Download Worse survival in elderly patients with extremity soft

3
Worse
survival
in elderly
patients with
extremity
soft-tissue
sarcoma
Miriam L. Hoven- Gondrie1, Esther Bastiaannet1,2, Vincent K.Y. Ho3, Barbara L. van Leeuwen1,
Gerrit-Jan Liefers2, Harald J. Hoekstra1, Albert J. H. Suurmeijer4
Department of Surgery, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands
2
Department of Surgery, Leiden University Medical Center, University of Leiden, Leiden, the
Netherlands
3
Comprehensive Cancer Center Netherlands, Utrecht, the Netherlands
4
Department of Pathology, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands
Introduction
1
Submitted
Abstract
Background Nearly half of soft-tissue sarcoma (STS) patients are over the age
of 65. The aim of this study was to assess the impact of age, sarcoma histotype,
grade, stage and treatment modalities on survival of extremity STS (ESTS) patients.
Methods Patients ≥18 years, diagnosed with ESTS between 1989 and 2008, were
selected from the Netherlands Cancer Registry (NCR). Survival rates and treatment
characteristics were analyzed for all patients. Treatment was categorized in no
treatment, monotherapy (surgery, radiotherapy or chemotherapy) and various
combined modality treatments. Relative survival and Relative Excess Risks of
death (RER) were estimated.
Results Overall, 3375 patients were included in this study. Histotype was different
between young and elderly patients (p < 0.001). The oldest elderly were diagnosed
more often with high-grade and stage IV disease (p < 0.001). The proportion of
patients who received no treatment increased from 3% in the youngest group to
17% in the oldest elderly. The elderly received fewer combined modality treatments
(p < 0.001). Age was significantly associated with relative 5-year survival (73.4%
for younger patients and 25.8% for the oldest elderly). In multivariate analysis,
adjusted for sex, histotype, grade and treatment, age still remained a significant
prognostic factor for stage II and III ESTS patients.
Conclusion Different distribution of sarcoma histotypes, a higher stage and more
high-grade sarcomas at diagnosis, less aggressive treatment and worse survival
rates in stage II and III ESTS urge the need for optimizing sarcoma care of the
elderly in order to improve their prognosis.
Soft-tissue sarcomas (STS) are relatively rare tumors and account for 1% of all cancers
in adults. The overall incidence of STS in the Netherlands is 2.7/100,000 (European
Standardized Rate 2009).1 There has been a slight increase in the incidence of STS
in men. Nearly 50% of the diagnosed patients are over 65 years of age.2 Fifty to
60% of STS are localized in the extremities. The most common sarcoma histotypes
are pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma),
liposarcoma, leiomyosarcoma and fibrosarcoma.2,3 Important prognostic factors
for STS are primary site, tumor size, histotype, grade and stage at presentation.3
Age at presentation determines survival in several distinct STS histotypes.4-9
The behavior of cancer in elderly patients is poorly understood. There is a
widespread misconception that the elderly are poorly tolerant of chemotherapy
and radiotherapy. In daily clinical practice, elderly patients may be undertreated
compared to young or middle-aged STS patients, and this may influence their
prognosis.2,10-12 Moreover, elderly patients are generally underrepresented in
cancer trials, which compromises our knowledge of the effectiveness of sarcoma
treatment for this age group.13 For extremity STS (ESTS) there is a well-defined
role for surgery and radiation therapy.14 In ESTS removed with narrow margins or
microscopically (R1) or macroscopically (R2) positive resection margins, 50-70 Gy
of external-beam radiation therapy (EBRT) is indicated.15,16 The main goal of this
study was to assess the impact of age on relative survival of adult ESTS patients
diagnosed in the Netherlands. Relevant prognostic factors for survival of STS were
included. Stage at diagnosis, sarcoma histotype, tumor grade and treatment
regimens were compared between young and elderly sarcoma patients and
analyzed in a multivariable fashion.
