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Papillary Carcinoma of Thyroid with Multiple and Diffuse Nodular Secondarisms of the Pulmonary Parenchyma

Short summary

78-year-old female with history of diabetes, and meningioma complicated by neurologic deficits following surgery, was diagnosed with progressive iodine-refractory metastatic papillary thyroid carcinoma (PTC). Her initial work-up revealed lung metastasis. She underwent a right thyroidectomy and then left thyroidectomy and laryngectomy, and subsequently received I-131 on 8 occasions. She had a drop in thyroglobulin levels to the early treatments, but most recently, thyroglobulin has steadily increased. The most recent imaging showed an increase in size and number of multiple lung nodules, and an increase in mediastinal and hilar adenopathy. The patient completed palliative external beam radiation to 2 lesions involving the chest wall that were associated with pain.

Patient's questions
In consideration of the development of the illness and in view of the modest or absence of uptake of radiomedication the following questions arise:
1)    Which is currently the best treatment possible? Specifically, in order to counter the development of the illness, is chemotherapy more useful administered according to a classical administration or should this be changed? If so, should this be associated to a Thyrogen stimulus before each chemotherapy sitting?

2)    In this specific case would you consider using any new drug tested for use in thyroid cancer not responsive to radioiodine treatment, such as vandetanib, sorafenib, motesanib, sunitinib, abitins or similar? Do you think it is already possible to test the effectiveness of this category of drugs in advanced papillary carcinoma? What would you consider to be the use and effectiveness of stereotaxic radiosurgery using a Gamma Knife on metastatic pulmonary lesions?

3)    Are you aware of other possible treatments (even experimental)?

4)    Could you indicate any treatment centres in Italy and/or Europe?

5)    Prognosis?
Medical Background
Age: 78 yrs, female
Diagnosis: Papillary Carcinoma of Thyroid with Multiple and Diffuse Nodular Secondarisms of the Pulmonary Parenchyma



In mid 30's : Radiation therapy of the neck to dry out lymph glands.
Apr 1982: Right occipital craniectomy for the radical removal of meningioma of the right pontocerebellar angle. Permanent results of surgery: deficit of the 5th, 6th and 7th cranial nerves; deafness in the right ear; alterations in standing balance with uncertain gait and a tendency to fall to the right; hypotrophy of the right facial muscles with deficit in motility and tactile hypoesthesia of the right hemiface; deficient taste and swallowing; right eye hyporeactive to light stimulus with reduction of abduction, as well as inconstant diplopia in all directions of vision.
Oct 1994: Stereotactic radiosurgery using a Gamma Knife on recurrent meningioma located at the apex of the right rocca and along the clivus, imprinting the trunk to the right. Results of surgery: reduction of visus in right eye.
Jan 1997: Surgical removal of right frontal meningioma .
Feb 2003: Appendectomy and lavage of the cavity following purulent faecal peritonitis of the right iliac fossa due to acute perforated appendicitis.
Dec 2004 Removal of paraesophageal abscess at the level of sutures for thyroid surgery.
Oct 2006 Removal of paraesophageal abscess at the level of sutures for thyroid surgery.
Diabetes mellitus.
Vaginal Prolapse.
Clinical History:
Sep 2002: Diagnosis of thyroid papillary carcinoma by means of ultrasound scan and subsequent needle biopsy.
Oct 2002: Chest CAT scan shows multiple nodulation and micronodulations, repetitive, bilateral and diffuse, subsequently diagnosed as metastasis of papillary carcinoma.
Oct 2002: Direct suspension microlaryngoscopy surgery with multiple biopsies of laryngeal neoformation, right hemithyroidectomy with laterocervical homolateral dissection and subisthmic tracheotomy. During surgery it was seen that neoplasy has infiltrated the wall of the right hemilarynx up to the submucous chorion, the piriform sinus, soft tissues, internal jugular vein, which was sacrificed, and the wall of the common carotid artery for a length of approx. 2-3 cm. Diagnosis of the subsequent histopathological results confirmed: Papillar carcinoma of the right hemithyroid infiltrating the skeletal muscular tissue and perithyroidal soft tissues, found on the margin of the surgical resection. Metastasis at ¼ perithyroideal lymph nodes, 2/5 right supraclavear, 1/1 right rear carotideal lymph node, 1/3 subisthmic lymph nodes.
Nov 2002 Balloon Test Occlusion of the right carotid circulation, with subsequent identification of a small ischemic area in the parietal-operculum area and right cortico-subcortical insular area.
Dec 2002 Surgery for total laryngectomy with left hemithyroidectomy and ligature of the common carotid, right internal and external. During surgery radial pulse temporarily absent. Histopathological Diagnosis: Papilliferous carcinoma of the thyroid infiltrating the wall of the right hemilarynx up to the submucous chorion, piriform sinus, soft tissues and the wall of the carotid. Neoplasy extends plurifocally to the posterio-lateral margin of the dissection and anteriorly in the soft tissues and at the margin of the inferior dissection of the carotid wall. Metastasis in 1/3 lymph nodes jugular external left.

