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![Results
Of the 265 indeterminate nodules, 85 were malignant. The
gene-expression classifier correctly identified 78 of the
85 nodules as suspicious (92% sensitivity; 95%
confidence interval [CI], 84 to 97), with a specificity of
52% (95% CI, 44 to 59).
The negative predictive values for “atypia (or follicular
lesion) of undetermined clinical significance,” “follicular
neoplasm or lesion suspicious for follicular neoplasm,”
or “suspicious cytologic findings” were 95%, 94%, and
85%, respectively.
Analysis of 7 aspirates with false negative results
revealed that 6 had a paucity of thyroid follicular cells,
suggesting insufficient sampling of the nodule.](https://image.slidesharecdn.com/boyagesrparecentadvancesinthyroidcancerfinal-131020181125-phpapp01/75/Recent-advances-in-the-diagnosis-and-treatment-of-thyroid-cancer-21-2048.jpg)
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Recent advances in the diagnosis and treatment of thyroid cancer
This document summarizes recent advances in the diagnosis and treatment of thyroid cancer by Professor Steven Boyages. It discusses the rising incidence of thyroid cancer in recent decades, which may be due to increased medical surveillance and technology. It describes a study that examined pathways to diagnosis for thyroid cancer patients in New South Wales, finding most were serendipitous discoveries. Factors like tumor size influenced diagnosis pathways. Minimally invasive thyroidectomy techniques and strategies for radioiodine ablation in low-risk thyroid cancer, including using recombinant human thyrotropin and lower radiation doses, are also summarized. Treatment of radioiodine-resistant thyroid cancer is an ongoing challenge.
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Recent advances in the diagnosis and treatment of thyroid cancer
- 1. Recent advances inthe diagnosis and treatment for thyroid cancer Professor Steven Boyages The University of Sydney Westmead Hospital
- 3. Change in incidencerates of cancer 1991-2009
- 4. Top 10 cancersand Top 10 cancer deaths
- 5. Trends in incidence(1982-2009) and death rates (1968-2007)
- 6.
- 7. Rising incidence ofthyroid cancer Over the past few decades an increase in the incidence of thyroid cancer has been recorded in many countries around the world, and has been particularly marked in the Australian state of New South Wales (NSW). The reasons for this increase remain unclear, but heightened medical surveillance and increased technological sensitivity could be contributing to greater detection of asymptomatic disease.
- 8. Objective To describe thepathways to diagnosis of thyroid cancer for a cohort of newly diagnosed patients in NSW and compare these pathways in groups of people defined by age, gender, place of residence, ethnic background and medical insurance status. Pathways to the diagnosis of thyroid cancer in New South Wales: a population-based cross-sectional study.Kahn C, Simonella L, Sywak M, Boyages S, Ung O, O'Connell D.Cancer Causes Control. 2012 Jan; 23(1):35-44. Epub 2011 Oct 15
- 9. Methods Newly diagnosed casesof thyroid cancer (n=452) were identified and recruited through the population-based NSW Central Cancer Registry. Participants completed a questionnaire and diary of doctor visits and investigations that led to their diagnosis. Tumour characteristics were obtained from pathology reports.
- 10. Pathways to cancerpaper recruitment
- 11. Results 60% of patientshad their cancer discovered serendipitously, while 40% initially presented to their doctor with a lump or symptom specific to thyroid cancer. The pathways to diagnosis varied significantly with tumour size (p=0.001) and also by age in men and place of residence in women (p=0.008 and p=0.05 respectively).
- 12. Pathways of detectionfor thyroid cancer NSW Pathway Patient detected Doctor detected Men n=108 Women n=344 Total n=452 Weighted n % n % n % %* 39 36.1 140 40.7 179 39.6 38.8 23 21.3 49 14.2 72 15.9 16.4 Imaging After benign disease 22 20.4 28 8.1 50 11.1 10.9 14 13 104 30.2 118 26.1 26.2 Other 10 9.3 23 6.7 33 7.3 7.6 Table 3: Pathways to the diagnosis of thyroid cancer in men and women in NSW, Australia * Weighted to population distribution by place of residence
- 13. Factors associated with pathways to diagnosis The pathways todiagnosis varied significantly by age group (p=0.009), sex (p<0.001), tumour size (p<0.001), spread of cancer at diagnosis (p=0.006), treatment for another disease at time of diagnosis (p=0.02), and current work status (p=0.001). Variables that were not statistically significantly associated with the pathways to diagnosis included health insurance status, education level, smoking, alcohol consumption, number of other illnesses, previous cancer, family history of thyroid cancer, time from last pregnancy for women, and cancer type.
