When combined with limb-salvage surgery, external beam radiation
therapy is effective for decreasing the rate of local recurrence of
soft-tissue
sar-comas1,2.
The use of radiation therapy for the treatment of soft-tissue sarcomas is not
without substantial complications. Adverse effects on bone include
fractures3-6,
osteonecrosis7,
growth plate
arrest8, and delayed
fracture-healing3-5,9,10.
Fractures that occur following radiation therapy are difficult to treat and
are associated with a high risk of delayed union and nonunion despite
aggressive
therapy3-5,9.
Factors previously reported to be associated with postradiation fractures
include female
gender5,
chemotherapy5,
periosteal
stripping3,5,
and tumor location3.
The majority of fractures that have been reported following radiation therapy
have occurred in the
femur3-5,9.
Although the relationship between radiation therapy and fractures has been
well established, no association has been reported between the timing, dosage,
or fractionation of radiation treatment and the occurrence of postradiation
fractures. The purpose of the present study was to determine if the dosage of
radiation therapy was correlated with the risk of pathologic fracture in
patients managed with limb-salvage surgery and external beam radiation for the
treatment of softtissue sarcoma of the lower extremity.
Aretrospective database review was used to identify patients with
lower extremity sarcomas who had undergone external beam radiotherapy and
limb-salvage surgery from 1986 to 1998. Patients who had received chemotherapy
or brachytherapy were excluded, as were patients in whom the tumor resection
had required amputation or excision of bone in order to achieve negative
margins. The minimum duration of follow-up was one year. Established criteria
for radiation complications were
followed5,11-14.
Three hundred and sixty-four patients who met these criteria were
identified.
Hospital, clinic, and radiotherapy treatment charts were reviewed in order
to obtain information on patient age and gender; tumor size and location;
radiation timing, dosage, field size, and fractionation; time to fracture;
fracture location; and fracture treatment. Time "zero" was defined
as the time of surgery.
A subset of patients with tumors involving the thigh was separately
evaluated with regard to radiation treatment, periosteal stripping, age,
gender, and tumor location (according to compartment). The extent of
periosteal stripping was defined, according to the system of Helmstedter et
al.3, as none,
minimal (<10 cm), moderate (10 to 20 cm), or extensive (>20 cm).
Compartments were recorded as anterior, medial, and posterior. It is
acknowledged that there is no discriminative value in this system of
describing periosteal stripping.
All patients received external beam radiation therapy as previously
described11. The
total radiation dose was 50, 60, or 66 Gy. For the purposes of analysis,
low-dose radiation was defined as 50 Gy and high-dose radiation was defined as
60 or 66 Gy. The timing of irradiation was defined as preoperative (50 Gy),
postoperative (60 or 66 Gy), or preoperative with a postoperative boost (total
dose, 66 Gy).
Eighty-nine patients had been a part of a prospective, randomized
study11 and had
been randomized to receive preoperative or postoperative radiotherapy. The
remaining patients had been managed with preoperative or postoperative
radiation on the basis of clinician preference. In general, preoperative
radiation was used when it was obvious that combined treatment with radiation
and surgery would be necessary, that soft-tissue reconstruction would be
indicated, or that critical neurovascular structures would be closely
dissected from the tumor. Patients who were selected to receive preoperative
radiation and a postoperative boost were determined to require more radiation
because of a positive histological margin (defined as histological evidence of
tumor at the painted surgical margin of resection).
For patients who were selected to receive preoperative radiation and a
postoperative boost, 50 Gy in twenty-five fractions was administered before
surgery and 16 Gy in eight fractions was administered once wound-healing was
complete.
Statistical Methods
The main end point was the time to fracture, which was calculated as the
time between the date of presentation with disease and the date of the first
fracture or most recent follow-up. If a patient did not experience a fracture,
the observation was considered censored. There were twenty-seven fractures in
the entire dataset. The factors that were considered in the analysis included
age, gender, and type of radiation treatment. Competing risk
analysis15,
univariate analysis, and multivariate analysis were used to test whether any
variables were associated with the risk of fracture. Wald statistics in a Cox
proportional-hazards model were used to test whether any of these factors were
significant. Stepwise selection was used to decide on the final model. The
percentages of patients who were free of fracture in various subgroups were
calculated with use of the cumulative incidence
approach15.