Patients and methods
Patients
Patients (age 18 and older) diagnosed with ESTS as first primary malignancy
in the period 1989-2008 were selected from the Netherlands Cancer Registry
(NCR). Patients with Kaposi sarcoma, dermatofibrosarcoma protuberans and
Ewing sarcoma were excluded (Table 1). PALGA, the Dutch nationwide network
of histopathology and cytopathology diagnosis, regularly submits reports of all
33
3
Table 1: Morphology codes included in the selection of patients with softtissue sarcoma
Group
Morphology (WHO 2002)
N
Dedifferentiated liposarcoma
8858
22
Myxoid & round cell liposarcoma
8852 & 8853
369
Pleomorphic liposarcoma
8854
87
Mixed-type liposarcoma
8855
30
Fibrosarcoma
8825, 8811, 8814, 8810, 8812 & 8813
330
Pleomorphic undifferentiated sarcoma 8830 & 8800-8809
1055
Leiomyosarcoma
8890, 8891 & 8896
644
Rhabdomyosarcoma
8900-8902, 8910, 8912, 8920 & 8921
84
Angiosarcoma
9120
57
Synovial sarcoma
9040-9043
262
MPNST
9540
106
Other
9581, 9044, 8963, 9231, 9180 & 8850
309
Overall
All
3375
MPNST, malignant peripheral nerve sheath tumor
Exclusion: Kaposi sarcoma, dermatofibrosarcoma protuberans, Ewing sarcoma
inhabitants’ vital status. The WHO Classification of soft tissue sarcoma was used for
histopathological classification of sarcoma histotypes.19 Because the latest WHO
Classification of STS appeared in 2002, the distribution of sarcoma histotypes
according to age was analyzed with data from 2003-2008.
Statistics
Age was categorized in the following groups: patients younger than 65 and elderly
aged 65-69, 70-74, 75-79, 80-84, 85-89 and older than 89. Missing data for grade
and stage were imputated using multiple imputation with five imputations using
a model with age, sex, year, morphology, status, stage and grade.20 Distribution
of sarcomas according to age was assessed for the years 2003 to 2008. Stage at
diagnosis was compared according to age categories. Treatment was categorized
into no treatment, monotherapy (surgery, radiotherapy and chemotherapy) and
several combinations of treatment.
Relative survival was calculated and Relative Excess Risks of death (RER) were
estimated using a multivariable generalized linear model with a Poisson error
structure, based on collapsed relative survival data, using exact survival times.
Survival time was calculated from the date of diagnosis and ended at the date
of death, date of last contact, or date of most recent linkage with the municipal
population registries, whichever came first. Relative mortality was calculated by
the equation: (observed deaths – expected deaths) / observed deaths. National
life tables were used to estimate expected survival. STATA SE 10.0 software was
used to perform statistical analyses.
Results
diagnosed malignancies to the cancer registries. The national hospital discharge
databank, which receives discharge diagnoses of admitted patients from all
Dutch hospitals, completed case ascertainment. After notification, trained registry
personnel collected data on diagnosis, stage and treatment from the medical
records, including pathology and surgery reports, using the registration and
coding manual of the NCR. Treatment was coded in sequence of administration.
Stage was assigned according to the American Joint Committee on Cancer
and grade according to Coindre.17,18 Vital status was established either directly
from the patient’s medical record or through linkage of cancer registry data
with the municipal population registries, which recorded information on their
34
Survival in young and elderly soft-tissue sarcoma patients
As shown in Table 2, 3375 patients were included in this study. At first diagnosis,
nearly 40% of patients were elderly, aged 65 years or older, nearly 75% had highgrade sarcomas, and 60% were diagnosed with stage I or II disease.
As shown in Figure 1, there were significant differences in distribution of sarcoma
histotypes in young versus elderly patients (p < 0.001). Using 65 years of age as
cut-off value, myxoid and round cell liposarcoma was diagnosed more often in
younger patients (p=0.002), whereas pleomorphic undifferentiated sarcoma was
recorded more often in the elderly (p=0.003). Leiomyosarcoma was predominantly
diagnosed in the 70-74 age group (p=0.05).
