Discussion
Radiation-induced
bone injury occurs in clinical conditions such as radio-osteonecrosis,
insufficiency fracture, abnormality of bone growth, and
development of secondary malignancy. Emami reported a
tolerance dose (TD5/5–TD50/5)
of mature bone as 60–77 Gy for radio-osteonecrosis of mandible.
However, there have been
no data for insufficiency fracture, and some have reported that
the incidence of insufficiency fracture increased above the
threshold dose of 40 Gy. In conventional pelvic RT,
irradiated dose of the pelvic bone is usually 45–50 Gy, and the
development of PIF after pelvic RT at this level has been
considered a rare complication, especially in the era of
mega-voltage equipment
However,
several recent studies
showed that the incidence of PIF after pelvic RT might have been
underestimated in gynecologic patients. They reported the
cumulative incidence of symptomatic PIF at 5 years as 8.2–17.9%.
In our series, the cumulative incidence of PIF was 19.7% at 5
years in all patients and 11.1% in symptomatic patients, which
was in accordance with other recent studies This
higher-than-previously-believed incidence may be due to wider
use of imaging modalities (e.g., CT, MRI, and bone scintigraphy)
that are more sensitive to detect PIF than conventional
radiography. Blomlie evaluated the incidence of PIF using MRI
prospectively and showed that 89% of patients had findings
compatible with PIF after pelvic RT. Abe showed a 34%
prevalence of PIF after pelvic RT using bone scintigraphy. We
tried to perform CT or MRI during the follow-up and bone
scintigraphy at least one time per year, so as to detect
asymptomatic patients (35 of 83, 42.2%) with PIF. The
characteristics of irradiated patients can affect the incidence
of PIF. As revealed in our study, older patients receiving
pelvic RT are more susceptible to the development of PIF.
In our study, the
cumulative incidence of PIF at 5 years in patients aged ≥55
years was 31.8%. In the study of Ogino PIF patients were
all postmenopausal, and the Baxter included patients aged
>65 years.
The
sacral ala adjacent to
SI joints is the most commonly involved site of PIF.
Solitary pubic bone or acetabulum fracture is rare (none in our
study), and most lesions are accompanied with SI joints. This
indicates that initial mechanical failure of the sacrum causes
other subsequent pelvic bone fracture. In addition, a single
site of fracture can progress to multiple sites. In our study,
initial single-site fracture subsequently progressed to multiple
fractures in 28.1% of patients (9 of 32).
As has been reported
by many investigators, our study showed that
symptoms of most
patients were mild and resolved after conservative management
based on analgesics and rest, but some patients (13.3%)
had severe pain and were managed with narcotics or admission.
Extent of lesions may correlate with severity of symptoms.
Blomlie showed that all patients without pain had smaller
lesions (<1 cm2) on MRI and
indicated the small fractures might be not painful. In our
study, symptomatic patients were more likely to involve multiple
sites of pelvic bone than asymptomatic patients.
The
risk factors of
osteoporosis are closely correlated with the development of PIF.
Blomlie showed that 95% of patients with PIF reported in
the literature were postmenopausal women. Ikushima reported that
the mean age of patients who developed PIF was significantly
higher than that of other patients (69 years vs. 59 years).
Ogino reported 57 cases of PIF after pelvic RT in postmenopausal
women. They showed that low body weight (≤49 kg) and more than
three deliveries were significant factors for the development of
symptomatic PIF. In our study both low body weight (<55 kg) and
older age (≥55 years) were significant predisposing factors for
PIF in multivariate analysis. Many medical illnesses or
medications, such as rheumatoid arthritis, hyperthyroidism, and
corticosteroids, are also reported as risk factors for
osteoporosis. Ogino investigated Type II diabetes mellitus and
showed no significant correlation with PIF. In our study 1
patient had a history of rheumatoid arthritis, and 5 had a
history of hyperthyroidism; none of them developed PIF, so we
did not perform statistical analysis.
