Retroperitoneal_sarcoma

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Retroperitoneal Sarcoma
A Population-Based Analysis of Epidemiology, Surgery, and Radiotherapy
Geoffrey A. Porter, M.D.
1
Nancy N. Baxter, M.D.
2
Peter W. T. Pisters, M.D.
3
1Department of Surgery and Department of Com-
munity Health and Epidemiology, Dalhousie Uni-
versity, Halifax, Nova Scotia, Canada.
2Department of Surgery, University of Minnesota
Medical School, Minneapolis, Minnesota.
3Department of Surgery, University of Texas M. D.
Anderson Cancer Center, Houston, Texas.
Supported in part by the Nova Scotia Clinical
Scholars Program.
Address for reprints: Geoffrey A. Porter, M.D., De-
partment of Surgery, 7-007 Victoria Building, QEII
Health Sciences Center, 1278 Tower Road, Halifax,
Nova Scotia B3H 2Y9, Canada; Fax: (902) 473-
6496; E-mail: Geoff.Porter@dal.ca
BACKGROUND. No population-based studies of retroperitoneal sarcoma (RPS) have
been conducted, and the use and timing of adjuvant radiotherapy for RPS is
controversial. The objective of this study was to examine the incidence and treat-
ment of RPS, specifically regarding the use of adjuvant radiotherapy.
METHODS. The Surveillance, Epidemiology, and End Results (SEER) database was
used to evaluate the incidence of RPS over a 29-year period (1973-2001). The rate
of surgery, the rate and timing of adjuvant radiotherapy, and the influence of
demographic factors on treatment were evaluated.
RESULTS. A total of 2348 cases of RPS were identified. The mean annual incidence
of RPS was 2.7 cases per 106 persons and did not change significantly over time (2.6
in 1973 vs. 2.8 in 2001; P � .92). Most patients (1654; 70.4%) underwent surgical
resection. Radiotherapy was used in 428 patients (25.9%) who underwent surgery;
radiation was given postoperatively in 366 (85.5%), preoperatively in 20 (4.7%), and
intraoperatively or unknown in 42 (9.8%). Patients who received any adjuvant
radiotherapy were on average 5 years younger than those who underwent surgery
alone (P � .0001). Radiotherapy was more commonly used among whites than
African Americans (25.8% vs. 16.7%; P � .02) and there was significant variation in
the use of adjuvant radiotherapy by geographic location (P � .003). On multivar-
iate analysis, race (P � 0.004), age (P � .0001), and geographic location (P � .006)
were independently associated with the use of adjuvant radiotherapy.
CONCLUSION. The incidence of RPS, a rare disease, appears stable. Most patients
who undergo surgery do not receive any adjuvant radiotherapy, and very few
receive preoperative radiotherapy. Differences in adjuvant radiotherapy use re-
lated to demographic and geographic factors suggest that at least some treatment
variations reflect differences in individual and institutional practice patterns.
Cancer 2006;106:1610 – 6. © 2006 American Cancer Society.
KEYWORDS: retroperitoneal sarcoma, epidemiology, surgery, radiotherapy.
Soft-tissue sarcomas represent a heterogeneous group of rare tu-
mors that arise predominantly from the embryonic mesoderm. It
is estimated that there will be 9420 new cases of soft-tissue sarcoma
in 2005 in the US; approximately 15% of such cases will arise in the
retroperitoneum.1 The prognosis for patients with retroperitoneal
sarcoma (RPS) is relatively poor, with a 36% to 58% overall 5-year
survival rate and a natural history characterized by late recurrence.2–7
Locoregional recurrence remains a frequent cause of death; only 28%
of patients do not experience such a recurrence within 5 years. The
only known potentially curative treatment is macroscopically com-
plete, margin-negative surgical resection.2,8,9
Although surgical resection remains the mainstay of RPS treat-
ment, the size and complexity of RPS tumors often results in micro-
scopic residual disease after surgery; thus, the use of adjuvant radio-
1610
© 2006 American Cancer Society
DOI 10.1002/cncr.21761
Published online 3 March 2006 in Wiley InterScience (www.interscience.wiley.com).
therapy has been proposed. To date, only one
randomized trial, performed more than 2 decades ago,
has been performed examining the role of intraoper-
ative radiation for RPS.10 That trial, which randomized
35 patients to receive postoperative external-beam ra-
diotherapy with or without intraoperative radiother-
apy, demonstrated a significant reduction in local re-
currence in the group randomized to the treatment
arm that included intraoperative radiotherapy. More
recently, 2 prospective, nonrandomized, single-insti-
tution trials have demonstrated the feasibility of pre-
operative radiotherapy for resectable RPS, and the
results suggest improved outcomes compared with
historical surgery-alone data.11,12 This body of evi-
dence prompted the American College of Surgeons
Oncology Group to initiate a large, randomized clini-
cal trial comparing surgery alone with preoperative
radiotherapy plus surgery (ACOSOG Z9031).
