1C OPYRIGHT Ó 2011 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

Exposure to Ionizing Radiation and Development ofBone Sarcoma: New Insights Based on Atomic-Bomb
Survivors of Hiroshima and Nagasaki
Dino Samartzis, DSc, Nobuo Nishi, MD, PhD, Mikiko Hayashi, BA, John Cologne, PhD, Harry M. Cullings, PhD,
Kazunori Kodama, MD, PhD, Edward F. Miles, MD, Sachiyo Funamoto, BS, Akihiko Suyama, MD, PhD,
Midori Soda, MD, and Fumiyoshi Kasagi, PhD
Investigation performed at the Radiation Effects Research Foundation, Hiroshima and Nagasaki, Japan

Background: Radiation-induced bone sarcoma has been associated with high doses of ionizing radiation from therapeutic or occupation-related exposures. However, the development of bone sarcoma following exposure to lower doses ofionizing radiation remains speculative.
Methods: A cohort analysis based on the Life Span Study (n = 120,321) was performed to assess the development ofbone sarcoma in atomic-bomb survivors of Hiroshima and Nagasaki followed from 1958 to 2001. The excess relative risk
per gray of ionizing radiation absorbed by the bone marrow was estimated. Additional subject demographic, survival, andclinical factors were evaluated.
Results: Nineteen cases of bone sarcoma (in eleven males and eight females) were identified among the 80,181
subjects who met the inclusion criteria, corresponding to an incidence of 0.9 per 100,000 person-years. The mean ages at
the time of the bombing and at diagnosis were 32.4 and 61.6 years, respectively. The mean bone marrow dose was 0.43 Gy.
Osteosarcoma was the most commonly identified bone sarcoma. The most common bone sarcoma site was the pelvis.
The overall unadjusted five-year survival rate was 25%. A dose threshold was found at 0.85 Gy (95% confidence interval,
0.12 to 1.85 Gy), with a linear dose-response association above this threshold. The linear slope equaled an excess
relative risk of 7.5 per Gy (95% confidence interval, 1.34 to 23.14 per Gy) in excess of 0.85 Gy.
Conclusions: On the basis of what we believe is one of the longest and largest prospective studies assessing the development of bone sarcoma in individuals exposed to ionizing radiation, it appears that the development of radiation-inducedbone sarcoma may be associated with exposure to much lower doses of ionizing radiation than have previously been reported.
Such new insights may potentially improve bone sarcoma prevention measures and broaden our understanding of the role ofionizing radiation from various sources on the development of malignant tumors. This study stresses the need to become
increasingly aware of the various health risks that may be attributable to even low levels of ionizing radiation exposure.
Level of Evidence: Prognostic Level I. See Instructions to Authors for a complete description of levels of evidence.

B

one sarcoma is relatively uncommon, accounting for
0.5% to 1% of malignant neoplasms1-5. Various causative
agents, including exposure to ionizing radiation6, havebeen associated with the development of bone sarcoma.

Disclosure: In support of their research for or preparation of thiswork, one or more of the authors received outside funding or grants
in excess of $10,000 from the U.S. Department of Energy. Neither
they nor a member of their immediate families received payments orother benefits or a commitment or agreement to provide such benefits from a commercial entity.

J Bone Joint Surg Am. 2011;93:1-8 d doi:10.2106/JBJS.J.00256

The development of bone sarcoma in adults and children
following therapeutic or occupational exposure to high-dose
ionizing radiation has been reported7-22. Other studies have also
demonstrated an association between exposure to relatively
A commentary by Charles M. Turkelson, PhD,
is linked to the online version of this article
at jbjs.org.

