1. MRI GBM

5. Aleck Hercbergs, 1; David Garfield, 2;
HYPOTHYROXINEMIA MEDIATED BY EXOGENOUS 3,5,3’-TRIIODO-L-THYRONINE [T3] IS ASSOCIATED WITH TUMOR RESPONSE IN CANCER PATIENTS: A COMPASSIONATE CARE EXPERIENCE
Aleck Hercbergs, 1; David Garfield, 2;
Osnat Ashur-Fabian,3 : 1.
Radiation Oncology, Cleveland Clinic, Cleveland , OH 1. Oncology, Promed Cancer Center 2, Shanghai , China.
. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 3

6. INTRODUCTION -1
Evidence has accumulated that L-thyroxine (T4) via a thyroid hormone receptor on plasma membrane integrin alpha(v)beta3 promotes solid tumor growth . In prior clinical studies of recurrent glioma, induced hypothyroxinemia was associated with prolonged survival and tumor regression. However, hypothyroidism-associated fatigue in patients has restricted compliance with this approach. Recent evidence suggests that (T3) in physiological concentrations is significantly less [1-2 logs concentration] potent at inducing cancer cell mitogenesis and proliferation (R Meng et al., PLoS 2011; 6[11]:e27547).
These data therefore suggest that , exogenous T3 in might be a preferable thyroid hormone supplement in hypothyroid cancer patients, supporting eumetabolism and lowering circulating endogenous T4 via TSH suppression.
A recent report[ASCO 2011   REF  ] suggested   significant  benefit in patients  thus treated  in a compassionate care setting

7. INTRODUCTION-continued
There are positive preclinical studies and clinical reports of favorable outcomes in association with chemical hpothyroidism but associated morbidity has limited patient compliance .There is recent data has physiological T4 [10 -7 molar] is pro-mitogenic and angiogenic   in various      experimental tumor models  in-vitro   but at physiological ( molar) concentrations T3 was significantly less active becoming comparably active only at significantly higher [1-2 logs] supra-physiological concentrations. .  
Since T4 is a metabolically inactive pro-hormone maximal depletion of blood free thyroxine [FT4] may be a clinically acceptable and achievable therapeutic goal by discontinuation of exogenous L-thyroxine[L-T4] supplementation while maintaining chemical euthyroidism with daily exogenous low dose T3 These data therefore suggest that attainment of selective T4 depletion in patients may be a feasible therapeutic goal .
Since a significant number of patients with active cancer are hypothyroid and on supplemental T4 a potentially less oncogenic hormone i.e. T3 might be a preferrable alternative supplement.
Exogenous T3 has dual utility in this protocol : i.e. It may also inhibit /lower TSH and and indirectly T4 .
    A recent report[ASCO 2012     ] suggested   significant  benefit in patients  thus treated  in a compassionate care setting.
       

8. Methods and Patients
.Inpatients this retrospective study, the courses of 3 hypothyroid solid tumor on L-T4 replacement were analyzed. The cancers were far-advanced and the patients were deteriorating clinically and radiologically . Patients were converted abruptly from L-T4 (75-88 mcg daily) to exogenous T mcg/day. An additional euthyroid patient [#1] received 25 μg T3 with 40 mg/ methimazole /day to induce hypothyroxinemia..
Follow -up was clinical , by regular blood TSH,FT4 testing and MRI imaging with central review.
Patients at geographically dispersed sites were managed and monitored by personal physicians .

9. Patient #1 F. 67 GBM- CLINICAL COURSE
67 year old woman on L-T4 supplementation pre and post CRANIOTOMY and biopsy - of 3.5x3.5 cm L. parieto-occipital glioblastoma[GBM].
Rapid Performance Status deterioration while on post –operative radiation therapy [3960cGy] and Temodar –From ECOG 1 TO 3[KPS80 to 40] –patient incapacitated
No response to high dose dexamethasone .Memory impairment and visual field loss..MRI shows significant tumor enlargement,6X5cm contralateral spread and vasogenic edema. Recovery not expected.
Patient‘s 75 ug /day L-T4 discontinued –exogenous T3 begun .After 7 days significant clinical and neurological improvement-patient becomes ambulatory .
At 3 weeks MRI shows significantly smaller tumor and decrease in vasogenic edema..

10. Patient #1 F. 67 Glioblastoma
TSH FT Tumor Size[cm.]
Pre L-T4 withdrawal / x5.2
Post L-T “ / x3.8
[Time from L-T4 withdrawal weeks]
Survival months
TSH( mU/L ) / FT4 ( ng/dL)

11. GBM ON L-T4
November ??

12. GBM Off L-T WEEKS
OFF L-T4
----On T3 .

13. GBM on L-T4

14. JJJ
OFF L-T4
----On T3 .

15. O
On –T4

16. GBM Off L-T WEEKS
OFF L-T4
----On T3 .

17. Patient #2 F.34 Recurrent Synovial sarcoma [grade 2]
CLINICAL COURSE
S/P Partial resection of a vascular 4x3 cm R. neck mass followed by adjuvant radiation therapy and chemotherapy.
One year later onset of hyperthyroidism [Graves] –had total thyroidectomy and then L-thyroxine supplementation 88 mcg/day.
Serial follow up MRI over 5 months showed gradually enlarging mass .
5/2011 L-thyroxine discontinued. Exogenous T3 initiated 6.25mcg x 3 /day.

