Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival

Abstract

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) benefits selected patients with peritoneal mesothelioma. We present the outcomes of this treatment strategy in a UK peritoneal malignancy national referral centre.

Methods: Observational retrospective analysis of data prospectively collected in a dedicated peritoneal malignancy database between March 1998 and January 2016.

Results: Of 1586 patients treated for peritoneal malignancy, 76 (4.8%) underwent surgery for peritoneal mesothelioma. Median age was 49 years (range 21–73 years). 34 patients (45%) were female. Of the 76 patients, 39 (51%) had low grade histological subtypes (mostly multicystic mesothelioma), and 37 (49%) had diffuse malignant peritoneal mesothelioma (DMPM; mostly epithelioid mesothelioma). Complete cytoreduction was achieved in 52 patients (68%) and maximal tumour debulking (MTD) was performed in 20 patients (26%); the remaining 4 patients (5%) underwent a laparotomy with biopsy only. HIPEC was administered in 67 patients (88%). Median overall (OS) and disease-free survival (DFS) after CRS was 97.8 (80.2–115.4) and 58.8 (47.4–70.3) months, respectively. After complete cytoreduction, 100% overall survival was observed amongst patients with low-grade disease. Ki-67 proliferation index was significantly associated with survival outcomes after complete cytoreduction for DMPM and was an independent predictor of decreased survival.

Conclusion: With adequate patient selection (guided by histological classification and Ki-67 proliferation index) and complete cytoreduction with HIPEC, satisfactory outcomes can be achieved in selected patients with peritoneal mesothelioma.

Keywords:

• Peritoneal mesothelioma
• cytoreductive surgery
• hyperthermic intraperitoneal chemotherapy

Introduction

The incidence of mesothelioma in developed countries varies from 14 to 35 cases per million per year and peritoneal mesothelioma accounts for 10–30% of all cases [1,2]. Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and fatal primary neoplasm of the serosal lining of the peritoneum with increasing incidence worldwide [3,4].

The aetiology, presentation, diagnostic and therapeutic management of peritoneal mesothelioma have been summarised in a recent review [5]. Several environmental and genetic risk factors contributing to the development of peritoneal mesothelioma have been identified [6–10]. Importantly, a proportion of patients who develop peritoneal mesothelioma, particularly cystic mesothelioma, have no definite history of exposure to asbestos [11,12].

Clinical presentations of DMPM are non-specific [1,12]. Patients usually present with signs and symptoms that reflect a diffuse progressive abdominal condition, including ascites and obstructive symptoms [5].

Standard initial investigation is by CT imaging and tumour specimens for histological assessment may also be obtained by CT guided biopsy [13]. Although CT and MRI have some utility in diagnosis, the extent of small bowel serosal involvement is often underestimated. Diagnostic laparoscopy has the added advantage of allowing direct visualisation of the peritoneal cavity and the assessment of the absence, or extent, of small bowel involvement which helps to select patients amenable to operative intervention. Ascites, if present, can also be drained at laparoscopy.

Until recently, systemic chemotherapy was considered standard treatment for both pleural and peritoneal mesothelioma. However, in peritoneal mesothelioma response rates after systemic chemotherapy are limited and associated with substantial toxicity [5,14,15]. Despite the development of new immunotherapy agents such as checkpoint inhibitor PD-1 and new gene-targeted therapies, there has been little change in overall outcomes over the last decade.

Surgery can be of benefit in selected patients, particularly where complete tumour removal can be achieved. Complete removal of macroscopic disease, by cytoreductive surgery (CRS) using peritonectomies and multivisceral resection, if necessary, combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to result in good outcomes and long-term survival [16]. If the small bowel is seen to be extensively involved at laparoscopy then CRS and HIPEC is unlikely to be of benefit. An exception to this is where there is a large omental cake and recurrent ascites, whereby a major tumour debulking with omentectomy (and, in patients with intestinal obstruction, total colectomy with ileostomy) combined with HIPEC may give good palliation by suppression of ascites [1,17]. The presence and extent of mesothelioma at crucial anatomical sites, such as the portal structures or small bowel serosa, limits the ability to achieve complete cytoreduction [18].