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V O LU M E 93-A N U M B E R 11 J U N E 1, 2 011dddhigh levels of internal sources of radiation and the developmentof an excess of bone sarcomas23-25. However, an increase in therisk of bone sarcoma following exposure to lower doses ofionizing radiation is speculative. In fact, various authors havereported no increase in the risk of bone sarcoma following
exposure to low doses of ionizing radiation in occupationalsettings26,27, from prenatal x-rays28, or from radiation therapy
for benign conditions29-32. High-dose radiation, ranging from10 to 290 Gy, for cancer therapy has been associated with anincreased risk of bone sarcoma33-40. According to reports fromthe United Nations Scientific Committee on the Effects of Atomic
Radiation (UNSCEAR)41 and the International Agency for
Research on Cancer (IARC)42, an increase in bone sarcoma
incidence following exposure to ionizing radiation has rarely
been reported at doses below 5 Gy and the appropriate predictive dose-response model for the risk of bone sarcoma due
to ionizing radiation is uncertain16,19,21,23,25,35,43.
The age distribution of individuals with bone sarcoma isdependent on the type of lesion44. Moreover, estimates of thelatency period for radiation-induced bone sarcoma have ranged
from 2.8 to fifty-five years33,34,36,39,45-48 and are potentially influenced by the age at the time of radiation exposure49. Althoughsome authors have postulated an inverse relationship between
the latency period and the radiation dose50,51, other authors havequestioned the existence of such a relationship1,13,46,52. In addition, bone sarcoma is associated with a relatively poor clinicalprognosis and a low survival rate, and some authors have suggested that radiation-induced bone sarcoma has a more aggressive nature than typical bone sarcoma does47,53,54.
The Radiation Effects Research Foundation’s Life Span Study(LSS), consisting of Japanese atomic-bomb survivors of Hiroshima
and Nagasaki, is a longitudinal population-based study performed
to characterize radiation-associated risks of cancer and other diseases55-59. Utilizing the data provided by the Life Span Study, weinvestigated the development of bone sarcoma associated with
exposure to low to moderately high levels of ionizing radiation.
As a secondary objective, we attempted to investigate the role ofage at exposure as well as the association of other factors with
anatomical location, morphological type, latency period, andsurvival.

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Hiroshima and Nagasaki Tumor Registries and verified with use of additional
information from death certificates, autopsy reports, and Tissue Registry re60
cords . According to the scheme proposed by the World Health Organization’sInternational Classification of Diseases for Oncology (ICD-O) (first, second,
and third editions), bone sarcomas were classified on the basis of anatomicalsite (ICD-O code 170 [1st edition] and codes C40 and C41 [2nd and 3rdeditions]) and morphological type. Tumors diagnosed outside of the tumor
registry catchment area were excluded from this study.
Additional information of interest regarding the bone sarcoma cases
included sex, city of exposure, age at the time of the bombing, age at diagnosis,
time from exposure to diagnosis, survival period, survival status at the time of
the latest follow-up, and cause of death. Furthermore, a review of the clinicalrecords was also conducted to determine the exact tumor location, the treatment type, the presence of metastatic disease, and any other relevant clinicalcharacteristics. In addition, the bone marrow dose (in grays) was estimated,with the neutron dose given a weight of 10 and the gamma radiation dose given
61
a weight of 1 to adjust for biological effectiveness . The estimated radiationdose to the bone marrow was based on an average skeletal dose calculated with61
the Dosimetry System 2002 (DS02) . With the DS02, which was developed byan international scientific working group, the dose to the skeleton was determined with use of an anthropometric model and information on each survivor’s location in relation to the hypocenter of the bomb as well as proximity toexternal shielding structures, age, position, and orientation, through a series of61detailed calculations based on a large body of theoretical and empirical work .
Pearson correlation tests (version 15.0; SPSS, Chicago, Illinois) wereconducted for bivariate analysis of continuous data. For parametric analysis,
independent-sample t tests were conducted for two independent samples, whereas,
for nonparametric analysis, the Mann-Whitney U test was performed. KaplanMeier survival analysis was conducted to determine the cumulative survival rate
following diagnosis. The AMFIT function of the Epicure statistical software program (version 1.4; HiroSoft International, Seattle, Washington) was used to per62
form Poisson regression of grouped survival data to compute rates . Person-year
observations for the subjects included in the study were calculated from January 1,
1958, to the time of tumor diagnosis, the date of death, or the December 31, 2001,
Life Span Study update. Various predictive dose-response models (i.e., linear,linear-quadratic, quadratic, spline, and threshold) were assessed to determine thebest fit for bone sarcoma development, adjusted for sex and age at diagnosis (age atrisk), and radiation dose. Radiation effects were modeled, accounting for background incidence rates, with use of the excess relative risk (ERR). The excess
relative risk, which is equal to the relative risk (RR) minus 1 (ERR = RR – 1), allows
for analysis of the radiation-related excess incidence separately from the back61
ground incidence and is the standard model used in radiation epidemiology .
Likelihood ratio tests were performed to make nested model comparisons. All pvalues were two-sided, with a threshold of significance set at p < 0.05.
The conduct of the Life Span Study was approved by the Human Investigation Committee of the Radiation Effects Research Foundation. The use of death