It is well known that
radiation toxicity is strongly correlated with irradiated volume
and dose. In our study, both the four-field box technique and
the AP/PA parallel opposing technique were used. In the
four-field box technique, lateral portals could spare the
irradiated volume of small bowel and rectum and also spare the
irradiated volume of the posterior portion of the sacrum and SI
joints. The incidence of
PIF was higher in patients receiving the AP/PA technique (35.8%
vs. 17.1% at 5 years) in univariate analysis, but there
was no significant difference between the two techniques in
multivariate analysis. This volume effect of the sacrum could be
confirmed more accurately by dose–volume histograms of the
irradiated sacral bone, but we could not get this information
because we did not use CT planning.
Patients who received
more irradiated dose to the sacrum had more risk of PIF (21.7%
vs. 2.1% at 5 years, p = 0.005) in both univariate and
multivariate analysis. It was uncertain whether the small
difference (median 45 Gy vs. 50.4 Gy) could affect the
development of PIF, but there might be a threshold dose for PIF
at approximately 45 Gy, as reported by Fu . Our results showed
that patients receiving curative RT had more risk of PIF than
patients receiving postoperative adjuvant RT (30.1% vs. 11.1% at
5 years, p < 0.001). The patients who received curative RT
received an additional dose of high-dose-rate intracavitary
brachytherapy. Fu calculated the brachytherapy dose
contribution to the pelvic bone and estimated it to be
approximately 10% of the central brachytherapy dose. It was
uncertain whether this small additional dose of sacral bone by
high-dose-rate intracavitary brachytherapy could be one of the
causes of this difference.
Concurrent
chemotherapy is used frequently in gynecologic cancer for
increasing tumor control, but it is well known that it also
increase the toxicity of radiation. Thus many investigators have
thought that combined therapy with chemotherapy might increase
the risk of PIF, but there have been few studies to evaluate
this. One report showed that combined treatment with radiation
and chemotherapy might predispose to pelvic fracture in cervical
cancer. In our study, although we had the limitation of being a
retrospective study, we showed that the use of cisplatin-based
concurrent chemotherapy did not increase the risk of pelvic bone
fracture.
To minimize the risk of
PIF, we can make an effort by two approaches. The first approach
is to improve the osseous environment by combined treatment of
osteoporosis. Bisphosphonate has been used as an
effective agent for treatment of osteoporosis, and it has also
been shown to be effective to reduce cancer-induced bone loss in
several studies. Further study is required to determine whether
it can reduce the risk of PIF in patients with high-risk factors
such as older age and lower body weight.
The second approach
is to reduce radiation toxicity. As mentioned above, our results
indicated that irradiated volume and dose to sacrum and SI
joints might correlate with the risk of PIF. Ogino suggested
that a multibeam arrangement by CT planning could shield the
posterior portion of the sacrum and SI joints without inadequate
coverage of the target volume. Intensity-modulated radiotherapy
(IMRT) can reduce the irradiated dose and volume of normal
tissue. Many studies showed that IMRT was associated with
decreased radiation toxicity.
Sacral bone-sparing IMRT
may reduce the radiation dose to the sacrum and SI joints.
However, it may be difficult to achieve significant sparing to
reduce the risk of PIF because of its proximity to the target
volume. Radiation-protecting agents such as amifostine (WR2721)
also may reduce the risk of PIF. One animal study showed that
amifostine improved bone density after RT compared with a
control group.
In conclusion, the
development of PIF is not a rare complication after pelvic RT
when CT-based planning is not used. The use of a multibeam
arrangement to reduce the volume and dose of irradiated pelvic
bone can be helpful to minimize the risk of fracture, especially
in elderly women with low body weight. We will perform a further
prospective study in such patients to evaluate dose–volume
effects on pelvic bone using three-dimensional conformal RT or
IMRT planning and to evaluate whether combined treatment of
osteoporosis using bisphosphonate can reduce the risk of
development of PIF.