Annals of Surgical Oncology

About the journal

Publisher: Springer
Published: 1994 to the present, United States
Language: English
ISSN: 1068-9265 (print), 1534-4681 (electronic)
Its record in the NLM Catalog

2020s

ASO Author Reflections: Hormonal Status May Impact Outcomes in Peritoneal Mesothelioma After CRS/HIPEC. K.C. Cummins, S.M. Ruff. 2026;33(6):5319-5320. PubMed · Publisher · Free full text
Hormonal Status May Contribute to Sex-Based Survival Differences in Epithelioid Peritoneal Mesothelioma. K.C. Cummins, O. Sears, E.R. Bitar, et al. 2026;33(6):5304-5314. PubMed · Publisher · Free full text

Abstract

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is central to treating patients with epithelioid peritoneal mesothelioma (EPM). Male sex is a negative prognostic factor in mesothelioma, but the reasons for this remain unclear. We evaluated the impact of sex and age, as a proxy for menopause status, on treatment patterns and survival for EPM.

Patients And Methods: Adults with unicavitary EPM were identified in the National Cancer Database (NCDB) (2006-2020). Predictors of CRS/HIPEC receipt were evaluated using logistic regression. Among patients who underwent CRS/HIPEC, variables impacting overall survival (OS) were evaluated using Cox regression. Patients were stratified by age (≤ 40 years and ≥ 60 years) into younger male, older male, premenopausal female, and postmenopausal female patients for subgroup analysis.

Results: Of 1868 patients meeting inclusion criteria, 28.1% (n = 526) received CRS/HIPEC; of those, 286 (54.4%) were male. Male sex (odds ratio, OR 1.054, p = 0.015), younger age (OR 0.996, p < 0.001), and treatment at an academic center (OR 1.253, p < 0.001) were independently associated with receiving CRS/HIPEC. Males had worse OS than females after CRS/HIPEC on multivariable regression (hazard ratio, HR 1.647, p = 0.003). Upon age-stratification of patients who underwent CRS/HIPEC, premenopausal females had significantly improved OS compared with younger male, older male, and postmenopausal female patients on Kaplan-Meier analysis (all p < 0.05). Female sex significantly predicted survival in younger (HR 0.267, p = 0.012) but not older patients (HR 0.676, p = 0.061).

Conclusions: Premenopausal women with EPM undergoing CRS/HIPEC had significantly improved OS compared with both males and postmenopausal females, suggesting a hormonal influence on outcomes. Future studies to elucidate the biological mechanisms underlying this sex-based disparity are necessary.

© 2026. The Author(s).
Clinicopathologic Characteristics and Clinical Outcomes of Patients with Testicular Mesothelioma. P. Agrawal, F. Baky, J. Sarungbam, et al. 2025;32(13):10285-10293. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma of the tunica vaginalis testes (testicular mesothelioma [TM]) is a rare tumor, comprising less than 5% of mesotheliomas. Surgical intervention is the current standard of care, whereas the role of systemic therapies remains undefined.

Methods: We retrospectively reviewed 36 patients with pathologically confirmed TM treated at Memorial Sloan Kettering Cancer Center (MSK) between January 1996 to May 2023. Clinicopathologic data, treatments received, and clinical outcomes were reported. Surgical pathology samples, when available, underwent next-generation sequencing (NGS) using MSK-IMPACT. Overall survival (OS) was calculated by using the Kaplan-Meier method.

Results: Median age at diagnosis was 64 years (range 24-93). Histologically, 22 (61%) tumors were epithelioid, ten (28%) were biphasic, three (8%) were sarcomatoid, and one (3%) was unable to be further classified. Ten patients (28%) had metastatic disease at initial diagnosis, and 13 more (36%) eventually developed metastatic disease. Orchiectomy was performed in 34 (94%) patients and retroperitoneal lymph node dissection (RPLND) in 12 (33%); 15 (42%) received systemic therapy and five (14%) radiation therapy. Ten samples underwent somatic NGS: five (50%) had CDKN2A/B, four (40%) had NF2, and two (20%) had BAP1 alterations. At a median follow up of 3.5 years, median OS was 4.5 years.

Conclusions: This is the largest single-institution series and genomic dataset for TM. We report unique clinicopathologic and genomic features that distinguish TM from other mesotheliomas, including a lower frequency of BAP1 alterations. Owing to the rarity of this disease, further refinement of the sequence and necessity of surgical and systemic treatment is necessary.

© 2025. The Author(s).
National Guidelines for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Malignancies: A Worldwide Systematic Review and Recommendations of Strength Analysis. M. Tonello, C. Cenzi, E. Pizzolato, et al. 2025;32(8):5795-5806. Systematic review PubMed · Publisher · Free full text

Abstract

Background: National guidelines (GLs) for surgical cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of peritoneal malignancies (PMs) vary across countries, scientific societies, and government agencies. This study aimed to systematically review and compare the recommendations for CRS/HIPEC in the treatment of ovarian cancer (EOC), gastric cancer, colorectal cancer (CRC), mesothelioma, and pseudomyxoma peritonei (PMP).

Methods: Medical databases, search engines, and national websites of 193 countries were queried using artificial intelligence (AI)-powered software for scientific societies and/or government agencies guidelines. The study excluded consensus statements and guidelines without appropriate references. Non-English guidelines were translated, and data, including GRADE strength of recommendations, were extracted.

Results: The study analyzed 138 guidelines, 24 for gastric cancer, 36 for colorectal cancer, 29 for primary ovarian cancer (p-)EOC, 28 for recurrent ovarian cancer (r-)EOC, 10 for mesothelioma, and 11 for PMP. Guidelines were retrieved from 51 (26.4%) nations, mostly from developed countries (62.1%; p < 0.001). The CRS procedure received robust positive recommendations (GRADE I/IIa) for CRC (74.2%), p-/r-EOC (100%/78.5%), PMP (90.9%), and mesothelioma (90.0%). Conversely, CRS was not indicated for gastric cancer (61.6%, GRADE III; p < 0.001). The HIPEC procedure had robust positive recommendations for PMP (90.9%) and mesothelioma (90.0%), but was controversial for p-EOC (42.3%) and CRC (38.0%) and contraindicated for r-EOC (80.0%) and gastric cancer (62.4%) (p < 0.001).

Conclusion: National guidelines concordantly recommend CRS for colorectal cancer, ovarian cancer, PMP, and mesothelioma. In contrast, HIPEC recommendations are less homogeneously shared, except for PMP and mesothelioma. No positive concordance exists among guidelines on gastric cancer for CRS nor HIPEC. Furthermore, high-level evidence is needed to strengthen future guidelines on peritoneal metastases.