Materials and MethodsW

ith use of the Life Span Study (n = 120,321), we identified cases of bonesarcoma among atomic-bomb survivors of Hiroshima and Nagasaki inJapan. For the purpose of this study, cartilage sarcomas were also included in
the category of bone sarcomas. The characteristics of the Life Span Study have
55-57
been previously described in the literature. Tumor registries were established in Hiroshima and Nagasaki on January 1, 1957, and January 1, 1958,
respectively. The subjects who were included in the Life Span Study were individuals who were in Hiroshima or Nagasaki at the time of the atomic
bombings, who were alive and not known to have cancer before January 1,
1958, and for whom bone marrow radiation dose estimates were calculated.
The time of sarcoma development was considered to be the date on
which the individual was initially diagnosed by the physician irrespective of thetime of onset of symptoms, the date of original consultation and medical
treatment for tumor-related symptoms, or tumor identification based on thedeath certificate. Tumors discovered at the time of autopsy were consideredclinically diagnosed. Thus, cases of bone sarcoma were identified with use of the

TABLE I Characteristics of Bone Sarcoma Cases That Fulfilled
the Inclusion Criteria

Variable

Mean and Standard
Deviation (Range)

Bone marrow dose (Gy)0.43 ± 0.90 (0-2.86)

Ground distance fromhypocenter (km)3.1 ± 1.6 (0.8-5.9)

Age at time of the bombing (yr)32.4 ± 18.4 (0-61)

Age at diagnosis (yr)61.6 ± 15.2 (18-81)

Time from exposure to diagnosis (yr)29.3 ± 12.1 (13-53)

Survival from time of sarcoma
diagnosis (yr)2.5 ± 4.3 (0-14.3)

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TABLE II Bone Sarcoma Rates by Bone Marrow Dose
Bone Marrow
Dose (Mean Weighted
by Person-Years) (Gy)

Person-Years

No. of Cancer
Cases

No. of Observed
Bone Sarcoma
Cases (No. Expected)*

Sarcoma Rateper 100,000
Person-Years<0.005 (0.001)

930,0392614

12 (8.2)

1.3

00.005-0.1 (0.030)

756,0146078

3 (6.5)0.4–0.7 (–0.93 to –0.02)

0.1-0.2 (0.14)

159,4454323

0 (1.4)0–1.0 (–N to –0.01†)

0.2-0.5 (0.32)

162,6483489

0 (1.4)0–1.0 (–N to –0.01†)

0.5-1 (0.71)

92,5602290

0 (0.8)0–1.0 (–N to 0.72†)

1-2 (1.36)

50,0863718

2 (0.5)4.0

2.0 (–0.54 to 10)>2 (2.67)

19,8872221

2 (0.2)10.0

7.0 (0.25 to 29)

Excess Relative
Risk (95% CI)*The expected number of cases is derived from the Poisson regression model adjusted for sex and log(age) but not for the radiation dose (i.e., noexcess relative risk). †The 95% confidence interval (CI) could not be computed directly because the upper and lower bounds did not converge whenthe estimated relative risk was calculated from the linear form of the model. In this case, calculations were performed by using the log-linear(log[relative risk]) form of the model for the dose group and subtracting 1 to obtain the excess relative risk. (For an individual dose group, theestimated relative risks [and confidence interval] for the log-linear model and for the linear model are identical except for the constant 1.)

certificates of the Life Span Study subjects was approved by the Ministry of Internal
Affairs and Communications. The respective committees of the Hiroshima City
Cancer Registry, Hiroshima Prefecture Tissue Registry, and Nagasaki Prefecture
Cancer Registry approved the use of cancer registry data for the present study.

