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Previous studies have suggested the presence of steroid receptors as a favourable prognostic factor in peritoneal mesothelioma (PM). This study aims to investigate possible hormonal effects on survival of PM. This is a retrospective study of prospectively collected data of 52 consecutive patients with PM who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by the same surgical team at St George Hospital in Sydney, Australia, between April 1996 and April 2013. Females were arbitrarily divided into assumed premenopausal (<51 years old; n = 15) and assumed postmenopausal (≥51 years old, n = 9). In each gender group, patients were furthered divided into three age groups (<40, 40-60, >60). A significant statistical difference was defined as p < 0.05. Females with epithelial mesothelioma had a significantly higher survival than males (p = 0.023). They also had a better overall median survival (>60 months) than males (43 months), although this difference was not statistically significant (p = 0.098). Survival of postmenopausal females became similar to males after excluding benign cystic mesothelioma. The better survival in premenopausal females could probably be explained by higher levels of oestradiol and progesterone. Also, our data suggests that higher rates of benign cystic mesothelioma in females was not the key reason for the better survival in female patients, further supporting the hypothesis of hormonal links with survival of PM. Therapeutic effects of sex steroid hormones on PM may be a valuable area to explore.
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R E S E A R C H Open Access
Effects of sex hormones on survival of
peritoneal mesothelioma
Yeqian Huang
1
, Nayef A. Alzahrani
2,4
, Winston Liauw
3
and David L. Morris
4*
Abstract
Background: Previous studies have suggested the presence of steroid receptors as a favourable prognostic factor
in peritoneal mesothelioma (PM). This study aims to investigate possible hormonal effects on survival of PM.
Methods: This is a retrospective study of prospectively collected data of 52 consecutive patients with PM who
underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by the same
surgical team at St George Hospital in Sydney, Australia, between April 1996 and April 2013. Females were arbitrarily
divided into assumed premenopausal (<51 years old; n= 15) and assumed postmenopausal (51 years old, n= 9).
In each gender group, patients were furthered divided into three age groups (<40, 4060, >60). A significant
statistical difference was defined as p< 0.05.
Results: Females with epithelial mesothelioma had a significantly higher survival than males (p= 0.023). They also
had a better overall median survival (>60 months) than males (43 months), although this difference was not
statistically significant (p= 0.098). Survival of postmenopausal females became similar to males after excluding
benign cystic mesothelioma.
Conclusions: The better survival in premenopausal females could probably be explained by higher levels of
oestradiol and progesterone. Also, our data suggests that higher rates of benign cystic mesothelioma in females
was not the key reason for the better survival in female patients, further supporting the hypothesis of hormonal
links with survival of PM. Therapeutic effects of sex steroid hormones on PM may be a valuable area to explore.
Keywords: Peritoneal mesothelioma, Hormone, Female, Survival
Background
Mesothelioma arises from serosal lining of the pleura,
peritoneum, pericardium or tunica vaginalis [1]. Histo-
logical appearance of mesothelioma ranges from a well-
differentiated cystic variant to a poorly differentiated
sarcomatoid variant [2]. The peritoneum is the second
most common site for mesothelioma, contributing one
third of all cases [3]. Common presentations of periton-
eal mesothelioma (PM) include increased abdominal
girth, abdominal pain, abdominal mass or ascites and
weight loss. Due to nonspecific symptoms, diagnosis is
often delayed [3, 4]. Systemic chemotherapy has shown
to have limited efficacy [5]. The current approach for
mesothelioma is a combined locoregional treatment
which consists of cytoreductive surgery (CRS) and
hyperthermic intraperitoneal chemotherapy (HIPEC) for
suitable patients. This approach has been shown to pro-
long the survival of PM and achieve a median survival of
up to 60 months [6].
There is a clear relationship between asbestos expos-
ure and mesothelioma. Higher incidence of asbestos-
related occupations among males has been suggested to
account for the higher risk of mesothelioma in males.
Nevertheless, mesothelioma also occurs in 20 % of pa-
tients without previous clearly identified asbestos expos-
ure, suggesting that other factors may be responsible for
the pathogenesis in this disease [7]. Female patients have
been consistently reported to have a better prognosis
than male patients in previous studies [4, 6, 811]. The
prognostic difference between sexes has suggested a pos-
sible hormonal link with the survival of this disease.
Also, a few histological studies have demonstrated the
* Correspondence: david.morris@unsw.edu.au
4
Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St
George Hospital, University of New South Wales, Level 3 Pitney Building,
Gray Street, Kogarah, Sydney, New South Wales 2217, Australia
Full list of author information is available at the end of the article
WORLD JOURNAL OF
SURGICAL ONCOLOGY
© 2015 Huang et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Huang et al. World Journal of Surgical Oncology (2015) 13:210
DOI 10.1186/s12957-015-0624-4
presence of sex steroid receptors in PM [3, 7, 12, 13].