© 2025. The Author(s).
Analysis of Treatment Strategies and Outcomes in Malignant Peritoneal Mesothelioma: Insights From a Multi-Center Study. S. Yaşar, F. Yılmaz, G. Utkan, et al. 2024;31(9):6228-6236. PubMed · Publisher · Free full text

Abstract

Background: This study aimed to evaluate the demographic," clinicopathologic, and prognostic characteristics of malignant peritoneal mesothelioma (MPeM), as well as the treatment options for the rare and heterogeneous MPeM population.

Methods: A retrospective multi-center observational cohort study was conducted to evaluate patients with MPeM. Due to the heterogeneity of the study population, the study divided them into two main groups in terms of treatments, follow-up periods, and prognostic features. The first group comprised the patients who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and the second group included the patients with metastatic disease for whom curative intent surgery was not possible. The patients' diagnostic procedures and treatments were identified from medical records. Patients older than 18 years old were included in the study regardless of asbestos exposure. Well-differentiated papillary and multicystic mesothelioma histologic types were not included in the study.

Results: The study evaluated 118 patients from five centers. Survival times, prognosis, and treatment responses were analyzed in both groups. The study showed that CRS-HIPEC was associated with longer overall survival (OS) and progression-free survival (PFS). Perioperative therapy was evaluated in subgroup analyses of this population and shown to provide survival benefits. The patients treated with chemotherapy (metastatic and medically inoperable patients and those for whom complete cytoreduction was not achievable) had a poorer prognosis than the surgery group. The study showed that life expectancy decreased significantly for the patients not suitable to undergo surgery for any reason.

Conclusions: According to data from experienced centers, CRS-HIPEC is a treatment option recognized as effective, cost-effective, and safe, with better OS and PFS , as well as low morbidity and mortality rates similar to those in the literature. In addition, the platinum-pemetrexed combination continues to be an effective and acceptable treatment option for metastatic patients, those who are medically inoperable, and those for whom complete or near-complete cytoreduction is not achievable.

© 2024. The Author(s).
ASO Author Reflections: Analysis of Treatment Strategies and Outcomes in Malignant Peritoneal Mesothelioma: Insights from a Multi-center Study. S. Yaşar. 2024;31(9):6276-6277. PubMed · Publisher · Free full text
Clinical Characteristics and Outcomes of Patients with Well-Differentiated Papillary Peritoneal Mesothelial Tumors. M. Offin, N. Aguirre, S.R. Yang, et al. 2024;31(12):7973-7977. PubMed · Publisher · Free full text

Abstract

Purpose: Well-differentiated papillary peritoneal mesothelial tumors (WDPMTs) are understudied and discrete from peritoneal mesotheliomas (PMs). We report clinicopathologic characteristics and outcomes of a large prospective WDPMT cohort.

Methods: Patients with WDPMT identified between August 2007 and December 2020 were followed through January 2023. Clinical characteristics and outcomes were annotated. Overall survival (OS) was assessed from pathologic diagnosis. Germline variants were analyzed, and targeted next-generation sequencing (NGS; MSK-IMPACT) data were compared to PMs and diffuse pleural mesotheliomas (DPMs).

Results: Among 54 patients, median age at diagnosis was 55 (range 20-76), 50% were female (n = 27), and 46% were smokers (n = 25; median 8 pack/years). Most (94%, n = 51) WDPMTs were found during surgical explorations for other indications, primarily other malignancies. Two patients underwent surgical resection for WDPMT; none received systemic therapy for WDPMT. Median OS was not reached (19/54; median follow up 4.5 years). Somatic NGS was available for 35% (19/54) of patients. TRAF7 alterations were enriched in WDPMT (89%; 17/19) compared with PM (0%; 0/50; p < 0.0001) and DPM (0%; 0/74; p < 0.0001). In WDPMT compared with PM and DPM, there were less BAP1 (0% [0/0] vs. 4% [8/50] vs. 46% [34/74]; p = 0.001 and p < 0.0001, respectively) and NF2 (0% [0/0] vs. 24% [12/50] vs. 31% [23/74]; p = 0.03 and p = 0.001 respectively) alterations. Pathogenic germline variants were present in 23% (4/17) of WDPMTs.

Conclusions: Well-differentiated papillary peritoneal mesothelial tumors were primarily incidental findings. There was no WDPMT-related mortality, so there was no distinct role for routine cytoreductive surgery or systemic therapy. Genomic profiles can help to differentiate WDPMT from DPM and PM.

© 2024. The Author(s).
Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury. L.F. Liesenfeld, E. Quiring, M. Al-Saeedi, et al. 2023;30(5):2646-2656. PubMed · Publisher · Free full text

Abstract

Background: Cisplatin (CDDP)-containing hyperthermic intraperitoneal chemotherapy (HIPEC) is frequently applied in selected patients with peritoneal malignancies derived from ovarian cancer, gastric cancer, and primary peritoneal mesothelioma. HIPEC with CDDP increases perioperative morbidity, in particular by inducing acute kidney injury (AKI). Factors contributing to occurrence of AKI after intraperitoneal perfusion with CDDP have not been sufficiently evaluated.

Patients And Methods: Data from 63 patients treated with a CDDP-containing HIPEC regimen were retrospectively analyzed concerning demographics, underlying disease, surgery, and HIPEC details to evaluate risk factors of AKI. A preclinical rat perfusion model was applied to assess the influence of temperature, concentration, perfusate volume, perfusion flow rate, and extent of peritonectomy on drug absorption upon intraperitoneal CDDP perfusion.

Results: AKI occurred in 66.1% of patients undergoing CDDP-containing HIPEC, with total intraoperative fluid influx being a negative and the extent of parietal peritonectomy being a positive independent predictor of postoperative AKI. In a preclinical model, bilateral anterior parietal peritonectomy significantly increased systemic CDDP absorption by 1.6 to 2-fold. CDDP plasma levels in animals were significantly higher after both perfusion with increased CDDP perfusate concentrations and bilateral anterior parietal peritonectomy.

Conclusion: CDDP-containing HIPEC is associated with relevant morbidity owing to its systemic toxicity. Extent of parietal peritonectomy is an independent predictor of AKI. CDDP dose reduction should be considered in case of extensive parietal peritonectomy. Cytostatic drug concentrations in HIPEC perfusate should be paid more attention to than total dose per body surface area. Further clinical studies are needed to confirm the presented preclinical findings.