Source of Funding
This study was funded by the Radiation Effects Research Foundation of Hiroshima and Nagasaki, Japan (a private, nonprofit foundation funded by theJapanese Ministry of Health, Labour and Welfare) (Research Protocol numbers
RP 1-75 and 18-61), and by the U.S. Department of Energy (in part through the
U.S. National Academy of Sciences).

Results
he Life Span Study cohort consisted of 120,321 subjects.
However, 8368 subjects were excluded because they had
died, were diagnosed with cancer, or lost to follow-up before
January 1, 1958. In addition, 6525 subjects were excluded because the radiation dose was unknown, and 25,247 subjects
who were not in the cities at the time of the bombing were also
excluded. Thus, 80,181 subjects fulfilled the inclusion criteria
and were included for further assessment (Fig. 1 and Table I).
Throughout the course of follow-up, 24,733 of the subjects
who fulfilled the inclusion criteria developed cancer, including
nineteen cases of bone sarcoma. (In addition, ten bone sarcoma
cases were documented among subjects who did not meet theinclusion criteria.) The total number of person-years, basedon the 80,181 subjects who met the inclusion criteria, was2,170,679. Table II illustrates the observed and expected bonesarcoma incidence rates for various radiation doses. The overall
incidence rate for the development of bone sarcoma in ourstudy population was 0.9 per 100,000 person-years.
Eleven of the subjects with bone sarcoma were male andeight were female. Nine were in Hiroshima at the time of thebombing, and ten were in Nagasaki. The incidence rate per
100,000 person-years for the development of bone sarcoma in
our study population was 1.4 for males and 0.6 for females. The
overall mean bone marrow radiation dose (and standard de-viation) of individuals with bone sarcoma was 0.43 ± 0.90 Gy(range, 0 to 2.86 Gy). There was no significant relationshipbetween the radiation dose and the city or sex (p > 0.05).
The mean age of the patients with bone sarcoma was
32.4 ± 18.4 years (range, zero to sixty-one years) at the time of
the bombing and 61.6 ± 15.2 years (range, eighteen to eighty-one

T

Fig. 1

Flow diagram illustrating the study population, which was derived from theLife Span Study (LSS) cohort population of Hiroshima and Nagasaki. ATB =at the time of the bombing.

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Fig. 2Kaplan-Meier survival analysis. Tick marks on the survival estimate represent subjects who remained alive at the time of the final follow-up assessment.

years) at the time of diagnosis. The mean time from exposure
to diagnosis was 29.3 ±12.1 years (range, thirteen to fifty-three
years). A negative correlation was found between the time fromexposure to diagnosis and the age at the time of the bombing(r = –0.57, p = 0.011), but no association was noted between

the time to diagnosis and the bone marrow dose (r = 0.11, p =0.670). However, our study had insufficient power to properly
investigate these factors.
The most commonly identified type of sarcoma was osteosarcoma (five cases). The most common sarcoma site was theFig. 3

Excess relative risk (ERR) of bone sarcoma as a function of the radiation dose in grays (Gy) to the bone marrow. The error bars indicate the 95% confidence interval.
The five curves represent the dose-response models tested. The baseline incidence in each model was adjusted for sex and age at diagnosis (age at risk).