Peritoneal mesothelioma is traditionally categorised into either low-grade peritoneal mesothelioma (LGPM) or DMPM. LGPM includes multicystic mesothelioma and well-differentiated papillary mesothelioma (WDPM) [19,20]. Though multicystic mesothelioma has historically been described as a benign disorder, its behaviour suggests that recurrence is likely, unless radical resectional surgery is combined with HIPEC [13,21]. DMPM includes epithelioid, biphasic and sarcomatoid subtypes [22,23]. Ki-67 proliferation index, which has been shown to correlate with prognosis in a number of tumours [24,25], has recently been demonstrated to influence outcome after CRS and HIPEC in patients with DMPM [26–28].

Here, we report the outcomes of a treatment strategy of CRS and HIPEC in patients with both low grade and DMPM and demonstrate the association of clinicopathological parameters with survival outcomes.

Methods

Patient and surgical procedures

Prospectively collected data in a dedicated peritoneal malignancy database between March 1998 and January 2016 were analysed. Patients undergoing surgery for peritoneal mesothelioma were included.

Suitability for surgery was assessed by a combination of clinical history, physical examination, CT scan and tumour marker analysis. At laparotomy, disease extent was quantified using the Peritoneal Cancer Index (PCI) [29]. The intra-operative strategy was to remove all visible tumour (complete cytoreduction); however, patients in whom a complete cytoreduction was not considered achievable (due to tumour extent and distribution on pre-operative investigations), were offered a planned maximal tumour debulking (MTD) procedure to achieve palliation of symptoms (mainly refractory ascites and obstructive symptoms) [30–32]. Complete cytoreduction was defined as CC0/1 (CC0 – no residual disease, CC1– esidual nodules up to 2.5 mm, CC2–nodules up to 2.5 cm and CC3–nodules >2.5 cm) and MTD as CC2/3 [32]. In patients who underwent a complete cytoreduction, a variety of peritonectomy procedures were used in combination with visceral resections, to remove all visible tumour or, if not possible, to reduce residual tumour deposits to less than 2.5 mm, the estimated maximum direct penetration of locally applied chemotherapy. As per the institutional policy, all patients with a rectal anastomosis were defunctioned with loop ileostomy.

HIPEC was administered at 42–43 °C for 1 h by an open abdominal perfusion technique using a combination of doxorubicin (15 mg/m²) and cisplatin (50 mg/m²). In selected patients, in addition to HIPEC, early postoperative chemotherapy (EPIC) using doxorubicin (3 mg/m²) and cisplatin (20 mg/m²) was administered for a maximum of 4 days following surgery. EPIC was administered to patients who had complete cytoreduction, were haemodynamically stable during and after operation and had no, or one, bowel anastomosis only.

Routine follow-up for patients who had complete cytoreduction was by annual CT and tumour marker assessment or at shorter intervals if clinically indicated. Tumour markers measured were CEA, CA19.9 and CA125. Though not specific to mesothelioma, if markers are elevated prior to surgery, measurement is useful in monitoring peritoneal disease recurrence [33–36].

Histopathological analysis

After referral, histopathology of previously resected specimens and ascitic fluid cytology, if available, was carefully reassessed by a histopathologist with a special interest in peritoneal mesothelioma. Specimens resected during definitive laparotomy in our unit were similarly assessed by a dedicated pathologist.

For determination of the Ki-67 proliferation index, monoclonal mouse anti-human Ki-67 antigen clone MIB-1 obtained from Dako was used. Positive control tissue from tonsil was stained in parallel with the study cases. The result of Ki-67 immunoreactivity for all assessments was expressed as the percentage of tumour cells with positive nuclear staining. Ki-67 expression was measured by two histopathologists with an interest and experience in peritoneal malignancy.

Statistical analysis

Continuous variables are presented with median and range, and categorical data with frequency and percentage. The Mann–Whitney U-test was used for continuous data and Pearson’s chi-square test for categorical data was used to detect differences between the groups where applicable. Statistical significance of the survival was analysed with the log-rank (Mantel-Cox) test and Kaplan–Meier curves. Multivariate analysis was performed with the Cox proportional hazards model. A p value of less than 0.05 was considered significant. Data were analysed using SPSS software (version 24) (IBM, Armonk, NY).