© 2022. The Author(s).
Long-Term Survival in Patients Treated with Cytoreduction and Heated Intraperitoneal Chemotherapy for Peritoneal Mesothelioma at a Single High-Volume Center. C.D. Valenzuela, I.B. Solsky, R.A. Erali, et al. 2023;30(5):2666-2675. PubMed · Publisher · Free full text

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare diagnosis with a dismal prognosis if untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is shown to significantly improve survival. Our institution is uniquely positioned to report long-term outcomes in MPM with CRS-HIPEC, due to our robust peritoneal surface disease program existing over the past three decades.

Methods: Our prospectively maintained, single-institution database of CRS-HIPEC cases was reviewed, identifying 111 consecutive patients with MPM over 28 years (1993-2021). Prognostic, operative, and pathologic factors were reviewed. Overall survival (OS) and conditional survival (CS) analyses were performed.

Results: The average age was 55.1 years; 58.6% of patients were male; 17 of 111 patients (15.3%) had a second CRS-HIPEC. At first CRS-HIPEC, the average PCI score was 18.7, and the perfusate drugs were platinum-based (72.1%) and mitomycin C (27.9%). The resection status at first CRS-HIPEC was R2a (46.4%), followed by R0-1 (29.1%), and R2b-c (24.5%). Median OS was 3.3 years for the entire cohort, with 75th and 25th percentiles at 10.7 months and 10.6 years. Median CS was improved if patients survived to the 1-year postoperative mark (4.9 years, p < 0.01) and trended toward further improvement with each passing year. If 3-year postoperative survival was achieved, the median CS improved to 6.1 years.

Conclusions: This represents one of the largest and lengthiest, single-center, longitudinal, case series of peritoneal mesothelioma treated with CRS-HIPEC. The OS suggests efficacy for CRS-HIPEC for MPM. Long-term survival improves significantly after patients achieve the 1-year, postoperative mark.

© 2023. Society of Surgical Oncology.
ASO Author Reflections: Co-Localization of Synchronous Gastrointestinal Stromal Tumors (GISTs) and Peritoneal Mesothelioma (PM): A Case Series. A.S. Courelli, A.K. Sharma, J.K. Sicklick. 2022;29(12):7549-7550. Comment PubMed · Publisher · Free full text
Co-Localization of Gastrointestinal Stromal Tumors (GIST) and Peritoneal Mesothelioma: A Case Series. A.S. Courelli, A.K. Sharma, L. Madlensky, et al. 2022;29(12):7542-7548. PubMed · Publisher · Free full text

Abstract

Purpose: Gastrointestinal stromal tumor (GIST) is associated with increased risk of additional cancers. In this study, synchronous GIST, and peritoneal mesothelioma (PM) were characterized to evaluate the relationship between these two cancers.

Methods: A retrospective chart review was conducted for patients diagnosed with both GIST and PM between July 2010 and June 2021. Patient demographics, past tumor history, intraoperative reports, cross-sectional imaging, peritoneal cancer index (PCI) scoring, somatic next-generation sequencing (NGS) analysis, and histology were reviewed.

Results: Of 137 patients who underwent primary GIST resection from July 2010 to June 2021, 8 (5.8%) were found to have synchronous PM, and 4 patients (50%) had additional cancers and/or benign tumors. Five (62.5%) were male, and the median age at GIST diagnosis was 57 years (range: 45-76). Seventy-five percent of GISTs originated from the stomach. Of the eight patients, one patient had synchronous malignant mesothelioma (MM), and the remaining had well-differentiated papillary mesothelioma (WDPM), which were primarily located in the region of the primary GIST (89%). The median PCI score was 2 in the WDPM patients. NGS of GIST revealed oncogenic KIT exon 11 (62.5%), PDGFRA D842V (25%), or SDH (12.5%) mutations, while NGS of the MM revealed BAP1 and PBRM1 alterations.

Conclusions: One in 17 GIST patients undergoing resection in this series have PM, which is significantly higher than expected if these two diseases were considered as independent events. Our results indicate that synchronous co-occurrence of GIST and PM is an underrecognized finding, suggesting a possible relationship that deserves further investigation.

© 2022. Society of Surgical Oncology.
Repeat Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Cancers with Peritoneal Metastasis: A 30-year Institutional Experience. C.D. Valenzuela, E.A. Levine, C.W. Mangieri, et al. 2022;29(6):3436-3445. PubMed · Publisher · Free full text

Abstract

Background: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival in abdominal cancer patients with metastatic disease limited to the peritoneal cavity. Patients are increasingly being offered repeat CRS-HIPECs for peritoneal recurrence. However, in this rare clinical scenario, the survival benefit of performing repeat CRS-HIPEC operations remains unclear.

Methods: A retrospective review of the CRS-HIPEC database at Wake Forest Baptist Medical Center was performed over a 30-year timespan. From 1547 patients with appendix cancers, colorectal cancers, mesotheliomas, and other miscellaneous cancers, 156 received more than one CRS-HIPEC. Kaplan-Meier survival analysis was performed using overall survival (OS) from the time of surgery as the primary endpoint. Multi-variable Cox proportional hazards regression modelling was performed on pertinent clinical variables.

Results: Patients who received multiple CRS-HIPECs had significantly better median OS (10.7 years) versus those who received one CRS-HIPEC (2.5 years), with appendix cancers faring best (12.9 years). Resection status R2a or better was achieved in 76.4% of repeat CRS-HIPECs. There were no significant changes in complication rates after repeat CRS-HIPEC. On multivariate analysis of repeat CRS-HIPEC, patients with appendix and colorectal cancers, heart disease, and poor functional status were independently associated with poor OS. Factors not independently associated with OS were age, sex, body mass index, race, diabetes, lung disease, smoking history, and systemic chemotherapy between CRS-HIPECs.

Conclusions: Performing multiple CRS-HIPEC operations on appropriate surgical candidates may significantly prolong survival. Appendix cancers derived the greatest benefit. Satisfactory resection margins and complication rates are comparable to first cases and achievable in repeat CRS-HIPEC procedures.

© 2022. Society of Surgical Oncology.
Complications and Predictive Factors for Air Leak > 10 Days with Neoadjuvant Chemotherapy Followed by Pleurectomy/Decortication for Malignant Pleural Mesothelioma. A. Nakamura, N. Kondo, T. Nakamichi, et al. 2021;28(6):3057-3065. PubMed · Publisher

Abstract

Background: A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D).

Objective: The aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D.

Methods: Data on 163 consecutive patients who underwent neoadjuvant chemotherapy (NAC) followed by P/D for malignant pleural mesothelioma between September 2012 and May 2020 at our institution were retrospectively analyzed. Postoperative complications and the significance of various preoperative risk factors for air leak > 10 days (AL10) to identify the group having a higher risk for particularly durable air leak were investigated. Risk factors for AL10 were sought using univariate and multivariate analyses.

