Ann Surg Oncol DOI 10.1245/s10434-014-3803-6
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Current Trends in the Management of Malignant Peritoneal Mesothelioma John T. Miura, MD, Fabian M. Johnston, MD, MHS, T. Clark Gamblin, MD, MS, and Kiran K. Turaga, MD, MPH Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
ABSTRACT Background. Historically, malignant peritoneal mesothelioma (MPM) has been considered an aggressive and lethal neoplasm. However, contemporary series have demonstrated improved outcomes following a combination of cytoreductive surgery and intraperitoneal chemotherapy. We sought to assess the trends in management and survival of patients with MPM in the United States. Methods. The Surveillance, Epidemiology, and End Results database was used to identify all patients diagnosed with malignant peritoneal mesothelioma from 1973 to 2010. Overall survival (OS) was studied with Kaplan– Meier curves and Cox regression analyses. Results. We identified 1,591 patients with MPM. Median age at diagnosis was 64 years (IQR 53–74 years) with the majority of patients presenting with metastatic disease (n = 962, 60.5 %). A total of 980 patients (61.6 %) did not receive surgical therapy. Receipt of radical cytoreduction for patients with metastatic MPM demonstrated a significant improvement in OS compared with patients not receiving surgery (20 vs. 4 months, p \ 0.01). A temporal increase was observed in OS for patients receiving surgery (1991–1995: 15 vs. 2006–2010: 38 months, p = 0.1). In multivariate models, limited (HR 0.55; 95 % CI 0.48–0.63; p \ 0.01) and radical (HR 0.66; 95 % CI 0.54–0.80; p \ 0.01) surgery were independently associated with improved survival. Conclusions. In the current era, approximately three of every five patients do not receive surgery when diagnosed with MPM, although a significant survival benefit is noted in select patients. The opportunity to improve patient
Ó Society of Surgical Oncology 2014 First Received: 29 January 2014 K. K. Turaga, MD, MPH e-mail: [email protected]
survival with surgical therapy is lost in a significant number of MPM patients. Currently, malignant peritoneal mesothelioma (MPM) accounts for *30 % of all mesothelioma tumors, with an annual incidence in the United States of 200–400 new cases.1 Although asbestos exposure is the primary risk factor for the development of MPM, only 33 % of patients with the disease report a history of prior contact with the mineral.2 Nonspecific clinical symptoms such as abdominal pain, weight loss, and increasing abdominal girth contribute to the difficulties and delay in diagnosing MPM. As a result, the majority of patients present with advanced disease. Although possessing an aggressive underlying biology, it is uncommon for MPM to extend beyond the peritoneal cavity.3 Lymph node and extra-abdominal metastasis are rare.4 However, without aggressive treatment, MPM is a universally lethal disease with a median overall survival ranging from 6 to 12 months.5–7 Cisplatin and pemetrexed based chemotherapy as solitary therapy has been used to treat MPM, but has poor tumor response rates and negligible improvement in overall survival in contrast with its use for pleural mesothelioma.8–12 As a result of the locoregional nature of the disease, contemporary treatment options have now evolved toward aggressive surgical approaches combined with delivery of intraperitoneal chemotherapy in the form of hyperthermic intraperitoneal chemoperfusion (HIPEC). Although at present there have not been any randomized trials assessing cytoreductive surgery (CRS) with HIPEC, recent prospective series have demonstrated improvement in overall survival, which ranged from 34 to 92 months, following this approach.5,6,13 The rarity of MPM creates challenges when attempting to assess population-based survival outcomes as most data has originated from single-institution series. Moreover, with the advancements in treatment of MPM within the last decade, recent trends in management and survival for
J. T. Miura et al.
MPM have not been investigated in a population-based manner, as the majority of studies have been conducted at highly specialized centers. Therefore, in the present study, the Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to assess the current practice patterns in the United States for patients with MPM.