- 14. Multi-regression model After adjustingfor all factors in the model the only factor that differed significantly across the pathway groups was tumour size (p=0.001). The odds of a patient with a large tumour (>3cm) being initially detected by a doctor (vs patient detected) were 66% (OR=0.34, 95% CI 0.1, 0.9) lower than a patient with a small tumour (<1cm). Patients with large tumours also had 60% (OR=0.4, 95% CI 0.2, 0.9) lower odds of being detected after treatment for benign thyroid disease (vs patient detected) than patients with a tumour less than 1cm. Patients with tumours between 2 and 3 cm had 6.85 greater odds (95% CI 2.3, 20.7) of being diagnosed as an incidental finding of imaging (vs patient detected) than patients with a tumour less than 1cm.
- 15. Conclusion As the majorityof participants had serendipitous diagnoses, the reported incidence of thyroid cancer is likely to be influenced by diagnostic technology and medical surveillance practices.
- 16. Dilemma Nodular thyroid diseaseis common and the incidence of thyroid cancer is rising Increasing cost of over-investigation leading to the potential for unnecessary surgery and unnecessary aggressive treatment for thyroid cancer Implications for Diagnosis; Surgery; and radioactive iodine therapy
- 18. Original Article Preoperative Diagnosisof Benign Thyroid Nodules with Indeterminate Cytology Erik K. Alexander, M.D., Giulia C. Kennedy, Ph.D., Zubair W. Baloch, M.D., Ph.D., Edmund S. Cibas, M.D., Darya Chudova, Ph.D., James Diggans, Ph.D., Lyssa Friedman, R.N., M.P.A., Richard T. Kloos, M.D., Virginia A. LiVolsi, M.D., Susan J. Mandel, M.D., M.P.H., Stephen S. Raab, M.D., Juan Rosai, M.D., David L. Steward, M.D., P. Sean Walsh, M.P.H., Jonathan I. Wilde, Ph.D., Martha A. Zeiger, M.D., Richard B. Lanman, M.D., and Bryan R. Haugen, M.D. N Engl J Med Volume 367(8):705-715 August 23, 2012
- 19. Study Overview • Asignificant fraction of fine-needle aspirates obtained from thyroid nodules are read as indeterminate. • A new molecular test accurately predicts whether a cytologically indeterminate nodule is benign 93% of the time, permitting a conservative approach to management.
- 20. The Afirma ThyroidFNA Analysis Process
- 21. Results Of the 265indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for “atypia (or follicular lesion) of undetermined clinical significance,” “follicular neoplasm or lesion suspicious for follicular neoplasm,” or “suspicious cytologic findings” were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule.
- 22. Algorithm for EvaluatingThyroid Nodules. Jameson JL. N Engl J Med 2012;367:765-767.
- 23. Conclusions • These datasuggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results.
- 24. Types of thyroidsurgery
- 25.