Results: Of 163 patients, 30- and 90-day mortality was 0.6% and 2.5%, respectively. Eighty-four (51.4%) patients experienced grade III or worse postoperative complications according to the Clavien-Dindo classification. The median duration of air leak was 7 postoperative days. AL10 occurred in 53 (32.5%) patients. Fifty-eight patients (35.6%) underwent pleurodesis and five patients (3.1%) underwent reoperation to control the air leak. On univariate analysis, performance status (PS; p = 0.003), prognostic nutritional index (p = 0.01), and pleural effusion (p = 0.04) were statistically significant risk factors for AL10, while on multivariate analysis, PS (odds ratio 4.0, 95% confidence interval 1.3-12.7; p = 0.02) remained the only variable predicted for AL10.

Conclusions: Recent postoperative mortality rates in NAC followed by P/D are quite acceptable. Approximately one in every three patients experienced AL10, and PS may be a risk factor associated with AL10.
Phase II Trial of Adjuvant Dendritic Cell Vaccine in Combination with Celecoxib, Interferon-α, and Rintatolimod in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases. R. Ramanathan, H. Choudry, H. Jones, et al. 2021;28(8):4637-4646. PubMed · Publisher · Free full text

Abstract

Background: Peritoneal metastases portend poor prognosis in the setting of standard chemotherapy. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves outcomes, but relapse is common. We report a phase II trial evaluating the safety and efficacy of adjuvant αDC1 vaccination with chemokine modulation (CKM) after CRS/HIPEC.

Methods: Patients undergoing CRS/HIPEC for appendiceal cancer, colorectal cancer, or peritoneal mesothelioma were enrolled. In addition to standard adjuvant chemotherapy, patients received intranodal and intradermal injections of autologous tumor-loaded αDC1 vaccine. After each vaccine booster, patients received CKM over 4 days, consisting of celecoxib, interferon (IFN)-α, and rintatolimod.

Results: Forty-six patients underwent CRS/HIPEC followed by αDC1 treatment, including 24 appendiceal primaries, 20 colorectal, and 2 mesotheliomas. DC maturation was successful, with 97% expressing HLA-DR and CD86. Tumor cell recovery from peritoneal tumors was challenging, resulting in only 17% of patients receiving the target dose of αDC1. The αDC1 and CKM regimen was well tolerated. CKM successfully modulated serum inflammatory cytokine and chemokine levels. Median progression-free survival (PFS) for appendiceal primaries was 50.4, 34.2, and 8.9 months for grade 1, 2, and 3 tumors, respectively, while median PFS for colorectal cancer was 20.5 and 8.9 months for moderately and poorly differentiated tumors, respectively.

Conclusions: Adjuvant autologous tumor antigen-loaded αDC1 vaccine and CKM is well tolerated. The mucinous nature of peritoneal metastases limits the feasibility of obtaining adequate autologous tumor cells. The improvement in median PFS did not meet our predefined thresholds, leading us to conclude that αDC1 vaccination is not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases.
Radical Hemiscrotectomy and En Bloc Orchidectomy: Surgical Technique and Perioperative and Oncologic Outcomes of a Supra-Regional UK Referral Centre. C.D. Fankhauser, A. Issa, E.W.C. Lee, et al. 2021;28(13):9217-9222. PubMed · Publisher · Free full text

Abstract

Background And Purpose: Hemiscrotectomy with en bloc orchidectomy represents a radical primary, completion, or salvage option in men with inguinoscrotal cancers. We describe our surgical technique and peri-operative and oncological outcomes.

Patients And Methods: Retrospective cohort study of 16 men treated at a supra-regional referral centre with open radical hemiscrotectomy with or without en bloc orchidectomy between 2010 and 2020. Peri-operative and survival outcomes were analysed.

Results: Radical hemiscrotectomy with or without en bloc orchidectomy was performed on 16 patients comprising 7 well-differentiated liposarcomas, 4 dedifferentiated liposarcomas, 2 leiomyosarcomas, 1 mesothelioma, 1 rhabdomyosarcoma and 1 mammary type myofibroblastoma. Primary hemiscrotectomy was performed in four, completion hemiscrotectomy in nine and salvage hemiscrotectomy in three. The median hospital stay was 2 days [interquartile range (IQR) 2-4]. Four patients (25%) had post-operative complications including wound infection or haematoma. During a median follow-up of 18 months (IQR 2-66), one patient (6%) died following a recurrence in the pelvis and retroperitoneum.

Discussion: and Conclusions If careful dissection is performed, radical hemiscrotectomy and en bloc orchidectomy is a radical but safe procedure with a short hospital stay. Haematoma and infection represent the main complications, and within limited follow-up most men showed no recurrence.

© 2021. The Author(s).
ASO Author Reflections: Expert Surgical Evaluation is Critical for Patients with Diffuse Malignant Peritoneal Mesothelioma: Lessons Learned from Assessing Outcomes of 2000 Patients. L. Bijelic, T. Cannon. 2020;27(8):2983-2984. PubMed · Publisher
ASO Author Reflections: Improving Outcomes in Diffuse Malignant Peritoneal Mesothelioma: Challenges and Opportunities. J.C. Leinwand, M.D. Kluger. 2020;27(Suppl 3):742-743. PubMed · Publisher
CRS/HIPEC with Major Organ Resection in Peritoneal Mesothelioma Does not Impact Major Complications or Overall Survival: A Retrospective Cohort Study of the US HIPEC Collaborative. D. Roife, B.D. Powers, M.Y. Zaidi, et al. 2020;27(13):4996-5004. PubMed · Publisher

Abstract

Introduction: CRS/HIPEC is thought to confer a survival advantage for patients with malignant peritoneal mesothelioma (MPM). However, the impact of nonperitoneal organ resection is not clearly defined. We evaluated the impact of major organ resection (MOR) on postoperative outcomes and overall survival (OS).

Patients And Methods: The US HIPEC collaborative database (2000-2017) was reviewed for MPM patients who underwent CRS/HIPEC. MOR was defined as total or partial resection of diaphragm, stomach, spleen, pancreas, small bowel, colon, rectum, kidney, ureter, bladder, and/or uterus. MOR was categorized as 0, 1, or 2+ organs.

Results: A total of 174 patients were identified. Median PCI was 16 (3-39). The distribution of patients with MOR-0, MOR-1, and MOR-2+ was 94, 45, and 35 patients, respectively. MOR-1 and MOR-2+ groups had a higher frequency of any complication compared with MOR-0 (57.8%, 74.3%, and 48.9%, respectively, p = 0.035), but Clavien 3/4 complications were similar. Median length of stay was slightly higher in the MOR-1 and MOR-2+ groups (10 and 11 days) compared with the MOR-0 cohort (9 days, p = 0.005). Incomplete cytoreduction, ASA class 4, and male gender were associated with increased mortality on unadjusted analysis; however, their impact on OS was attenuated on multivariable analysis. MOR was not associated with OS based on these data (MOR-1: HR 1.67, 95% CI 0.59-4.74; MOR-2+ : HR 0.77, 95% CI 0.22-2.69).

