Spontaneous Remission of Metastatic Lung Cancer Following Myxedema Coma--an Apoptosis-Related Phenomenon?

Full text

Thyroid hormones and cancer: clinical studies of hypothyroidism
in oncology
Aleck H. Hercbergs
a
, Osnat Ashur-Fabian
b
and David Garfield
c
Introduction
A relationship between the thyroid gland and cancer was
first alluded to by Beatson in 1896 [1]. Much experimen-
tal, clinical and epidemiological effort has subsequently
been directed at defining and clarifying this putative and
controversial relationship. The possibility that a severe
deficiency in ambient thyroid hormone levels might have
a therapeutic impact on metastatic cancer was originally
suggested by Hercbergs and Leith [2]. In that report, a
complete, sustained regression of metastatic nonsmall
cell lung cancer (NSCLC) occurred in a man who had
lapsed into and was then successfully resuscitated from
myxedema coma. He lived 5 years without recurrence
before dying of unrelated causes. This unique event
found support in preclinical studies that revealed
that thyroid hormone deprivation slowed solid tumor
growth rates, whereas thyroid hormone supplementation
increased tumor growth rates [3 –6]. If endogenous thyr-
oid hormone in euthyroid patients may in fact influence
cancer development [7], then the spontaneous or induced
hypothyroid state might be associated with a more favor-
able prognosis in cancer patients.
The possible association between thyroid hormone and
cancer may now be better understood following the
discovery of a membrane receptor for L-thyroxine
(T
4
)and3,5,3
0-triiodo-L-thyronine (T
3
)onastructural
protein of the plasma membrane, integrin avb3[8,9].
This integrin and the cell surface thyroid hormone
receptor appear to mediate the proliferative action of
the hormone on blood vessel cells and on tumor cells
[9]. Integrin avb3 is primarily expressed on rapidly
dividing cells. This recently understood molecular
mechanism of thyroid hormone action may shed light
on the numerous and controversial clinical studies of
thyroid hormone and cancer that have sporadically
appeared in the literature.
After a brief review of experimental thyroid hormone
actions relevant to cancer, we review clinical studies and
reports of outcomes in cancer patients with primary
hypothyroidism, spontaneous and iatrogenic.
Cell biology of thyroid hormones and
tumorigenesis and tumor cell proliferation
More than 20 years ago, Guernsey et al. [10] found
that removal of T
3
and T
4
from serum eliminated
X-ray-induced neoplastic transformation without modify-
ing cell survival. Moreover, addition of T
3
to thyroid
hormone-depleted medium re-established the expected
frequency of transformation. Borek et al. [11] also found
that T
3
facilitated chemical carcinogenesis. Using pro-
pylthiouracil (PTU) to induce hypothyroidism in intact
rats, Goodman et al. [12] showed that hypothyroidism
reduced the risk of breast cancer after 7,12-dimethylben-
z(a)anthracene (DMBA) exposure to 7% from 63% in
a
Department of Radiation Oncology, Cleveland Clinic,
Cleveland, Ohio, USA,
b
Translational Hematology
Oncology, Meir Medical Center, Kfar-Saba, Israel and
c
Promed Cancer Center, Shanghai, P.R. China
Correspondence to Aleck Hercbergs, Department of
Radiation Oncology, Cleveland Clinic, Cleveland,
OH 44195, USA
E-mail: hercbergs@gmail.com
Current Opinion in Endocrinology, Diabetes &
Obesity 2010, 17:432– 436
Purpose of review
To collect and assess clinical reports of a putative relationship between thyroid state
and the biology of cancers of various types.
Recent findings
A number of prospective case–control studies reviewed here have suggested that
subclinical hyperthyroidism increases risk of certain solid tumors and that spontaneous
hypothyroidism may delay onset or reduce aggressiveness of cancers. Small case
studies have reached similar conclusions. A controlled prospective trial of induced
hypothyroidism beneficially affected the course of glioblastoma. A context in which
to interpret such findings is the recent description of a plasma membrane receptor for
thyroid hormone on cancer cells and dividing tumor-associated endothelial cells.
Summary
Accumulating clinical evidence may justify new, broadly-based controlled studies in
cancer patients of the possible contribution of thyroid hormone to tumor behavior.
