1. Radioactive Iodine Refractory Patients : Definition and Treatment of Radioactive Iodine Refractory Thyroid Cancer Patients
방사성 옥소치료에 내성을 가진 갑상선암의 진단과 치료에 대해 말씀드리겠습니다
Good morning ladies and gentlemen! first of all, let me thank you all for being here today
As you probably know, I’m the director of endocrinology department in Kangnam severance hospital, seoul, Korea
My name is Chulwoo Ahn.
Today, We'll be talking about the definition and treatment of radioactive iodine, RAI refractory thyroid cancer.
Chul woo Ahn
Director of Endocrinology department
Gangnam Severance Hospital
Yonsei University College of Medicine, Seoul, Korea

2. Table of Contents Incidence of Thyroid cancer
Definition of RAI refractory Thyroid cancer
Treatment of RAI refractory Thyroid cancer
Summary and Conclusions
갑상선암의 발생률과 정의, 그리고 치료, 결론 순서대로 말씀드리겠습니다
Table of contents are incidence of thyroid cancer, definition and treatment of RAI refractory thyroid cancer and the conclusion .

3. 7 major countries: 64,570 estimated new cases in 2008
US: 37,340
EU (5 key countries): 18,100
Japan : 9130
Fastest increase in US SEER incidence among all cancer types
6.2% annual rate of increase in
May reflect early disease detection
Second fastest increase in US SEER death rate among all cancer types
0.5% annual rate of increase in
이것은 2008년 미국과 유럽 주요 5개국, 일본등의 국가에서의 갑상선암 발생률을 본 것인데 미국에서는 해마다 6.2% 의 빠른 발생증가율을 보이고 있습니다
This slide shows the incidence of thyroid cancer in the United States, major European countries and Japan.
In the year of 2008, annual growth rate in the US is 6.2%.
SEER = Surveillance, Epidemiology and End Results Program.
1. National Cancer Institute Web site. Thyroid Cancer.

4. Thyroid cancer increased dramatically in KOREA !!!
20-25%
RAI-refractory
Estimated Thyroid Cancer Incidence in
5000
10000
15000
20000
25000
30000
35000
40000
Annual Incidence
31977
또한 한국에서는 더욱더 급격히 갑상선암의 발생이 증가하고 있는데 2009년 한해에만 약 31977명의 한자가 새로 발생하여 모든 암종을 통틀어 1위를 차지했습니다
이 중 약 20-25% 는 RAI –refractory thyroid cancer 입니다
In South Korea, the incidence of thyroid cancer has more sharply increased.
In 2009 alone, approximately 32,000 people of all newly occurring throughout the carcinoma accounted #1.
And 20 to 25% of these are RAI-refractory.

5. 131I-Refractory Thyroid Cancer
20%-25% of metastatic thyroid cancer loses the ability to uptake iodine and therefore becomes 131I refractory1
Loss of iodine uptake inversely correlates with survival
Expected survival is years1
No effective systemic therapy currently available
Conventional cytotoxic agents show minimal efficacy
Doxorubicin: 5% PR, 47% SD, median PFS 7 months2
Novel, effective systemic therapy is needed
알려진 대로 갑상선암은 표준치료인 수술과 방사성 옥소치료, 장기간 TSH 억제치료로 매우 좋은 예후를 나타내나 전이된 갑상선암의 20-25% 는 요오드 섭취 능력을 잃고 옥소내성이 됩니다.
이러한 요오드섭취능력의 소실은 예후와 밀접하게 관련이 있어 기대 여명이 년밖에 되지 않고,현재 효과적인 치료가 없는 실정입니다
As you know, thyroid cancer represents a very good prognosis with standard treatment of surgery, radioiodine therapy and long-term TSH suppression therapy.
However, 20-25% of metastatic thyroid cancer loses the ability to uptake iodine and therefore it becomes 131I refractory.
Loss of iodine uptake inversely correlates with survival and expected survival is ( two and half to three and half) years.
There is currently no effective systemic therapy currently available for them.
Thus, novel effective systemic therapy is needed in this situation.
Schlumberger et al. Nat Clin Pract Endocrinol Metab. 2007:3:
Matuszczyk et al. Horm Metab Res. 2008;40:

6. Definition of RAI refractory thyroid cancer
Patients who have at least one lesion without radioiodine uptake or that has progressed within a year following radioiodine treatment.
The median survival of these patients after the discovery of distant metastases ranges from 3 to 6 years.
Slow tumor growth is common, and a long survival rate is observed in young patients who are not candidates for therapy trials.
However, the majority of metastases will progress, and these patients will then be candidates for other treatment modalities.
방사성옥소치료내성의 정의를 말씀드리면 방사성옥소섭취를 나타내지 않거나 옥소치료 후 1년이 되기 전에 진행하는 하나 이상의 병변을 가지고 있을 때를 말합니다
이러한 환자들의 median survival 은 3-6년정도입니다.
천천히 자라는 경우도 흔하고 치료의 대상이 되지 않는 젊은 환자들은 long survival rate 를 갖기도 하나,
대부분의 전이가 진행하고 이러한 환자들은 다른 치료방법이 필요하게 됩니다
This slide is about Definition of Radioiodine refractory thyroid cancer.
It means patients who have at least one lesion without radioiodine uptake or has progressed within a year following radioiodine treatment.
The median survival of these patients is 3-6 years. Slow tumor growth is common, and a long survival rate is observed in young patients who are not candidates for therapy trials.
However, the majority of metastases will progress, and these patients will be candidates for other treatment modalities.