Conclusions: MOR was not associated with an increase in major complications or worse OS in patients undergoing CRS/HIPEC for MPM and should be considered, if necessary, to achieve complete cytoreduction for MPM patients.
Dextrose-Containing Carrier Solution for Hyperthermic Intraperitoneal Chemotherapy: Increased Intraoperative Hyperglycemia and Postoperative Complications. R.J. Torphy, C. Stewart, P. Sharma, et al. 2020;27(13):4874-4882. PubMed · Publisher

Abstract

Purpose: Intraoperative hyperglycemia is associated with infectious complications in general surgery patients. This study aimed to determine if the use of lactated Ringer's (LR) carrier solution during hyperthermic intraperitoneal chemotherapy (HIPEC) would lower the incidence of intraoperative hyperglycemia and improve postoperative outcomes when compared with a standard 1.5% dextrose peritoneal dialysate carrier solution.

Patients And Methods: This is a retrospective cohort study of 134 patients who underwent HIPEC at the University of Colorado. Perioperative glucose levels and outcomes were compared between patients who were perfused with 1.5% dextrose peritoneal dialysate carrier solution (n = 68) versus LR carrier solution (n = 66).

Results: The study population consisted of patients undergoing HIPEC for appendiceal (50%), colorectal (34%), mesothelioma (8%), and ovarian cancer (5%). Intraoperative severe hyperglycemia (glucose ≥ 180 mg/dL) was significantly more common among patients perfused with a dextrose-containing carrier solution versus those perfused with LR (88% vs. 21%; p < 0.001). Patients in the dextrose cohort had significantly more severe complications (39% vs. 12%; p = 0.034), infectious complications (35% vs. 15%; p = 0.011), and organ space infections (18% vs. 5%: p = 0.026) than the LR cohort. On multivariable analysis, dextrose-containing carrier solution was significantly associated with an increased risk of postoperative infectious complications (HR 5.16; p = 0.006).

Conclusions: Intraoperative hyperglycemia is common when dextrose-containing carrier solution is used during HIPEC, and severe intraoperative hyperglycemia is strongly associated with an increased risk for infectious of complications following HIPEC. LR carrier solution should be routinely used to reduce intraoperative hyperglycemia and its associated risks.
Effect of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy on Quality of Life in Patients with Peritoneal Mesothelioma. Y.M. Ali, J. Sweeney, P. Shen, et al. 2020;27(1):117-123. PubMed · Publisher · Free full text

Abstract

Introduction: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is an accepted treatment for peritoneal mesothelioma. In this study, we evaluated QOL after HIPEC for peritoneal mesothelioma.

Methods: This was a prospective study performed after HIPEC for peritoneal mesothelioma between 2002 and 2015. Patients completed QOL surveys, including the Short Form-36 (SF-36), Functional Assessment of Cancer Therapy + Colon (FACT-C), Brief Pain Inventory (BPI), and Center for Epidemiologic Studies Depression Scale (CES-D) preoperatively and at 3, 6, 12, and 24 months postoperatively.

Results: Overall, 46 patients underwent HIPEC for peritoneal mesothelioma and completed QOL surveys. Mean age was 52.8 ± 13.8 years and 52% were male. Good preoperative functional status was 70%. Median survival was 3.4 years, and 1, 3, and 5-year survivals were 77.4, 55.2, and 36.5%, respectively. CES-D score decreased at 3 months postoperatively, but increased at 24 months (p = 0.014); SF-36 physical functioning scale decreased at 3 months but returned to baseline at 12 months (p = 0.0045); and the general health scale decreased at 3 months, then improved by 6 months (p = 0.0034). Emotional well-being (p = 0.0051), role limitations due to emotional problems (p = 0.0006), social functioning (p = 0.0022), BPI (p = 0.025), least pain (p = 0.045), and worst pain (p < 0.0001) improved. FACT-C physical well-being decreased at 3 months but returned to baseline at 6 months (p = 0.020), and total FACT-C score improved at 6 months (p = 0.052).

Conclusion: QOL returned to baseline or improved from baseline between 3 months and 1 year following surgery. Despite the risks associated with this operation, patients may tolerate HIPEC well and have good overall QOL postoperatively.
Predictors and Outcomes of Surgery in Peritoneal Mesothelioma: an Analysis of 2000 Patients from the National Cancer Database. L. Bijelic, K. Darcy, J. Stodghill, et al. 2020;27(8):2974-2982. PubMed · Publisher

Abstract

Introduction: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy associated with poor outcomes. Recent reports have shown longer survival with radical surgery, usually combined with intraperitoneal chemotherapy. However, surgical interventions in these patients have not been extensively studied at a population level. The objective of this retrospective cohort study is to assess the prevalence of surgical and nonsurgical interventions for DMPM patients, the influence of surgery on survival outcomes, and the associations between demographic and clinical factors with treatments and outcomes.

Methods: This study included adult patients diagnosed with DMPM from 2003 to 2014 and registered in the National Cancer Database (NCDB). The primary outcome was overall survival. Histologically confirmed mesothelioma was defined using International Classification of Diseases (ICD)-3 codes 9050/3, 9051/3, 90523, and 9053/3 and peritoneum as primary affected organ using ICD codes C17-19, C22-24, C26, C42, C48, and C76. Relationships between demographic and clinical variables, surgical treatments, and survival outcomes were evaluated using logistic and Cox modeling and log-rank tests.

Results: A total of 2062 patients were identified, of whom 1055 (51%) did not receive any surgery while 701 (34%) received radical surgery. Patients receiving radical surgery had overall survival of 38.4 months compared with 7.1 months for patients without surgery (p < 0.001) and 41.8 months in patients who received both radical surgery and systemic chemotherapy.

Conclusions: Patients selected for and treated with radical surgery had significantly better overall survival compared with those receiving nonsurgical treatment. Patients newly diagnosed with DMPM should be evaluated for the possibility of receiving radical surgery.
Preoperative Risk Score for Predicting Incomplete Cytoreduction: A 12-Institution Study from the US HIPEC Collaborative. M.Y. Zaidi, R.M. Lee, A.C. Gamboa, et al. 2020;27(1):156-164. PubMed · Publisher · Free full text

Abstract

Background: For patients with peritoneal carcinomatosis undergoing cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC), incomplete cytoreduction (CCR2/3) confers morbidity without survival benefit. The aim of this study is to identify preoperative factors which predict CCR2/3.