Although there have been several, primarily
single-institution, cohort studies of this rare di-
sease,2–9,13,14 it is unclear whether their findings can
be generalized to the majority of RPS patients. Given
the lack of population-based studies of RPS, as well as
the controversy surrounding the use and timing of
adjuvant radiotherapy, the goal of the present study
was to examine the incidence and treatment of RPS in
a population-based cohort, specifically regarding the
use of adjuvant radiotherapy.
MATERIALS AND METHODS
Data
We used data from the Surveillance, Epidemiology,
and End Results (SEER) cancer registry to conduct this
study. SEER is a population-based cancer registry
sponsored by the National Cancer Institute that was
created in 1973. More than 3.5 million cancer cases are
included in the SEER database, with approximately
170,000 new cases added annually. It collects informa-
tion on cancer incidence and survival from 11 popu-
lation-based cancer registries and 3 supplemental ar-
eas; these 11 registries include approximately 14% of
the US population.15 Epidemiologically distinct sub-
groups focusing on race, socioeconomic status, and
education are incorporated in SEER to enhance its
generalizability to the US population. For example,
12% of SEER compared with 13% of the US population
is below the poverty level.15 Of the 11 registries, 2 were
added in 1992. The information collected by SEER
includes patient characteristics, county of residence,
primary tumor site, tumor type, first course of treat-
ment (through completion of the initial treatment
plan, including treatment within the first year after
diagnosis or until there is evidence either of disease
progression or of treatment failure within the first
year), timing of radiation, and follow-up for vital sta-
tus.15
Patients
Included in our study were all patients � 18 years old
in the SEER database who were diagnosed with RPS
from January 1, 1973, through December 31, 2001. For
the purposes of this study, the patients included were
those reported to have a primary tumor of the retro-
peritoneum (ICD-0-2 topography site code C480), as
well as histologic morphology consistent with RPS;
these tumor histologies included soft tissue (ICD-0-2
880), fibromatous (ICD-0-2 881-883), myxomatous
(ICD-0-2 884, 889-892), lipomatous (ICD-0-2 885-888),
complex mixed/stromal (ICD-0-2 893-899, excluding
endometrial stromal, mullerian mixed, and nephro-
blastoma), fibroepithelial (ICD-0-2 900-903), synovial
(ICD-0-2 904), angiosarcoma (ICD-0-2 9120), heman-
giopericytoma (ICD-0-2 9150), neurofibrosarcoma
(ICD-0-2 9540), and alveolar soft part sarcoma (ICD-
0-2 9581).
SEER routinely collects data on the first course of
treatment, including surgery and/or radiation. For our
study, we examined the use of adjuvant radiotherapy
among patients undergoing surgical resection. Only
patients undergoing surgical resection were catego-
rized as having surgery; patients undergoing open bi-
opsy or palliative procedures such as ostomy creation
were not categorizedas having surgery. The use of
adjuvant radiotherapy was categorized as none, pre-
operative, postoperative, intraoperative, or other.
Analysis
The crude annual incidence of RPS for the 29-year
period was calculated by dividing the total number of
new RPS cases each year by the population included
in the registries (1973-1992, 9 registries; 1993-2001, 11
registries). We then calculated age-adjusted annual
incidence rates, standardized to the 2001 US popula-
tion (10 year age groups were used). To test for signif-
icant trends in age-adjusted RPS incidence from 1973
to 2001, we performed a nonparametric test for trends
using the Cochran-Armitage test based on 1 degree of
freedom.16,17
We calculated the rate of surgical resection as a
proportion of all new cases of RPS; the use and timing
of adjuvant radiotherapy was examined among pa-
tients undergoing surgical resection. We then assessed
the association of the following factors on treatment:
patient age (evaluated in 10-year increments), gender,
race (white vs. African American), marital status (mar-
ried vs. unmarried), year of diagnosis, and geographic
location (SEER registry) on treatment. Univariate anal-
ysis was done using the chi-square test. Multivariate
Sarcoma Epidemiology and Treatment/Porter et al. 1611
analysis, by logistic regression, was performed to eval-
uate factors associated with the use of adjuvant radio-
therapy using a forward stepwise approach incorpo-
rating all clinicodemographic variables examined as
well as all 2-way interaction terms; acceptance in the
final model required significance at P�0.10. No inter-
action terms were found to be statistically significant;
however, we kept the interaction between registry and
year of diagnosis in the final model given that 2 of the
registries contributed data only during 1993-2001. All
analyses were performed by using SPSS for Windows
11.0 (Chicago, IL). As this analysis used publicly avail-
able data with no personal identifiers, the Research
Ethics Board at Dalhousie University determined that
it was exempt from review.