35
3
23.3
23.5
25.7
27.5
23.3
23.5
25.7
27.5
Grade
Low
High
Missing
736
2252
387
21.8
66.7
11.5
25.2
74.8
Stage
I
II
III
IV
Missing
615
451
308
322
1679
18.2
13.4
9.1
9.5
49.8
33.5
26.4
20.1
20.0
3375
100
100
Survival in young and elderly soft-tissue sarcoma patients
Pleomorphic liposarcoma
Pleomorphic undifferentiated sarcoma
Angiosarcoma
Other
785
794
868
928
Myxoid & round cell liposarcoma
Fibrosarcoma
Rhabdomyosarcoma
MPNST, malignant peripheral
nerve sheath tumor
1989-1993
1994-1998
1999-2003
2004-2008
Dedifferentiated liposarcoma
Mixed-type liposarcoma
Leiomyosarcoma
Synovial sarcoma
Year
80%
53.5
46.5
60%
53.5
46.5
40%
1806
1569
20%
Male
Female
3
0%
Sex
<65
61.4
9.5
8.8
8.6
6.5
3.7
1.6
65-69
61.4
9.5
8.8
8.6
6.5
3.7
1.6
70-74
2071
321
296
289
218
126
54
75-79
< 65
65-69
70-74
75-79
80-84
85-89
90+
80-84
%
85-89
%
Age
(years)
Total
36
N
90+
Variable
Multiple
imputation
Figure 1: Distribution of sarcomas (2003-2008) according to age
Original dataset
100%
Table 2: Characteristics of the population (n=3375)
37
32
28
20
21
80-84
85-89
34
39
31
27
25
17
0%
<65
65-69
Stage I
38
70-74
Stage II
75-79
Stage III
Stage IV
Survival in young and elderly soft-tissue sarcoma patients
90 and older
< 0.001
0
0.6
0
0
0
0
< 0.001
0
3.4
1.3
1.4
0.5
0
< 0.001
18.5
42.7
43.9
36.3
36.2
28.6
< 0.001
0
5.0
3.4
1.7
2.7
0
< 0.001
1.8
4.4
4.7
2.4
1.8
2.4
< 0.001
1.8
1.2
2.0
4.1
4.1
2.4
< 0.001
61.1
38.3
36.5
48.4
40.4
50.0
< 0.001
16.7
4.4
8.1
5.5
14.2
16.7
p-value*
%
%
%
%
%
%
%
90+
65-69 70-74 75-79 80-84 85-89
< 65
3
*p-value for trend over age
29
0.8
20%
29
Chemotherapy & radiotherapy
28
40%
4.8
25
Surgery & radiotherapy & chemotherapy
26
38.1
24
Surgery & radiotherapy
60%
5.1
24
Surgery & chemotherapy
18
3.9
25
80%
Chemotherapy (monotherapy)
22
23
0.6
21
26
Radiotherapy (monotherapy)
23
43.9
24
Surgery (monotherapy)
23
2.8
18
18
No treatment
100%
Treatment
Figure 2: Stage at diagnosis according to age groups (all years)
Table 3: Treatment of soft-tissue sarcoma in the extremities
Stage at diagnosis was different between age categories (p < 0.001). The relative
proportion of Stage I diminished from 39% in the younger patients to 17% for the
oldest elderly. Stage II was more prominent among the elderly (34% compared to
25% in patients younger than 65). The proportion of Stage III was equal between
age categories, approximately 20-25%. The proportion of patients with stage IV
was higher among the elderly, ranging from 18% in patients younger than 65 years
to approximately 25% among the elderly (Figure 2). Elderly patients presented
with high-grade disease more often, ranging from 69.9% high-grade in patients
younger than 65 to 87.5% in the 85-89 age group and 83.7% in patients over 90
years (p < 0.001).
As shown in Table 3, the proportion of patients that received no treatment was
remarkably higher among the elderly, particularly patients older than 80. About
15% of patients older than 80 received no treatment compared to 2.8% of patients
younger than 65 (p < 0.001). Surgery as sole treatment was administered more
often to the elderly (ranging from 44% in the young to 61% in the oldest elderly;
p < 0.001). A combination of surgery and radiotherapy was given less often to the
elderly, particularly patients older than 85 years of age: 38% of patients younger
than 65 compared to 19% of the oldest elderly (p < 0.001).
Patients younger than 65 had a 5-year relative survival (all stages) of 73.4% (95%CI
72.5-74.3). For elderly patients the 5-year relative survival was significantly worse,
decreasing with age to 25.8% for the oldest elderly (Table 4). When adjusted for
sex, year, sarcoma histotype, grade and treatment in multivariate analysis, this
survival difference was mainly found in stage II and III ESTS patients (Figure 3).