7. Treatment of persistent/recurrent DTC
General information of DTC (Differentiated Thyroid Cancer)
85% DTC: limited dis % DTC: persistant/recurrent dis.
25% of persistant/recurrent DTC: distant metastasis (lung. Bone)
10yr OS of DTC with distant metastasis: 25-45%
1/3 of DTC with distant metastasis: RAICR
Additional surgery, local therapy
RAI uptake
(+) : RAI treatment
() : RAI-Refractory Disease
25-50% of metastatic DTC lose ability to take up Iodine.
Iodine Uptake inversely correlates with survival.
Limited treatment options
Cytotoxic chemotherapy
Doxorubicin: Only FDA approved agent for the treatment of thyroid cancer
재발되거나 지속되는 분화갑상선암의 치료에 대해 말씀드리겠습니다
일반적으로 분화갑상선암의 85%가 limited 이고 이중, 10-15%가 persistant/recurrent disease 입니다
이중, 25%가 주로 lung, bone 에 전이를 보입니다
Distant meta의 10-yr survival rates는 25-42% 이며
Distant meta의 1/3은 RI 로 CR 을 보일 수 있습니다
그러나 말씀드리려고 하는 방사성옥소치료 내성에서는 제한된 치료옵션을 가지고 있습니다
Let me tell you about the treatment of recurrent differentiated thyroid caner so called DTC. 85% of DTC is limited disease and % is persistant or recurrent disease 25% appears mainly in the lung and bone metastasis. 10-yr survival rates of DTC is 25-45% and 1/3 (one third) of the Distant metastasis can be CR (complete remission) by RAI. However, radioiodine therapy refractory disease has limited treatment options.

8. Failure of traditional systemic chemotherapy
Doxorubicin vs Cisplatin
17% vs 26% (12% CR)
Bleomycin, Doxorubicin, + Cisplatin
42% response, median survival 11 months
Etoposide
0% response (failure to recruit)
기존 항암치료는 25% 미만의 제한된 효과를 보입니다.
블레오마이신과 독소루비신 그리고 시스플라틴의 병합요법이 42%의 반응률로 median survival 11 개월의 결과를 보여주었습니다
We can treat the RAI refractory thyroid cancer with systemic chemotherapy.
However, conventional single agent chemotherapy has Limited effect less than 25%. Meanwhile, Bleomycin and doxorubicin, and cisplatin combination therapy showed response rate of 42%, median survival was 11 months.

9. Selection of metastatic thyroid cancer patients for therapy
Candidates for radioiodine treatment
Younger age
Well-differentiated papillary and follicular thyroid tumor
High radioiodine uptake in the metastases
Small metastases
Location in lungs
Apparently stable or slowly progressive disease
Low uptake of FDG
Candidates for other treatment modalities
Older age
Poorly differentiated thyroid tumor
No or low radioiodine uptake
Large metastases, Rapidly progressive disease
High uptake of FDG
Refractory to radioiodine: should be considered for therapeutic trials
전이된 갑상선암의 치료선별 기준으로서
젊은 나이이거나 분화된 유두암이나 여포암에서는 방사성옥소치료가 원칙이며
노령층이거나 분화가 나쁘거나 방사성 옥소치료 내성을 보이는 경우 다른 치료 trial 을 생각해 보아야 합니다
Now we’ll be going over selection of metastatic thyroid cancer patients for therapy.
Firstly, candidates for radioiodine treatment are younger age or well differentiated papillary or follicular cancer
or High radioiodine uptake or Small metastases or Location in lungs or apparently stable or slowly progressive disease or Low uptake of FDG
Secondly, Candidates for other treatment are Older age or Poorly differentiated thyroid tumor or low radioiodine uptake
or Large metastases or Rapidly progressive disease or High uptake of FDG.
These patients with Refractory to radioiodine: should be considered for therapeutic trials.

10. 2011년 NCCN 가이드라인으로서 방사성옥소치료 내성인 경우 small molecule kinase inhibitor 나 systemic therapy 를 고려해보아야 한다고 말하고 있습니다
This slide is about 2011 NCCN guidelines. It says that you should consider small molecule kinase inhibitor or systemic therapy if radioiodine therapy-resistant.