RESULTS
We identified 2348 patients with newly diagnosed RPS
registered in the SEER database during the specified
study period. The median age of the study cohort was
64 years. Other sociodemographic characteristics are
summarized in Table 1. The annual incidence of RPS,
both crude and age-adjusted using rolling 3-year av-
erages, is displayed in Figure 1. No significant trends
in incidence of RPS over time were identified.
Surgical resection was performed in 1654 (70.1%)
patients. The proportion of patients undergoing sur-
gical resection increased significantly over the study
period (Fig 2). The average resection rate was 54.8%
over the first 6 years of the study, compared with
78.5% over the last 6 years (P � 0.0001).
Adjuvant radiotherapy was used in 428 of the 1654
patients who underwent surgery (25.9%); most such
patients received radiotherapy postoperatively (366,
85.5%), whereas 20 patients (4.7%) received radiother-
apy preoperatively (Table 2). Factors associated with
the use of adjuvant radiotherapy are shown in Table 3.
Patients who received adjuvant radiotherapy were on
average 5 years younger than those who underwent
surgery alone (median age � 59 vs. 64 years; P �
.0001). Adjuvant radiotherapy was used more often
among whites than African Americans (25.8% vs.
16.7%; P � .02) and there was significant variation in
the use of adjuvant radiotherapy by geographic loca-
tion (P � 0.003). No significant associations were
identified between the use of adjuvant radiotherapy
and sex, marital status, or year of diagnosis.
To further investigate the variation in use of ad-
juvant radiotherapy by geographic location, we cate-
gorized the 11 registries into high- and low-volume
locations, based on the average number of RPS cases
per year, dichotomized around the 50th percentile of
cases per year. Three registries were in the high-vol-
ume group (9.1-21.8 cases/yr) and eight registries in
the low-volume group (1.9-7.1 cases/yr). No differ-
ences in the use of adjuvant radiotherapy were iden-
tified between low- and high-volume registries (26.6%
vs. 25.1%, respectively; P � 0.5).
On multivariate analysis using logistic regression,
race (P � .01), age (P � .0001), and geographic loca-
tion (P � .02) were found to be independently associ-
ated with the use of adjuvant radiotherapy (Table 3).
DISCUSSION
This study demonstrated, at a population level, a sta-
ble incidence of RPS over a 29-year period. Although
no published incidence data specific to RPS exist, sta-
ble incidence of all cases of soft-tissue sarcoma has
been reported within the National Cancer Database.18
In SEER, the incidence of extremity soft-tissue sar-
coma did not change from 1973 to 1998.19
The overall resection rate of 70.4% identified in
TABLE 1
Demographic and Patient Characteristics of the Study Cohort
(N � 2348)
No. of Patients %
Gender
Male 1121 47.7
Female 1227 52.3
Age at diagnosis, y
� 60 932 39.7
60–79 1134 48.3
� 80 282 12.0
Race
White 1977 84.2
African American 209 8.9
Other/unknown 162 6.9
Marital status
Ever married 2015 85.8
Never married 285 12.1
Unknown 48 2.1
Year of diagnosis*
1973–1979 423 18.0
1980–1986 456 19.4
1987–1993 580 24.7
1994–2001 889 37.9
Registry
San Francisco 385 16.4
Connecticut 291 12.4
Detroit 431 18.4
Hawaii 92 3.9
Iowa 264 11.2
New Mexico 87 3.7
Seattle 228 9.7
Utah 114 4.9
Atlanta 121 3.2
San Jose-Monterey* 49 2.1
Los Angeles* 286 12.1
* Nine registries were available until 1991; San Jose-Monterey and Los Angeles were added in 1992.