Table 5 shows the RER for age stratified according to sarcoma histotype diagnosed
in 2003-2008. For all sarcomas, age was a significant prognostic factor with an
RER of 1.1 (95%CI 1.0-1.1) per 5-year increase in age. Concerning sarcoma histotype,
age was a significant prognostic factor for patients with myxoid and round cell
liposarcoma (RER 1.3 (1.1-1.6; p=0.002)) and pleomorphic undifferentiated sarcoma
(RER 1.1 (95%CI 1.0-1.2; p=0.003)).
Figure 4 clearly illustrates that the estimated deaths (the equation of observedexpected deaths/observed deaths) due to sarcoma after 10 years of follow-up
rapidly decreases among the elderly, although the proportion does not decrease
below 50% of all deaths.
Figure 3: Relative survival according to age and stage*
3
*Adjusted for sex, histotype, grade and treatment
Table 4: Relative survival (RS) according to age
Age
5-years RS
RER (95%CI) p-value
Adjusted* RER
p-value
< 65
73.4 (72.5-74.3)
Reference
65-69
67.7 (64.8-70.4)
1.2 (1.0-1.6)
0.06
1.1 (0.9-1.4)
0.4
70-74
58.9 (55.6-62.1)
1.8 (1.4-2.2)
< 0.001
1.5 (1.2-1.9)
0.001
75-79
59.6 (55.9-63.3)
1.9 (1.5-2.4)
< 0.001
2.0 (1.6-2.6)
< 0.001
80-84
55.4 (50.4-60.4)
2.0 (1.5-2.7)
< 0.001
1.6 (1.2-2.2)
0.001
85-89
53.7 (45.3-62.6)
2.7 (1.9-3.9)
< 0.001
1.5 (1.0-2.2)
0.046
90+
25.8 (15.2-40.5)
3.7 (2.2-6.4)
< 0.001
2.1 (1.1-4.0)
0.03
Figure 4: Observed–Expected deaths (10-year follow-up) as proportion of
the observed deaths in the population of sarcoma patients according to age
Reference
*Adjusted for sex, year, sarcoma histotype, grade and treatment.
40
Survival in young and elderly soft-tissue sarcoma patients
41
Table 5: Survival analysis to assess whether age (per 5-year increase)
is a prognostic factor for relative survival according to morphology
(2003-2008)
Morphology
RER for age (95%CI)
p-value
Dedifferentiated liposarcoma
1.6 (0.9-2.6)
0.08
Myxoid & round cell liposarcoma
1.3 (1.1-1.6)
0.002
Pleomorphic liposarcoma
1.0 (0.7-1.4)
0.8
Mixed-type liposarcoma
1.0 (0.9-1.1)
0.6
Fibrosarcoma
1.0 (0.7-1.4)
0.9
Pleomorphic undifferentiated sarcoma
1.1 (1.0-1.2)
0.003
Leiomyosarcoma
1.1 (1.0-1.2)
0.05
Rhabdomyosarcoma
1.1 (0.9-1.3)
0.3
Angiosarcoma
1.1 (0.9-1.3)
0.3
Synovial sarcoma
1.0 (0.8-1.2)
0.8
MPNST
1.1 (1.0-1.2)
0.2
Other
0.9 (0.7-1.0)
0.07
All soft-tissue sarcomas
1.1 (1.0-1.1)
< 0.001
MPNST, malignant peripheral nerve sheath tumor
Discussion
Since the elderly population is growing fast and incidence of STS increases with
age, elderly cancer care has become a growing challenge to the world health care
systems. In keeping with most other series, we found worse survival outcomes
among elderly STS patients. Several tumor and treatment characteristics have
been mentioned as possible explanations for this inferior prognosis.9,21-24 Part of
the reason older patients do worse is that they often present with larger and
more high-grade tumors. This increased rate of high-grade tumors may reflect a
different tumor biology and more genetic alterations and molecular aberrations
in the older population.25 Age can also be associated with a decline in antitumor
42
Survival in young and elderly soft-tissue sarcoma patients
cell-mediated immunity.26 Concerning sarcoma histotype, more pleomorphic
undifferentiated sarcomas are diagnosed in the elderly, which are known to have
a relatively adverse prognosis.24 Strikingly, for this histotype and for myxoid and
round cell liposarcomas we found significantly worse survival rates for elderly
patients compared to their younger counterparts. Growing knowledge of the
molecular biology of these diseases has led to the suggestion that the various
subtypes of sarcomas should be approached individually.27 As molecular testing
also contributes to distinguishing between sarcomas of similar morphology,
molecular-based classification of sarcoma should be as important as histological
subtype classification in the future.28 For prognosis, treatment or response to
treatment, molecular characterization already has clinical implications for some
subtypes of sarcoma and new targets for therapy are increasingly being revealed.27
In this series the elderly patients had more stage IV and less stage I disease at
presentation. This may be a function of late presentation, often seen in elderly
patients with malignancy.21 However, after stratifying for stages there are still
significant differences in relative survival between young and elderly ESTS
patients. This survival difference was found mainly in stage II and III ESTS patients.