11. Treatment of RAI-refractory thyroid cancer
Standard treatment of thyroid cancer
Surgery
Radioactive iodine (I131, RAI)
Inoperable, iodine-refractory advanced/metastatic thyroid cancer
No effective treatment
Doxorubicin as single agent (RR of 30% and up to 45% in some)
Local treatment by hyperfractionated radiation
Cytotoxic agents and combination
Targeted therapy (molecular based)
따라서 이러한 옥소 내성 갑상선 암에서는 독소루비신이 single agent 로 쓰일 수 있으며 hyperfractionated radiation, targeted therapy 등의 option 이 있을 수 있겠으나
여기서는 targeted therapy 들에 대해 말씀드리겠습니다
This slide is about Treatment of RAI-refractory thyroid cancer.
Usually, standard treatment of thyroid cancer is surgery and radioactive Iodine.
Inoperable or Iodine refractory advanced metastatic thyroid cancer has no good effective treatment with surgery and radioactive iodine.
So, Doxorubicin can be used as a single agent in RAI-refractory thyroid cancer, And we can have the options of hyper fractionated radiation and targeted therapy.
But, Here, we'll be talking about targeted therapy.

12. Pathways and targets in thyroid cancer
VEGF, FGF, IGF
RAS
PI3K
BRAF
MEK
AKT
Erk
갑상선암의 pathway 와 target 을 나타내는 그림으로서 VEGF, RAS 등을 Target 으로 한 targeted agent 를 생각해 볼 수 있습니다
This figure shows the pathway and target in thyroid cancer, we can think about the targeted agent such as VEGF and RAS.
mTor
Transcription
Proliferation
Differentiation
Survival
Nucleus

13. Drugs & Targets -Multi-targeted TKIs-
Agent
Subtypes
Known targets
Sunitinib
DTC, MTC
VEGFR, PDGFR, c-kit, RET
Sorafenib
VEGFR-2, VEGFR-3, PDGFR-, Flt-3, C-Kit, RET, RAF and FGFR-1
Pazopanib
DTC
VEGFR, PDGFR, c-kit
Axitinib
VEGFR-1, 2, 3; PDGFR-, ; KIT (but not RET)
Motesanib
Lenvatinib (E7080)
VEGFR-1, 2, 3, FGFR-1~4, RET, c-kit, PDGFR
Vandetanib (ZD6474)
MTC
RET, VEGFR2-3, EGFR
Cabozatinib (XL184)
MET, VEGFR2, and RET
이런 targeted agent 들은 angiogenesis inhibitor 들로서 RET inhibition 이 갑상선암에서는 중요한데 특히 수질암에서 중요하고 RAF inhibition 은 유두암에서 중요하겠습니다
These targeted agents are angiogenesis inhibitor.
RET inhibition is important in thyroid cancer, especially in the medullary carcinoma.
while RAF inhibition is important in papillary thyroid cancer.

14. Summary : Targeting therapy for thyroid cancer
Unresectable/metastatic/persistent/recurrent, non responsive to RAI thyroid cancer
Novel TKIs : impressive result but many question…
Clinical trial enroll
Side effect
More detailed understanding of the genetics and biology of thyroid cancer
Search of other molecular targeted therapy
진행된 갑상선 암의 치료는 내분비종양학자, 외과의, 핵의학전문가, 방사선치료사 등의 협진이 필요합니다
현재로서 치료가 어려운 전이성, 재발성, RAI 불응성 갑상선 암에 대해서 TKI 가 연구중이지만 더욱 많은 연구가 필요할 것으로 생각됩니다.
We will wrap up in summary.
For Unresectable/metastatic/persisitant/recurrent, non responsive to RAI, thyroid cancer, Novel TKIs shows impressive result
But there are still many questions remained about Clinical trial outcome and Side effect.
What we should do is that, above all, more detailed understanding of the genetics and biology of thyroid cancer .
Then we will be able to search other molecular targeted therapy in the future.

15. Conclusion
The ultimate goal of thyroid cancer treatment is to extend the duration of life without unduly harming the quality of patients’ life.
Presently, no novel treatment has yet demonstrated improved
survival for thyroid cancer patients.
Low rate of partial response, the absence of CR, and emergence of resistance in monotherapy trials identify the need to develop either more effect agents.
For advanced thyroid cancer treatment
Multi-displinary approach : Endocrine oncologist, surgeon, nuclear medicine specialist, radiotherapist…
갑상선 암치료의 최종 목표는 QOL 을 해치지 않으면서 삶을 연장하는 것입니다
그러나 현재로서는 아직 확실한 치료가 증명되지 않았고
낮은 PR 비율, 치료에 대한 저항성 등으로 인해 더 효과적인 약제가 필요합니다
Finally , in conclusion,
The ultimate goal of thyroid cancer treatment is to extend the duration of life without unduly harming the quality of patients life.
Presently, no novel treatment has yet demonstrated improved survival for thyroid cancer patients.
Low rate of partial response, the absence of complete remission, and emergence of resistance in monotherapy trials identify the need to develop either more effect agents.
As for Advanced thyroid cancer treatment, Multidisplinary approach such as Endocrine oncologist, surgeon, nuclear medicine specialist, radiotherapist will be required.
This was all about today’s presentation. Thank you for your attention. I appreciate your time and attendance.
If you have any questions, feel free to ask me. I would be glad to answer your questions even though I am not ready. HaHaHa…