METHODS A retrospective case series analysis was performed using the prospective SEER database. Patients with pathologically confirmed MPM were identified from 1973 to 2010 using ICD-3 histology codes 9050–9055 (mesothelioma, malignant) combined with site codes 48.0, retroperitoneum; 48.1, specified parts of the peritoneum; 48.2, peritoneum not otherwise specified (NOS); 76.2, abdomen NOS; 76.3, pelvis NOS; and 16.9–25.9 (abdominal solid organs). Patients with mesothelioma originating from the pleura or genital tracts were excluded from analysis. Data was abstracted using the SEER Stat Software, version 8.4 and included patient demographics and treatment characteristics. For purposes of staging, extent of disease was classified by SEER stage: local, regional (either direct tumor extension into adjacent organs, or confined to regional lymph nodes), or distant/metastatic (disseminated throughout abdomen). It was assumed that patients with metastatic disease did not have extra-abdominal involvement of other mesothelial lined organs. Studies first describing the role of CRS with HIPEC began in 1989.14,15 To assess temporal changes in management and survival outcomes, patients were grouped into 5-year periods according to the year of diagnosis starting from 1990. Extent of surgery was also reclassified into 4 groups: no surgery, surgery not otherwise specified (NOS), limited, and radical resections. Surgery NOS was defined according to the SEER site specific surgery code 90. Limited resection was defined as either partial or total operative removal of only the primary site. Radical resection was defined as partial or total removal of the primary site with resection in continuity with other organs. For patients with survival coded as 0 months, this was replaced to 5 months with epidemiological convention. Statistical analyses were performed with Stata/MP 10.0 for Windows (StataCorp, College Station, TX). Alpha was set at 0.05. Continuous variables were described as medians and interquartile range, whereas categorical variables were described as frequencies and relative frequencies. Nonparametric comparisons between groups were analyzed using the Kruskal–Wallis and Chi square test as appropriate. Overall survival (OS) was calculated from the time of diagnosis. The Kaplan–Meier method and Cox proportional hazards models were used to assess survival and evaluate independent predictors of survival respectively.
RESULTS Patient Characteristics From 1973 to 2010, a total of 1,591 patients with MPM were identified from the SEER registry (Table 1). The median age of the entire cohort was 64 years (IQR 53–74 years; total range 14–98 years) with 43.2 % (n = 688) being female. The majority of patients (60.5 %, n = 962) had metastatic disease at the time of diagnosis, which includes peritoneal metastases. However, 16.3 % (n = 259) of patients did not have complete SEER staging. Of the 1,591 patients with MPM, 38.4 % (n = 611) were managed with surgery. Although they had undergone surgery, 8.7 % (n = 139) of patients were missing surgery type. However, radical resection was the most common TABLE 1 Demographic characteristics and overall survival of patients with malignant peritoneal mesothelioma Variable
Total
No. of patients
1,591
Median age (years) at diagnosis (IQR)
64 (53–74)
No. of females (%)
688 (43.2)
Race, n (%) White
1,449 (91.1)
Black
73 (4.6)
Other
69 (4.3)
Histology, n (%) Mesothelioma, NOS
1,125 (70.7)
Epithelioid
415 (26.1)
Biphasic/mixed
51 (3.2)
SEER stage, n (%) Local Regional
161 (10.1) 209 (13.1)
Metastatic
962 (60.5)
Unknown
259 (16.3)
Primary site Abdomen/pelvis NOS
62 (3.9)
Peritoneum/retroperitoneum
1,529 (96.1)
Radiation, n (%)
64 (4.1)
Surgery No surgery
980 (61.6)
Limited
188 (11.8)
Radical/debulking
284 (17.9)
Surgery NOS
139 (8.7)
Median OS, months (IQR)
9 (2–36)
By SEER stage Local/regional Metastatic
21 (5–74) 7 (2–25)
IQR interquartile range, NOS not otherwise specified, OS overall survival
Management of Peritoneal Mesothelioma
Limited
Variable
HR
p value
Age \ 40 years
Ref
–
–
40–65 years [ 65 years
2.42 3.57
1.81–3.23 2.67–4.77
\0.01 \0.01
Female gender
0.75
0.66–0.84
\0.01
White
Ref
–
–
Black
0.76
0.56–1.02
0.07
Other
0.80
0.61–1.05
0.11
Abdomen/pelvis NOS
Ref
–
–
Peritoneum/retroperitoneum
0.9
0.67–1.22
0.50
2
4
6
8
10
1.00
Time (years)
Limited
0.75