Methods: All patients who underwent curative-intent CRS/HIPEC of low/high-grade appendiceal, colorectal, or peritoneal mesothelioma cancers in the 12-institution US HIPEC Collaborative from 2000 to 2017 were included (n = 2027). The primary aim is to create an incomplete-cytoreduction risk score (ICRS) to predict CCR2/3 CRS utilizing preoperative data. ICRS was created from a randomly selected cohort of 50% of patients (derivation cohort) and verified on the remaining patients (validation cohort).

Results: Within our derivation cohort (n = 998), histology was low-grade appendiceal neoplasms in 30%, high-grade appendiceal tumor in 41%, colorectal tumor in 22%, and peritoneal mesothelioma in 8%. CCR0/1 was achieved in 816 patients and CCR 2/3 in 116 patients. On multivariable analysis, preoperative factors associated with incomplete cytoreduction were male gender [odds ratio (OR) 3.4, p = 0.007], presence of ascites (OR 2.8, p = 0.028), cancer antigen (CA)-125 ≥ 40 U/mL (OR 3.4, p = 0.012), and carcinoembryonic antigen (CEA) ≥ 4.2 ng/mL (OR 3.2, p = 0.029). Each preoperative factor was assigned a score of 0 or 1 to form an ICRS from 0 to 4. Scores were grouped as zero (0), low (1-2), or high (3-4). Incidence of CCR2/3 progressively increased by risk group from 1.6% in zero to 13% in low and 39% in high. When ICRS was applied to the validation cohort (n = 1029), this relationship was maintained.

Conclusion: The incomplete cytoreduction risk score incorporates preoperative factors to accurately stratify the risk of CCR2/3 resection in CRS/HIPEC. This score should not be used in isolation, however, to exclude patients from surgery.
The Pathologic Peritoneal Cancer Index (PCI) Strongly Differs From the Surgical PCI in Peritoneal Metastases Arising From Various Primary Tumors. A. Bhatt, Y. Yonemura, S. Mehta, et al. 2020;27(8):2985-2996. PubMed · Publisher

Abstract

Background: The surgical peritoneal cancer index (sPCI) is calculated based on a subjective evaluation of the extent of peritoneal disease during surgery. The pathologic PCI (pPCI) may be a more accurate and objective method for determining the PCI. This study aimed to compare the sPCI and pPCI and to study the potential pitfalls and clinical implications of using the pPCI.

Methods: This prospective study (July to December 2018) included all patients undergoing cytoreductive surgery (CRS). The pPCI was calculated for each patient and compared with the sPCI. The impact of potential confounding factors on the difference between pPCI and sPCI was evaluated.

Results: Among 191 patients undergoing CRS at four centers, the pPCI and sPCI were concordant for 37 patients (19.3%). The pPCI was lower than the sPCI for 125 patients (65.4%) and higher for 29 patients (15.1%). The concordance between the two groups was maximum for gastric cancer (38.8%) and colorectal cancer (27.6%) and least for mesothelioma (6.7%) and rare primary tumors (5.6%) (p = 0.04). The difference was 0 to 3 points for 119 patients (62.3%), 4 to 5 points for 27 patients (14.1%), and more than 5 points for 45 patients (23.5%). The rate of concordance was not influenced by the use of neoadjuvant chemotherapy (NACT) (p = 0.4), but the difference was greater when NACT was used (p = 0.03).

Conclusions: The pPCI strongly differs from the sPCI for patients undergoing CRS for peritoneal disease and may provide a more accurate evaluation of the peritoneal disease extent. Further studies are needed to determine its prognostic value compared with sPCI, and consensus guidelines are needed for calculating it.
The Safety of Iterative Cytoreductive Surgery and HIPEC for Peritoneal Carcinomatosis: A High Volume Center Prospectively Maintained Database Analysis. E. Bekhor, J. Carr, M. Hofstedt, et al. 2020;27(5):1448-1455. PubMed · Publisher

Abstract

Introduction: Offering iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for recurrence of peritoneal carcinomatosis (PC) poses a surgical dilemma. Safety of this repeated operation in the short and long term has not been largely investigated.

Methods: Patients with PC who underwent 377 CRS/HIPEC procedures between 2007 and 2018 at our institution were included from a prospectively maintained database. Outcomes for patients who had singular CRS/HIPEC were compared with those for patients who had repeated CRS/HIPEC.

Results: Overall, there were 325 singular and 52 iterative CRS/HIPEC procedures performed during this time period. Age, sex, and ASA class were comparable between cohorts (p = NS). Optimal cytoreduction, mean operative time, mean length of hospital stay, 90-day major morbidity, and 90-day mortality were also similar. At a median follow-up of 24 months, there was no significant difference in recurrence rate (%, 60 vs 63, p = 0.76), disease-free survival (mean months, 19 vs 15, p = 0.30), and overall survival (mean months, 32 vs 27, p = 0.69). The iterative CRS/HIPEC group had significantly higher rates of major late complications than the singular CRS/HIPEC group (%, 18 vs 40, p < 0.01).

Conclusion: Repeated CRS/HIPEC for PC has similar perioperative morbidity and mortality, as well as long-term oncological benefits, when compared with singular CRS/HIPEC. However, more than twice as many patients undergoing iterative CRS/HIPEC suffered from major late complications.
Two-Stage Cytoreductive Surgery and Intraperitoneal Chemotherapy for Diffuse Malignant Peritoneal Mesothelioma: Predictors of Overall Survival in an Intention-to-Treat Series. J.C. Leinwand, R.N. Taub, J.A. Chabot, et al. 2020;27(7):2539-2547. PubMed · Publisher

Abstract

Purpose: Cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy is standard of care for diffuse malignant peritoneal mesothelioma (DMPM), but there is variability among institutions in the administration of adjuvant chemotherapy. Characterization of the largest series of DMPM patients treated at a single institution and identification of the demographic, disease, and treatment factors associated with overall survival were sought.

Patients And Methods: All DMPM patients who underwent initial cytoreductive surgery with the intention to undergo intraperitoneal chemotherapy and a second-look operation from 1995 to 2016 at our institution were retrospectively reviewed. The primary endpoint was overall survival.

Results: A total of 204 DMPM patients underwent initial cytoreduction. Median overall survival was 32 months from initial cytoreduction. Independent baseline prognostic factors of improved overall survival were female sex, age < 60 years, and epithelioid histology. Independent treatment factors associated with improved overall survival were attempted resection at initial operation, residual disease < 0.5 cm at the end of the initial operation, and dwell intraperitoneal chemotherapy.