Thus, the aim of this study was to assess hormonal ef-
fects on survival of PM.
Methods
Settings
This is a retrospective study of prospectively collected
data of 52 consecutive patients with PM who underwent
CRS and HIPEC by the same surgical team at St George
Hospital in Sydney, Australia, between April 1996 and
April 2013. All the clinical and treatment-related data
were collected and entered into a computerised database
in order to evaluate the survival outcomes of patients
with peritoneal mesothelioma. A signed informed con-
sent to use their clinical data for research purposes was
obtained from all patients prior to their surgery. This
study was ethically approved by South Eastern Sydney
Local Health District Human Research Ethics Committee,
New South Wales, Australia.
Patients
Patients had a good performance status (World Health
Organization Performance Status 2) and had a histo-
logical diagnosis of peritoneal mesothelioma. Histological
diagnosesinthisstudyincluded benign cystic mesotheli-
oma, epithelial mesothelioma, sarcomatoid mesothelioma
and biphasic mesothelioma (mixed epithelial and sarcoma-
toid variants). All patients were managed by a standard
treatment protocol which includes CRS and HIPEC. Suit-
ability to undergo CRS and perioperative intraperitoneal
chemotherapy (PIC) was evaluated during a regular weekly
meeting attended by a multidisciplinary team including
surgical oncologists, medical oncologists, radiologists, can-
cer care nurses and research staff. Survival differences be-
tween sexes were analysed. All patients were then further
divided into three groups for survival analysis including
premenopausal females, postmenopausal females and
males. Premenopause was defined as less than 51 years old
(n= 15) whereas postmenopause was defined as at least
51 years old (n= 9). Subgroup analysis compared survival
outcomes of different mesothelioma subtypes within
each gender group. Also, survival of three age groups
(i.e. aged less than 40, between 40 and 60 and greater
than 60 years old) was also compared within each gen-
der group (Females: <40 group n=7; 4060 group n=
14; >60 group n= 3; Males: <40 group n=5; 4060
group n= 16; >60 group n=7).
Preoperative management
All patients underwent standard preoperative investigations
which included physical examination, double contrast-
enhanced computed tomography scans of the chest, abdo-
menandpelvis,aswellaspositronemissiontomography.
CRS
A standardised treatment protocol combining CRS and
PIC was performed by the surgical team. An initial assess-
ment of the volume and extent of disease was recorded
using the peritoneal cancer index (PCI), as described by
Jacquet and Sugarbaker [14]. This assessment combines
thickness of lesion size (LS) (LS 0: no macroscopic tumour;
LS 1: tumour <0.5 cm; LS 2: tumour 0.55cm;andLS3:
tumour >5 cm) with tumour distribution (abdominopelvic
region 012) to quantify the extent of disease as a numer-
ical score (PCI 039). The aim of CRS was to remove all
macroscopic intraperitoneal and visceral tumour deposits.
CRS was performed using Sugarbakers technique [15].
All sites and volumes of residual disease following CRS
were recorded prospectively using the completeness of
cytoreductive (CC) score (CC0no macroscopic residual
cancer remained; CC1no nodule >2.5 mm in diameter
remained; CC2nodules between 2.5 mm and 2.5 cm in
diameter remained; CC3nodules >2.5 cm in diameter
remained) [14].
HIPEC
After CRS, but prior to intestinal anastomosis or repair of
seromuscular tears, HIPEC was performed by installation
of a heated chemoperfusate into the abdomen using the
coliseum technique. Cisplatin (100 mg/m
2
in 1000 ml nor-
mal saline) and mitomycin (12.5 mg/m
2
in 1000 ml nor-
mal saline) were given simultaneously over 90 min.
Statistical analysis
All statistical analyses were performed using IBM SPSS
for Windows version 22. Comparison of normally dis-
tributed variables was performed using analysis of vari-
ance (one-way ANOVA) test. Categorical variables were
analysed using chi-square test or Fisherexact test where
appropriate. Median survival was calculated based on
the last time of contact or death in the unit of months.
Survival analysis was performed using the Kaplan-Meier
curves and log-rank test for comparison. A significant
difference was defined as pvalue less than 0.05.