A possible explanation might be that less extensive treatment regimens often
suffice in patients with stage I disease, so age will not be the reason to withhold
any patient from optimal treatment. For stage IV disease we know that overall
prognosis is poor for all patients, regardless of the extent of treatment. This leads
to the speculation that suboptimal treatment in the elderly might contribute
to worse survival rates in stage II and III ESTS patients. A former study from the
cancer registry in the northern part of the Netherlands showed that referral to a
specialized center declined in a linear fashion with increased age, which might
explain this possible suboptimal treatment of elderly patients.10
The mainstay of ESTS treatment is surgery.29 There might be reluctance of surgeons
to perform, or of patients to accept, morbid surgeries with increasing patient age,
leading to inferior surgical treatment.30,31 Lahat and colleagues already advocated
radical surgery in the elderly, as properly selected patients can safely undergo
extensive STS resections. Their study showed that even in the group of patients
aged ≥ 75, more than half survived 5 years or more when treated with aggressive
surgery.22 However, a large but highly select group of patients was investigated
in this series. Patients with incomplete resection, insufficient follow-up and nonspecific pathological diagnoses were excluded; this might be a patient group
with unfavorable prognostic characteristics, but which could actually benefit from
43
3
better staging, referral or customized treatment. Buchner et al. also justify extensive
surgery in bone and soft-tissue sarcoma patients aged > 70. They state however
that general condition and comorbidity should be given due consideration.32
Fitness for general anesthesia should be the determinant for suitability for surgery
in elderly patients, rather than chronological age.33
Patients with gross disease will benefit from preoperative radiotherapy and those
with less than adequate margins after surgery from adjuvant radiotherapy.29 In this
study, radiotherapy in combination with surgery was particularly less administrated
in the elderly. Logistical problems and patient preferences are often the reason for
long courses of external radiation not being offered to elderly patients.21 Horton et
al. showed that patients aged ≥ 70 with high-grade ESTS were less likely to receive
radiotherapy, and furthermore that not receiving radiotherapy was associated with
mortality and disease-specific death.34 In the population-based study of Al-Refaie
et al., sarcoma-directed surgery and administration of adjuvant radiotherapy after
limb-sparing surgery for T2 or high-grade tumors was only decreased for ESTS
patients aged ≥ 85.23
The role of chemotherapy in the treatment of ESTS remains controversial, and
toxicity may be significant.29 As expected, administration of chemotherapy with
or without surgery and/or radiotherapy declines with age in our series. There is
however a widespread misconception that the elderly are always poorly tolerant
of chemotherapy. Most adult cancer patients can tolerate it with limited impact
on independence, comorbidity and quality of life (QoL) levels.35
The proportion of patients who received no treatment at all increased significantly
with age. Former studies from our own center show that the decision to refrain
from cancer treatment was mostly disease-related and less often based on poor
general health status.12
In conclusion, the principles of treatment for elderly patients are similar to those
for younger patients.21 For most ESTS, a combined treatment modality is assumed
to be the optimal therapy and will be offered to every patient fit enough to
undergo this treatment. Sometimes single treatment (e.g. radical surgery) is the
best option for the elderly. Potential undertreatment might thus be appropriate
in some clinical situations.31 As there are no data on patient frailty in the cancer
registry, we cannot comment on the just or unjust allocation of treatment.