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V O LU M E 93-A N U M B E R 11 J U N E 1, 2 011dddpelvis (six cases), followed by the lower extremities (five), thespinal column (five), the head (two), and the ribs (one). The
subjects who developed ameloblastoma (n = 1; 1.21 Gy) or
chondrosarcoma (n = 2; 1.43 ± 2.02 Gy; range, 0.002 to 2.86
Gy) were exposed to the greatest radiation dose at the time of
the bombing. No significant association was noted betweenbone marrow dose and sarcoma location or morphologicaltype (p > 0.05).
Of the nineteen patients with sarcoma identified at thetime of the 2001 Life Span Study update, two remained alive.
Kaplan-Meier survival analysis indicated a 25% overall fiveyear survival rate (45% for males and 0% for females) (Fig. 2).
Although the mean survival time was longer for males (3.8
years; 95% confidence interval [CI], 0.71 to 8.31 years) than forfemales (0.8 years; 95% CI, 0.21 to 1.31 years) during the entire
follow-up period, this difference did not reach significance (p >0.05). Stratification of survival by treatment type was notpossible because of insufficient clinical information. Althoughchart review revealed the development of metastasis in six ofthe subjects, it could not be determined if metastasis occurredin the remaining nine. Of the seventeen deaths, ten were thedirect result of the bone sarcoma. No information regarding
genetic or syndromic factors, occupation, or smoking status
was available for assessment.
The excess relative risk due to radiation exposure wasmodeled with adjustment of the background incidence for sex
and age at risk. After examination of the fit of the various
models (linear [deviance = 221.9], linear-quadratic [deviance =212.3], quadratic [deviance = 218.3], spline [deviance = 214.1],
and linear-threshold [deviance = 216.70]) relating bone sarcoma incidence to bone marrow radiation dose, it was determined that a linear-threshold model exhibited a good fit to
the data (Fig. 3). Assessment of the likelihood profile and its
bounds showed the best fit to be a linear model with a thresholdat 0.85 Gy (95% CI, 0.12 to 1.85 Gy). The model showed alinear dose response, with an excess relative risk of 7.5 (95% CI,
1.34 to 23.14; p = 0.002) per Gy in excess of the threshold of
0.85 Gy (Fig. 3).
Discussion
he role of ionizing radiation as a potential environmental
risk factor for the development of bone sarcoma was initially reported in 1922 by Beck63 in his account of sarcomas
arising from the radiation treatment of tuberculous arthritis.
Shortly thereafter, in 1929, the causal relationship between ionizing radiation and bone sarcoma was confirmed by Martlandand Humphries64 in their report noting an excessive frequency
of bone sarcoma occurring in American radium dial painters,
who ingested large quantities of 226Ra and 228Ra by licking thetips of paintbrushes containing radium used to color the facesof watches to obtain a fluorescent glow. Radium was found tocause bone necrosis, anemia, osteitis, and osteosarcoma. In
studies of 1474 women employed in the radium dial industry
before 1930, sixty-one cases of bone sarcoma were noted with amean radiation dose to bone of 17 Gy9,12. In subsequent studiesof 2383 women, no bone sarcoma occurred in individuals withT