The analysis of the subset of patients with thigh tumors included an
evaluation of two additional factors specific to the site: the location of the
tumor (anterior, medial, or posterior) and the extent of periosteal stripping
(none, minimal, moderate, or extensive). The main concern was whether
periosteal stripping or tumor location has an impact on the fracture rate.
Each of these two factors was tested with use of the Cox proportional-hazards
model, both independently and also when adjusted for the factors that were
found to be significant in the analysis of the whole dataset. This subset
included twenty incidences of fracture.
Of the 364 patients with lower extremity soft-tissue sarcomas who
were evaluated in the present study, 183 were female and 181 were male. The
median duration of follow-up for the study population was fifty-eight months
(range, eight to 181 months), and the median age was fifty-six years (range,
fifteen to ninety-five years). One hundred and ninety-two patients received
high-dose radiation (60 or 66 Gy), and 172 received low-dose radiation (50
Gy). In the group managed with high-dose radiation, 172 patients were managed
with postoperative radiation alone and twenty were managed with preoperative
radiation followed by a postoperative boost. With regard to tumor location,
twenty tumors involved the pelvis, 244 involved the thigh, and 100 involved
the leg or foot. The median duration of follow-up for the entire population
was fifty months (range, zero to 187 months); two patients who died
perioperatively were considered to have had "zero" months of
follow-up. Fifty-two other patients were excluded because of perioperative
administration of chemotherapy; eight, because of treatment with
brachytherapy; nineteen, because of bone resection for margin control;
thirty-one, because of primary amputation; and fifty, because they had been
followed for less than one year. Patients who presented without metastatic
disease were not managed with adjuvant chemotherapy.
A total of twenty-seven postradiation fractures were identified in
twenty-three patients (6.3%). Twenty-four fractures occurred in twenty
patients who had been managed with high-dose radiation. Seventeen of these
patients had received postoperative radiation (with fifteen patients receiving
66 Gy and two receiving 60 Gy), and three had received preoperative radiation
with a postoperative boost (total dose, 66 Gy). Three fractures occurred in
three patients who had received preoperative, low-dose radiation (50 Gy). Of
the twenty-three patients who sustained a pathologic fracture, eighteen were
female and five were male.
The crude median time to fracture was forty-one months (range, twelve to
153 months). The median age at the time of diagnosis in the group of patients
who had a subsequent fracture was sixty-five years (range, forty-two to
eighty-nine years). The fracture sites included the femoral shaft (twelve),
femoral neck (nine), femoral condyle (one), patella (two), metatarsals (two),
and tibia (one). Fracture sites, treatment, and follow-up are listed in the
Appendix.
All fractures occurred within the radiation treatment field. Twenty-one
fractures occurred in the central 50% of the radiation field, four occurred
within the periphery or outside the central 50% of the radiation field, and,
in one patient with two fractures, one fracture occurred within the central
50% of the field and one fracture occurred in the periphery. All fractures
were diagnosed as pathologic (resulting from minimal or no trauma) on the
basis of patient history.
The overall crude frequency of fracture was 10% among patients managed with
high-dose radiotherapy, compared with 2% among those managed with low-dose
radiotherapy. The overall frequency of fracture at five years was 4%. The
frequency of fracture at five years was 7% among patients managed with
high-dose radiotherapy, compared with 0.6% among those managed with low-dose
radiotherapy (p = 0.007). The frequency of fracture was higher for female
patients (6% compared with 2%, p = 0.02) and for patients more than fifty-five
years old (7% compared with 1%, p = 0.004). Age as a continuous variable,
gender, and type of radiation treatment also were found to be independently
significant in the Cox proportional-hazards model (p = 0.001, 0.04, and 0.009,
respectively). The frequency of fracture at five years was 7% for patients
managed postoperatively and 0.6% for those managed preoperatively (n = 344) (p
= 0.008).