Keywords
cancer, hypothyroxinemia, integrin avb3, L-thyroxine, triiodothyronine
Curr Opin Endocrinol Diabetes Obes 17:432 –436
!2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1752-296X
1752-296X !2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MED.0b013e32833d9710

controls. PTU and thyroid hormone replacement resulted
in a 78% incidence of mammary cancer in DMBA-treated
animals. Such studies were not widely cited, at least in
part because the traditional concept of genomic thyroid
hormone action – through nuclear receptor proteins
(thyroid hormone receptors) (see review [9]) – resulted
in transcription of genes that supported homeostasis of
the activities of normal cells [13,14]. Further, there were
at the time of publication of these reports no substantial
clinical studies of thyroid hypofunction or hyperfunction
and cancer risk.
A plasma membrane receptor for thyroid hormone is the
basis for a nongenomic mechanism of hormone action
that appears to contribute to proliferation of integrin
avb3-bearing cells [9,15
!
,16]. As noted above, such cells
are usually tumor cells or dividing endothelial or vascular
smooth muscle cells. In this context, earlier animal
studies of thyroid hormone and cancer [3–6] may be
more understandable. Similarly, there are recent studies
on animals of tetraiodothyroacetic acid (tetrac), a thyroid
hormone analogue that disrupts the function of the integ-
rin avb3 receptor on human cancer xenografts and induces
tumor regression and slower growth [15
!
,16,17]. This
receptor also is apparently required for induction by thyr-
oid hormone of angiogenesis, including that relevant to
tumor support [8,9].
Cancer and thyroid function
Epidemiological studies of cancer and thyroid function.
Does hyperthyroidism increase and hypothyroidism
reduce cancer risk?
In a prospective study of almost 30 000 individuals fol-
lowed for 9 years, a low thyrotropin (TSH) level, sugges-
tive of subclinical hyperthyroidism (TSH <0.5 mU/l),
was associated with increased cancer risk specifically with
lung (hazard ratio 2.60) and prostate cancers (hazard ratio
1.96). Hypothyroid function was not associated with
cancer risk [18
!
].
In a population-based case–control study, hyperthyroid-
ism was identified as a significant ovarian cancer risk
factor, with an odds ratio (OR) of 1.8 [19].
Of 1362 breast cancer patients and 1250 controls,
women with untreated hypothyroidism or goiter had a
significantly reduced risk of breast cancer [relative risk
(RR) ¼0.3]. If they had received thyroid hormone for
fertility issues, the RR rose to 4.2. If there was a family
history of breast cancer, RR was 2.6, or if late age at first
childbirth, 2.4 [20]. Postmenopausal women with breast
cancer who had the elevated thyroid hormone and
reduced TSH levels consistent with subclinical
hyperthyroidism, as well as an increased thyroid hor-
mone/estradiol ratio, had more breast cancers than
matched controls [21].
A large population-based case –control study involving
532 pancreatic cancer patients found that a history of
hyperthyroidism gave an OR of 2.1 for its development
[22].
In women with renal cell carcinoma (RCC), a statistically
significantly higher use of thyroid hormone was observed
(P¼0.041) [23].
Is the onset of cancer delayed in hypothyroid patients?
Hypothyroidism was associated with older age at cancer
(breast, lung cancers) diagnosis in several studies. In the
breast cancer group, hypothyroid patients were 7
(P<0.001) [24], 7 [25] and 6 years older (P<0.035)
[26] at diagnosis in three studies. Breast cancer incidence
was significantly lower in the hypothyroid group
(P<0.003). Tumors were also smaller in the hypothyroid
group (P<0.047) and were more likely to be localized.
Euthyroid patients were also more likely to have meta-
static disease [24].
In a case–control study of lung cancer, patients with lung
cancer and a history of thyroid hormone requirement
(¼thyroid hormone replacement) had a mean age at
diagnosis of 73 years vs. 64 years for euthyroid patients
(P¼0.0006). The thyroid hormone group median survi-
val was 14.5 vs. 11.1 months (P¼0.014) [27].
A possible explanation is that hypothyroidism takes a
number of years to evolve to a clinical requirement for
thyroid hormone supplementation, which might then
elicit progression of a pre-existing, indolent, subclinical
cancer [28]. This sequence is wholly speculative.
Does cancer chemotherapy-induced hypothyroidism
contribute to outcome?
