions, and prevents the need for a second surgery if no primary is identified. The addition of neck dissection to tonsillectomy and tongue base mucosectomy also involves relatively minor additional surgical morbidity in the context of a patient already undergoing pharyngeal surgery. In some instances, upfront surgical treatment of the neck may complete definitive treatment at the earliest opportunity. Patients with intermediate-volume neck disease, who require dual-modality treatment, also benefit from no further surgical delay and can proceed to radiotherapy following a single surgical encounter. An upfront neck dissection is also the gold standard for lymph node evaluation and may down-stage patients into a unimodality approach, thereby avoiding additional toxicity. For example, if imaging suggests multiple involved ipsilateral nodes in an HPV-mediated PUK patient, conventional treatment would involve dual-modality therapy. Pathological staging may down-stage this patient into a unimodality paradigm, sparing them significant toxicity.
In this randomized phase II trial, the study team hypothesizes that omitting mucosal radiation will lead to improved quality of life, decreased toxicity, and low rates of primary tumour emergence. Further, the researchers hypothesize that neck dissection alone for low-volume HPV-mediated PUK will result in excellent oncologic and functional outcomes.
The main objective is to assess the impact of omitting mucosal radiation on oncologic outcomes, toxicity, functional outcomes, and quality of life (QOL) in patients with p16-positive PUK.
The primary endpoint is to determine the rate of primary emergence of a mucosal p16-positive SCC in the upper aerodigestive tract compared to historical controls.
The secondary endpoints include:
Quality of life (using MDADI, EORTC QLQ-C30 and H\&N35, EQ-5D-5L, NDII) Overall survival (OS) Disease-free survival Regional recurrence within the neck Distant recurrence outside the upper aerodigestive tract and neck levels Rate of salvage treatment for primary emergence Rate of unsalvageable primary emergence Rate of percutaneous feeding tube insertion and use at 1 year Swallowing function (DIGEST score, FOIS) Toxicity (CTCAE version 5) Patients will be randomized 1:2 between the standard of care (Arm 1) and omission of radiation to mucosal surfaces (Arm 2).
Combining neck dissection with tonsillectomy and tongue base mucosectomy accelerates treatment, reduces costs, and avoids additional surgery. This approach involves minor additional surgical morbidity and can complete definitive treatment at the earliest opportunity. Upfront neck dissection also allows for accurate lymph node evaluation and potential down-staging, thereby sparing patients from additional toxicity.
The SUPERIOR trial aims to determine whether omitting mucosal radiation improves quality of life and reduces toxicity in HPV-mediated PUK patients, while evaluating the efficacy of neck dissection alone for low-volume disease. The study seeks to establish evidence-based guidelines for the optimal management of HPV-mediated PUK.
Conditions
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Head and Neck Squamous Cell Carcinoma
HPV Positive Oropharyngeal Squamous Cell Carcinoma
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
This is a randomized phase II study. Patients will be randomized between current standard of care treatment (Arm 1) vs. omission of radiation mucosal surfaces (Arm 2) in a 1:2 ratio.
Primary Study Purpose
TREATMENT
Blinding Strategy
SINGLE
Outcome Assessors
The SUPERIOR trial employs a 1:2 randomization ratio using a permuted block design with block sizes known only to the statistician. Stratification factors include smoking status (\>10 pack-years vs. ≤10 pack-years) and pathologic nodal burden (1 node positive vs. \>1 node positive). Although participants and treating clinicians are aware of the treatment allocations, outcome assessors and data analysts are blinded to the treatment arms to ensure unbiased assessment and analysis of trial results.
Study Groups
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Arm1: Standard of Care Treatment
Radiotherapy to Ipsilateral Neck and to risk Mucosa
There are two possible dose levels:
* 60 Gy in 30 fractions over 6 weeks (CTV60)
o This applies to the dissected levels of the neck
* 54 Gy in 30 fractions over 6 weeks (CTV54)
* This applies to the mucosal surfaces. Patients randomized to Arm 2 will not have the mucosal surfaces treated
Group Type
ACTIVE_COMPARATOR
Intensity Modulated Radiotherapy (IMRT) to Mucosa at Risk
Intervention Type
RADIATION
Patients in Arm 1, after the surgical procedure, will receive radiotherapy to the at-risk mucosa.
Surgical Intervention
Intervention Type
PROCEDURE
These patients will undergo Neck dissection, TORS tonsillectomy (unilateral vs bilateral tonsillectomy at the discretion of the treating physician) + ipsilateral tongue base mucosectomy.
Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck
Intervention Type
RADIATION
For Arm1, after the surgical procedure, the patients will receive radiotherapy to the ipsilateral neck. For Arm2, the patients will only receive IMRT to neck, if multiple ipsilateral nodes or single ipsilateral node \>3 cm is observed
Arm 2: Omission of IMRT to Risk Mucosa but conditional IMRT to Neck
* If N1 with single node \<= 3cm, no further treatment
* If multiple ipsilateral nodes or single ipsilateral node \>3 cm, radiation to Neck only
Group Type
EXPERIMENTAL
Surgical Intervention
Intervention Type
PROCEDURE
These patients will undergo Neck dissection, TORS tonsillectomy (unilateral vs bilateral tonsillectomy at the discretion of the treating physician) + ipsilateral tongue base mucosectomy.
Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck
Intervention Type
RADIATION
For Arm1, after the surgical procedure, the patients will receive radiotherapy to the ipsilateral neck. For Arm2, the patients will only receive IMRT to neck, if multiple ipsilateral nodes or single ipsilateral node \>3 cm is observed
Interventions
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Intensity Modulated Radiotherapy (IMRT) to Mucosa at Risk
Patients in Arm 1, after the surgical procedure, will receive radiotherapy to the at-risk mucosa.
Intervention Type
RADIATION
Surgical Intervention
These patients will undergo Neck dissection, TORS tonsillectomy (unilateral vs bilateral tonsillectomy at the discretion of the treating physician) + ipsilateral tongue base mucosectomy.
Intervention Type
PROCEDURE
Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck
For Arm1, after the surgical procedure, the patients will receive radiotherapy to the ipsilateral neck. For Arm2, the patients will only receive IMRT to neck, if multiple ipsilateral nodes or single ipsilateral node \>3 cm is observed
Intervention Type
RADIATION
Eligibility Criteria
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Inclusion Criteria
* p16 positive PUK SCC of the neck
* Age 18 years or older
* Willing to provide informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Clinical nodal stage N1, AJCC 8th edition (i.e. clinical unilateral nodal disease, none larger than 6 cm)
* Complete clinical work-up, including CT neck, physical examination with nasopharyngoscopy, and PET/CT, with no evidence of a primary tumor. The PET/CT scan must be without focal metabolic activity concerning for a primary tumor, in the opinion of the nuclear medicine physician. Metabolic activity, particularly in the tonsils and base of the tongue which is within normal physiologic range, does not exclude participation.
* Completed ipsilateral tonsillectomy and base of tongue mucosectomy with no evidence of a primary tumor
o Note, patients who had a PET/CT that was initially positive, and therefore not meeting criteria in 4.10, but panendoscopy with biopsies of the fluorodeoxyglucose (FDG)-avid areas do not show malignancy, can then be enrolled and would be returned the OR for a neck dissection prior to randomization
* Ipsilateral nodal disease on pathology with no evidence of extranodal extension
* Age 18 years or older
* Willing to provide informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Clinical nodal stage N1, AJCC 8th edition (i.e. clinical unilateral nodal disease, none larger than 6 cm)
* Complete clinical work-up, including CT neck, physical examination with nasopharyngoscopy, and PET/CT, with no evidence of a primary tumor. The PET/CT scan must be without focal metabolic activity concerning for a primary tumor, in the opinion of the nuclear medicine physician. Metabolic activity, particularly in the tonsils and base of the tongue which is within normal physiologic range, does not exclude participation.
