External Beam Radiation Therapy for Thyroid Cancer

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1 External Beam Radiation Therapy for Thyroid Cancer C. Jillian Tsai, M.D, PH.D. Assistant Attending Director of Head and Neck Cancer Research Department of Radiation Oncology Memorial Sloan Kettering Cancer Center

2 Overview General information of thyroid cancer Define the role of external beam radiation therapy (EBRT) for: Differentiated thyroid cancer (DTC) Medullary thyroid cancer (MTC) Anaplastic thyroid cancer (ATC) Radiation Target Volume Delineation and Treatment Planning

3 General Information of Thyroid Cancer

4 Lymphatic Drainage

5 Continuum of Papillary Thyroid Cancer Classic PTC Tall Cell Variant Moderately Differentiated Poorly Differentiated FDG PET Positivity Anaplastic RT Use RAI Avidity Courtesy of Rich Wong, M.D.

6 Increasing FDG PET Positivity as Tumor Becomes Less Differentiated Courtesy of Mike Tuttle, M.D.

7 General Principles of EBRT use in DTC (Papillary, Follicular) Post-Operative Adjuvant Setting Highly Controversial

8 EBRT as Adjuvant Therapy for Completely Resected DTC No randomized studies to define the role of EBRT after surgical resection. Different patient selection (positive margin, multiple lymph nodes, ETE, ECE, EBRT techniques, EBRT doses, and EBRT irradiated volumes) all confound the interpretation of the available retrospective studies. Retrospective studies are mixture of resected and unresected patients from single institutions reported experience (EBRT LRC 55% to 90%). Practice variations among different centers.

9 The Multicentre Study on Differentiated Thyroid Cancer (MSDS) Biermann et al, 2009

10 The Multicentre Study on Differentiated Thyroid Cancer (MSDS) Biermann et al, 2009

11 Courtesy of Nancy Lee, M.D.

12 Courtesy of Nancy Lee, M.D.

13 General Principles of EBRT use in DTC In Recurrent Setting Less Controversial

14 EBRT as Adjuvant Therapy for Completely Resected Recurrent DTC Not for all recurrences. Most recurrences can be effectively treated with additional surgery and RAI, without the addition of routine EBRT. Use of EBRT when further salvage surgeries not possible or feasible. Conversation with the surgeon. Most literature centers on these types of patients and LRC when EBRT is added is in the upwards of 80-90%.

15 General Principles of EBRT use in DTC Unresectable or Gross Residual Disease RT Strongly Indicated

16 EBRT as Adjuvant Therapy for Completely Resected Recurrent DTC Multiple retrospective single institution studies showing the benefit of EBRT enhancing locoregional control and may even lead to improvement of OS. Mixture of resected and unresected cases in these reports but when focusing on unrespectable or gross residual disease, control rates increased from 20-40% to 70-90% with the use of EBRT (changed from lower dose around 45-50Gy and conventional RT techniques to higher dose >60Gy using IMRT). At our institution, EBRT is rarely indicated for young patient with limited gross residual disease which concentrates RAI.

17 EBRT +/- Concurrent Chemotherapy in Non-Anaplastic Thyroid Cancer with Unresectable or Gross Residual Disease

18 Patient Population months (range months) 32% had CCRT Predominantly Adriamycin 10mg/m2

19 Locoregional Progression-Free Survival

20 Locoregional Progression-Free Survival

21 IMRT +/- Concurrent Chemotherapy in Non-Anaplastic Thyroid Cancer with Unresectable or Gross Residual Disease Updated data with a homogenous RT and chemo cohort -all IMRT, uniform dosing -Dox 10mg/m2 Thomas Beckman and Nancy Lee

22 Locoregional Progression-Free Survival 48 month LPFS: Overall: 77.4% IMRT alone: 68.9% CC-IMRT: 85.8% Thomas Beckman and Nancy Lee

23 Univariate and Multivariate Analyses Thomas Beckman and Nancy Lee

24 Prospective Phase II Trial on Use of EBRT for Gross Residual/Unresectable Thyroid Cancer Excluded anaplastic and medullary thyroid cancer IMRT to 70Gy over 33 days at 2.12Gy per day Given compelling retrospective data on the benefit of chemotherapy to EBRT, Along with manageable toxicity, we amended the protocol after patient 13 to include chemotherapy Prospectively studies swallowing dysfunction using MBS IMP scales at defined time points

25 ATA EBRT for DTC - Summary EBRT should only be considered in a select group of patients with: (1) gross residual disease except for young patients with limited gross residual disease that concentrates RAI (2) patients with recurrent disease that cannot be adequately controlled with additional surgery and RAI (3) older patients with microscopic residual disease remaining after meticulous resection of tumor invading surrounding structures who are at high risk for recurrence and unlikely to respond to RAI therapy (4) EBRT is rarely indicated for young patient with limited gross residual disease which concentrates RAI

26 EBRT for DTC Important Checklist Is the case discussed in multidisciplinary setting Is there careful reading of the surgical & path reports Did you speak to the surgeon? Is there gross residual disease? Does the tumor concentrate RAI? Is the tumor FDG PET avid? Is there a salvage option?