The tyrosine kinase inhibitor, sunitinib, as used in RCC,
induces unintended hypothyroidism in up to 71% of
patients [29]. Of interest is that, in a recent study,
progression-free survival (PFS) in such patients seemed
better than that in euthyroid cohorts, even with and in
spite of T
4
supplementation (P¼0.07) [30]. However,
there are as yet no studies comparing replacement with
nonreplacement thyroid hormone so that any relationship
between sunitinib-induced hypothyroidism and tumor
behavior is speculative.
Hypothyroidism, chemoradiation therapy, disease
response and survival
Hypothyroidism may increase response rates to chemo-
therapy and radiation therapy of a variety of solid tumors
[31–36]. Certain of these observations have appeared
only in preliminary form [32,34].
Thyroid hormones and cancer Hercbergs et al. 433

434 Thyroid
Table 1 Cancer outcomes across a spectrum of thyroid functions
Thyroid function Type of research No. of cases Cancer type/disease Clinical outcome References
Spontaneous
hyperthyroid
Prospective
population study
29 691 Several malignancies Significantly higher hazard
ratios for lung and
prostate cancer vs.
significantly lower for HT
Hellevik et al.
[18
!
]
Case– control 532 Pancreas Increased risk with prior
hyperthyroidism
Ko et al. [22]
Case– control 26 pts, 22
matched
controls
Breast Subclinical hyperthyroidism
associated with more
frequent cancers
Saraiva et al.
[21]
Spontaneous
hypothyroid
Case report 1 NSCLC, metastatic ‘Spontaneous’ CR following
myxedema coma
Hercbergs and
Leith [2]
Series 28 Various solid tumors 100% response (CR and PR)
rate to radiation therapy in
chemically HT pts
Hercbergs [32]
Primary hypothyroidism-
Thyroid hormone
supplemented
Population-based 1136 pts, 1088
controls
Breast, primary Less aggressive disease in
HT group, fewer
metastases, 7 years older
age at onset, smaller
tumors
Cristofanilli
et al. [24]
Comparative
study
280 Breast, all stages 5 years older for HT Backwinkel and
Jackson [25]
Comparative
study
68, 91 matched
controls
Breast, all stages 6 years older, smaller tumors,
lower stage, lower
S phase for HT
Hercbergs
et al. [26]
Comparative
study
85, 85 matched
controls
Lung, all stages 4.3 years older, longer
survival for HT
Hercbergs
et al. [27]
Comparative
study
247, 234 matched
controls
RCC, all stages Greater use of TH in
RCC pts
Rosenberg
et al. [23]
Case report 1 Breast Apparent tumor stimulation
with TH
Hercbergs [7]
Case report/
review
1 NSCLC Apparent tumor stimulation
with TH
Hercbergs [33]
Case report 1 Anaplastic thyroid Apparent tumor stimulation
with TH, CR while clinically
HT, 10-year survival
Hercbergs
et al. [44]
Series 5 Pancreas, CRC Long-term survival while on
lower dose; TH/TH
discontinued
Hercbergs
et al. [34]
Series 176 Breast Pts taking TH before
diagnosis had
greater relapse rate,
larger tumors
Burt and Schapira
[37]
Hypothyroid -[iatrogenic]
2
0
to XRT/CHEMORX/
SURG/Biologics
Retrospective 54 RCC treated with
sunitinib
Pts becoming HT with
sunitinib and treated
with TH seemed to have
worse outcome
Sabatier 2009
et al. [30]
Retrospective 155, with 59
developing HT
HNSCC Pts developing HT seemed
to have better survival
Nelson et al. [35]
Population-based 5916 (age >65) HN (excluding thyroid,
larynx, prior HT)
Longer survival in those
developing HT
Smith et al. [36]
Phase II, subset
analysis
34 RCC, melanoma treated
with IL-2/LAK cells
Higher responses with
development of HT
Atkins et al. [39]
Phase II, subset
analysis
16 RCC, metastatic,
treated with
IL-2/LAK cells
Development of HT
correlated with
better response rate
Weijl et al. [40]
Interventional
hypothyroxinemia
Phase I– II 36 Recurrent, high-grade
gliomas made HT
with PTU
Early-onset HT associated
with improved survival
Hercbergs et al.