* Completed ipsilateral tonsillectomy and base of tongue mucosectomy with no evidence of a primary tumor
o Note, patients who had a PET/CT that was initially positive, and therefore not meeting criteria in 4.10, but panendoscopy with biopsies of the fluorodeoxyglucose (FDG)-avid areas do not show malignancy, can then be enrolled and would be returned the OR for a neck dissection prior to randomization
* Ipsilateral nodal disease on pathology with no evidence of extranodal extension
Exclusion Criteria
* Radiological or pathological extra-nodal extension
* Epstein-Barr Virus (EBV)-positive
* Clinical nodal stage (i.e. before neck dissection) N2-3, AJCC 8th edition (ie. bilateral nodes or node \>6cm)
* Pathological nodal stage (i.e. after neck dissection) pN3
* Prior history of head and neck cancer within 2 years
* Any other active invasive malignancy, except non-melanotic skin cancers, low-risk prostate cancer, and stage I-IVA papillary or follicular thyroid cancer
* Known metastatic disease
* Unable to complete QOL questionnaires
* Pregnant or lactating women
* Epstein-Barr Virus (EBV)-positive
* Clinical nodal stage (i.e. before neck dissection) N2-3, AJCC 8th edition (ie. bilateral nodes or node \>6cm)
* Pathological nodal stage (i.e. after neck dissection) pN3
* Prior history of head and neck cancer within 2 years
* Any other active invasive malignancy, except non-melanotic skin cancers, low-risk prostate cancer, and stage I-IVA papillary or follicular thyroid cancer
* Known metastatic disease
* Unable to complete QOL questionnaires
* Pregnant or lactating women
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Dr. Jake Jervis-Bardy
UNKNOWN
Sponsor Role
collaborator
Dr. David Palma
UNKNOWN
Sponsor Role
collaborator
Dr. Adam Mutsaers
UNKNOWN
Sponsor Role
collaborator
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
OTHER
Sponsor Role
lead
Responsible Party
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Adrian Mendez
Study Principal Investigator
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Adrian I Mendez, MD
Role: PRINCIPAL_INVESTIGATOR
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Jake Jervis-Bardy, MD
Role: PRINCIPAL_INVESTIGATOR
Royal Adelaide Hospital
Locations
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Royal Adelaide Hospital
Adelaide, South Australia, Australia
Site Status
Flinders Medical Centre
Adelaide, South Australia, Australia
Site Status
London Health Sciences Centre
London, Ontario, Canada
Site Status
Countries
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Australia
Canada
Central Contacts
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Facility Contacts
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Jake Jervis-Bardy
Role: primary
+6182045511
References
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Ferris RL, Flamand Y, Weinstein GS, Li S, Quon H, Mehra R, Garcia JJ, Chung CH, Gillison ML, Duvvuri U, O'Malley BW Jr, Ozer E, Thomas GR, Koch WM, Gross ND, Bell RB, Saba NF, Lango M, Mendez E, Burtness B. Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311). J Clin Oncol. 2022 Jan 10;40(2):138-149. doi: 10.1200/JCO.21.01752. Epub 2021 Oct 26.
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Sivars L, Nasman A, Tertipis N, Vlastos A, Ramqvist T, Dalianis T, Munck-Wikland E, Nordemar S. Human papillomavirus and p53 expression in cancer of unknown primary in the head and neck region in relation to clinical outcome. Cancer Med. 2014 Apr;3(2):376-84. doi: 10.1002/cam4.199. Epub 2014 Feb 10.
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Takhar A, Wilkie MD, Srinivasan D, King E. Head and Neck Squamous Cell Carcinoma of Unknown Primary-Who Can Be Offered Surgery as the Sole Treatment Modality? A Systematic Review. Clin Otolaryngol. 2025 May;50(3):399-414. doi: 10.1111/coa.14279. Epub 2025 Jan 12.
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Strojan P, Kokalj M, Zadnik V, Anicin A, Plavc G, Didanovic V, Sifrer R, Lanisnik B. Squamous cell carcinoma of unknown primary tumor metastatic to neck nodes: role of elective irradiation. Eur Arch Otorhinolaryngol. 2016 Dec;273(12):4561-4569. doi: 10.1007/s00405-016-4172-5. Epub 2016 Jun 30.
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Grewal AS, Rajasekaran K, Cannady SB, Chalian AA, Ghiam AF, Lin A, LiVolsi V, Lukens JN, Mitra N, Montone KT, Newman JG, O'Malley BW Jr,, Rassekh CH, Weinstein GS, Swisher-McClure S. Pharyngeal-sparing radiation for head and neck carcinoma of unknown primary following TORS assisted work-up. Laryngoscope. 2020 Mar;130(3):691-697. doi: 10.1002/lary.28200. Epub 2019 Aug 14.
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Lauer MS, D'Agostino RB Sr. The randomized registry trial--the next disruptive technology in clinical research? N Engl J Med. 2013 Oct 24;369(17):1579-81. doi: 10.1056/NEJMp1310102. Epub 2013 Aug 31. No abstract available.
Reference Type
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Other Identifiers
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5007
Identifier Type: OTHER
Identifier Source: secondary_id
15080
Identifier Type: -
Identifier Source: org_study_id
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