Thyroid Cancer I 131 Dosing and Treatment: An update on risk stratification, RAI therapy optimization and radiation risk reduction

Transcription

1 Thyroid Cancer I 131 Dosing and Treatment: An update on risk stratification, RAI therapy optimization and radiation risk reduction 2017 AACE Advances in Medical & Surgical Management of Thyroid Cancer, Tampa Stephanie L. Lee, MD, PhD, FACE, ECNU Director, Thyroid Health Center Section of Endocrinology, Diabetes and Nutrition Boston Medical Center

2 No disclosures Disclosures

3 Objectives Thyroid cancer I 131 dosing and treatment: An update on risk stratification, RAI therapy optimization and radiation risk reduction Judicious use of RAI with changes in practice style over the decades Current 2015 ATA recomendations Optimization of RAI treatment (avoiding under/overdosing) Lower dose I131 is equally effective as high doses Tg s can be used without RAI ablation Avoidance or reduction of collateral exposure to other tissue to reduce long term effects I131 complications are dose-related

4 Radioactive Iodine: The Original Molecularly Targeted Therapy Traditional Treatment Paradigm One Size Fits All Surgery Radioiodine Treatment RAI WBS Thyroid hormone therapy ANTERIOR POSTERIOR

5 Rise in the Numbers of Patients Treated with RAI in the US US National Cancer Database SEER Database Haymart JAMA 2011;306:721-8 Iyer and Tuttle Cancer 2011

6 CASE 1: Remnant Ablation With Radioiodine A 46 year-old female has a RIGHT 2.3 cm thyroid nodule with no adenopathy on US FNA is Bethesda VI: diagnostic for papillary thyroid cancer Total thyroidectomy removed a 2 cm FV-PTC Partially encapsulated, no ETE, no lymphovascular invasion, no nodes, BRAF neg Should she receive radioactive iodine for remnant ablation?

7 Haugen, et al. Thyroid 2016;26:1

8 Will You Recommend 131 I Therapy? No treatment protocols proven by published randomized controlled trials 1995: Test case of 2 cm PTC, 61% ATA recommended 131 I Rx but 30% did not Stephanie 2000 yes hypothyroid 100 mci Stephanie 2010 yes rhtsh 100mCi Stephanie 2011 yes rhtsh 50 mci Stephanie yes rhtsh 30 mci Stephanie 2013 maybe no Stephanie 2015 NO!!

9 Update on Thyroid Cancer Some Current Clinical Issues January 2016 American Thyroid Association Guideline for Thyroid Nodules & Cancer Moving toward a more individualized management approach Ongoing risk assessment: AJCC + ATA stage SIGNIFICANT CHANGE: LOW dose or NO RAI in low risk patients

10 2015 ATA Guidelines Suggestion for RAI Therapy ATA Risk Description Evidence Reduces DEATH Evidence Reduces RECURRENCE RAI indicated? INTRATHYROIDAL MICRO-ETE, + NODES BAD LOW <1cm uni or NO NO NO multifocal LOW >1-4 cm NO Conflicting Not routine; consider aggressive histology, vascular invasion LOW to INTERMEDIATE LOW to INTERMEDIATE LOW to INTERMEDIATE LOW to INTERMEDIATE >4 cm Conflicting Conflicting Not routine, consider if older Micro ETE NO Conflicting Generally favored for recurrence risk LEVEL VI metastases LATERAL or MEDIASTINAL metastases NO, except > 45 NO, except > 45 Conflicting Conflicting HIGH Gross ETE YES YES YES HIGH Distant YES YES YES metastasis Generally favored for recurrence risk, NOT <5 micro nodes Generally favored for recurrence risk, NOT <5 micro nodes

11 WE SHOULD GIVE EVERYONE RAI REMNANT ABLATION? OLD REASONING: Staging with post therapy scan Reduce recurrence Reduce disease specific death Remnant ablation allows for use of Tg testing for recurrence

12 Why You Should NOT Give All Patients High Dose RAI For Remnant Ablation? REASONS TO LIMIT RADIATION Low dose of RAI equally as effective as high dose for remnant ablation as long as you have a good surgeon RAI does not change recurrence rates or death in Low and Intermediate Risk thyroid cancer RAI is not necessary use Tg as a tumor marker as long as you have a good surgeon Avoid acute and long-term complications of RAI RX

13 131 I Therapy 250% increase in diagnosis of differentiated thyroid cancer in the last 30 years Incidental diagnosis from imaging studies Increase in numbers of 131 I therapies Results in large numbers of patients who are living longer with complications of 131 I therapy Early age of diagnosis compared to other cancers Longer time for complications to impact lives Review the short and long term risks of 131 I therapy American Cancer Society Facts and Figures 2016