[41] Hercbergs
et al. [42]
Phase II 20 Recurrent, high-grade
gliomas made HT
with PTU
HT associated with
improved survival
Linetsky et al.
[43]
Recurrent disease
following [re-]
initiation of
L-thyroxine in
HT pts
Case reports 4 Breast 7/9 women given TH after
mastectomy developed
recurrence, 4 of which
were late
Burt and Schapira
[37]
Case report 1 Breast Rapid progression, death
after re-starting TH,
3þyears after being in CR
Hercbergs [7]
CR, complete response; CRC, colorectal cancer; HN, head and neck; HNSCC, head and neck squamous cell carcinoma; HT, hypothyroidism; IL-2,
interleukin 2; LAK, lymphokine-activated killer; NSCLC, nonsmall cell lung cancer; PR, partial response; pts, patients; PTU, propylthiouracil; RCC, renal
cell carcinoma; TH, thyroid hormone; XRT, radiation therapy.

Progression or relapse of disease following L-thyroxine
[T
4
] supplementation
The records of 1465 patients with breast cancer, of whom
176 had taken thyroid hormone, were reviewed. Patients
who had taken thyroid hormone for more than 2 years
within 10 years of developing breast cancer showed a
greater relapse rate compared with controls at 3 years
(43.9 vs. 18.8%, P¼0.002). Their tumors were also larger
(P¼0.01) [37].
The incidence of breast cancer was significantly higher
among patients receiving thyroid hormone in comparison
to control patients. The risk increased with duration of
use, being almost 20% in those receiving it for more than
15 years. The risk was more than three-fold higher in
nulliparous women receiving thyroid hormone, reaching
33%, whereas it was only 9.25% in those not receiving
thyroid hormone [38].
Induced hypothyroidism in cancer patients
A significantly increased rate of tumor regression (5/
7¼71%) was seen in patients with advanced RCC and
melanoma who became hypothyroid, even transiently,
from interleukin-2 (IL-2) and lymphokine-activated
killer (LAK) cell therapy, compared with euthyroid
patients (5/27 ¼19%) who did not (P<0.02) [39]. A
meta-analysis similarly found a significant correlation
of response with hypothyroidism (P¼0.001) [40].
A prospective study of PTU-induced mild hypothyroid-
ism revealed that hypothyroidism was associated with
tumor regression and a statistically significant pro-
longation of survival and time-to-progression in patients
with recurrent/progressive primary brain tumors [41].
PTU induced hypothyroidism in 36 such patients and
early onset chemical hypothyroidism (within 2 months)
was seen in 18 patients. The 6-month PFS of patients
with at least two consecutive monthly readings of serum-
free [F]T4 levels below the reference range (hypothyr-
oxinemia) was 58 vs. 0% for nonhypothyroid patients
(P<0.002). Initial FT4 decline was an independent
prognostic variable and the nadir of FT4 decline also
correlated positively with overall survival (P<0.003)
[42].
A preliminary report of recurrent glioma patients ren-
dered hypothyroid similarly found that survival was sig-
nificantly prolonged with an associated clinical improve-
ment (8/12). This led to withdrawal of steroid therapy
in two patients and dose reduction in the other six.
Responding patients also had marked decrease in seizure
activity. Median time to tumor progression (TTP) was
significantly longer in the hypothyroid group (5 vs.
2.7 months; P¼0.002) with 6-month PFS of 33 vs. 0%
in the euthyroid group [43] (see Table 1) [44].
Conclusion
Review of published clinical studies and accumulating
preliminary data in cancer patients with spontaneous,
chemically, or iatrogenically induced hypothyroidism
heightens suspicion that thyroid hormone is a permissive
factor in some patients with solid tumors. Validation or
refutation of this concept requires additional prospective,
controlled studies of induced, clinically mild hypothyr-
oidism in cancer patients. A consensus statement of the
American Thyroid Association (ATA) [45] recommends
withholding thyroid hormone replacement in asympto-
matic patients – without cancer – who have modest
elevation of serum TSH concentration above the refer-
ence range. This recommendation provoked controversy
[46]. Until additional information is available from pro-
spective studies of hypothyroidism and cancer, however,
we suggest it is prudent to consider the ATA consensus
recommendation on thyroid hormone replacement when
managing chemically hypothyroid patients with cancer.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
!of special interest
!! of outstanding interest
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