As elderly patients are also generally underrepresented in cancer trials, this
compromises the generalizability of the effectiveness of sarcoma treatments to
this age group, and future efforts should identify methods to improve low accrual
44
Survival in young and elderly soft-tissue sarcoma patients
rates of the elderly in clinical cancer trials or explore other research designs to
study the elderly.13,36
The results of this study are based on data from the cancer registry, used in order to
gain insight into the disease and discover differences in treatment and survival for
different age groups. Histopathological diagnosis and grade are most important for
individual, customized therapy and require a central pathology review for optimal
histopathological diagnosis and tumor grading. A study comparing primary diagnosis
and systematic review by expert showed that 46% of diagnoses were modified at
second reading and that in 19% of cases there was a discordance in the histological
type.37 Although grade was demonstrated to be the predominant prognostic
factor in STS and there is a reproducible histopathological grading system, it often
remained unmentioned in the primary pathology report.18 Accurate reports in the
medical records on diagnosis, staging, treatment and follow-up details are essential
for reliable registration and analysis. Efforts to improve and facilitate registration are
made continuously by the cancer registry and checklists for standardized pathology
reporting of STS are becoming more and more available.38 Fortunately, a promising
trend has been observed in recent years, with more accurate and less missing data.
Furthermore, adequate staging is necessary but a complete investigation for distant
metastases is not always performed, especially when small STS are completely
excised without preoperative suspicion of this diagnosis (the so-called “whoops”
operation) and no further treatment is needed, or when advanced STS are diagnosed
in fragile patients who abandon further staging or treatment. Strikingly, in contrast
to most other types of cancer and despite continuous efforts to improve sarcoma
treatment, more individual customized therapy, relatively new treatment modalities
(like hyperthermic isolated limb perfusion for locally advanced STS of the extremity)
and better compliance with guidelines, other series show that survival rates have not
improved over time for all age groups.39 Further research is thus extremely important
to discover the gaps in sarcoma treatment and find out the areas accessible for
improvement. Currently research efforts are directed at molecular pathways in the
various sarcoma subtypes and the development of new targeted therapies.27,40
Conclusions
Studies on soft-tissue sarcoma care in the elderly are extremely important to
gain better insight into treatment and survival differences; the current norm of
individual, customized sarcoma treatment also applies to elderly ESTS patients.
45
3
Different distribution of sarcomas, more high-grade sarcomas and a higher stage
at diagnosis, less aggressive treatment and lower survival of the elderly urge the
need for optimizing sarcoma care and improving survival rates among the elderly.
References
1. Cancer Incidence in the Netherlands. 2013. Ref Type: Internet Communication
2. Nijhuis PH, Schaapveld M, Otter R et al. Epidemiological aspects of soft tissue sarcomas
(STS)--consequences for the design of clinical STS trials. Eur J Cancer 1999; 35:1705-1710.
3. Zagars GK, Ballo MT, Pisters PW et al. Prognostic factors for patients with localized softtissue sarcoma treated with conservation surgery and radiation therapy: an analysis of
1225 patients. Cancer 2003; 97:2530-2543.
4. ten Heuvel SE, Hoekstra HJ, van Ginkel RJ et al. Clinicopathologic prognostic factors in
myxoid liposarcoma: a retrospective study of 49 patients with long-term follow-up. Ann
Surg Oncol 2007; 14:222-229.
5. Pautier P, Genestie C, Rey A et al. Analysis of clinicopathologic prognostic factors for 157
uterine sarcomas and evaluation of a grading score validated for soft tissue sarcoma.
Cancer 2000; 88:1425-1431.
6. Brooks AD, Bowne WB, Delgado R et al. Soft tissue sarcomas of the groin: diagnosis,
management, and prognosis. J Am Coll Surg 2001; 193:130-136.
7. Pisters PW, Leung DH, Woodruff J et al. Analysis of prognostic factors in 1,041 patients
with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996; 14:1679-1689.
8. LeVay J, O’Sullivan B, Catton C et al. Outcome and prognostic factors in soft tissue
sarcoma in the adult. Int J Radiat Oncol Biol Phys 1993; 27:1091-1099.
9. Parsons HM, Habermann EB, Tuttle TM et al. Conditional survival of extremity soft-tissue
sarcoma: results beyond the staging system. Cancer 2011; 117:1055-1060.
10. Nijhuis PH, Schaapveld M, Otter R et al. Soft tissue sarcoma--compliance with guidelines.
Cancer 2001; 91:2186-2195.
11. Levi F, La Vecchia C, Randimbison L et al. Descriptive epidemiology of soft tissue
sarcomas in Vaud, Switzerland. Eur J Cancer 1999; 35:1711-1716.
