Post-radiation Hypothyroidism After IMRT for Nasopharyngeal Carcinoma
Condition: Hypothyroidism; Complications
MeSH terms: Carcinoma; Nasopharyngeal Carcinoma; Hypothyroidism
Study type: Observational [Patient Registry]

Summary: 
      The investigators evaluate if there are radiation dosimetric parameters for the prediction of
      biochemical and clinical hypothyroidism after intensity-modulated radiation therapy (IMRT)
      for non-metastatic nasopharyngeal carcinoma (NPC).
    

Detailed description: 
      Eligible patients include those with previously untreated non-metastatic nasopharyngeal
      carcinoma (NPC) who will receive only one course of radical IMRT with or without adjunct
      chemotherapy for their NPC as curative treatment. Patients who have a history of any thyroid
      disorders, pituitary disorders, prior thyroid surgery or a drug history of thyroxine (T4) or
      triiodothyronine (T3) are excluded. Patients who have a history of radiation therapy to other
      areas are also excluded. Pretreatment investigations and workup include serum hematology,
      biochemistry, antibodies against Epstein-Barr virus (EBV) viral capsid antigen (VCA) and
      early antigen (EA), fabrication of customized head and neck thermoplastic cast for subsequent
      contrast-enhanced computed tomography (CT) scan of the head and neck region down to
      mid-thoracic region in IMRT treatment position with 3mm thickness, as well as T1-sequence,
      T2-sequence and gadolinium-enhanced magnetic resonance imaging (MRI) of the head and neck
      region by a 3-tesla scanner with the images co-registered with the planning head and neck CT
      images for detailed target and organ-at-risk (OAR) delineation and IMRT planning. A separate
      contrast-enhanced CT scan of the thorax and abdomen will also be performed to rule out
      distant metastasis.

      The gross tumour volumes of both the primary tumour (GTV-P) and the radiologically involved
      cervical nodes (GTV-N) are outlined on the planning CT images with the aid of co-registered
      MRI images. Subsequently clinical target volume (CTV-70) and planning target volume
      containing CTV-70 with a 3mm margin (PTV-70) are generated to take into account the
      microscopic disease spread, physiological body motions and set-up errors respectively.
      Another CTV-66 encompassing the high risk areas including the posterior half of the maxillary
      sinuses, nasal cavities, parapharyngeal spaces, styloid processes, basi-occiput,
      basi-sphenoid, clivus, foramina rotunda and ovale, pterygopalatine fossae, pterygomaxillary
      fissures, infra-orbital fissures, cavernous sinuses and level Ib and level V nodal stations
      is also contoured. A corresponding PTV-66 with a 3mm margin encompassing CTV-66 is created by
      boolean operations of the treatment planning system which is also used for IMRT optimization
      and planning. All OARs including brainstem, spinal cord, globes, optic nerves, optic chiasm,
      lenses, temporomandibular joints, temporal lobes, auditory nerves, cochleae, mandible, oral
      cavity, larynx, parotid glands, vestibules, pituitary and thyroid are to be contoured
      manually. During IMRT optimization, the maximum dose of brainstem, optic nerves and chiasm
      must be <=54 Gy (allowing 0.1cc brainstem <60 Gy) and spinal cord <=45 Gy (allowing 0.1cc
      spinal cord <48 Gy). Efforts will also made to limit mean dose of parotid glands to 26 Gy
      whenever possible and dose to the lenses and temporal lobes as low as reasonably achieved
      without compromising dose coverage to the PTVs. No dose constraint is to be given to the
      thyroid and pituitary during optimization of all IMRT plans.

      A 7 to 9 field IMRT plan delivered by step-and-shoot technique with a 6-megavoltage linear
      accelerator will be generated by Eclipse Treatment Planning System. A total dose of 70 Gy and
      66 Gy was prescribed to PTV-70 and PTV-66 respectively, all in 33 to 35 fractions over 6.5 to
      7 weeks by simultaneous accelerated radiation therapy technique (SMART). The whole neck was
      irradiated with IMRT and no matching anterior field to the lower neck was noted. This has
      been the standard prescription and practice in our institution for the past 10 years.
      Positional verification with on-board imaging was performed before IMRT commencement. It was
      repeated again daily immediately before the first 3 fractions of IMRT and then weekly
      afterwards during the whole course of IMRT, to track any anteroposterior and lateral body
      displacements.

      All patients had routine 6-site nasopharyngeal biopsies at 8 weeks after IMRT to confirm
      local clinical remission. Repeated nasopharyngeal biopsies were performed at 10 weeks and 12
      weeks after IMRT if residual tumour cells were still observed in previous post-IMRT
      nasopharyngeal biopsies. Additional radiation therapy in the form of intracavitary
      brachytherapy, stereotactic radiation therapy or IMRT would be given if patients developed
      local persistence at 12 weeks after IMRT. For patients confirmed to be local clinical
      remission, they received regular clinical follow up and imaging surveillance every 3 to 4
      months for the 1st year after IMRT, then every 4 to 6 months for the 2nd and 3rd year and
      yearly afterwards to monitor for any treatment-related chronic complications and relapse.
      Blood tests for thyroid function tests including free T4 and thyroid stimulating hormone
      (TSH) will be arranged at least once yearly to monitor post-IMRT hypothyroidism. Biochemical
      hypothyroidism is defined as either elevation of TSH above the upper normal limit or reduced
      free T4 below the lower normal limit or both, without the presence of clinical symptoms of
      hypothyroidism. Clinical hypothyroidism is defined as the presence of biochemical
      abnormalities of thyroid function same as that defined for biochemical hypothyroidism
      together with the presence of clinical symptoms of hypothyroidism. Those who are found to
      have clinical hypothyroidism will receive thyroxine supplement starting with 50 micrograms
      daily with repeated serum thyroid function tests 2 to 3 months later followed by dose
      titration if necessary, then every 6 to 12 months thereafter when therapeutic dosage was
      reached.

      Univariable and multivariable binary logistic regression will be performed for dosimetric
      predictors of biochemical and clinical hypothyroidism. All statistical analyses will be
      performed by Statistical Package for Social Sciences (SPSS) and statistical significance is
      defined as p-value <0.05 (two-sided).
    

Intervention name(s): Intensity-modulated radiation therapy
Intervention type(s): Radiation
Intervention description(s): All patients will receive intensity-modulated radiation therapy with or without chemotherapy as usual standard of care in our institution.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Eligible patients included those with previously untreated non-metastatic nasopharyngeal
        carcinoma (NPC) who received only one course of radical IMRT with or without adjunct
        chemotherapy for their NPC as curative treatment.
      
Keywords: Nasopharyngeal carcinoma; Intensity-modulated radiation therapy; Hypothyroidism; Predictors