Results

Study population

Between March 1998 and January 2016, 1586 patients underwent surgery for peritoneal malignancy; of these, 76/1586 (4.8%) underwent surgery for peritoneal mesothelioma. The study population and distribution of histological subtypes are shown in Figure 1.

Figure 1. Study population and distribution of histological subtypes.

Demographic and surgical characteristics, as well as Ki-67 proliferation index of the study population are shown in Table 1. Ki-67 proliferation index data was available for 63/76 patients (83%); of the 52 patients undergoing a complete cytoreduction, data on Ki-67 proliferation index was available for 46 (89%). Patients with DMPM had significantly greater disease extent (as quantified by PCI) and higher Ki-67 proliferation index than those with LGPM.

Table 1. Demographic and surgical characteristics of 76 peritoneal mesothelioma patients.

	Study population (n = 76)	LGPM (n = 39)	DMPM (n = 37)	p value
Gender (female)
Number (%)	34 (44.7%)	22 (56.4%)	12 (32.4%)	0.036^a
Age (years)
Median (range)	49 (21–73)	44 (21–69)	56 (32–73)	0.001^b
Complete cytoreduction
Number (%)	52 (68.4%)	34 (87.2%)	18 (48.6%)	0.001^a
LOS (days)
Median (range)	15 (5–62)	15 (7–32)	15 (5–62)	0.576^b
Surgical duration (minutes)
Median (range)	420 (30–720)	420 (30–630)	420 (120–720)	0.559^b
Blood loss (L)
Median (range)	1.0 (0.2–2.5)	0.5 (0.2–2.0)	1.0 (0–2.5)	0.079^b
PCI
Median (range)	15 (3–39)	9 (3–39)	18 (3–39)	0.001^b
Ki-67 proliferation index (%)
Median (range)	7 (0–50)	3.5 (0–50)	9.2 (0–49)	0.003^b

DMPM: diffuse malignant mesothelioma; LOS: length of stay; LGPM: low-grade peritoneal mesothelioma; PCI: Peritoneal Cancer Index.

^aPearson’s chi-square test.

^bMann–Whitney U test.

Surgical treatment

Of the 76 patients undergoing laparotomy for peritoneal mesothelioma, a complete cytoreduction (CC0 or CC1) was achieved in 52 (68%); MTD was performed in 20 patients (26%) and 4 patients (5%) had a biopsy procedure only. Of the 52 patients with a complete cytoreduction, CC0 was achieved in 37 (71%) and CC1 in 15 (9%). As shown in Table 1, complete cytoreduction rates were significantly lower in patients with DMPM (18 patients; 49%) than in those with low-grade disease (34 patients; 87%). Amongst the patients with low-grade disease, rates of complete cytoreduction were significantly higher for multicystic versus WDPM (93 versus 55%; p = 0.006).

HIPEC was administered in 67 patients (88%), with 57 treated with cisplatin and doxorubicin, while the remaining 10 patients received mitomycin C. Overall 50/52 patients with complete cytoreduction received HIPEC; the remaining two had major haemodynamic instability which prevented safe HIPEC administration. Of the 20 patients undergoing MTD, 17 received HIPEC to suppress re-accumulation of ascites [30–32]. Median operative time was 420 min (range 30–720) with median estimated blood loss of 1 L (range 0.2–2.5). EPIC was administered in 11 patients (15%). Median postoperative length of stay was 15 days (range 5–62). There was no 30-day postoperative mortality. Mortality within 90 days occurred in 2/76 patients (2.6%), one of whom was revealed to have pleural mesothelioma on post-mortem examination. 5 patients (7%) developed Clavien-Dindo grade III/IV complications.

Survival outcomes

Median follow-up time was 34 months (range 6–152). For the entire study population, median overall survival (OS) was 97.8 months (95% CI: 80.2–115.4), with 3- and 5-year OS rates of 75.8 and 67.7%, respectively. Median disease-free survival (DFS) was 58.8 months (95% CI: 47.4–70.3) with 3- and 5-year DFS of 67.5 and 60.4%, respectively.