Results
Descriptive characteristics
Table 1 demonstrates the background characteristics of
our patients with mesothelioma. There was a significant
statistical significance in terms of histological diagnosis
(p= 0.045). Of females, 29.1 % were diagnosed with the
benign cystic form of mesothelioma as compared to
3.7 % in males. More males (18.5 %) were diagnosed
with malignant biphasic mesothelioma as compared to
8.3 % in females. There was no statistical difference in
terms of age, mean PCI, CC score, transfusion units and
HIPEC between females and males.
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 2 of 7
Survival analysisepithelial type of mesothelioma
Due to the small numbers of patients with sarcoma and
mixed variants, the statistical analysis of all histological
subtypes could not be performed. However, survival was
significantly higher in females with epithelial type of
mesothelioma (p= 0.023). As half of the female patients
with epithelial mesothelioma were still alive at the time
of analysis, median survival could not be calculated for
female patients. However, according to the survival
curve, the median survival in females with epithelial type
of mesothelioma was greater than 60 months as com-
pared to survival in males (median = 22.0 months, 95 %
confidence interval (CI) = 7.936.1) (Fig. 1)
Survival analysisfemales vs. males
As more than 50 % of patients remained alive at the end
of this study, median survival of all females, premeno-
pausal and postmenopausal females was unable to be
calculated. It was shown that females had a better me-
dian survival (>60 months as shown in Fig. 2) than
males (median = 43.0 months, 95 % CI = 5.580.5), al-
though this difference did not reach a statistical signifi-
cance (p= 0.098).
Survival analysispremenopausal females vs.
postmenopausal females vs. males
Figure 3 compares the survival curve including benign cys-
tic mesothelioma with the curve excluding benign cystic
mesothelioma. Two survival curves showed similar trends
in all three groups. However, survival of postmenopausal
females became more similar to males after excluding be-
nign mesothelioma. It also showed that premenopausal fe-
males have better survival then the other two groups.
However, there was no statistical significance in terms of
Table 1 Background characteristics
Female Male
Total n=52 p
N(%) 24 (46.2) 28 (53.8)
Age mean (SD) 46.8 (49.5) 51.8 (50.0) 0.147
Diagnosis n(%) 0.045
Benign cystic 7 (29.1) 1 (3.7)
Epithelial 14 (58.3) 21 (77.8)
Sarcomatoid 1 (4.2) 0 (0)
Biphasic 2 (8.3) 5 (18.5)
PCI mean (SD) 17 22 0.099
CC n(%) 0.117
0 17 (73.9) 13 (46.4)
1 6 (26.1) 14 (50.0)
2 0 1 (3.6)
300
Transfusion mean (SD) 4.75 (4.54) 7.21 (7.81) 0.180
HIPEC n(%) 0.872
Yes 22 (91.7) 26 (92.9)
No 2 (7.7) 2 (7.1)
Fig. 1 Survival curve for epithelial mesothelioma
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 3 of 7
median survival among premenopausal females, postmen-
opausal females and males (p= 0.253).
Subgroup survival analysis: <40 vs. 4060 vs. >60
Since more than 50 % of patients remained alive at the
end of this study, median survival of females aged <40
and females aged between 40 and 60 was unable to be
calculated. The median survival of females aged >60 was
23 months (95 % CI could not be calculated). The sur-
vival curve showed that patients aged 60 have a better
median survival than those aged greater than 60 (Fig. 4).
However, such a difference did not reach a statistical sig-
nificance (p= 0.952).
Inthemalegroup,mediansurvivalofthoseagedless
than 40, between 40 and 60 and greater than 60 was
62 months (95 % CI could not be calculated),
43 months (95 % CI = 13.572.5) and 18 months (95 %
CI = 15.420.6), respectively. Although the difference
was not statistically significant (p= 0.486), the survival
graph showed a trend of improving survival in younger
male patients (Fig. 4).
Discussion
Mesothelioma is aggressive and fatal. The differential ex-
pression of hormonal receptors has been suggested to be
correlated with survival differences between sexes in PM
[3]. A recent study done by our group, Pillai et al. [7], in-
vestigated the role of oestrogen receptors in malignant
PM (MPM). They identified nuclear oestrogen receptor-
β(ER-β(n)) as a favourable prognostic factor in PM and
suggested that high level of oestradiol may explain the
survival difference in sexes, since ER-β(n) is oestradiol-
dependent [7]. Also, the study done by Horita et al. sug-
gested that progesterone induces apoptosis in malignant
mesothelioma cells. Our data is consistent with these
hormonal findings. We have seen a significantly better
survival in females with the epithelial type in this study.