- 27. Should Prophylactic Central(Level 6) Lymph Node Dissections be Performed? There is agreement that therapeutic central and lateral lymph node dissections should be performed at the time of total thyroidectomy when lymph nodes are suspicious or proved to harbor cancer by sonographic appearance or by FNA analyses preoperatively or when suspicious lymph nodes are found at operation. Prophylactic lateral lymph node dissections were common in the past, but have been abandoned for several decades or longer. Recently, Delbridge and his group and others have proposed that unilateral or bilateral prophylactic central lymph node dissections (level 6 dissections) with parathyroid autotransplantation be performed in all cases of papillary thyroid cancer at the time of total thyroidectomy. This, they state, might decrease mortality from thyroid cancer, would greatly decrease recurrence of cancer, and would further clarify who needs radioiodine therapy postoperatively. Some studies by very experienced surgeons demonstrate no increase in hypoparathyroidism or recurrent laryngeal nerve injuries after this procedure, while other equally competent surgeons have found an increase in permanent hypoparathyroidism. We and others do not routinely perform this procedure because of the increased risk of hypoparathyroidism, but reserve it for cases in which ipsilateral central lymph nodes are clearly involved with tumor. 27d
- 28. Minimally invasive thyroidectomy •No visible neck scar Axillae, Chest • Smaller scar Video assisted endoscopic approach • Robotic transaxillary thyroidectomy
- 29. Original Article Strategies ofRadioiodine Ablation in Patients with Low-Risk Thyroid Cancer Martin Schlumberger, M.D., Bogdan Catargi, M.D., Ph.D., Isabelle Borget, Pharm.D., Ph.D., Désirée Deandreis, M.D., Slimane Zerdoud, M.D., Boumédiène Bridji, M.D., Ph.D., Stéphane Bardet, M.D., Laurence Leenhardt, M.D., Ph.D., Delphine Bastie, M.D., Claire Schvartz, M.D., Pierre Vera, M.D., Ph.D., Olivier Morel, M.D., Danielle Benisvy, M.D., Claire Bournaud, M.D., Françoise Bonichon, M.D., Catherine Dejax, M.D., Marie-Elisabeth Toubert, M.D., Sophie Leboulleux, M.D., Marcel Ricard, Ph.D., Ellen Benhamou, M.D., for the Tumeurs de la Thyroïde Refractaires Network for the Essai Stimulation Ablation Equivalence Trial N Engl J Med Volume 366(18):1663-1673 May 3, 2012
- 30. Study Overview • Thistrial compared two thyrotropin-stimulation methods and two 131I doses for postoperative ablation in patients with low-risk thyroid cancer. • Rates of ablation were similar in all treatment groups. • Doses lower than those currently recommended may be adequate for this condition.
- 31. Randomization and Follow-upof the Study Patients. Schlumberger M et al. N Engl J Med 2012;366:1663-1673
- 32. Initial Characteristics ofthe 752 Randomized Patients, According to Thyrotropin-Stimulation Method and 131I Dose. Schlumberger M et al. N Engl J Med 2012;366:1663-1673
- 33. Follow-up Testing ofThyroid Ablation 6–10 Months after 131I Administration in the 684 Patients Who Could Be Evaluated, According to Thyrotropin-Stimulation Method and 131I Dose. Schlumberger M et al. N Engl J Med 2012;366:1663-1673
- 34. Adverse Events, Accordingto Thyrotropin-Stimulation Method and 131I Dose. Schlumberger M et al. N Engl J Med 2012;366:1663-1673
- 35. Conclusions • The useof recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer.
- 36. Original Article Ablation withLow-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer Ujjal Mallick, F.R.C.R., Clive Harmer, F.R.C.P., Beng Yap, F.R.C.P., Jonathan Wadsley, F.R.C.R., Susan Clarke, F.R.C.P., Laura Moss, F.R.C.P., Alice Nicol, Ph.D., Penelope M. Clark, F.R.C.Path., Kate Farnell, R.C.N., Ralph McCready, D.Sc., James Smellie, M.D., Jayne A. Franklyn, F.Med.Sci., Rhys John, F.R.C.Path., Christopher M. Nutting, M.D., Kate Newbold, F.R.C.R., Catherine Lemon, F.R.C.R., Georgina Gerrard, F.R.C.R., Abdel Abdel-Hamid, F.R.C.R., John Hardman, F.R.C.R., Elena Macias, M.D., Tom Roques, F.R.C.R., Stephen Whitaker, M.D., Rengarajan Vijayan, F.R.C.R., Pablo Alvarez, M.Sc., Sandy Beare, Ph.D., Sharon Forsyth, B.Sc., Latha Kadalayil, Ph.D., and Allan Hackshaw, M.Sc. N Engl J Med Volume 366(18):1674-1685 May 3, 2012
- 37. Study Overview • Inthis trial, low-dose radioiodine was as effective as high-dose radioiodine in patients with differentiated thyroid tumors, and recombinant human thyrotropin (thyrotropin alfa) was as effective as thyroid hormone withdrawal.