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a radiation exposure of <10 Gy50. Throughout the years, various
accounts have confirmed that bone sarcoma is associated withradiation exposure, primarily at very high doses7-22,65.
Our current understanding of the impact of radiation
exposure on the risk of bone sarcoma has been aided by studies
such as those of patients in various countries who had been
administered Thorotrast (a contrast medium containing thorium); Mayak nuclear facility workers exposed to plutonium;
individuals who received internal or external radiation for thetreatment of ankylosing spondylitis, cervical cancer, Hodgkindisease, childhood cancers, retinoblastoma, and benign gynecological disease; and the atomic-bomb survivors of Hiroshima
and Nagasaki7-25,56,65. The Life Span Study cohort of atomicbomb survivors, comprising more than 120,000 individuals
followed since 1958, constitutes one of the best populations forassessing the risk of sarcoma due to low-to-moderate radiation
doses. In the recent cancer incidence report involving atomicbomb survivors of Hiroshima and Nagasaki in the Life Span
Study cohort, Preston et al. found that, on the basis of a linear
model, sarcomas as a group exhibited an excess relative risk per
Gy of 0.48 (90% CI, 0.07 to 1.4), with an excess absolute risk of
0.39 (90% CI, 0.08 to 1.04) per 10,000 person-years per Gy at
age seventy in individuals exposed at age thirty56.
The current analysis, which did not involve any new
design or data collection but rather was based on all available
data from the already ongoing Life Span Study cohort followup, was performed to explicitly investigate bone sarcoma.
Among the explored models, all of which gave similar overall
fits to the data, the linear model with a threshold at 0.85 Gy
appeared the most plausible from a statistical and biologicalperspective. More specifically, the spline and, in particular, thelinear-quadratic model yielded lower degrees of deviance than
did the linear-threshold model, but if these models were acceptable they would have produced an unexplained reductionof risk (e.g., excess relative risk = –1.0 at 0.5 Gy and –0.6 at
0.85 Gy for the linear-quadratic model), which does not seemplausible. The evidence suggests that the fit of the linear nonthreshold model is poorer than that of the other models (Fig.
3). Therefore, the current study suggests that acute exposure toa radiation dose in excess of 0.85 Gy results in an increased riskof development of bone sarcoma. Furthermore, a significant
excess relative risk of 7.5 per Gy in excess of the threshold of
0.85 Gy was noted. This study provides further confirmationthat radiation-associated bone sarcoma appears to follow an
overall threshold dose-response relationship, substantiating thefindings of previous studies involving radium dial painters in
the United States50 and United Kingdom66 as well as various
studies of animals; however, our findings differ, in some respects, from those of other reports that support the use of linear
or quadratic dose-response models16,19,21,43.
The prognosis for radiation-associated bone sarcoma is
influenced by the type, size, and location of the lesion, which
may determine its growth, aggressiveness, and potential forrecurrence67-70. Survival rates may improve and are dependent
on the time of detection, tumor size, tumor grade, and natureof surgical and other oncological treatments. In a study of6
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forty-two patients presenting with radiation-induced bone sarcoma (mean radiation dose, 50 Gy), Kalra et al.53 reported that,
although the overall five-year survival rate was 35%, the survival
rate was 0% for patients treated with a palliative intent and 41%
for patients treated with a curative intent. The authors further
noted that the most common site of bone sarcoma development
was the pelvis (in 33% of their patients). Our study also showed
the pelvis to be the most common bone sarcoma site. The fiveyear survival rate of subjects in our study was 25%, with a clear
distinction between males (45%) and females (0%). However,the sex difference in survival rate did not reach significance, andmay have been due to differences in the therapeutic care received. Additionally, various authors have noted that a tumor
located on the periphery of the bone is associated with a longer
survival period than one that is more centrally located or isincompletely resected53,71,72. Further analysis to investigate theeffects of treatment type on survival could not be done becauseof the lack of available clinical information.
Previous studies of atomic-bomb survivors have notfocused on the increased risk of bone sarcoma induced by radiation56. The current finding of a linear model with a 0.85 Gy
threshold and a ninefold excess relative risk of bone sarcoma
induction at 2 Gy has certain implications for radiation therapy
techniques. However, because of the very low absolute risk, thevery wide confidence limits on the risk estimate, and the longlatency period between radiation exposure and clinical detection of radiation-induced sarcoma, the full implications of thisnew finding are uncertain.
A review of the Surveillance, Epidemiology and End
Results (SEER) database by Brenner et al.73 demonstrated a 35%
increase in second cancers over a ten-year period following radiation therapy to the prostate; 8% of these cancers were sarcomas. In three-dimensional conformal radiation therapy, as
the central-axis dose increases, the adjacent, normal, in-fieldtissues also receive a higher dose74. In a large pelvic field, a
substantial portion of such tissue, including a large portion of
the osseous pelvis and proximal portions of the femora, may besubjected to a dose higher than the threshold for bone sarcoma
induction.
Additionally, with intensity-modulated radiation therapy, there is some evidence that the integral dose is increased
and that adjacent volumes receiving a low dose may also be
increased75-77. This effect may be attributed to the entry and exitof the greater number of beams used to achieve the greatertarget conformality in intensity-modulated radiation therapy
than in conventional conformal therapy. There is also increased
leakage from the gantry head and through the multileaf collimator due to the greater number of monitor units required todeliver the dose78. Treatment of deep-seated pelvic tumors withuse of higher-energy beams in intensity-modulated radiation
therapy for dose escalation79 and the sparing of normal tissue80,81 can also be accompanied by an increased exposure of
normal tissue to radiation due to secondary neutrons82,83. Particularly with prostate cancer, diagnosis is being made at younger
ages and earlier stages, and long-term control of the cancer iscommon. In this setting, the benefit of the increased ability to