27 General Principles of EBRT use in MTC Limited Roles

28 Medullary Thyroid Cancer Indolent disease Surgery upfront Radiation rarely used LC ranges from 65-85%

29 RT should be considered for those with recurrent disease, R2 resection, unresectable disease, extensive ETE, positive margin

30 General Principles of EBRT use in ATC EBRT Plays A Significant Role

31 Anaplastic Thyroid Cancer Asphyxiation a significant concern. Half of patients will die from Asphyxiation or upper airway problems. Improvement in Local Control leads to Improvement in Overall Survival - median OS improved in met. patients from 8 months vs. 2 months if local control achieved. Hence EBRT plays a significant role.

32 Different Flavors of ATC De novo: uniformly do poorly [probably should consider palliation or hospice [WORSE] Multiple recurrent papillary with progression to ATC Resected papillary thyroid with incidental findings of anaplastic thyroid cancer [BEST] Published series tent to lump all of these as anaplastic thyroid cancer

33 ATC Report Series MDACC: N=53 patients; Median Dose was 55Gy (range: 4-70Gy) 74% received chemotherapy 1 year OS was 29%; Median OS: 9.3 mo. vs. 1.6 mo. If 50Gy Mayo: N=10; Surgery, IMRT (~60-70Gy), chemo 50% Alive and cancer free followed > 32 months OS at 1 and 2 years was 70% and 60%, respectively. PMH: Median OS was 11 months if >40Gy vs. 3 months if <40Gy.

34 MSKCC Experience: Importance of Pathology Prior MSKCC showed 1 year OS of 50% and 2 year LC rate of 68% Results were outstanding prompted re-review of all the slides by expert pathologist [n=37] 1 year LR-PFS 45% and OS 28% Median OS was 8.5 months with RT 50Gy Median OS was 14.1 months if >60Gy

35 RTOG 0912 A RANDOMIZED PHASE II STUDY OF CONCURRENT INTENSITY MODULATED RADIATION THERAPY (IMRT), PACLITAXEL AND PAZOPANIB (NSC )/PLACEBO, FOR THE TREATMENT OF ANAPLASTIC THYROID CANCER Eric Sherman, Nancy Lee, Keith Bible Completed accrual

36 RTOG 0912 Schema Pre-RT Paclitaxel 80 mg/m2 weekly x 2-3 Pazopanib Slurry 400 mg daily x 2-3 weeks or placebo Concurrent Phase Radiation Therapy 66 Gy SF IMRT Paclitaxel 50 mg/m2 weekly x 7 weeks Pazopanib Slurry 300 mg daily x 7 weeks or placebo

37 Patients with stage IVA/IVB resectable surgery, RT, and chemotherapy When possible, use >60Gy of RT, use IMRT with chemotherapy Patients with IVC disease should be on clinical trial, palliative therapy (QUAD shot can be considered), hospice

38 External Beam Radiation Target Volume Delineation and Treatment Planning

39 Recurrent/Poorly Differentiated Thyroid Carcinoma

40 Courtesy of Nancy Lee, M.D.

41 Courtesy of Nancy Lee, M.D.

42 Palliative Quad Shot for Metastatic ATC

43 Courtesy of Nancy Lee, M.D.

44 Courtesy of Nancy Lee, M.D.

45 Multiply Recurrent Papillary Thyroid Cancer

46 Palliative Proton Re-Irradiation

47 Patterns of Failure: Implication for Target Coverage Lack of papers on this topic. Keep in mind when you are delineation your target volume, you are likely the last stop for this patient. Japanese and German surgical series: though rare, medistinal recurrences do occur. Level VII (superior mediastinum): superior edge of the manubrium to the brachiocephalic veins Compartment 4: lymph nodes on both sides of the trachea in the anterior and posterior mediastinum which extend from the level of brachiocephalic veins to the tracheal bifurcation(carina). Typically target central compartment, level VI and VII to Carina,? Whether Lateral neck (speak to Surgeon regarding ND as salvage).

48

49 Acknowledgement XIX Congress of the Brazilian Society of Radiotherapy MSKCC Radiation Oncology Faculty Nancy Lee (Chief of Head and Neck) Sean McBride Nadeem Riaz Dan Higginson MSKCC Radiation Oncology Residents Jonathan Leeman Thomas Beckman Amy Xu

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