All three patients who sustained more than one fracture within the
treatment field had received high-dose, postoperative radiation therapy for
the treatment of a sarcoma involving the thigh. The first patient had a
subtrochanteric femoral fracture, located at the periphery (but within the
central 50%) of the radiation field, that healed after treatment with a
standard antegrade femoral nail. The other fracture in this patient was a
patellar fracture, located at the periphery of the radiation field, that
healed following open reduction and fixation with tension band wiring. The
second patient with multiple fractures had a femoral neck fracture that healed
after treatment with a dynamic hip screw, a subtrochanteric fracture that
healed after treatment with a longer side plate, and a diaphyseal fracture,
distal to the second plate, that united completely after revision with a
standard antegrade femoral nail. All fractures in this patient occurred within
the central 50% of the radiation field, without periosteal stripping. The
third patient with multiple fractures had a femoral neck fracture that went on
to nonunion after treatment with percutaneous pinning. Before revision, the
patient sustained a subtrochanteric femoral fracture. The patient was
subsequently managed with hardware exchange, with a dynamic hip screw being
used to address both fractures. At the time of the most recent followup, both
fractures were asymptomatic but were not united radiographically. Both of
these fractures were within the central portion of the radiation field.
Subset of Patients with Thigh Tumors
Two hundred and thirty-nine patients with thigh tumors were evaluated
separately. One hundred and thirty-six patients were managed with high-dose
radiotherapy (122 postoperatively and fourteen preoperatively with a
postoperative boost), and 103 patients were managed with preoperative,
low-dose radiotherapy. Twenty-four fractures were identified in twenty
patients. Twenty-one fractures occurred in seventeen patients who had received
high-dose radiotherapy (with fourteen patients having received postoperative
radiotherapy and three having received preoperative radiotherapy with a
postoperative boost). Three fractures occurred in three patients who had
received preoperative, low-dose radiotherapy.
This subgroup of patients with tumors involving the thigh included 116
female patients and 123 male patients. The median age at the time of
presentation was fifty-five years (range, fifteen to eighty-nine years).
Periosteal stripping was characterized as none for 146 patients (61%), as
minimal for thirty-two (13%), as moderate for forty (17%), and as extensive
for twenty-one (9%). Of the twenty patients with fractures, nine had had
extensive or moderate periosteal stripping and eleven had had no or minimal
periosteal stripping. With regard to location, 114 tumors (48%) involved the
anterior compartment, forty-four (18%) involved the medial compartment, and
eighty-one (34%) involved the posterior compartment.
The frequency of fracture at five years in the subset of patients who had a
tumor involving the thigh was 5%. The frequency of fracture at five years was
higher for patients managed with high-dose radiation than it was for those
managed with low-dose radiation (9% compared with 1%, p = 0.03). The frequency
of fracture at five years was higher for female patients (8% compared with 3%,
p = 0.05) and for older patients (9% compared with 2%, p = 0.01).
Multivariate analysis revealed that the occurrence of a fracture was
significantly associated with age (p = 0.002) and treatment with high-dose
radiotherapy (p = 0.02). With the numbers available, multivariate analysis
failed to show a significant effect in association with periosteal stripping
(p = 0.2 on univariate analysis and p = 0.4 when adjusted for age and type of
radiation) or tumor compartment location (p = 0.3 on univariate analysis and p
= 0.2 when adjusted for age and type of radiation).
The present study demonstrated a significantly higher frequency of
fracture among patients managed with highdose radiotherapy as compared with
low-dose radiotherapy. There was also a significantly higher frequency of
fracture among patients managed with postoperative radiotherapy as compared
with preoperative radiotherapy.
Evaluation of the overall population demonstrated that female patients with
an age of more than fifty-five years who had been managed with high-dose
radiotherapy were at a significantly greater risk of fracture when compared
with other patients who had been managed in a similar fashion. A higher risk
of fracture in women with an age of more than fifty-five years has been
observed
previously5, but a
significant difference between radiotherapy regimens has not been shown
previously.
We acknowledge that timing and dosage are inseparable factors because of
the conventions of radiotherapy administration. That is, 50 Gy is a standard
preoperative dose and 66 Gy is a standard postoperative dose. Because the
categories are the same, statistical evaluation appears similar. Although
preoperative radiation with a postoperative boost was considered as a separate
category, the small size of the group managed with preoperative radiation and
a postoperative boost in the present study precluded definitive comparison of
risk in this group.
In the present study as well as in
others3-5,9,
the majority of fractures following combined therapy occurred in the thigh.
When this population was evaluated independently, patients with an age of more
than fifty-five years who had received high-dose radiotherapy were found to
have the greatest risk of fracture. In contrast with the findings of previous
reports3,5,
periosteal stripping was not shown to be associated with a higher risk of
fracture. Although chemotherapy has been previously cited as a risk factor for
fracture following radiotherapy, this issue was not addressed in the present
study because our patients did not receive
chemotherapy4,5.