- 38. Days of HospitalIsolation, According to Radioiodine Dose. Mallick U et al. N Engl J Med 2012;366:1674-1685
- 39. Baseline Characteristics ofthe Patients. Mallick U et al. N Engl J Med 2012;366:16741685
- 40. Symptoms Reported byPatients during the 4 Weeks before Ablation. Mallick U et al. N Engl J Med 2012;366:1674-1685
- 41. Conclusions • Low-dose radioiodineplus thyrotropin alfa was as effective as highdose radioiodine, with a lower rate of adverse events.
- 42. RAI resistance The curerates for DTC are generally high when patients are treated with surgery or RAI. However, between 5% and 15% of patients develop RAI resistance, and these patients typically have an expected survival of 2.5 to 3.5 years. No standard therapy exists for patients who experience disease progression. New agents that either induce sodium iodide symporter activity or that inhibit tyrosine kinase inhibitor o Sorafenib o Selumetinib
- 44. Sorefenib Sorafenib, a tyrosinekinase inhibitor, inhibits multiple kinases, including the Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET, which are associated with tumor cell proliferation and angiogenesis. The drug is currently approved by the FDA to treat unresectable hepatocellular carcinoma and advanced renal cell carcinoma.
- 45. Original Article Selumetinib-Enhanced RadioiodineUptake in Advanced Thyroid Cancer Alan L. Ho, M.D., Ph.D., Ravinder K. Grewal, M.D., Rebecca Leboeuf, M.D., Eric J. Sherman, M.D., David G. Pfister, M.D., Desiree Deandreis, M.D., Keith S. Pentlow, M.Sc., Pat B. Zanzonico, Ph.D., Sofia Haque, M.D., Somali Gavane, M.D., Ronald A. Ghossein, M.D., Julio C. Ricarte-Filho, Ph.D., José M. Domínguez, M.D., Ronglai Shen, Ph.D., R. Michael Tuttle, M.D., Steve M. Larson, M.D., and James A. Fagin, M.D. N Engl J Med Volume 368(7):623-632 February 14, 2013
- 46. Study Overview • Inhibitionof mitogen-activated protein kinase resulted in an increase in expression of the sodium–iodide symporter in 12 of 20 patients, 8 of whom had sufficient uptake to warrant treatment with radioiodine. • Five patients had a response, and 3 had stable disease.
- 47. Protocol Design andChanges in Iodine Uptake. Ho AL et al. N Engl J Med 2013;368:623-632
- 48. Iodine-124 PET-CT ScansObtained before and after Selumetinib Treatment in Selected Patients with Positive Responses. Ho AL et al. N Engl J Med 2013;368:623-632
- 49. Quantification of Iodine-124PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine. Ho AL et al. N Engl J Med 2013;368:623-632
- 50. Conclusions • Selumetinib producesclinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease.
Editor's Notes
- #23 Figure 1. Algorithm for Evaluating Thyroid Nodules. The gene-expression classifier profile allows cytologically indeterminate fine-needle aspirates to be divided into either benign or suspicious groups, thereby informing the need for and extent of surgery. AUS–FLUS denotes atypical or follicular lesion of undetermined significance, FNA fine-needle aspiration, and FN–SFN follicular neoplasm or lesion suggestive of follicular neoplasm.
- #32 Figure 1 Randomization and Follow-up of the Study Patients. The tumor–node–metastasis (TNM) stage noted was ascertained on pathological examination of a surgical specimen of the tumor (pT) and lymph node (N). Stage Nx indicates that the lymph nodes could not be evaluated; stage N0, that tumor cells were absent from regional lymph nodes; and stage N1, that tumor cells were present in regional lymph nodes. Fifteen patients could not be evaluated because not all diagnostic tests were performed.
- #33 Table 1 Initial Characteristics of the 752 Randomized Patients, According to Thyrotropin-Stimulation Method and 131I Dose.