Conclusions: Cytoreductive surgery with intraoperative and dwell intraperitoneal chemotherapy is a feasible approach for DMPM. Expanded access to these therapies may offer benefit to a larger population of patients. Demographic and operative parameters associated with overall survival in this large cohort are consistent with previous reports. In the context of this treatment protocol, dwell intraperitoneal chemotherapy is associated with longer overall survival.

2010s

ASO Author Reflections: Postoperative Radiotherapy for Patients with Mesothelioma-Past, Present, and Future. G.D. Lewis, B.S. Teh. 2019;26(Suppl 3):635-636. Comment PubMed · Publisher
How Old is Too Old to Operate for Mesothelioma?. J.M. Karush. 2019;26(8):2311-2312. Editorial PubMed · Publisher
Malignant Peritoneal Mesothelioma: Patterns of Care and Survival in the Netherlands: A Population-Based Study. N.L. de Boer, J.P. van Kooten, R.A.M. Damhuis, et al. 2019;26(13):4222-4228. PubMed · Publisher · Free full text

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. Recently, focus has shifted toward a more aggressive and multimodal treatment approach. This study aimed to assess the patterns of care and survival for MPM patients in the Netherlands on a nationwide basis.

Methods: The records of patients with a diagnosis of MPM from 1993 to 2016 were retrieved from the Dutch Cancer Registry. Data regarding diagnosis, staging, treatment, and survival were extracted. Cox regression analyses and Kaplan-Meier survival curves were used to study overall survival.

Results: Between 1993 and 2016, MPM was diagnosed for 566 patients. Overall, the prognosis was very poor (24% 1-year survival). The most common morphologic subtype was the epithelioid subtype (88%), followed by the biphasic (8%) and sarcomatoid (4%) subtypes. Surgical treatment has become more common in recent years, which most likely has resulted in improved survival rates. In this study, improved survival was independently associated with hyperthermic intraperitoneal chemotherapy (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.21-0.55) and surgery with adjuvant systemic chemotherapy (HR, 0.33; 95% CI, 0.23-0.48). Nonetheless, most patients (67%) do not receive any form of anti-cancer treatment.

Conclusion: This study indicated that MPM still is a rare and fatal disease. The survival rates in the Netherlands have improved slightly in the past decade, most likely due to more aggressive treatment approaches and increased use of surgery. However, most patients still do not receive cancer-directed treatment. To improve MPM management, and ultimately survival, care should be centralized in expert medical centers.
Management of Malignant Pleural Mesothelioma in the Elderly Population. V. Verma, R.E. Wegner, E.B. Ludmir, et al. 2019;26(8):2357-2366. PubMed · Publisher

Abstract

Background: The median age at diagnosis for malignant pleural mesothelioma (MPM) is approximately 72 years. Elderly patients pose unique management challenges because of the increased risk of therapy-related toxicities and mortality. Because there are no high-volume retrospective studies, prospective trials, or dedicated treatment recommendations for this population, this investigation addresses a major knowledge gap by examining national practice patterns and postoperative/survival outcomes in elderly MPM patients.

Methods: The National Cancer Database was queried for patients aged ≥ 80 years with newly diagnosed nonmetastatic MPM. Multivariable logistic regression ascertained factors associated with observation and surgery. Kaplan-Meier analysis assessed overall survival (OS), and multivariable Cox proportional hazards modeling examined factors associated with OS. Survival was also calculated following propensity matching. Additionally, postoperative outcomes were evaluated in surgical patients.

Results: Of 4526 patients, 2% received surgery and chemotherapy, 22% underwent chemotherapy alone, and 63% were observed. Respective median OS was 12.2, 9.5, and 4.1 months (p < 0.001). Differences between all groups persisted following propensity matching (all comparisons p < 0.05). For the 8% of patients who underwent specified definitive surgery (95% of whom received pleurectomy/decortication), 30- and 90-day mortality rates were 11.0% and 28.5%, respectively. The median length of postoperative hospitalization was 6 days, with 30-day readmission occurring in 7.5% of patients.

Conclusions: The majority of elderly MPM patients in the US are observed, which was associated with poorer OS than chemotherapy and/or surgery. Although highly selected surgery/chemotherapy patients were associated with the longest OS, given the high biases in database studies and high perioperative mortality rates, careful patient selection for combined modality approaches in this population is imperative.
The Role of Adjuvant Radiotherapy in the Treatment of Pleural Mesothelioma. G.D. Lewis, S.M. Dalwadi, A. Farach, et al. 2019;26(6):1879-1885. PubMed · Publisher

Abstract

Background: Pleural mesothelioma is a rare but aggressive form of cancer. Local recurrence represents the majority of treatment failures and overall survival (OS) outcomes remain dismal. Adding locoregional treatment with radiotherapy after surgical resection has been considered but its role remains uncertain.

Objective: The purpose of this study was to evaluate the outcomes of adjuvant radiation therapy (RT) for patients with malignant pleural mesothelioma.

Methods: The National Cancer Data Base (NCDB) was queried (2004-2013) for patients with malignant mesothelioma. Patients were divided into three groups: observation, surgery alone, and surgery followed by adjuvant RT. Statistics included Fisher's exact or Chi square tests to analyze categorical proportions between groups, Kaplan-Meier analysis to evaluate OS, and Cox proportional hazards modeling to determine variables associated with OS. Propensity matching was performed to make comparisons between homogenous groups.

Results: Overall, the surgery plus radiotherapy group had a higher median survival (21.4 months) compared with surgery alone (16.59 months) [p < 0.001]. RT was more likely to be delivered after extrapleural pneumonectomy than with lung-sparing surgical approaches. On multivariable analysis, receipt of surgery plus radiotherapy, chemotherapy administration, and higher socioeconomic status were associated with improved OS (p < 0.0001). After propensity matching, receipt of surgery plus radiotherapy and chemotherapy administration were still associated with improved OS (p < 0.05).

Conclusions: In the treatment of malignant pleural mesothelioma, adjuvant radiotherapy after surgical intervention was associated with improved OS. This study is the largest study of adjuvant radiotherapy to date, and our findings highlight the need for additional prospective data.
ASO Author Reflections: C-Reactive Protein/Albumin Ratio as a Prognostic Factor in Patients with Malignant Pleural Mesothelioma: What Does the Novel Index Represent?. S. Takamori, M. Takenoyama. 2018;25(Suppl 3):958-959. Comment PubMed · Publisher
ASO Author Reflections: Long-Term Survival Is Feasible After Complete CRS/HIPEC for Biphasic Peritoneal Mesothelioma. K. Chouliaras, K.I. Votanopoulos. 2018;25(Suppl 3):770-771. Comment PubMed · Publisher
ASO Author Reflections: Management of Malignant Peritoneal Mesothelioma. T.R. Cushman, V. Verma, C.B. Simone. 2018;25(Suppl 3):767-768. Comment PubMed · Publisher
Current Management and Future Opportunities for Peritoneal Metastases: Peritoneal Mesothelioma. H.R. Alexander, C.Y. Li, T.J. Kennedy. 2018;25(8):2159-2164. Review PubMed · Publisher

Abstract

Purpose: Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity.