No Surgery Radical/Debulking
p
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Current Trends in the Management of Malignant Peritoneal Mesothelioma John T. Miura, MD, Fabian M. Johnston, MD, MHS, T. Clark Gamblin, MD, MS, and Kiran K. Turaga, MD, MPH Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
ABSTRACT Background. Historically, malignant peritoneal mesothelioma (MPM) has been considered an aggressive and lethal neoplasm. However, contemporary series have demonstrated improved outcomes following a combination of cytoreductive surgery and intraperitoneal chemotherapy. We sought to assess the trends in management and survival of patients with MPM in the United States. Methods. The Surveillance, Epidemiology, and End Results database was used to identify all patients diagnosed with malignant peritoneal mesothelioma from 1973 to 2010. Overall survival (OS) was studied with Kaplan– Meier curves and Cox regression analyses. Results. We identified 1,591 patients with MPM. Median age at diagnosis was 64 years (IQR 53–74 years) with the majority of patients presenting with metastatic disease (n = 962, 60.5 %). A total of 980 patients (61.6 %) did not receive surgical therapy. Receipt of radical cytoreduction for patients with metastatic MPM demonstrated a significant improvement in OS compared with patients not receiving surgery (20 vs. 4 months, p \ 0.01). A temporal increase was observed in OS for patients receiving surgery (1991–1995: 15 vs. 2006–2010: 38 months, p = 0.1). In multivariate models, limited (HR 0.55; 95 % CI 0.48–0.63; p \ 0.01) and radical (HR 0.66; 95 % CI 0.54–0.80; p \ 0.01) surgery were independently associated with improved survival. Conclusions. In the current era, approximately three of every five patients do not receive surgery when diagnosed with MPM, although a significant survival benefit is noted in select patients. The opportunity to improve patient
Ó Society of Surgical Oncology 2014 First Received: 29 January 2014 K. K. Turaga, MD, MPH e-mail: [email protected]
survival with surgical therapy is lost in a significant number of MPM patients. Currently, malignant peritoneal mesothelioma (MPM) accounts for *30 % of all mesothelioma tumors, with an annual incidence in the United States of 200–400 new cases.1 Although asbestos exposure is the primary risk factor for the development of MPM, only 33 % of patients with the disease report a history of prior contact with the mineral.2 Nonspecific clinical symptoms such as abdominal pain, weight loss, and increasing abdominal girth contribute to the difficulties and delay in diagnosing MPM. As a result, the majority of patients present with advanced disease. Although possessing an aggressive underlying biology, it is uncommon for MPM to extend beyond the peritoneal cavity.3 Lymph node and extra-abdominal metastasis are rare.4 However, without aggressive treatment, MPM is a universally lethal disease with a median overall survival ranging from 6 to 12 months.5–7 Cisplatin and pemetrexed based chemotherapy as solitary therapy has been used to treat MPM, but has poor tumor response rates and negligible improvement in overall survival in contrast with its use for pleural mesothelioma.8–12 As a result of the locoregional nature of the disease, contemporary treatment options have now evolved toward aggressive surgical approaches combined with delivery of intraperitoneal chemotherapy in the form of hyperthermic intraperitoneal chemoperfusion (HIPEC). Although at present there have not been any randomized trials assessing cytoreductive surgery (CRS) with HIPEC, recent prospective series have demonstrated improvement in overall survival, which ranged from 34 to 92 months, following this approach.5,6,13 The rarity of MPM creates challenges when attempting to assess population-based survival outcomes as most data has originated from single-institution series. Moreover, with the advancements in treatment of MPM within the last decade, recent trends in management and survival for
J. T. Miura et al.
MPM have not been investigated in a population-based manner, as the majority of studies have been conducted at highly specialized centers. Therefore, in the present study, the Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to assess the current practice patterns in the United States for patients with MPM.
