The parathyroid as a target for radiation damage.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 365;7 nejm.org august 18, 2011676
recent study showed that quality-adjusted time
was actually increased with the ixabepilone-
capecitabine combination, despite the toxic ef-
fects.1 We know that people facing death from
cancer have a very different perspective, they value
small increments of time even with toxic effects,
and life with treatment is often better than life with
growing symptomatic cancer. That is why these
issues are so hard, they must be considered disease
by disease, and we must have some leeway. Saying
“no” to fourth-line chemotherapy will be difficult
in breast cancer because patients often do have a
clinical benefit.2 That does not apply to patients
with lung cancer, pancreatic cancer, or prostate
cancer. There is no a priori reason why ixabepilone
should cost $6,000 a cycle; it could have an accept-
able cost-effectiveness ratio at $2,000 a cycle.3
Field et al. show that only 27% of patients
with stage III colorectal cancer who were 80 years
of age or older were alive at 5 years, and 59%
had died from other causes. Other studies have
shown that the elderly receive about as much
benefit as the nonelderly from adjuvant chemo-
therapy, with a hazard ratio for death reduced by
50%.4 They show just how small a “drop in the
bucket” adjuvant chemotherapy for the very old
would be — just 3% of patients with colorectal
cancer would receive this treatment. If patients
are otherwise well enough to receive chemother-
apy, we do not think they should be denied just
on the basis of their age.
Meaningful cost control will require tailoring
treatment to patients who can benefit, reducing
the overuse of expensive supportive drugs such
as pegfilgrastim,5 reducing the cost of drugs, and
avoiding unwanted end-of-life hospitalizations.
Thomas J. Smith, M.D.
Bruce E. Hillner, M.D.
Virginia Commonwealth University
Richmond, VA
Since publication of their article, the authors report no further
potential conflict of interest.
1. Corey-Lisle PK, Peck R, Mukhopadhyay P, et al. Q-TWiST
analysis of ixabepilone in combination with capecitabine on
quality of life in patients with metastatic breast cancer. Cancer
2011 May 19 (Epub ahead of print).
2. Dufresne A, Pivot X, Tournigand C, et al. Impact of chemo-
therapy beyond the first line in patients with metastatic breast
cancer. Breast Cancer Res Treat 2008;107:275-9.
3. Hillner BE, Smith TJ. Efficacy does not necessarily trans-
late to cost effectiveness: a case study in the challenges associ-
ated with 21st-century cancer drug pricing. J Clin Oncol 2009;
27:2111-3.
4. Wildes TM, Kallogjeri D, Powers B, et al. The benefit of ad-
juvant chemotherapy in elderly patients with stage III colorectal
cancer is independent of age and comorbidity. J Geriatr Oncol
2010;1:48-56.
5. Potosky AL, Malin JL, Kim B, et al. Use of colony-stimulat-
ing factors with chemotherapy: opportunities for cost savings
and improved outcomes. J Natl Cancer Inst 2011;103:979-82.
The Parathyroid as a Target for Radiation Damage
To the Editor: Exposure to radiation may result
in late adverse effects. Here we describe the con-
sequences of irradiation for the endocrine sys-
tem, particularly the parathyroid glands, in a co-
hort of 61 “liquidators,” or cleanup workers, who
participated in the effort to contain the contami-
nation at the Chernobyl nuclear power plant in
Ukraine subsequent to the 1986 explosion. For
these persons, who were among the most heavily
irradiated workers on the site, we conducted an-
nual clinical follow-up for 24 years, until 2009.
For purposes of comparison, we recruited 687
healthy controls in Swabia, Germany, with the
use of a population-based survey; the controls
were followed for the same period of time. Clini-
cal data obtained 14 years after the accident
showed that the radiation exposure had dichoto-
mous effects on levels of parathyroid hormone
(PTH) and that hypercalcemia and nephrolithia-
sis remained evident. The risk of primary hyper-
parathyroidism in this cohort of workers was
substantial, with an odds ratio of 63.4 (95% con-
fidence interval [CI], 35.7 to 112.5). Elevated PTH
levels were associated with stages 1 and 2 of
acute radiation syndrome.
Twenty-five years after the Chernobyl accident,
the main point of contention is the long-term
effects of the radiation on those who were ex-
posed. In the wake of the accident, a significant
excess in the incidence of thyroid cancer was
observed in children.1 Surprisingly, in this cohort
of liquidators, who were exposed to high local
doses of beta particles and gamma irradiation,2
with whole-body exposure in the range of 0.3 to
8.7 Gy, little effect on the thyroid was detected.
(Clinical outcomes and the results of laboratory
examinations for the cohort are summarized in
Table 1 of the Supplementary Appendix, available
with the full text of this letter at NEJM.org.)
Seven members of the cohort died during follow-