12. Farshadpour F, Schaapveld M, Suurmeijer AJ et al. Soft tissue sarcoma: why not treated?
Crit Rev Oncol Hematol 2005; 54:77-83.
13. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age
or older in cancer-treatment trials. N Engl J Med 1999; 341:2061-2067.
14. Hoekstra HJ, Thijssens K, van Ginkel RJ. Role of surgery as primary treatment and as
intervention in the multidisciplinary treatment of soft tissue sarcoma. Ann Oncol 2004;
15 Suppl 4:iv181-iv186.
15. Thijssens KM, van Ginkel RJ, Pras E et al. Isolated limb perfusion with tumor necrosis
factor alpha and melphalan for locally advanced soft tissue sarcoma: the value of
adjuvant radiotherapy. Ann Surg Oncol 2006; 13:518-524.
16. Yang JC, Chang AE, Baker AR et al. Randomized prospective study of the benefit of
adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J
Clin Oncol 1998; 16:197-203.
17. Edge SB, Byrd DR, Compton CC et al. (eds). AJCC Cancer Staging Manual. New York:
Springer; 2010.
46
Survival in young and elderly soft-tissue sarcoma patients
18. Coindre JM, Trojani M, Contesso G et al. Reproducibility of a histopathologic grading
system for adult soft tissue sarcoma. Cancer 1986; 58:306-309.
19. WHO Classification of Soft Tissue Tumours. http://www.iarc.fr/en/publications/pdfsonline/pat-gen/bb5/bb5-classifsofttissue.pdf. 2012
20. Nur U, Shack LG, Rachet B et al. Modelling relative survival in the presence of incomplete
data: a tutorial. Int J Epidemiol 2010; 39:118-128.
21. Boden RA, Clark MA, Neuhaus SJ et al. Surgical management of soft tissue sarcoma in
patients over 80 years. Eur J Surg Oncol 2006; 32:1154-1158.
22. Lahat G, Dhuka AR, Lahat S et al. Complete soft tissue sarcoma resection is a viable
treatment option for select elderly patients. Ann Surg Oncol 2009; 16:2579-2586.
23. Al-Refaie WB, Habermann EB, Dudeja V et al. Extremity soft tissue sarcoma care in the
elderly: insights into the generalizability of NCI Cancer Trials. Ann Surg Oncol 2010;
17:1732-1738.
24. Gutierrez JC, Perez EA, Franceschi D et al. Outcomes for soft-tissue sarcoma in 8249
cases from a large state cancer registry. J Surg Res 2007; 141:105-114.
25. Marusyk A, DeGregori J. Declining cellular fitness with age promotes cancer initiation
by selecting for adaptive oncogenic mutations. Biochim Biophys Acta 2008; 1785:1-11.
26. Dunn GP, Bruce AT, Ikeda H et al. Cancer immunoediting: from immunosurveillance to
tumor escape. Nat Immunol 2002; 3:991-998.
27. Verweij J, Baker LH. Future treatment of soft tissue sarcomas will be driven by histological
subtype and molecular aberrations. Eur J Cancer 2010; 46:863-868.
28. Ducimetière F, Lurkin A, Ranchère-Vince D et al. Incidence of sarcoma histotypes and
molecular subtypes in a prospective epidemiological study with central pathology
review and molecular testing. PLoS One 2011; 6:e20294.
29. Mendenhall WM, Indelicato DJ, Scarborough MT et al. The management of adult soft
tissue sarcomas. Am J Clin Oncol 2009; 32:436-442.
30. Biau DJ, Ferguson PC, Turcotte RE et al. Adverse effect of older age on the recurrence of
soft tissue sarcoma of the extremities and trunk. J Clin Oncol 2011; 29:4029-4035.
31. Al-Refaie WB, Habermann EB, Jensen EH et al. Surgery alone is adequate treatment for
early stage soft tissue sarcoma of the extremity. Br J Surg 2010; 97:707-713.
32. Buchner M, Bernd L, Zahlten-Hinguranage A et al. Primary malignant tumours of bone
and soft tissue in the elderly. Eur J Surg Oncol 2004; 30:877-883.
33. Carreca I, Balducci L, Extermann M. Cancer in the older person. Cancer Treat Rev 2005;
31:380-402.