Permanent results of the surgeries described: aphonia, aggravation of difficulty in walking with the presence of left crural hemisyndrome, aggravation of difficulty to taste and swallow with the impossibility of ingesting solid foods. Radiometabolic treatment and most recent diagnostics tests:

Feb 2003 - 1st Metabolic treatment with Iodine-131: 5550 MBq. Intense radioiodine uptake at both pulmonary fields.
Jun 2003 - 2nd Metabolic treatment with Iodine-131: 4850 MBq.
Dec 2003- 3rd Metabolic treatment with Iodine-131: 5550 MBq. In the neck presence of an uptaking ovalar area in the right thyroid bed at paramedian level. Fair widespread uptake of radioiodine in the median and distal fields of the two lungs. Thyroglobulin (off from L-Tiroxine): 395 ng/ml.
Jul 2004 - 4th Metabolic treatment with Iodine-131: 5550 MBq. Confirmed presence in the neck of an uptaking ovalar area in the right thyroid bed. Uptaking punctiform focus at right pulmonary base. Thyroglobulin (off from L-Tiroxine): 188 ng/ml.
May 2005 - 5th Metabolic treatment with Iodine-131: 5550 MBq. Confirmed presence in the neck of an uptaking ovalar area in the median part of the neck in the paramedian level and another in the distal part of the right thyroid bed. Upper mediastinic rounded area fairly fixating and another with similar level of uptake of the right lung, towards the base, in the front part. Thyroglobulin (off from L-Tiroxine): 295 ng/ml.
Jun 2006 - 6th Metabolic treatment with Iodine-131: 5550 MBq. Focal fixation in the neck at the medial suprajugular level. No evidence of fixation at pulmonary level. Thyroglobulin (off from L-Tiroxine): 341 ng/ml.
Jul 2007- 7th Metabolic treatment with Iodine-131: 5550 MBq. Widespread and dishomogenous fixation of tracer near pulmonary and chest fields. Thyroglobulin (off from L-Tiroxine): 1,139 ng/ml.
Feb 2008 CT chest: at current check up there are multiple nodular parenchymal formations localized in both lungs; some show minimal increase in size, others are stationary. Slight increase of nodular formation near left pulmonary veins currently measuring diameter 2,7 cm. Mediastinic lymph nodes unchanged.
Sep 2008 - 8th Metabolic treatment with Iodine-131. Dose administered 5550 MBq (Total dose administered: 43660 MBq = 1180 mCi of Iodine-131). At a pulmonary level we see a slight widespread uptake and single uptaking ovalar area that projects to the third median of left lung towards the back. Presence of an uptaking punctiform area in the upper median area of the neck. Thyroglobulin (off from L-Tiroxine): 2134 ng/ml.
Jan 2009 CT chest: at current check up there is a clear increase in number, but largely in size, of multiple nodular parenchymal pulmonary formations of a secondary nature that are partly confluent and at present diameter varies from a few millimeters to 3,5 cm. Increase of periaortic lymph nodes, in Barety's Space and in the bilateral hilar region (see attached files). The patient received a total of 43660 MBq (1180 mCi) of Iodine-131 in 8 treatments. The administration of 5550 MBq (150 mCi) per single treatment was never exceeded because the patient is of small build and weighs approximately 50 kg. Response to treatment was excellent in the first three with progressive decrease in thyroglobulin. From the 4th treatment response was increasingly limited also due to a progressive differentiation with the consequent weak fixation of radioiodine in the known pulmonary lesions. Attempts had already been made to increase radioiodine fixation with Isotretinoin in 2003 and 2004 and with Rosoglitazone in 2008. In 2003 tests were done to check for the possible presence of somatostatin receptors, without positive results.
Feb 2009 - End of radiation treatment at Villa Maria Ceciglia in Cotignola. In fact, considering the recent radiological history, it was deemed appropriate to submit the patient for radiation treatment for cytoreductive symptomatic purposes only on 2 lesions adhering to the chest wall, therefore painful. A total dose of 3000 (1000 cGy/fraction) has been distributed on this area, by means of 15 MV X photons and appropriately conformed fields. Clinical tolerance to treatment was on the whole within the norm.
A CAT scan of the chest - abdomen for reassessment was recommended in 6-8 weeks time and complete blood count in 1 week.