14 Complications from I-131 RX Are Modifying Who and How Much I-131 Short term Nausea, emesis Long term Sialadenitis (chronic and acute) Dry mouth with difficulty speaking, eating Mouth pain Tooth loss Pulmonary fibrosis (only at very high dose therapies with military pulmonary mets) Fertility/fetal malformation Solid tumor induction and leukemia

15 Best way to manage side effects of radioiodine therapy is to avoid the side effects is by limiting RAI exposure Lee J Natl Comp Cancer Network 8(2010)1

16 Loss of Taste after I 131 Direct irradiation of lingual taste buds by I 131 secreted by salivary glands into saliva Loss of taste may occurs with or without metallic or chemical taste Varma reported 41/85 after mci Incidence is dose dependent Lost of taste generally lasts 1-2 months Long term changes in taste have not been reported Lee J Natl Comp Cancer Network 8(2010)1

17 Salivary Gland Complications of I 131 Therapy Salivary gland concentrates iodine 30-40x plasma by the sodium iodide symporter ( NIS) Parotid glands more sensitive than submandibular gland Parotid secretions are more watery Scans provided by Dr. Susan Mandel

18 Salivary Gland Complications of I 131 Therapy Dose related decrease in saliva function after I131 With salivary duct stricture and obstruction by mucous and stones causing symptoms Infection is secondary to the obstruction Most profound symptoms after higher doses of I-131, prior external radiation or preexisting sialadenitis Spiegel J Nucl Med 26(1985)816 Mandel and Mandel Thyroid 13(2003)265

19 Sialadenitis: Prevention of Long-Term Complications Conventional wisdom for I-131 RX: increase saliva with good hydration and frequent use of sour candy or lemons Radiation exposure = UPTK% Reduced permanent xerostomia if delay in starting sour candies (every 2-3 hrs for 5 d) 116 patients started immediately: 14.3% 139 patient started 24 hr later: 5.6% (p<0.05) Decrease in deliver of radiation to the salivary gland Nakada et al. J Nucl Med. 2005,46:261-6

20 Treatment of Sialoadenitis Treatment: parotid gland massage, hydration, sialogogues, parotid massage If persistent: antibiotics if infection, duct probing ~70% of symptoms responds to medical therapy or spontaneous improves Sialadenitis unresponsive to medical therapy 10 months after an average of 143 mci I-131 patient had sialendoscopy 32 glands in (20 parotid and 12 submandibular) treated Ductal stenosis 30% and mucus plugs 44% 75% improved symptoms Provided by Dr. Susan Mandel Bomeli Laryngoscope 119(2009)864; Kim Laryngoscope 117(2007)133

21 Nausea and Vomiting MIRD calculations show large GI radiation dose after I 131 Gut is radio-resistent so there is no direct effect Nausea is a common symptom but emesis is rare Prospective study: 50% of 50 patients given 150 mci Starting as early as 2 hr and lasting 2 days Usually no RX is needed but oral Ondansetron is very effective Van Nostrand J Nucl Med 27(1986)1519 Kahn J Nucl Med 35 (1994)15P

22 Nausea and Vomiting Acute radiation sickness with fatigue, nausea and vomiting if dose > 200 mci or exposure > 200cGy to the blood More severe than the usual nausea <5% if radiation exposure blood < 200 cgy 200 mci would exceed 200cGy with normal creatinine 8%-15% <70 y old 22%-38% > 70 y old Consider dose reduction in >70 yo Van Nostrand J Nucl Med 27(1986)1519 Kahn J Nucl Med 35 (1994)15P Tuttle J Nucl Med 47(2006)1587

23 Severe Nausea and Vomiting Mild-Mod N/V: Ondansetron 8-24 mg BID PO Moderate N/V: Ondansetron 8 mg PO or 0.15 mg/kg IV BID NCCN guidelines: Severe N/V BID-TID: Dexamethasone 4 mg IV Ativan ½ - 1 mg IV Metoclopramide 1-2 mg/kg but start with 10 mg and then increase to 20 mg Resistant N/V: Haldol mg BID Ettinger J Natl Compr Canc Netw. 5(2007)12; Hesketh NEJM 358(2008)2482

24 Gonadal Radiation and I 131 Radiation exposure from Free iodine in blood (short halflife) Iodinated protein in blood (long halflife) Urine Reduction in gonadal exposure in first 3 days after treatment with Good hydration Frequent urination