Better survival outcomes in assumed premenopausal fe-
males and similar survival trends between postmeno-
pausal females and males shown in our study could be
explained by a high level of oestradiol and progesterone
in premenopausal patients (Fig. 3). Although we have
not measured sex hormones or their receptors in this
study, our finding is consistent with previous literature
in pleural mesothelioma [16, 17]. The study done by
Taioli et al. reviewed 14,228 patients with MPM and
showed less apparent difference in survival for females
over age 50 years. Wolf et al. studied 715 cases of pa-
tients with MPM and showed that young females are
disproportionately represented among long-term survi-
vors of MPM [18]. They suggested that hormonal status
may contribute to better survival in female patients
with MPM.
Our subgroup analysis findings suggest that females
have a better survival in the epithelial mesothelioma
group as compared with males. Given that epithelial
variant was suggested to be a favourable prognostic fac-
tor, such a significant difference may further suggest the
Fig. 2 Survival curve for males and females
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 4 of 7
key role of sex steroids and/or hormonal receptors in
the survival of PM. In addition, our findings also show
that younger patients have better survival in both gender
groups. This could be contributed by a high level of
oestradiol in females. Also, free and bioavailable oestradiol
levels decline significantly with ageing in males [19]. This
could contribute to the much higher survival in male
patients aged <40 as compared with those aged >60 (62
vs. 18 months, respectively). However, the evidence to
support these possible explanations is insufficient from
our data.
Overall survival was higher in females with PM than
males, which is consistent with previous studies [3, 5, 710].
A higher incidence of MPM in males was also demon-
strated. Nevertheless, our data suggests that higher rate of
benign cystic mesothelioma in females was not the key rea-
son for greater survival in female patients given similar sur-
vival curves shown in Fig. 3, supporting the hypothesis of a
hormonal link with the survival of PM.
Our study is the one of the few clinical studies that eval-
uated the link between sex steroid hormones and survival
of patients with PM. However, this is a retrospective study
Fig. 3 Survivalpremenopausal females vs. postmenopausal females vs. males (aincludes benign cystic mesothelioma; bexcludes benign
cystic mesothelioma)
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 5 of 7
conducted at a single centre. Given that suitability of pa-
tients for peritonectomy was discussed during weekly
meetings and only selected patients were offered this com-
bined therapy, there was selection bias in this study. Also,
our study was limited by the small sample size due to the
low incidence of this disease. A similar study design could
potentially be applied for a greater population in order to
further explore the link between sex steroid hormones
and survival of PM.
Conclusions
In conclusion, oestrogen and progesterone may prolong
the survival of patients with PM. Therapeutic effects of
sex steroid hormones on PM may be a valuable area to
Fig. 4 Survival subgroup: <40 vs. 4060 vs. >60
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 6 of 7
explore. Potential topics for future research include the
survival outcomes of young females with and without
hysterectomy, as well as postmenopausal females on
hormonal replacement therapy.
Competing interests
The authors declare that they have no competing interests.
Authorscontributions
YH acquired and analysed the data, participated in the interpretation of the
data and drafted the manuscript. NAA participated in the interpretation of
the data and revised the manuscript. WL contributed to the conception and
design of this study. DLM contributed to the conception and design, revised
the draft critically and gave the final approval of the version to be published.
All authors read and approved the final manuscript.
Acknowledgements
The authors give their special thanks to Jing Zhao, MD, for maintaining the
peritonectomy database.
Author details
1
St George Clinical School, University of New South Wales, Sydney, New
South Wales, Australia.
2
College of Medicine, Imam Muhammad ibn Saud
Islamic University, Riyadh, Saudi Arabia.
3
Department of Medical Oncology, St
George Hospital, University of New South Wales, Sydney, New South Wales,
Australia.
4
Hepatobiliary and Surgical Oncology Unit, Department of Surgery,
St George Hospital, University of New South Wales, Level 3 Pitney Building,
Gray Street, Kogarah, Sydney, New South Wales 2217, Australia.
Received: 21 March 2015 Accepted: 11 June 2015
References
1. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic
intraperitoneal chemotherapy for malignant peritoneal mesothelioma:
multi-institutional experience. J Clin Oncol. 2009;27(36):623742.
2. Averbach AM, Sugarbaker PH. Peritoneal mesothelioma: treatment approach
based on natural history. Peritoneal carcinomatosis: drugs and diseases.
USA: Springer; 1996. p. 193211.
3. Chua TC, Yao P, Akther J, et al. Differential expression of Ki-67 and sex steroid
hormone receptors between genders in peritoneal mesothelioma. Pathol
Oncol Res. 2009;15(4):6718.
4. Feldman AL, Libutti SK, Pingpank JF, et al. Analysis of factors associated with
outcome in patients with malignant peritoneal mesothelioma undergoing
surgical debulking and intraperitoneal chemotherapy. J Clin Oncol.