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sculpt the dose around target tissues and avoid organs in thepelvis that are at risk with higher-energy intensity-modulated
radiation therapy beams must continue to be weighed against
the potential for increased short-term and long-term risk ofharm to the patient, specifically induction of second malignant
tumors, including sarcomas.
Although this is one of the largest and longest longitudinal population-based studies assessing the occurrence ofradiation-associated bone sarcoma, it has inherent limitations.
Complete, detailed information was not available regarding
any underlying genetic susceptibilities, occupational hazards,
smoking status, or history of radiation treatment that may havepredisposed individuals to the development of bone sarcoma.
However, because of the proper sampling methods involved in
our large population, we believe that such variables may be
assumed to be randomly distributed among the cohort. Also,
because of the small size of our group of subjects with bonesarcoma, it is difficult to discern the effect, if any, of radiationdose on the development of specific morphological types ofsarcoma, age at diagnosis, and time from exposure to diagnosis.
However, our study did suggest that the time from exposure to
diagnosis was greater in children. This is in agreement with aprevious study by Weatherby et al.48, although others havesuggested that the latency period is shorter in children than in
adults3, or that no difference exists between these age groups84.
Alternately, the inverse correlation of the age at the time of thebombing to the age at diagnosis may be an artifact of the longer
time that individuals exposed at an earlier age will live before
reaching middle or older age—i.e., the age when people may be
more likely to develop sarcoma. A final limitation resulting
from our sample size is the inability to determine how the timefrom exposure to diagnosis and the prognosis depend on thesarcoma type.
In conclusion, this investigation involving the Life Span
Study cohort of atomic-bomb survivors of Hiroshima andNagasaki suggests that the development of bone sarcoma is
associated with exposure to lower doses of ionizing radiation thanthose previously reported in the literature. In this study, a linearthreshold dose-response model with an estimated threshold of
0.85 Gy and a significant excess relative risk of 7.5 per Gy inexcess of the threshold level was found to be preferable to several
other models in describing the risk of radiation-induced bonesarcoma. Associations between factors other than the radiationdose and the sarcoma type or the time from exposure to diagnosis could not be discerned from this study. The findings of thisstudy may help to further clarify concerns about radiation exposure associated with medical diagnostic procedures or occupational hazards, and may aid in the design of adjustments toradiotherapeutic techniques to minimize the risk of developing
radiation-induced bone sarcoma. n

Dino Samartzis, DSc
Department of Orthopaedics & Traumatology,
University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road,7
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Professorial Block, Room 515, Pokfulam, Hong Kong, SAR, China.
E-mail address: dspine@hku.hk; dsamartzis@msn.com

Radiation Effects Research Foundation, 5-2 Hijiyama Park,
Minami-Ku, Hiroshima City, Japan

Nobuo Nishi, MD, PhD
Mikiko Hayashi, BA
John Cologne, PhD
Harry M. Cullings, PhD
Kazunori Kodama, MD, PhD
Sachiyo Funamoto, BS
Fumiyoshi Kasagi, PhD
Departments of Epidemiology (N.N., M.H., and F.K.),
Statistics (J.C., H.M.C., and S.F.), and Chief Scientist (K.K.),

Edward F. Miles, MD
Department of Radiation Oncology, Box 3085,
Duke University Medical Center, Durham, NC 27710
Akihiko Suyama, MD, PhD
Midori Soda, MD
Department of Epidemiology,
Radiation Effects Research Foundation,
8-6 Nakagawa 1-chone, Nagasaki City, Japan

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2. Fletcher CDM, Unni KK, Mertens F. Pathology and genetics of tumors of soft
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