25 Testicular Function and Fertility Male fertility not changed with moderate doses 40 children treated mean dose 196 mci I 131 at 14.6 yo with 18.7 yr F/U Infertility 12%, miscarriage 1.4%, congenital abnormality 1.4% Two subjects with 454 and 691mCi were fertile Sawka 2008 performed systematic review of the literature Biochemical abnormalities usually resolve within 18 months after < 150 mci Persistent gonadal dysfunction increases after repeated or high cumulative RAI Ceccarelli J Nucl Med. 1999;40: Sarkar J Nucl Med 17(1976)460 Sawka Clin Endocrinol (Oxf). 2008,68:610-7

26 Female Fertility and I 131 Therapy 2008 Garci with 10 year update of Schlumberger s initial 1996 report 2673 pregnancies Contrary to initial report, no increase miscarriage within first year of up to 100mCi I-131 RX No difference in incidence of stillbirths, preterm births, low birth weight, congenital malformations, or death during the first year of life Thyroid and non-thyroid cancers were similar in children born either before or after the mother's exposure to radioiodine Dottorini J Nucl Med 36(1995)21 Schlumberger J Nucl Med. 1996;37: Garci J Nucl Med. 2008;49:845-52

27 Nasolacrimal Drainage System Obstruction Kloos described bilateral nasolacrimal duct obstruction 4 months after 450 mci 131 I 3% (10/390) patients with 131 I developed epiphora (watery eye, overflow of tears) Received multiple doses of 131 I Mean cumulative 131 I dose 467 mci with average individual dose mci Symptoms onset 18 5 months Management of partial obstruction is dilation or stent placement but complete obstruction requires surgery Kloos JCEM 87(2002)5817 Burns Ophthal Plast Reconstr Surg 20(2004):126-9

28 Increase Risk of Second Malignancy after I 131 Treatment POOLED EUROPEAN AND AMERICAN DATA HAVE GIVEN NEW INSIGHTS INTO SECOND MALIGNANCIES AFTER I-131 Conventional wisdom that malignancies occur only after 600 mci is INCORRECT Review by Elaine Ron and Editorial by Ernie Mazzaferri in Clinical Thyroidology August studies published between 2003 and did NOT show a significant increased risk of second malignancy 5 showed a significant increased risk leukemia and GI (stomach, duodenal, colon, rectal)

29 Risk of Second Malignancies from SEER Database 2008 Brown used data between ,278 patients 2338 (7%) second malignancies in 2158 patients Greatest risk in ages Period of 5 years after diagnosis Most radiation induce malignancies have latent periods >10-15 years (excepting Chernobyl) Brown et al. JCEM 2008,3:504

30 Brown et al. JCEM 2008,3:504

31 Increased Concerns of Solid Tumors After 131 I Rubino : 2003 European cohort of thyroid cancer patients 6841 patients with mean age of 44 years 17% external radiotherapy and 62% 131 I therapy 2 yr latency, mean follow up 13 yrs, mean dose 162 mci 576 patients with secondary primary malignancy (SPM) Compared to general population increased risk of SPM 27% (95% CI: 15-40) after RAI but not XRT Risk of solid tumor (bone, colorectal and salivary) and leukemia increases with higher I 131 dose Rubino Br J Cancer 2003,89:

32 What are the Real Numbers? Dose (mci) SOLID TUMORS LEUKEMIA # RR # RR <5 184/ / / / / / / >400 12/ /853 - Rubino Br J Cancer 2003,89:

33 Perspective Increase risk of uncommon tumors so small increase in # s leads to a large foldincrease Rubino s study predicts 16.2 excess stomach cancers over 20years in 1,000 people who received 162 mci Review of data suggests a dose response Risks are increased even before the 600 mci threshold How many of your patients have had leukemia or GI malignancies after RAI?

34 Considerations to Reduce Complications of RAI Need to be more thoughtful about the use of 131 I in low risk patients Consider NO therapy especially intrathyroidal tumors in the young Consider smaller doses for initial remnant ablation Consider therapy with rhtsh stimulation Significant decrease in whole body radiation because of faster clearance compared to hypothyroid Assure good hydration Sialogogues 24 hours after I-131 dose

35 Best way to manage side effects of radioiodine therapy is to avoid the side effects is by limiting RAI exposure Lee J Natl Comp Canc Network 8(2010)1

36 Why Less or No RAI? Less acute and long-term complications of RAI RX Low dose of RAI equally as effective as high dose for remnant ablation as long as you have a good surgeon