2003;21(24):45607.
5. Plaus WJ. Peritoneal mesothelioma. Arch Surg. 1988;123(6):7636.
6. Yan T, Popa E, Brun E, Cerruto C, Sugarbaker P. Sex difference in diffuse
malignant peritoneal mesothelioma. Br J Surg. 2006;93(12):153642.
7. Pillai K, Pourgholami MH, Chua TC, Morris DL. Oestrogen receptors are
prognostic factors in malignant peritoneal mesothelioma. J Cancer Res Clin
Oncol. 2013;139(6):98794.
8. Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone
G. Prognostic factors in patients with pleural mesothelioma: the European
Organization for Research and Treatment of Cancer experience. J Clin
Oncol. 1998;16(1):14552.
9. Adams VI, Unni KK, Muhm JR, Jett JR, Ilstrup DM, Bernatz PE. Diffuse
malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
Cancer. 1986;58(7):154051.
10. Metintas M, Metintas S, Ucgun I, et al. Prognostic factors in diffuse
malignant pleural mesothelioma: effects of pretreatment clinical and
laboratory characteristics. Respir Med. 2001;95(10):82935.
11. Rusch VW, Venkatraman ES. Important prognostic factors in patients with
malignant pleural mesothelioma, managed surgically. Ann Thorac Surg.
1999;68(5):1799804.
12. Barnetson RJ, Burnett RA, Downie I, Harper CM, Roberts F.
Immunohistochemical analysis of peritoneal mesothelioma and primary and
secondary serous carcinoma of the peritoneum antibodies to estrogen and
progesterone receptors are useful. Am J Clin Pathol. 2006;125(1):6776.
13. Horita K, Inase N, Miyake S, Formby B, Toyoda H, Yoshizawa Y. Progesterone
induces apoptosis in malignant mesothelioma cells. Anticancer Res.
2000;21(6A):38714.
14. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and
staging of patients with peritoneal carcinomatosis. Peritoneal
carcinomatosis: principles of management. USA: Springer; 1996. p. 35974.
15. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221(1):2942.
16. Taioli E, Wolf AS, Camacho-Rivera M, Flores RM. Women with malignant
pleural mesothelioma have a threefold better survival rate than men. Ann
Thorac Surg. 2014;98(3):10204.
17. Sugarbaker DJ, Wolf AS, Chirieac LR, et al. Clinical and pathological features
of three-year survivors of malignant pleural mesothelioma following extra-
pleural pneumonectomy. Eur J Cardiothorac Surg. 2011;40(2):298303.
18. Wolf AS, Richards WG, Tilleman TR, et al. Characteristics of malignant pleural
mesothelioma in women. Ann Thorac Surg. 2010;90(3):94956.
19. Leifke E, Gorenoi V, Wichers C, Von Zur MA, Von Büren E, Brabant G. Age-related
changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone
binding globulin levels in men: cross-sectional data from a healthy male cohort.
Clin Endocrinol. 2000;53(6):68995.
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Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 7 of 7
... Given that women have a lower risk of developing mesothelioma and have a higher survival rate when compared to men, some studies hypothesized that hormones, in addition to epidemiological differences such as occupational trends, could be a factor [10]. ...
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Background Multicystic peritoneal mesothelioma (MCPM) is a rare, slowly growing, condition prone to recur after surgery. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) added to complete cytoreductive surgery (CRS) remains controversial and difficult to assess. As patients are mostly reproductive age women, surgical approach, and fertility considerations are important aspects of the management. This observational retrospective review aimed to accurate treatment strategy reflections. Methods The RENAPE database (French expert centers network) was analyzed over a 1999–2019 period. MCPM patients treated with CRS were included. A special focus on HIPEC, mini-invasive approach, and fertility considerations was performed. Results Overall 60 patients (50 women) were included with a median PCI of 10 (4–14) allowing 97% of complete surgery, followed by HIPEC in 82% of patients. A quarter of patients had a laparoscopic approach. Twelve patients (20%) recurred with a 3-year recurrence free survival of 84.2% (95% confidence interval 74.7–95.0). The hazard of recurrence was numerically reduced among patients receiving HIPEC, however, not statistically significant (hazard ratio 0.41, 0.12–1.42, p = 0.200). A severe post-operative adverse event occurred in 22% of patients with five patients submitted to a subsequent reoperation. Among four patients with a childbearing desire, three were successful (two had a laparoscopic-CRS-HIPEC and one a conventional CRS without HIPEC). Conclusion MCPM patients treatment should aim at a complete CRS. The intraoperative treatment options as laparoscopic approach, fertility function sparing and HIPEC should be discussed in expert centers to propose the most appropriate strategy.