1612 CANCER April 1, 2006 / Volume 106 / Number 7
this study falls within the wide range of 50% to 95%
reported in single-institution cohort studies.2,4,6,14 To
the authors’ knowledge, no population-based data on
RPS resection rates exist. It is possible that improve-
ments in pretreatment radiologic staging, particularly
the widespread introduction and use of computed
tomography (CT), and secondary progressive im-
provements in CT image quality, might have signifi-
cantly contributed to the increased resection rate over
time in our analysis. It is also possible that changes in
surgical technique over time, particularly the in-
creased use of extensive resection with en-bloc re-
moval of adjacent organs, may have contributed to the
increase in resection rate. In a review of 192 RPS
patients undergoing surgery at the Mayo Clinic be-
tween 1960 and 1995, complete resection rates in-
creased from 49% (during 1960-1982) to 78% (during
1983-1995), with a concomitant reduction in biopsy-
only procedures.20 The authors attributed the increase
in resections to a more liberal use of multivisceral
resection but did not consider the possible role of
improved pretreatment staging.
The use of adjuvant radiotherapy in RPS has been
debated for more than 40 years. Although the only
randomized clinical trial of therapy for this disease
suggests a benefit of intraoperative radiotherapy with
postoperative radiotherapy,10 the small study size (35
patients), significant radiation-related toxicity, lack of
widespread availability of intraoperative radiotherapy,
and high rates of recurrence in both arms of this trial
have prevented the widespread acceptance of its re-
sults. Several retrospective studies have suggested that
postoperative radiotherapy yield better outcomes
than surgery alone,7,21 although other similarly de-
signed studies have shown no advantage to radiother-
apy.2,20,22 Moreover, the potential advantages of pre-
operative radiotherapy, and demonstration of its
feasibility, have provided sufficient clinical equipoise
to launch a large Phase III trial of surgery versus
preoperative radiotherapy plus surgery (ACOSOG
Z9031).11,12
Our data demonstrate that surgery alone is the
most common treatment administered to patients
with localized RPS; 74.1% of patientsin this study were
treated in this fashion. Among the 25.9% of patients in
whom adjuvant radiotherapy was used, the most com-
mon approach was postoperative (85.5%). The more
common use of postoperative radiation was likely re-
lated to the common use of diagnostic and therapeutic
FIGURE 1. Crude and age-adjusted (to 2001 US census) incidence of
retroperitoneal sarcoma from 1973-2001, using 3-year rolling averages. In the
nonparametric test for trends, crude P � .92; age-adjusted P � .84.
FIGURE 2. Percentage of all retroperitoneal sarcoma patients (N � 2348)
undergoing surgical resection during 1973-2001, using 3-year rolling aver-
ages.
TABLE 2
Type of Adjuvant Radiotherapy Used Among Patients Undergoing
Surgical Resection (N � 1654)
No. of
Patients
% of All
Patients
% of RT
Patients
No RT 1226 74.1 —
RT 428 25.9
Postoperative 366 22.1 85.5
Preoperative* 20 0.9 4.7
IORT† 22 1.0 5.1
Unknown sequence 20 0.9 4.7
RT: radiotherapy; IORT: intraoperative radiotherapy.
* Includes 5 patients receiving both preoperative and postoperative RT.
† Includes 13 patients undergoing IORT and either preoperative or postoperative RT.
Sarcoma Epidemiology and Treatment/Porter et al. 1613
primary tumor resection as the initial treatment for
most patients with radiologically resectable retroperi-
toneal neoplasms. In the absence of a pretreatment
diagnosis or clear evidence suggesting that radiother-
apy would improve outcome, most patients are of-
fered surgical resection as the initial treatment for
localized disease. Once the pathologic diagnosis has
been made and margin assessment done, selected
patients (e.g., microscopic margin-positive) are subse-
quently referred for consideration of radiotherapy.
Unfortunately, the SEER data do not reliably distin-
guish R0 from R1 resections, making it impossible to
determine whether this practice was followed in this
study. It is important to note that no conclusive evi-
dence supports an outcome difference between pa-
tients undergoing an R0 versus R1 resection, and sim-
ilarly, no evidence points to a preferential benefit
of radiotherapy in patients undergoing R1 resec-
tions.2,4,23
Variation in the use of cancer therapies among
different populations has been documented in many
cancers, such as those of the breast, cervix, colorectal
tract, lung, and prostate.24-31 As with any medical ther-
apy, factors involved in such nonrandom variation can
be categorized as patient, structural barriers, and phy-
sician/clinical.32 The racial disparity identified in this
study, specifically that African Americans were signif-
icantly less likely than whites to receive adjuvant ra-
diotherapy, has been demonstrated for rectal carci-
noma and breast carcinoma.25,28,32 In an analysis of
SEER data from 1973 to 1999, Alderman et al.19 found
that African Americans were half as likely as Cauca-
sians to receive adjuvant radiotherapy for upper ex-
tremity sarcomas, with a magnitude of difference vir-
tually identical to that found in our study. Our data
add to the vast body of literature demonstrating that
African Americans receive less medical care and have
poorer outcomes than whites.32 Further research is
required to better delineate possible explanations for
this pattern, which may include physician/provider
bias, differences in patient acceptance/compliance,
differences in access to care, or race serving as a
surrogate for socioeconomic status.