After complete cytoreduction, median OS was 127.0 months (95% CI: 111.0–143.0) with 3- and 5-year survival rates of 87.6 and 79.7%, respectively; however, even after MTD median OS of 43.2 months (95% CI: 20.0–66.4), i.e. nearly 4 years, was achieved, with 3- and 5-year survival of 45.0 and 36.1%, respectively. Survival rates after MTD were significantly higher in patients with low-grade mesothelioma versus DMPM, with median OS 85.1 months (95% CI: 28.2–142.0) and 29.0 months (95% CI: 14.3–43.7), respectively. Of the 5 patients with low-grade mesothelioma not undergoing a complete cytoreduction, 4 patients died of disease progression during follow-up.

Survival after complete cytoreduction

Amongst the 52 patients undergoing a complete cytoreduction, OS and DFS were significantly lower in DMPM patients as compared to those with low-grade mesothelioma, as outlined in Table 2 and Figure 2. All patients with low-grade disease, who had complete cytoreduction, were alive at the end of follow-up. Overall and disease-free survival rates did not differ significantly between patients with multicystic and WDPM.

Figure 2. Kaplan–Meier curves for overall (A) and disease-free (B) survival for patients with low-grade peritoneal mesothelioma (LGPM) and diffuse malignant peritoneal mesothelioma (DMPM).

Table 2. Survival outcomes after complete cytoreduction by histological subtype.

	LGPM	DMPM	p value
Overall survival (months)
Mean (95% CI)	152.0	45.7 (28.2–63.2)	0.001^a
3 years (%)	100	62.5
5 years (%)	100	37.5
Disease-free survival (months)
Mean (95% CI)	74.7 (62.3–87.0)	28.5 (15.0–42.0)	0.001^a
3 years (%)	88.4	34.7
5 years (%)	83.3	34.7

DMPM: diffuse malignant peritoneal mesothelioma. LGPM: low-grade peritoneal mesothelioma.

^aLog-rank test.

The effect of PCI and Ki-67 proliferation index on survival following complete cytoreduction in DMPM patients was investigated. Median values (used as cut-off values) for PCI and Ki-67 proliferation index in this group were 15 and 7%, respectively. PCI had no significant association with survival outcomes. In contrast, Ki-67 proliferation index was significantly associated with OS, as shown in Figure 3. In patients with Ki-67 proliferation index <7%, mean OS was 70.0 months (95%CI: 47.5–92.0), with 3-year and 5-year OS of 86.5 and 59.0%, respectively. In patients with Ki-67 proliferation index ≥7%, mean OS was 32.8 months (95% CI: 15.0–50.0), with 3- and 5-year OS of 42.2% and 21.9%.

Figure 3. Kaplan–Meier curve showing significant difference in overall survival after complete cytoreduction between DMPM patients with high or low Ki-67 proliferation index.

Multivariate analysis

Cox proportional hazard model was used to identify independent predictors of overall survival after complete cytoreduction in patients with DMPM. Gender, age, tumour markers, PCI and Ki-67 proliferation index were included in multivariate analysis. Ki-67 proliferation index was demonstrated to be an independent predictor of decreased overall survival (HR 3.4; 95% CI: 1.7–18.1; p = 0.040).

Discussion

Malignant mesothelioma, whether pleural or peritoneal, generally has a poor prognosis, and there are few treatment options for these patients [12,37]. Due to the rarity of the disease, histological diagnosis is challenging, and often delayed, and may require review by an experienced pathologist for expert pathological classification [14,38]. Once the diagnosis has been made there are few chemotherapy options with no new systemic drug regimes in the last decade since Vogelzang demonstrated that the addition of pemetrexed to cisplatin improved survival in patients with pleural mesothelioma [14]. Systemic treatment using this combination of cisplatin and pemetrexed is associated with median overall survival of just 13 months [39]. In the absence of effective chemotherapeutic agents, the only treatment to show any real promise has been CRS with HIPEC.