18. F.34 Recurrent Synovial sarcoma (G2)
TSH FT TUMOR [cm.]
On L-T / x1.3
Off L-T WEEKS
92 / x0.6
SURVIVAL [mo.]
TSH( mU/L ) / FT4 ( ng/dL)

19. F. 34 -Recurrent Synovial Sarcoma Off L-T4 5 WEEKS
----On T3 .

20. F. 34 -Recurrent Synovial Sarcoma Off L-T4 5 WEEKS

21. F. 34 -Recurrent Synovial Sarcoma Off L-T4 5 WEEKS

22. MRI - 5 weeks post discontinuation of L-Thyroxine
OFF L-T4
----On T3 .
1. Interval decrease in blood supply or loss of solid enhancement
compatible with successful treatment or successful interruption of
tumor angiogenesis.
2. Interval decrease in size of the residual lesion now with thin
peripheral enhancement.  This may represent early cystic necrosis or
post radiation change.  
3. Updated volumetric measurements indicate decrease to approximately
42% or 48% depending on whether one includes the adjacent cystic
component.
Interval decrease in blood supply or loss of solid enhancement compatible with successful treatment or interruption of tumor angiogenesis

23. Patient #3 M 62 GBM Clinical history
s/p remote subtotal thyroidectomy-papillary ca. thyroid ..on 88 mcg L-thyroxine
S/p craniotomy –GBM .Re-operation at 6 weeks for recurrence following radiation and Temodar..additional XRT given .
L-T4 discontinued . Exogenous T3 initiated .

24. M.62 Recurrent Glioblastoma
TSH /FT TUMOR SIZE[cm.]
Pre 0.34/ x 2.6
. Post 2.86 / x1.3
SURVIVAL months
TSH( mU/L ) / FT4 ( ng/dL)

25. Clinical Course
Stable but residual tumor associated nodule 0ver next 30 months.
At 31 mo. diagnosis of CLL /non-Hodgkins lymphoma refractory to first line chemotherapy requiring frequent blood transfusions .
Single treatment with Bendamustine ..however elicits brain tumor response -see below.

26. On L-T4
Post R. Craniotomy _

27. MRI Brain 2/14/2011 2/14/2011 + mass effect
OFF L-T4
----On T3
18 MO.
2/14/2011
+ mass effect
MRI Right Parietal lobe mass measures
1.8 cm x 2.1 cm x 2.5 cm in AP, TR, and CC

28. MRI BRAIN 4/15/2011 4/15/2011- after single Bendamustine treatment
OFF L-T4
----On T3
22 MO.
4/15/2011- after single Bendamustine treatment
Axial post contrast
1.5 cm x 1.3 cm x
2.0 cm in AP, trans, CC

29. Patient #4 Adenoid Cystic Ca. Clinical History
s/p resection of pharyngeal adenoid cystic carcinoma.
At 8 years retro/peri-orbital mass and brain metastases
R. eye proptosis and peri-orbital edema
no response to palliative radiation
Exogenous T3 and methimasole initiated
At two months regression of proptosis,peri-orbital edema and on MRI regression of retro-orbital mass

30. F. 58 Adenoid Cystic Ca.-metastatic retro-orbital mass
TSH FT TUMOR SIZE[cm.]
Pre / x3.0
Post 48.55/ x2.0
Time to FT4 Depletion weeks
SURVIVAL [months]
TSH( mU/L ) / FT4 ( ng/dL)

31. ADENOID CYSTIC CA –RETRO-ORBITAL MASS

32. Adenoid cystic ca.-
-On exogenous T3 and methimasole
3 months.

33. Adenoid cystic ca
-On exogenous T3 and methimasole
3 months.

34. RESULTS
All four patients experienced clinical benefit and radiological improvement including reversal of neurological deficits [ GBM].
Quality of life was significantly improved [pain and orbital edema reduction] and restoration of ambulatory status[GBM]
No clinical hypothyroidism.

35. DISCUSSION All patients were treated on a compassionate care basis.
Three of these four high risk, advanced and progressing ,deteriorating ,poor prognosis solid tumor patients demonstrated tumor regression or arrest subsequent to abrupt discontinuation of exogenous L-thyroxine supplementation.Tumor regression was evident shortly [within 3 and 5 weeks] and in one patient treated with exogenous T3 and methimasole at first follow up MRI at 8 weeks.
All patients subsequently continued on exogenous T3 and with the exception of case #3 who developed NHL and pancreatic ca. at 32 months are on follow-up .
Exogenous T3 was very well tolerated .
We have previously reported on 23 euthyroid patient treated with exogenous T3 and methimasole to achieve euthyroid hypothyroxinemia[selective T4 depletion] ASCO proceedings

36. Summary of Conclusions
Three patients experienced significant tumor regression and clinical improvement coincident with selective T4 depletion following abrupt discontinuation of exogenous T4 and in one case exogenous T3/methimasole administration .
The abrupt decrease in T4 hormonal availability followed by objective tumor regression and clinical improvement suggest a cause/effect relationship
In the relatively short period under review T3 supplementation was not associated with tumor regrowth
T3 may be the preferred and ‘safer ‘ supplement in hypothyroid patients with active cancer.

37. Bibliography
R Meng et al., PLoS 2011; 6[11]:e27547 Crosstalk between Integrin αvβ3 and Estrogen Receptor-α Is Involved in Thyroid Hormone-Induced Proliferation in Human Lung Carcinoma Cells
Lin HY, Sun M, Tang HY, et al. L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol. 2009;296:C
Hercbergs A Garfield D Ashur –Fabian O . Triiodothyronine [T3]-induced hypothyroxinemia: Response and survival in a compassionate care cancer patient population. Abstract No: e J Clin Oncol 30, 2012 (suppl; abstr e19573)
Davis FB , Tang HY, Shih A et al. Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells. Cancer Res 2006; 66(14):
Hercbergs A et al. Propylthyiouracil-induced chemical hypothyroidism with high dose tamoxifen prolongs survival with increased response rate in recurrent high-grade gliomas. Anticancer Res, 23, , 2003.