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38 Factorial Design, Unblinded, Non-inferiority, Multi-center RCTs: Mallick et al. NEJM 2012, Schlumberger et al. NEJM 2012 Differentiated Thyroid Ca, No Aggressive Variants, No Residual Disease Total Thyroidectomy (w/ or w/o central LN dissection) Pathologic Stage: T1-T2, N0/Nx/N1a (T3 in Mallick trial only) Randomized rhtsh (on thyroid hormone) Thyroid Hormone Withdrawal I-131 Remnant Ablation: Randomize Dose I-131 Remnant Ablation: Randomize Dose 30 mci (Group A) 100 mci (Group B) 30 mci (Group C) 100 mci (Group D)

39 RRA TSH Stim Activity RCTs Review RCTs: TT/NTT, Stim Tg outcome < 2 ng/ml 2 RCTs evaluated remnant ablation success at 6-12 months: Similar remnant ablation success rate rhtsh vs THW using I-131 dose activities 30 to 100 mci Stage of disease included in trials: Most T1/T2, some T3, N0 or N1 (low volume N1a, not N1b) Short-term QOL better with rhtsh in weeks preceding RAI Rx, no difference 3 to 9 months Paucity long-term outcomes, no difference 1 trial N=51 Chianelli 2009, Lee 2010, Mallick 2012, Pacini 2006, Schlumberger 2012, Taieb 2009

40 Results RAI Remnant Ablation Dose RCTs Author (Year) (Country) Low Dose (mci) High Dose (mci) N analyze Percent success Low RAI group (6-12 months) Percent Success High RAI Group (6-12 months) Comparison Stat Caglar (2012) Fallahi (2012) % 64% P=NS % 61% P< Maenpaa (2008) % 56% P=NS Pilli (2007) % 67% P=0.46 Zaman (2006) Mallick (2012) Schlumberger (2012) % 60% % 89% % 94% No stats reported Not inferior (<10% margin) Not inferior (<10% margin)

41 Why Are Some Low Dose Ablation More Effective in Some Studies? Maxon answered this 20 years ago! Dosimetry performed to deliver 30,000 rad to thyroid remnant 30 = <45 = >45 mci Extent of thyroid surgery <2g 96% success >2g 67% success TT or NT 94% success Less surgery 29% success SUCCESS OF LOW DOSE RRA DEPENDS ON HAVING AN EXCELLENT SURGEON Maxon et al. J Nucl Med 1992;33:1132

42 What Happens to Low Risk Patients Who do NOT Receive RRA?

43 217 Low risk Patients with NO RRA Waisman et al, Clin Endo, 2012 AJCC:89% stage 1, 4% stage 2, 7% stage 3 % ATA 73% low risk, 27% intermediate risk. 4 yr median follow up Total thyroidectomy (n=217) Structural Recurrence 2.3% (n=5) No evidence Of Disease 97.7% (n=121) 2.3% structural disease detected by US 2 from low risk 3 from intermediate risk All patients with thyroglobulin <0.6 ng/ml 60% with structural disease with rising Tg F Waisman, A Shaha, S Fish, RM Tuttle. Clin Endo 2011

44 Don t We Need RAI Remnant Ablation to Follow Tg Levels?

45 Study of Natural History Tg, no RAI Durante et al, JCEM, 2012 Retrospective analysis ATA low risk pts after TT/NTT Multicenter study performed in Italy Median 5 year follow-up 290 consecutive RAI-Negative patients compared to 490 RAI-treated pts TG <1 in 99% RRA and 95% no RR patients after 6yr Durante et al, JCEM :

46 Serum basal Tg after TT without RAI in 78 patients For 78 RRA-neg patients, stimulated Tg <0.2 ng/ml: 60% at 3-12 months 79% after 5 yrs Durante et al, JCEM :

47 Thyroglobulin With or Without RAI RX Tg increased in 1 RRA-neg patient with disease recurrence Tg can be followed without RRA in low risk patients with an excellent total thyroidectomy Durante et al, JCEM : YEARS

48 CASE 1: Remnant Ablation With Radioiodine A 46 year-old female has a RIGHT 2.3 cm thyroid nodule with no adenopathy on US FNA is Bethesda VI: diagnostic for papillary thyroid cancer Total thyroidectomy removed a 2 cm FV-PTC Partially encapsulated, no ETE, no lymphovascular invasion, no nodes, BRAF neg Should she receive radioactive iodine for remnant ablation?

49 SUMMARY: Update on RAI RX and Thyroid Cancer Thyroid cancer I 131 dosing and treatment: An update on risk stratification, RAI therapy optimization and radiation risk reduction Judicious use of RAI with changes in practice style over the decades Current 2015 ATA recommendations Optimization of RAI treatment (avoiding under/overdosing) Lower dose I131 is equally effective as high doses Tg s can be used without RAI ablation Avoidance or reduction of collateral exposure to other tissue to reduce long term effects I131 complications are dose-related

50 Thank you for your attention! QUESTIONS?