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Mesothelioma is a rare neoplasm arising from the mesothelial cells lining the pleura, peritoneum, pericardium, and tunica vaginalis layer of testis [1]. Diffuse malignant peritoneal mesothelioma (DMPM) represents about one-fifth to one-third of all forms of mesothelioma.
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Background: Mesothelioma is a rare and deadly form of cancer, linked to asbestos exposure. Although the United Kingdom has banned asbestos, the incidence rate remains high. Previous research has indicated that female individuals have better survival than male individuals, but this has never been examined in the United Kingdom. Materials and methods: Pleural mesothelioma cases from 2005 to 2014 were extracted from the United Kingdom Lung Cancer Dataset. Multivariable logistic regression was used to assess the clinical and demographic factors associated with gender. A multivariable Cox proportional hazards model and propensity matching methods were used to assess gender differences in overall survival while accounting for potential confounders. Results: There were 8479 (87.8%) male and 1765 (17.2%) female individuals included in the analysis. Female individuals were significantly younger, with more epithelial histology than male individuals. Female individuals had significantly better overall survival (adjusted hazard ratio, 0.85, 95% confidence interval, 0.81-0.90). Results remained similar when stratifying by age and performance status, and when limiting to patients with epithelial histology. Conclusions: The study increases knowledge about gender differences in mesothelioma survival and is the first to directly examine this in the United Kingdom. It further disentangles the effects of age, histology, and health status. Increased estrogen may improve survival and could provide a potential target for future therapies.
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Peritoneal mesothelioma (PM) is a rare and aggressive primary peritoneal malignancy characterized by widespread multiple metastatic tumour nodules originating from the peritoneum. The conventional classification distinguishes diffuse malignant peritoneal mesothelioma (DMPM) and border-line forms: multicystic peritoneal mesothelioma (MCPM) and well-differentiated papillary peritoneal mesothelioma (WDPPM). Despite the novel achievements in the management of PM, there is difficulty in conducting randomized trials due to its rarity and aggressive biology in many cases. As there is, a necessity to standardize diagnosis and management of PM, the Peritoneal Surface Oncology Group International (PSOGI) commissioned a steering committee to elaborate clinical guidelines.
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Chapter
Peritoneal mesothelioma (PM) is an uncommon and locally aggressive tumor encompassing a wide spectrum of biological behaviors, from clinically indolent to rapidly fatal disease. PM has been historically treated with debulking (DBK) surgery and/or palliative systemic chemotherapy (sCT), resulting in a median survival of only 1 year in the malignant variants. The biology of this disease has been poorly understood until recent years when mechanisms of resistance to therapy and new potential molecular therapeutic targets have been thoroughly investigated. Pathological and histological classifications of PM are still evolving. The clinical management of these conditions has improved during the last 30 years with the advent of a comprehensive treatment approach involving cytoreductive surgery (CRS) and intraperitoneal drug administration, such as hyperthermic intraperitoneal chemotherapy (HIPEC), resulting in increased patient survival. This review addresses relevant clinical and biological issues of PM, including molecular features, diagnosis, pathology, role of modern systemic and targeted therapies, patient selection for combined surgical treatment, surgical technique, and prognostic factors.
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Background: Many studies have reported that women with malignant pleural mesothelioma (MPM) experience longer survival compared with men, whereas others have not. To date, no large population-based studies have evaluated MPM outcome and its determinants in female patients. Methods: All pathologically confirmed cases of MPM in the Surveillance, Epidemiology and End Results database from 1973 to 2009 were evaluated. Age, year of diagnosis, race, stage, cancer-directed surgery, radiation, and vital status were analyzed according to gender. Cox proportional hazard models were derived to assess the association between prognostic factors and survival. Results: There were 14,228 cases of MPM, of which 3,196 (22%) were women. Despite similar baseline characteristics for both genders, 5-year survival was 13.4% in women and 4.5% in men (p < 0.0001). The effect of female gender on survival persisted when stratified by age (dichotomized at 50 years), stage, or race, but differed depending on treatment. Even when adjusted for age, stage, race, and treatment, female MPM patients experienced longer survival than men (hazard ratio = 0.78; 95% confidence interval 0.75 to 0.82). Conclusions: This large data set confirms that although MPM is less common in women, they present with similar stage and are offered similar treatment options compared with men. Nevertheless, survival is far better in women compared with men, independent of confounders such as age, stage, and treatment. Differences in asbestos exposure, tumor biology, and the impact of circulating hormones on host response must be investigated to understand this survival advantage and improve prognosis for patients of both genders.