Three patients who had a tumor of the thigh were identified as having
sustained multiple fractures within the radiation field, at separate
time-intervals. All of these patients had been managed with high-dose,
postoperative radiation therapy. Of the sixteen patients with postradiation
fractures reported by Helmstedter et
al.3, the four
patients who sustained multiple fractures had been treated with high-dose,
postoperative radiation. This combined information suggests that patients who
sustain a fracture in a high-dose radiation field should be closely evaluated
for subsequent fractures. In this setting, it would be prudent to review the
extent of the field of radiation and to consider fracture fixation that will
encompass the entire area.
Radiation therapy, whether administered preoperatively or postoperatively,
has been shown to decrease the rate of local tumor recurrence when combined
with surgical resection of soft-tissue
sarcomas13,16,17.
This fact, despite the well-documented skeletal morbidity associated with
radiotherapy, often results in the use of radiation as an adjunct to
limbsalvage surgery. Multiple adverse effects on bone have been described,
with fractures following radiation therapy being one of the more difficult
problems to
treat3,5,9.
Contemporary radiation protocols are derived from a number of radiobiology
principles18. Most
preoperative radiation protocols provide a lower dose than postoperative
protocols do because tumor cell hypoxia is not as great a concern when tumors
are treated with radiation prior to
surgery11.
The postoperative radiation field is also larger than the preoperative
radiation field because of the extent of the tissues that are potentially
contaminated during
surgery14. The
extent of injury to normal tissues is therefore likely to be greater in
association with postoperative radiation protocols because of the delivery of
higher doses of radiation to a greater volume of tissue.
The use of radiotherapy for the treatment of large tumors abutting bone
frequently will provide a large dose to the bone as well as to the tumor when
standard treatment techniques are used. Previous studies have demonstrated
that reduction of the radiation dose, although effective for decreasing
incidental morbidity attributable to radiotherapy, increases the risks of
local recurrence and
amputation19,20.
A reduction in the treatment dosage therefore cannot be recommended.
Radiation therapy may be delivered preoperatively or postoperatively
without affecting the risk of local tumor
recurrence11.
Preoperative radiotherapy is associated with an increased risk of wound
complications11,
whereas postoperative radiotherapy, as reported here, is associated with a
higher risk of postradiation fractures. Armed with this knowledge, the
physician must use additional patient information such as age and gender to
choose the best method of combined treatment.
In addition to altering current radiation delivery regimens to avoid
postradiation fractures, improving radiation delivery techniques and
pharmacologic therapy could improve the management of patients requiring
radiotherapy for the treatment of soft-tissue sarcomas.
Emerging radiation delivery methods may reduce the toxicity to local normal
tissue without increasing the risk of disease recurrence. Suit and colleagues
first described techniques for reducing the radiotherapy field in order to
maximize radiation treatment and to decrease incidental
morbidity21,22.
This notion has been expanded with the concept of precise field sculpting with
intensity modulated radiotherapy. Intensity modulated radiotherapy involves
the use of computerized optimization techniques to deliver nonuniform
radiation-beam intensities to a field that is planned with use of
three-dimensional computerized tomographic scanning
techniques23. This
precise delivery of radiotherapy avoids incidental treatment of surrounding
tissues. The avoidance of bone within the radiation field (when possible)
probably would decrease the risk of fracture in the lower extremity. The
results of a preliminary study in which intensity modulated radiotherapy was
compared with conventional conformal radiotherapy with regard to the potential
to spare bone were extremely promising in this
regard24. It is
recognized, however, that it may be difficult to spare bone with use of
intensity modulated radiotherapy when the tumor abuts the periosteal
surface.
As patients live longer after the treatment of soft-tissue sarcomas,
complications associated with treatment will continue to emerge. Predicting
which patients are at risk for complications allows for improved preoperative
planning, prevention of morbidity, and better surveillance. The data presented
here suggest that female patients with an age of more than fifty-five years
who are managed with high-dose, postoperative radiotherapy in combination with
limb-salvage surgery for the treatment of soft-tissue sarcoma have an
increased risk of postradiation fracture.
A table presenting details on all twenty-three patients with fractures is
available with the electronic versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?