correspondence
n engl j med 365;7 nejm.org august 18, 2011 677
up (15 to 24 years after the accident). In four in-
stances, death was associated with a malignant
disease (latency period, 13 to 17 years). In 15 co-
hort members, high-resolution ultrasonography
of the thyroid and neck revealed multiple solid
and cystic intrathyroidal lesions. The first lesion
was detected in 1990. In 2001, one liquidator
underwent thyroidectomy because of a stage 3
papillary thyroid carcinoma. Ten of the workers
presented with recurrent episodes of nephrolithi-
asis (latency period, 3 to 23 years).
Neither hypothyroidism nor hyperthyroidism
developed in any of the 61 workers during follow-
up (data not shown). Signs of primary hyper-
parathyroidism were detected in 15 workers (close
to 25% at 14 years and 24 years), characterized by
elevated serum levels of PTH and ionized calci-
um. The elevation of PTH levels was not a sec-
ondary effect, since calcium levels were elevated
and levels of 25-hydroxyvitamin D were within
the normal range (Fig. 1). Primary hyperparathy-
roidism was less prevalent in liquidators with
stage 0 or stage 3 acute radiation syndrome, clus-
tering in those with stage 1 or 2. As compared
with healthy controls, liquidators with primary
hyperparathyroidism had increased PTH levels
and liquidators without primary hyperparathy-
roidism had significantly reduced levels (Fig. 1
and Table 1). The risk of primary hyperparathy-
roidism associated with radiation exposure in
the cohort of liquidators was significantly higher
(P <0.001) when compared with the overall preva-
lence of primary hyperparathyroidism in a non-
exposed background population (as reported for
incidence in the U.S. population in 2001), with
an odds ratio of 63.4 (95% CI, 35.7 to 112.5) (see
the Supplementary Appendix for further details).
To address the specificity of the radiation-
associated effects on the endocrine system, we
also measured testosterone levels in the male
liquidators. No association was found between
testosterone levels in men and stage of acute
radiation syndrome, and there was only a weak
correlation between testosterone levels and du-
ration of radiation exposure (determined with the
use of Spearman’s rank correlation coefficient,
calculated as 0.27). These findings suggest that
the parathyroid gland, rather than the thyroid
70
60
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
40
30
10
50
20
0
0 20 40 60 80 100 120
Controls (N=687)
Liquidators, survivors (N=54)
Liquidators, nonsurvivors (N=7)
Cutoff levels:
PTH >65 pg/ml
Ionized calcium >1.32 mmol/liter
25
-H
yd
ro
xy
vi
ta
m
in
D
(n
g/
m
l)
PTH (pg/ml)
Ionized Calcium
(mmol/liter)
Figure 1. Serum Levels of PTH, Ionized Calcium, and 25-Hydroxyvitamin D 14 Years after Irradiation Exposure
in Liquidators as Compared with Healthy Controls.
The distribution of levels of parathyroid hormone (PTH) and ionized calcium was dichotomous, with 15 of 61 liqui-
dators having elevated levels of both PTH and ionized calcium and 46 having low-to-normal levels of both.