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PURPOSE Identification of prognostic factors in patients with malignant pleural mesothelioma based on prospectively collected international data. PATIENTS AND METHODS From October 1984 to October 1993, 204 eligible adult patients with malignant pleural mesothelioma were entered into five consecutive prospective European Organization for Research and Treatment of Cancer (EORTC) phase II clinical trials designed to assess the efficacy of various anticancer drugs (mitoxantrone, epidoxorubicin, etoposide, and paclitaxel). The Cox model was used to assess 13 factors related to biology and disease history with respect to survival. RESULTS The median survival duration was 12.6 months from diagnosis and 8.4 months from trial entry. In the multivariate analysis, poor prognosis was associated with a poor performance status, a high WBC count, a probable/possible histologic diagnosis of mesothelioma, male gender, and having sarcomatous tissue as the histologic subtype. Taking these five factors into consideration, patients were classified into two groups: a good-prognosis group (1-year survival rate, 40%; 95% confidence interval [CI], 30% to 50%) and a poor-prognosis group (1-year survival, 12%; 95% CI, 4% to 20%). CONCLUSION These results may help to design new clinical trials in pleural mesothelioma by selecting more homogenous groups of patients.
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Background: Malignant peritoneal mesothelioma (MPM) is a rare and fatal cancer. Females are found to survive longer than males after treatment, suggesting a possible involvement of hormonal factors. Estradiol is involved in cellular proliferation of a number of cancers and acts mainly through oestrogen receptors (ERs). Hence, we examined the expression of oestrogen receptors with correlation to prognosis. Methods: Oestrogen receptors expression was examined using immunohistochemistry on 42 paraffin-embedded sections of MPM tumours. Kaplan-Meier survival curves were analysed to determine the significance of ER expression in relation to prognosis. Results: ER-β (nuclear) was detected in 33 (79 %) patients. ER-β was also detected in the cellular cytoplasm of 9 (21 %) patients. Presence of ER-β (nuclear) was associated with favourable survival (univariate analysis, P = 0.001), whereas the presence of ER-β (cytoplasm) was associated with a poor survival (P = 0.014). Multivariate Cox regression analysis revealed the absence of ER-β (nuclear) and the presence of ER-β (cytoplasm) to be independent predictive factors for poor disease outcome (hazard ratio 5.4, 95 % confidence interval 1.86-15.75; P = 0.002 and hazard ratio 8.0, 95 % confidence interval 1.8-34; P = 0.005), respectively. ER-α (nuclear) was detected in only 4 (9 %) of patients and not statistically significant (univariate analysis, P = 0.066). Conclusion: The presence of ER-β (cytoplasm) is associated with poor prognosis. The favourable survival association observed in patients with ER-β (nuclear) raises a question about the molecular mechanisms of the tumorigenic roles of ER-β in each cellular compartment and requires further studies.
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Clinical, radiographic, surgical, and pathologic findings and survival in 92 patients with diffuse malignant mesothelioma (DMM) of the pleura who were examined at the Mayo Clinic between 1950 and 1980, were studied retrospectively. With the use of defined criteria and ordinary tissue stains, the 92 cases were classified into the following histologic subtypes: purely epithelial, 42 cases; mixed, 29 cases; and sarcomatous, 21 cases. Eight of the sarcomatous cases were desmoplastic. Median survivals were 12, 5, and 3 months for the patients in the epithelial, mixed, and sarcomatous groups, respectively. Survival was significantly longer for patients with epithelial DMM. Women survived longer than men but more often had epithelial DMM. Early disease manifested as multiple discrete pleural nodules, predominantly on the parietal pleura. However, nine patients had a dominant mass. Radiographic signs especially suggestive of DMM were nodular pleural thickening, irregular thickening of interlobar fissures, a dominant mass, or decreased volume of the affected hemithorax.