Variations in cancer treatment have also been
noted between institutions and geographic ar-
eas.19,30,33 Such variations have been attributed to
clinical volume of the area or institution.33-37 Interest-
ingly, we found that the variation in use of adjuvant
radiotherapy for RPS across the 11 SEER registries did
not appear to be related to the volume of RPS cases
within individual registries. It is plausible that RPS in
the high-volume registries was still so uncommon that
simple individual institution practice patterns, rather
than ‘experience,’ explains the treatment differences.
Limitations of this study include the potential for
unmeasured factors that could confound results. The
benefits of a large database such as SEER in terms of
generalizability can come at the cost of a lack of the
detailed sociodemographic and clinical data that are
characteristic of smaller clinical cohort studies. For
example, data on RPS grade are not reliably available
through SEER for the entire 29-year study period. Ad-
ditionally, coding of race for such groups as Native
Americans, Asians, and Hispanics was not consistent
over the SEER data collection periods, making more
detailed race analyses impossible. Our approach of
categorizing race as “White,” “African American,” and
TABLE 3
Univariate and Multivariate Associations between
Clinicodemographic Factors and the Use of Adjuvant Radiotherapy
(RT) among 1654 Patients Who Underwent Surgical Resection
Univariate
Multivariate*
% Receiving
RT P OR 95% CI P
Gender .12 — — —
Male 27.9
Female 24.2
Age at diagnosis � .0001 � .0001
� 60 30.7 4.6 2.5–8.4
60–79 24.5 3.3 1.8–5.9
� 80† 9.1 1.0 —
Race‡ .02 .004
White 25.8 2.0 1.2–2.3
African American† 16.7 1.0 —
Marital status .18 — — —
Ever married 21.8
Never married 26.6
Unknown 15.4
Year of diagnosis .14 — — —
1973–1979 23.3
1980–1986 31.0
1987–1993 25.9
1994–2001 24.5
Registry .003 .006
San Francisco 28.3 1.9 1.2–3.0
Connecticut 22.9 1.5 0.9–2.4
Detroit 27.5 1.9 1.2–3.0
Hawaii 44.4 3.7 0.8–2.3
Iowa 21.5 1.4 1.3–4.7
New Mexico 34.5 2.4 0.8–2.3
Seattle 23.2 1.4 1.2–3.7
Utah 31.5 2.1 1.1–3.6
Atlanta 30.5 2.1 1.1–3.6
San Jose-Monterey 27.9 3.3 0.9–4.4
Los Angeles† 17.8 1.0 —
RT: adjuvant radiotherapy; OR: odds ratio; CI: confidence interval.
* Includes nonsignificant interaction between registry and year of diagnosis (P � .24).
† Reference group for logistic regression.
‡ Does not include “other” because definitions for “Asian” and “Hispanic” were not consistent over
1973-2001.
1614 CANCER April 1, 2006 / Volume 106 / Number 7
“Other” is congruent with other publications using
SEER data from 1973 to 2001.19,28 Detailed data on
radiation dose or field was also not available. How-
ever, the data for use of both surgery and radiotherapy
collected by SEER are accurately recorded for breast,
endometrial, colorectal, lung, pancreatic, and prostate
carcinomas.38,39 There is, therefore, no apparent rea-
son to believe that these data would not be the case for
RPS. Finally, this study did not include any measure-
ment or analysis of population-based outcomes, mak-
ing it impossible to determine the impact of temporal
changes in resectability rates on survival.
In conclusion, the incidence of RPS, a rare dis-
ease, appears stable and resection rates have in-
creased over time. Most patients who undergo surgery
do not receive any adjuvant radiotherapy, and very
few receive preoperative radiotherapy. Differences in
adjuvant radiotherapy use that seem to be based on
demographic and geographic factors may, at least in
part, reflect differences in individual and institutional
practice patterns. These data, representing current
practice, will be important in considering how to im-
plement future results of an ongoing randomized trial
(ACOSOG Z9031) comparing preoperative radiother-
apy and surgery with surgery alone. A demonstrated
benefit to preoperative radiotherapy would require a
significant change to the current practice patterns.
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1616 CANCER April 1, 2006 / Volume 106 / Number 7