n engl j med 365;7 nejm.org august 18, 2011678
correspondence
gland or gonadal function, was subject to the
predominant radiation-specific effect. Since what
is believed to be the first known report of hyper-
parathyroidism in a previously irradiated patient
was published in 1975,3 several cohort studies
have reported elevated PTH levels and an in-
creased risk of hyperparathyroidism in irradiated
populations.3-4
Our observational study does not address
the mechanisms of the development of the para-
thyroid adenomas; however, we speculate that
both high and low levels of exposure to radia-
tion per se, and more specifically, to radioactive
strontium-90, which is a ligand for the calcium-
sensing receptor molecules expressed by parathy-
roid cells, may be the cause of the hyperparathy-
roidism observed in this cohort of 61 liquidators.
Notably, both the Chernobyl accident and the
recent nuclear accidents in Fukushima, Japan,
resulted in a massive release of strontium-90.
The long latency period between the time of ra-
diation exposure and the time at which its effects
on the endocrine system can be detected suggests
that long-term follow-up should be performed in
areas exposed to nuclear radiation and that fol-
low-up should include evaluation of the parathy-
roid, which should be viewed as a radiation-
sensitive endocrine organ.5
Bernhard O. Boehm, M.D.
Silke Rosinger, Ph.D.
Ulm University Medical Center
Ulm, Germany
bernhard.boehm@uniklinik-ulm.de
David Belyi, M.D.
Research Center for Radiation Medicine
Kiev, Ukraine
Johannes W. Dietrich, M.D.
Ruhr University of Bochum
Bochum, Germany
Supported by the Center for Excellence in Metabolic Diseases,
Baden-Wuerttemberg, Germany.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Baverstock K, Egloff B, Pinchera A, Ruchti C, Williams D.
Thyroid cancer after Chernobyl. Nature 1992;359:21-2.
2. Boehm BO, Steinert M, Dietrich JW, et al. Thyroid examina-
tion in highly radiation-exposed workers after the Chernobyl
accident. Eur J Endocrinol 2009;160:625-30.
3. Rosen IB, Strawbridge HG, Bain J. A case of hyperparathy-
roidism associated with radiation to the head and neck area.
Cancer 1975;36:1111-4.
4. Fujiwara S, Sposto R, Shiraki M, et al. Levels of parathyroid
hormone and calcitonin in serum among atomic bomb survi-
vors. Radiat Res 1994;137:96-103.
5. Peplow M. Chernobyl’s legacy. Nature 2011;471:562-5.
Correspondence Copyright © 2011 Massachusetts Medical Society.
Table 1. Biochemical Status of Liquidators 14 Years after the Chernobyl Accident as Compared with Healthy Controls.
Characteristic
Liquidators with
Hyperparathyroidism
(N = 15)
Liquidators without
Hyperparathyroidism
(N = 46)
Healthy Controls
(N = 687)
Age at exposure (yr) Not applicable
Median 34.5 33.4
Range 21.6–56.5 20.6–60.5
Age at 14-yr follow-up (yr)
Median 48.5 47.4 49.7
Range 35.6–70.5 34.6–74.5 17.3–58.5
Sex (no.)
Male 14 44 652
Female 1 2 35
PTH (pg/ml) 81.6±12.8†‡ 25.52±11.7‡ 38.2±12.7
Ionized calcium (mmol/liter)§ 1.54±0.06†‡ 1.22±0.05‡ 1.28±0.06
25-Hydroxyvitamin D (ng/ml) 24.8±6.5¶ 20.5±6.1 18.4±9.4
1,25-Dihydroxyvitamin D (pg/ml) 76.2±17.6†‡ 52.1±12.9‡ 37.5±14.8
* Plus–minus values are medians ±SD. PTH denotes parathyroid hormone.
† P<0.001 for the comparison of affected with unaffected liquidators.
‡ P<0.001 for the comparison of liquidators with controls.
§ Ionized calcium levels were measured at a pH of 7.4.
¶ P<0.05 for the comparison of liquidators with controls.

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage.
N Engl J Med 2011;365:676-8.

Manuscript ID: 11-04982.R2

The parathyroid is a target for radiation damage
Bernhard O. Boehm et al.

Supplementary Information

Clinical and biochemical work-up.

Liquidators
Liquidators were exposed to ionized radiation at the Chernobyl accident and were
extensively re-examined 14 years after the Chernobyl accident (N=61; male 58 probands).
These probands were among the most severely exposed to high doses of beta-particles and
gamma-radiation1. Whole-body exposure was in the range between 0.3-8.7 Gy. ARS severity
level classification was applied as described in Mettler2 and coworkers and Belyi3 and
coworkers. :
Clinical examination was performed on a yearly basis until the year 2009.

Healthy Controls
Healthy normal controls (N=688; male 652 control probands) were recruited from an age and
sex-matched population based cohort in Germany 14 years after the Chernobyl accident and
classified as a non-radiation exposed background population. The time period of the blood
sampling in controls and the liquidators was the same.
Study probands provided written informed consent for the study.

High-resolution ultrasound examination of the thyroid
Thyroid nodules were defined by using high-resolution ultrasound, 7.5-MHz transducer
(Aloka 630, Japan). Number of affected probands with a single or multiple nodules was
recorded. The prevalence of single nodules and/or multiple thyroid nodules was not different
in the group of liquidators versus the controls.

Biochemical work-up

Bio-intact PTH was measured by a chemiluminescence immunoassay (Nichols Institute
Diagnostics). Ionized calcium levels were determined using standard automated techniques
and equilibrated at pH 7.4. 25-OH vitamin D and 1,25-OH vitamin D levels were determined
using radioimmunoassays (IBL International, Hamburg, Germany).
Total testosterone levels were measured using a RIA test system (T; DSL-4000 ACTIVE™
Testosterone Radioimmunoassay, DSL GmbH Germany; intraassay coefficients of variation
(CVs) were 7.8-9.6%). For healthy adult men, the normal range for testosterone was 2.8–8.0
ng/ml. All samples were collected at the same time, between 07:00 and 9:00 a.m.