34. Horton JK, Gleason JF Jr., Klepin HD et al. Age-related disparities in the use of radiotherapy
for treatment of localized soft tissue sarcoma. Cancer 2011; 117:4033-4040.
35. Chen H, Cantor A, Meyer J et al. Can older cancer patients tolerate chemotherapy? A
prospective pilot study. Cancer 2003; 97:1107-1114.
36. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and
age-based disparities. JAMA 2004; 291:2720-2726.
37. Lurkin A, Ducimetière F, Vince DR et al. Epidemiological evaluation of concordance between
initial diagnosis and central pathology review in a comprehensive and prospective series
of sarcoma patients in the Rhone-Alpes region. BMC Cancer 2010; 10:150.
38. Recommendations for the reporting of soft tissue sarcoma. Association of Directors of
Anatomic and Surgical Pathology. Virchows Arch 1999; 434:187-191.
39. Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved
knowledge with unchanged survival over time. J Clin Oncol 2003; 21:2719-2725.
40. Wunder JS, Nielsen TO, Maki RG et al. Opportunities for improving the therapeutic ratio
for patients with sarcoma. Lancet Oncol 2007; 8:513-524.
47
3
Attachment 1: Univariate analysis Relative Survival (RS)
Univariate analysis
5-year RS
RER (95%CI) p-value
Age (years)
< 65
65-69
70-74
75-79
80-84
85+
73 (73-74)
68 (65-70)
59 (56-62)
60 (56-63)
55 (50-60)
46 (39-54)
1 (ref )
1.3 (1.0-1.6)
1.8 (1.4-2.2)
1.9 (1.5-2.4)
2.0 (1.5-2.7)
3.0 (2.2-4.0)
< 0.001
Sex
Male
Female
70 (69-71)
67 (66-68)
1 (ref )
1.1 (1.0-1.3)
0.2
Period
1989-1993
1994-1998
1999-2003
2004-2008
67 (65-69)
69 (67-71)
68 (66-70)
71 (69-73)
1 (ref )
1.0 (0.8-1.2)
1.0 (0.8-1.2)
0.9 (0.8-1.2)
0.9
Grade
Low
High
89 (88-90)
61 (60-62)
1 (ref )
4.2 (3.1-5.7)
< 0.001
Stage
I
II
III
IV
< 0.001
92 (91-93)
1 (ref )
76 (74-77) 3.0 (1.6-5.9)
60 (58-62) 5.8 (2.6-12.6)
29 (27-31) 16.4 (9.0-29.8)
Morphology Dedifferentiated liposarcoma
Myxoid & round cell liposarcoma
Pleomorphic liposarcoma
Mixed-type liposarcoma
Fibrosarcoma
Pleomorphic undifferentiated
sarcoma
Leiomyosarcoma
Rhabdomyosarcoma
Angiosarcoma
Synovial sarcoma
MPNST, malignant peripheral
nerve sheath tumor
Other
53 (41-65)
88 (86-90)
61 (56-67)
92 (84-97)
85 (83-88)
1.1 (0.5-2.5)
0.3 (0.2-0.4)
0.9 (0.6-1.3)
0.3 (0.1-0.8)
0.3 (0.2-0.5)
59 (58-61)
67 (65-69)
47 (41-52)
37 (30-44)
61 (58-64)
1 (ref )
0.7 (0.6-0.9)
1.6 (1.1-2.2)
2.1 (1.4-3.1)
0.9 (0.7-1.1)
56 (50-61)
82 (79-84)
1.3 (0.9-1.8)
0.5 (0.4-0.6)
Treatment
18 (15-21)
78 (77-79)
15 (10-21)
20 (17-24)
44 (40-48)
75 (74-77)
55 (50-59)
34 (24-44)
1 (ref )
0.1 (0.1-0.1)
1.0 (0.7-1.5)
0.6 (0.4-0.7)
0.3 (0.2-0.4)
0.1 (0.1-0.1)
0.2 (0.1-0.3)
0.4 (0.2-0.8)
No treatment
Surgery (monotherapy)
Radiotherapy (monotherapy)
Chemotherapy (monotherapy)
Surgery & chemotherapy (CT)
Surgery & radiotherapy (RT)
Surgery & RT & CT
Chemotherapy & radiotherapy
< 0.001
< 0.001
157