Outcomes from a multi-institutional study of 401 patients with malignant subtypes of peritoneal mesothelioma (excluding multicystic and WDPM) demonstrated overall median survival of 53 months with 3 and 5 year survival rates of 60 and 47%, respectively. The predominant histological subtype was epithelioid which had the best survival after complete cytoreduction and HIPEC, if there were no lymph nodes involved [16]. Baratti reported similar findings in 108 patients treated with CRS and HIPEC identifying a Ki-67 proliferation index of <10% as an indicator of prolonged survival [2,28]. A subset of 26 patients from the same multi-institutional group had multicystic mesothelioma. After a median follow up of 54 months all 26 were alive after complete cytoreduction with HIPEC [12]. which is similar to our experience.

This current study reports outcomes of CRS and HIPEC in peritoneal mesothelioma, including low-grade histological types as well as DMPM. The patients in the current series included a relatively high proportion with low-grade lesions (multicystic and WDPM), and there were no patients with sarcomatoid mesothelioma. This distribution of cases reflects the pattern of referral to the unit. The results support the classification of multicystic and WDPM as low-grade and demonstrate that even these low-grade subtypes can recur after CRS and HIPEC.

The relatively high rate of incomplete cytoreduction in our series is caused by our strategy of routinely offering MTD to those patients who with refractory symptoms who are not considered candidates for a complete cytoreduction, in contrast to most previous reports, where such patients were not offered CRS at all. Our data show that, in patients in whom complete cytoreduction is not possible, a strategy of MTD still achieves survival outcomes superior than those achieved historically with palliative systemic chemotherapy [40]. This is in keeping with previously demonstrated results of MTD in pseudomyxoma peritonei [32]. The addition of HIPEC in the majority of patients undergoing debulking is based on previous findings in patients with refractory malignant ascites, where a combination of debulking and HIPEC significantly improved quality of life and ascites inhibition [30,31].

The present study shows that, in DMPM, outcomes after complete CRS and HIPEC is influenced by the Ki-67 proliferation index; patients with a proliferation index ≥7% had significantly decreased survival rates. Moreover, Ki-67 proliferation index was found to be an independent predictor of decreased overall survival after complete cytoreduction for DMPM. This has clear implications for patient selection and indications for either neo-adjuvant or adjuvant systemic chemotherapy in this patient population; moreover, this finding underlines the importance of determining Ki-67 proliferation index in pre-treatment biopsy specimens.

In contrast to Ki-67 proliferation index, PCI score was not associated with outcome after complete cytoreduction. This finding is in contrast to a recent study of 117 patients with DMPM, where PCI was found to be an independent predictor of survival after CRS and HIPEC, along with the Ki-67 proliferation index [28]. However, this study included 23 patients with an incomplete cytoreduction in the survival analysis; it is possible that the negative association of PCI found in this study was due to the impact of PCI on completeness of cytoreduction. In our study, this effect is filtered out by limiting the survival analysis to patients undergoing a complete cytoreduction. However, the relatively small study population in our study may also have impacted the ability to identify any association between PCI and survival outcome.

The results also demonstrate that CRS and HIPEC is a relatively safe treatment in patients with peritoneal mesothelioma, with major morbidity occurring in approximately 7% of patients. This is in keeping with previously published rates of morbidity in our peritoneal malignancy institute [41]. Some patients will develop recurrent disease and there is a role for repeat CRS and HIPEC in selected patients with favourable histopathology and a longer interval from surgery to recurrence [42]. Long term intraperitoneal chemotherapy has also been proposed using indwelling intraperitoneal ports but we have no experience with this approach [43]. New immunotherapy agents, such as checkpoint inhibitor PD-1, are showing some activity in solid tumours and may herald the next treatment modality for peritoneal mesothelioma [44,45]. Despite these novel agents, CRS and HIPEC is likely to continue as a key part of the management of selected patients with peritoneal mesothelioma. The results in this series suggest that CRS and HIPEC, even when complete cytoreduction is not achieved, is of benefit to patients with either low-grade or malignant mesothelioma and at present is the only treatment which has the potential for cure.

Disclosure statement

The authors declare no conflicts of interest pertaining to the subject of this manuscript.