Other treatment: Oral Antidiabetic medications Use of a pessary

Medical opinion
1) What are the best treatment options? Chemotherapy? With Thyrogen stimulation?
Chemotherapy is generally not entertained as a viable treatment option for patients with iodine-refractory metastatic PTC because of the poor response rates to chemotherapy seen in this disease. Moreover, chemotherapy for PTC, such as with adriamycin or paclitaxel, tends to cause more symptoms related to the chemotherapy than patients otherwise experience from their thyroid cancer. The risk: benefit ratio is not favorable for standard chemotherapy. Therefore, chemotherapy is used rarely in PTC, even when patients have iodine-refractory metastatic disease. Thyrogen stimulation prior to chemotherapy has not been studied, but would not be expected to offer any additional benefit beyond that of chemotherapy alone.
2) Would you consider using any new drug?
Yes! There are now several studies that have been presented that demonstrate activity in PTC with oral angiogenesis/multikinase inhibitors, such as AMG 706 (Sherman, NEJM, 2008) and sorafenib (Gupta, JCO, 2008). At present, there is no one targeted therapy that has emerged as a definitive standard of care for iodine-refractory metastatic papillary thyroid carcinoma. For this reason, clinical trials, when available, are the preferred approach. In the absence of an available clinical trial, treatment with either sorafenib or sunitinib with standard dosing can be considered. Both drugs have been approved for the treatment of other malignancies, including renal cell carcinoma and hepatocellular carcinoma, have well-established safety profiles, are fairly well-tolerated, and have proven activity in some patients with advanced thyroid cancer.
3) Are you aware of other possible treatments?
Other oral multikinase inhibitors are being studied in advanced thyroid cancer, including axitinib and E7080. There is also interest in other targeted therapies, such as mTOR inhibitors or c-met inhibitors, however there is no published clinical data to date on these drugs, so they could only be considered in the setting of a clinical trial. There is an ongoing clinical trial with axitinib that may be open in Italy. The pharmaceutical sponsor is Pfizer, and more information may be available from Pfizer Oncology Clinical Trial Information Service.  
4) Lisa Licitra, MD from the Instituto Nazionale dei Tumori in Milan has extensive experience with advanced thyroid cancers, and Martin Schlumberger, MD from the Institut Gustave Roussy in France is a renowned expert in thyroid cancer.
5) Prognosis?
The prognosis of patients with advanced iodine-refractory metastatic PTC can vary widely. Without further information regarding this patient’s particular performance status and co-morbid illnesses, it is difficult to speculate on her particular life expectancy. However, life expectancy can be in the range of years, even in patients with advanced, progressive disease. The response rates to angiogenesis/multikinase inhibitors is approximately 25%, but clinical benefit can be seen in more than half of patients treated.