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Surgery-based multimodality therapy is associated with long-term survival in a significant number of pleural mesothelioma patients. We explored factors associated with 3-year survival in patients with malignant pleural mesothelioma, who underwent extrapleural pneumonectomy, to help refine patient selection criteria for surgery and other therapies. With Institutional Review Board approval, we reviewed records in the International Mesothelioma Program Patient Data Registry to identify all patients, who underwent extrapleural pneumonectomy for malignant pleural mesothelioma between 1 January 1988 and 31 May 2007. Vital status as of 31 May 2010 was confirmed. Fisher's exact test was used to compare dichotomous variables for patients who survived at least 3 years with those who did not. Kaplan-Meier analysis was used to estimate the cumulative survival probability for all 3-year survivors. Among 636 patients who underwent extrapleural pneumonectomy, 117 (18%) survived at least 3 years following surgery, including 26 remaining alive and four lost to follow-up. Of the 3-year survivors, 39 (33%) were female, 61 (52%) had left-sided disease, and the median age was 56 years (range 27-77). Relatively more 3-year survivors were younger than, or at the median age (p=0.0005), or female (p=0.0007), had epithelial tumor histology (p<0.0001) and/or had normal white blood cell count (p=0.0001), hemoglobin (p<0.0001), or platelet count (p<0.0001) preoperatively. The median survival of the 117 patients who survived 3-years was 59 months. Among these patients, a significant association between age and survival was found only for women. A significant proportion of patients undergoing extrapleural pneumonectomy for pleural mesothelioma experienced extended survival. Although favorable prognostic features were more common, the cohort of 3-year survivors included a substantial number of patients with late-stage disease. The longest survival (median greater than 7 years) was experienced by women under the median age of 56 years. These data support the role of macroscopic cytoreduction through extrapleural pneumonectomy in the context of multimodality therapy to extend survival for malignant pleural mesothelioma. Further efforts to treat micrometastatic disease and improve patient selection are warranted.
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The incidence of malignant pleural mesothelioma (MPM) is higher in men than in women, likely due to increased occupational asbestos exposure among men. Women also appear to experience better long-term survival. This study evaluates the role of gender in relation to established prognostic factors in MPM. We reviewed 715 cases of MPM treated with extrapleural pneumonectomy at our institution between July 1987 and December 2008. Data for patients with epithelial and nonepithelial tumors were analyzed separately. Kaplan-Meier and Cox regression analyses were used to estimate survival for various cohorts to assess the relationship between gender and survival independent of age at surgery, stage, side, and preoperative laboratory studies. Of the 702 patients with complete data available, 114 out of 450 patients with epithelial tumors and 31 out of 252 patients with nonepithelial histology were women. Women with epithelial (and not nonepithelial) disease were found to differ significantly from men with respect to younger age, higher rate of thrombocytosis, and longer survival after surgery. The effect of gender on survival of patients with epithelial disease persisted when controlling for age, stage, thrombocytosis, leukocytosis, and anemia with a multivariable analysis. No significant differences in survival were seen among patients with nonepithelial disease with regard to gender, age, or anemia. In the absence of other negative prognostic factors, women with epithelial MPM demonstrated a survival advantage. These findings support an aggressive approach to treating MPM including extrapleural pneumonectomy in individuals with favorable prognostic predictors, particularly women with epithelial histology and no other risk factors.
Article
• Peritoneal mesothelioma is a rare neoplasm often related to previous asbestos exposure. In 14 cases the diagnosis before surgery was virtually impossible, as patients presented with vague abdominal complaints and nonspecific physical examination findings. Laboratory testing (including computed tomography) was of no added diagnostic help. Widespread peritoneal neoplastic growth was the common finding at laparotomy. The tumor was grossly indistinguishable from other types of abdominal carcinomatosis. Electron microscopy proved to be the diagnostic tool of choice. Routine histologic techniques often gave nondiagnostic results. Intraperitoneal asbestos fibers were not observed. Treatment with radiation, chemotherapy, or both produced a 50% partial response rate, but survival was not affected. Malignant ascites was effectively palliated without complication in two of three patients with peritoneovenous shunting. An unusual case occurred in which histologic material from a second-look laparotomy documented complete response to a new regimen of intraperitoneal chemotherapy. (Arch Surg 1988;123:763-766)
Article
Peritoneal mesothelioma is a rare tumor that is considered a terminal disease with only palliative treatment options. The natural history and actual incidence of disease are poorly documented because most reports include pleural and peritoneal mesothelioma together as a single disease. The estimated incidence of both pleural and peritoneal mesothelioma in the United States in 1975 was 2.2 cases per million population [1]. According to the experience at the University of Minnesota, the incidence of the disease has been on the rise in last few decades, probably due to more precise diagnosis [2]. Now it would be reasonable to estimate that 2,200 new cases (range 1,000–3,000+) of mesothelioma occur in the United States annually [3]. In most reports peritoneal and pleural mesotheliomas are considered as a single entity. Pleural mesothelioma is encountered more often and constitutes 60–90 percent of all cases [4,5]. Nevertheless, it has been reported that the natural history and prognosis of peritoneal and pleural mesotheliomas differ somewhat. Antman and colleagues [4,5] suggested that patients with peritoneal mesothelioma survive better. At autopsy tumor remained confined to the abdomen in two thirds of the cases and in 78 percent of them death was a direct result of complications of intraabdominal disease.