- #34 Table 3 Follow-up Testing of Thyroid Ablation 6–10 Months after 131I Administration in the 684 Patients Who Could Be Evaluated, According to Thyrotropin-Stimulation Method and 131I Dose.
- #35 Table 4 Adverse Events, According to Thyrotropin-Stimulation Method and 131I Dose.
- #39 Figure 1 Days of Hospital Isolation, According to Radioiodine Dose. Shown are the proportions of patients receiving low-dose radioiodine (1.1 GBq) or high-dose radioiodine (3.7 GBq) who spent 1 to 4 or more days in hospital isolation after ablation (P<0.001 by the chi-square test).
- #40 Table 1 Baseline Characteristics of the Patients.
- #41 Table 3 Symptoms Reported by Patients during the 4 Weeks before Ablation.
- #48 Figure 1 Protocol Design and Changes in Iodine Uptake. Panel A shows the protocol design. Baseline iodine avidity in the lesion was first assessed with thyrotropin alfa–stimulated iodine-124 positron-emission tomographic–computed tomographic (PET-CT) scanning. Patients were then treated with selumetinib at a dose of 75 mg given orally twice a day for 4 weeks. In the final week of treatment, a second thyrotropin alfa–stimulated 124I PET-CT study was performed. The double arrows indicate the two thyrotropin alfa injections. Patients with 124I dosimetry that predicted tumor uptake of less than 2000 cGy discontinued the study. If the absorbed dose of radioiodine in the lesion was predicted to be 2000 cGy or greater, full dosimetry with iodine-131 was performed to calculate the maximum tolerable activity that could be administered safely. Patients then received a therapeutic dose of radioiodine the next week after preparation with thyrotropin alfa. Selumetinib was continued until 2 days after the administration of therapeutic radioiodine. Thyroglobulin levels and the radiographic response were assessed at 2 and 6 months after radioiodine administration. Panel B shows a summary of the changes in iodine uptake quantified by 124I PET-CT and the number of patients who met the criteria for treatment with iodine-131.
- #49 Figure 2 Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses. Panel A shows whole-body maximum-intensity projection images of a patient with a BRAF-mutant papillary thyroid cancer. New iodine uptake is shown in nearly all previously negative lung and neck metastases. Panel B shows fused axial PET-CT images of a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Both new and significantly increased iodine uptake in lung metastases is shown. Panels C and D show PET-CT images from another patient with an NRAS-mutant, poorly differentiated thyroid cancer. In Panel C, fused axial PET-CT images show significantly increased iodine uptake in a sacroiliac bone metastasis after administration of selumetinib (right). In Panel D, fused axial images (top and bottom left) show new iodine uptake in a previously negative site as well as increased avidity in a large left parietal skull metastasis. Three-dimensional rendering highlights changes in the left parietal skull metastasis before and after selumetinib (top and bottom right).
- #50 Figure 3 Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine. Panel A shows the maximal standardized uptake value (SUVmax) for iodine in all tumors in a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Each bar represents one malignant lesion identified on the iodine-124 PET-CT scan. The bars to the left indicate the increases in iodine-124 avidity achieved after selumetinib administration in lesions that absorbed some iodine at baseline. The bars on the right indicate selumetinib-induced changes in lesions that were negative for iodine at baseline. Panel B shows the SUVmax in every metastatic lesion identified in the same patient before and after the administration of selumetinib. The dashed lines mark points on the graph corresponding to different degrees of change in the SUVmax in the lesion after the administration of selumetinib. The red dashed line demarcates no change in iodine uptake after the administration of selumetinib (0%). Dashed lines to the left of the red dashed line represent graded percentage increases in iodine-124 uptake (+25%, +50%, and +100%), whereas the lines to the right represent graded percentage decreases (−25%, −50%, and −75%). Nearly all the metastatic lesions in this patient (circles) had more than a 100% increase in iodine uptake after administration of selumetinib. The SUVmax for a sternal metastasis was off the scale (it increased from 220 to 599 with selumetinib) and thus could not be included in these graphs without obscuring the data for the other 54 lesions analyzed.