METHODS A retrospective case series analysis was performed using the prospective SEER database. Patients with pathologically confirmed MPM were identified from 1973 to 2010 using ICD-3 histology codes 9050–9055 (mesothelioma, malignant) combined with site codes 48.0, retroperitoneum; 48.1, specified parts of the peritoneum; 48.2, peritoneum not otherwise specified (NOS); 76.2, abdomen NOS; 76.3, pelvis NOS; and 16.9–25.9 (abdominal solid organs). Patients with mesothelioma originating from the pleura or genital tracts were excluded from analysis. Data was abstracted using the SEER Stat Software, version 8.4 and included patient demographics and treatment characteristics. For purposes of staging, extent of disease was classified by SEER stage: local, regional (either direct tumor extension into adjacent organs, or confined to regional lymph nodes), or distant/metastatic (disseminated throughout abdomen). It was assumed that patients with metastatic disease did not have extra-abdominal involvement of other mesothelial lined organs. Studies first describing the role of CRS with HIPEC began in 1989.14,15 To assess temporal changes in management and survival outcomes, patients were grouped into 5-year periods according to the year of diagnosis starting from 1990. Extent of surgery was also reclassified into 4 groups: no surgery, surgery not otherwise specified (NOS), limited, and radical resections. Surgery NOS was defined according to the SEER site specific surgery code 90. Limited resection was defined as either partial or total operative removal of only the primary site. Radical resection was defined as partial or total removal of the primary site with resection in continuity with other organs. For patients with survival coded as 0 months, this was replaced to 5 months with epidemiological convention. Statistical analyses were performed with Stata/MP 10.0 for Windows (StataCorp, College Station, TX). Alpha was set at 0.05. Continuous variables were described as medians and interquartile range, whereas categorical variables were described as frequencies and relative frequencies. Nonparametric comparisons between groups were analyzed using the Kruskal–Wallis and Chi square test as appropriate. Overall survival (OS) was calculated from the time of diagnosis. The Kaplan–Meier method and Cox proportional hazards models were used to assess survival and evaluate independent predictors of survival respectively.
RESULTS Patient Characteristics From 1973 to 2010, a total of 1,591 patients with MPM were identified from the SEER registry (Table 1). The median age of the entire cohort was 64 years (IQR 53–74 years; total range 14–98 years) with 43.2 % (n = 688) being female. The majority of patients (60.5 %, n = 962) had metastatic disease at the time of diagnosis, which includes peritoneal metastases. However, 16.3 % (n = 259) of patients did not have complete SEER staging. Of the 1,591 patients with MPM, 38.4 % (n = 611) were managed with surgery. Although they had undergone surgery, 8.7 % (n = 139) of patients were missing surgery type. However, radical resection was the most common TABLE 1 Demographic characteristics and overall survival of patients with malignant peritoneal mesothelioma Variable
Total
No. of patients
1,591
Median age (years) at diagnosis (IQR)
64 (53–74)
No. of females (%)
688 (43.2)
Race, n (%) White
1,449 (91.1)
Black
73 (4.6)
Other
69 (4.3)
Histology, n (%) Mesothelioma, NOS
1,125 (70.7)
Epithelioid
415 (26.1)
Biphasic/mixed
51 (3.2)
SEER stage, n (%) Local Regional
161 (10.1) 209 (13.1)
Metastatic
962 (60.5)
Unknown
259 (16.3)
Primary site Abdomen/pelvis NOS
62 (3.9)
Peritoneum/retroperitoneum
1,529 (96.1)
Radiation, n (%)
64 (4.1)
Surgery No surgery
980 (61.6)
Limited
188 (11.8)
Radical/debulking
284 (17.9)
Surgery NOS
139 (8.7)
Median OS, months (IQR)
9 (2–36)
By SEER stage Local/regional Metastatic
21 (5–74) 7 (2–25)
IQR interquartile range, NOS not otherwise specified, OS overall survival
Management of Peritoneal Mesothelioma
Limited
Variable
HR
p value
Age \ 40 years
Ref
–
–
40–65 years [ 65 years
2.42 3.57
1.81–3.23 2.67–4.77
\0.01 \0.01
Female gender
0.75
0.66–0.84
\0.01
White
Ref
–
–
Black
0.76
0.56–1.02
0.07
Other
0.80
0.61–1.05
0.11
Abdomen/pelvis NOS
Ref
–
–
Peritoneum/retroperitoneum
0.9
0.67–1.22
0.50
2
4
6
8
10
1.00
Time (years)
Limited
0.75
No Surgery Radical/Debulking
p