Categorization to primary hyperparathyroidism (pHPT) included presence of an elevated
intact PTH, elevated ionized calcium or ionized calcium in the upper range of the normal and
high-normal or elevated 1,25-OH vitamin D as a function of PTH. The classification also
included lack of 25-vitamin D (< 10 ng/ml) as well as an impaired kidney function using
glomerular filtration rate according to MDRD2 formula4.

References
1. Boehm BO, Steinert M, Dietrich JW, et al. Thyroid examination in highly radiation-
exposed workers after the Chernobyl accident. Eur J Endocrinol 2009;160:625-30.
2. Mettler FA, Gus'kova AK, Gusev I. Health effects in those with acute radiation sickness
from the Chernobyl accident. Health Physics 2007;93: 462-469.
3. Belyi D.A., Khomenko V.I., Bebeshko V.G. Emergency preparedness of Research Center
for Radiation Medicine and its hospital to admit and treat the patients with signs of acute
radiation sickness. Radiat Prot Dosimetry 2009;134: 159-162.
4. Lin J, Knight EL, Hogan ML, Singh AK. A comparison of prediction equations for
estimating glomerular filtration rate in adults without kidney disease. J Am Soc Nephrol.
2003;14:2573-80. Erratum in: J Am Soc Nephrol. 2005;16:2814.

Statistics

Levels of PTH, ionized calcium and vitamin D metabolites were compared with respect to
group, gender and ARS stage with two-way ANOVA. Post-hoc testing and correction for
alpha error accumulation in the setting of multiple testing were performed with Tukey’s
honest significance difference test (Tukey-Kramer method) and a Benjamini-Hochberg
procedure.

Survival data and frequency of pHPT in dependency of ARS stage, gender and duration of
radiation exposure were investigated with multiple logistic regression.

Spearman's rank correlation was used in order to investigate the relation between duration of
radiation exposure and levels of ionized Ca (iCa), PTH, vitamin D metabolites, and thyroid
autoantibody titers.

Epidemiological data and frequency outcomes were compared with Pearson’s Chi-squared
test with Yates’ continuity correction.

All statistical tests were performed with custom S scripts that were executed in the statistical
environment R 2.10.1 1.

References

1. R Development Core Team. R: A Language and Environment for Statistical Computing.
In Vienna, Austria: R Foundation for Statistical Computing; 2009.


Epidemiological comparisons

1. Prevalence based estimation of pHPT risk

1.1 Comparison with population prevalence in Sweden1:

Liquidators Population1
pHPT 15 1.07
No pHPT 46 98.93
X-squared = 20.8, df = 1, p-value = 5.1e-06.
RR: 23.0 (95% CI: 3.3 to 159.2)
OR: 30.1 (95% CI: 4.1 to 221.0).

1.2 Comparison with population prevalence estimation in USA2:

Liquidators Population2
pHPT 15 1
No pHPT 46 999
X-squared = 216.0, df = 1, p-value < 2.2e-16.
RR: 245.9 (95% CI: 33.0 to 1831.0)
OR: 325.8 (95% CI: 42.1 to 2519.7).

2. Incidence based estimation:
2.1 Comparison with lower bound of population incidence estimation in USA3:

Liquidators Population3
pHPT 15 387.8
Persons at risk 61 100000
X-squared = 664.5, df = 1, p-value < 2.2e-16.
RR: 51.0 (95% CI: 32.1 to 81.3)
OR: 63.4 (95% CI: 35.7 to 112.5).
Population incidence figure expressed as 14-year incidence.

2.2 Comparison with upper bound of population incidence estimation in USA3:
Liquidators Population3
pHPT 15 588
Persons at risk 61 100000
X-squared = 436.2, df = 1, p-value < 2.2e-16

RR: 33.8 (95% CI: 21.3 to 53.5)
OR: 41.8 (95% CI: 23.6 to 74.0).
Population incidence figure expressed as 14-year incidence.
References
1. Palmer M, Jakobsson S, Akerstrom G, Ljunghall S. Prevalence of hypercalcaemia in a
health survey: a 14-year follow-up study of serum calcium values. European journal of
clinical investigation 1988;18:39-46.
2. Boonstra CE, Jackson CE. Serum calcium survey for hyperparathyroidism: results in
50,000 clinic patients. American journal of clinical pathology 1971;55:523-6.
3. Melton LJ, 3rd. Epidemiology of primary hyperparathyroidism. J Bone Miner Res 1991;6
Suppl 2:S25-30; discussion S1-2.