Methods: The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM.

Results: The condition afflicts men and women equally and the peak incidence is between 55 and 60 years of age although it can arise in the young and elderly. Patients afflicted with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for MPM patients without treatment is < 1 year. The couplet of systemic pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year.

Conclusion: The available data, almost all retrospective in nature, have shown that in selected patients, operative cytoreduction (CRS) and regional chemotherapy administered as hyperthermic intraoperative peritoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) is associated with long-term survival. Studies on the molecular biology of MPM have yielded new insights relating to the potentially important role of the phosphoinsitide-3-kinase/mammalian target of rapamycin (PI3 K/mTOR) pathways and immune checkpoint inhibitors that may translate into new therapeutic options for patients with diffuse MPM.
Dose-Dependent Effect of Red Blood Cells Transfusion on Perioperative and Long-Term Outcomes in Peritoneal Surface Malignancies Treated with Cytoreduction and HIPEC. E. Nizri, S. Kusamura, G. Fallabrino, et al. 2018;25(11):3264-3270. PubMed · Publisher

Abstract

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with increased red blood cell transfusion (RBT) demand. Although the deleterious effects of RBT are documented in various settings, its effect in this setting is obscure. In this study, we evaluated the effects of different-grade RBT on the short- and long-term outcomes of CRS and HIPEC.

Methods: We analyzed 231 patients with diffuse malignant peritoneal mesothelioma (DMPM) and 273 patients with pseudomyxoma peritonei (PMP) operated in our unit. RBT was categorized according to the amount of packed red blood cell units (PRBCs) administered (0, 1-2, 3-5, > 6). The effects of RBT on long-term oncological outcomes [progression-free survival (PFS) and overall survival (OS)] were assessed by using multivariate analysis.

Results: Overall, 74% of the patients were transfused with a median of 2 PRBCs (range 0-37). Transfusion level correlated with operative time, surgical extent (as measured by the peritoneal carcinomatosis index), and age. Postoperatively, patients with major transfusion (> 6 PRBCs) had increased mortality rate (11.1%, p = 0.01) and length of hospital stay (31.2 ± 16.8 days, p = 0.01) compared with other levels of RBT. RBT was dose-dependently associated with oncological outcomes in both DMPM and PMP for both PFS [hazard ratio (HR) = 1.40, 95% confidence interval (CI) 1.12-1.74, p = 0.003; HR = 1.44, 95% CI 1.15-1.81, p = 0.001, respectively] and OS (HR = 1.57, 95% CI 1.21-2.03, p = 0.001; HR = 1.43, 95% CI 1.15-1.90, p = 0.01, respectively).

Conclusions: Our data show a dose-dependent relationship between RBT and oncological outcomes. Further research to develop transfusion sparing protocols is needed in this extensive surgical procedure.
Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study. B. Malgras, E. Gayat, O. Aoun, et al. 2018;25(11):3271-3279. PubMed · Publisher

Abstract

Background: The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM).

Objective: The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM.

Methods: From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age ≤ 80 years, performance status ≤ 2, and no extraperitoneal metastases.

Results: Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group 1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype.

Conclusions: This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial.
Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry. K.I. Votanopoulos, P. Sugarbaker, M. Deraco, et al. 2018;25(3):667-673. PubMed · Publisher · Free full text

Abstract

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant.

Methods: A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease.

Results: Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant.

Conclusions: Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved.
Malignant Peritoneal Mesothelioma: National Practice Patterns, Outcomes, and Predictors of Survival. V. Verma, R.L. Sleightholm, C.G. Rusthoven, et al. 2018;25(7):2018-2026. PubMed · Publisher

Abstract

Purpose: This study of a large, contemporary national database evaluated management patterns, outcomes, and prognostic factors of malignant peritoneal mesothelioma (MPM) in the USA.

Methods: The National Cancer Data Base was queried for newly diagnosed nonmetastatic MPM. Patients were divided into five cohorts: observation, chemotherapy alone, cytoreductive surgery (CRS) alone, CRS/chemo [referring to any non-hyperthermic intraperitoneal chemotherapy (HIPEC) chemotherapy], and CRS/HIPEC. Statistics included multivariable logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling.

Results: Of 1514 patients, 379 (25%) underwent observation, 370 (24%) received chemotherapy only, 197 (13%) CRS alone, 352 (23%) CRS/chemo, and 216 (14%) CRS/HIPEC. No major temporal trends in management were noted. Factors predictive of CRS administration included younger age, female gender, insurance status, residence in educated areas, living farther from treating institutions, and treatment at academic centers (p < 0.05 for all). Compared with epithelioid histology, those with sarcomatoid and biphasic histology were less and more likely to undergo CRS, respectively (p < 0.05 for both). In all CRS patients, 30- and 90-day mortality rates were 0.8 and 1.2%, respectively. At median follow-up of 50 months, median OS in the respective groups was 6, 17, 21, 52, and 61 months (p < 0.001). Poor prognostic factors included advanced age, male gender, uninsured/Medicaid insurance, and sarcomatoid/biphasic histology (p < 0.05 for all).

Conclusions: In the USA, MPM is treated using a wide variety of strategies. Many factors impact the type of treatment delivered, including age, sociodemographics, geography, histology, and facility type. Although these data do not imply causation, combined-modality management seems associated with the longest OS.
Poor Prognostic Factors in Patients with Malignant Pleural Mesothelioma Classified as Pathological Stage IB According to the Eighth Edition TNM Classification. T. Takuwa, M. Hashimoto, A. Kuroda, et al. 2018;25(6):1572-1579. PubMed · Publisher

Abstract

Introduction: The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group.

Methods: Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models.

Results: Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3-year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3-year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (p = 0.015).

Conclusions: Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy.
Postoperative Complications Independently Predict Cancer-Related Survival in Peritoneal Malignancies. M.H.A. Choudry, Y. Shuai, H.L. Jones, et al. 2018;25(13):3950-3959. PubMed · Publisher

Abstract

Background: The authors hypothesized that postoperative complications after cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) have a negative impact on perioperative and oncologic outcomes and that the novel Comprehensive Comorbidity Index (CCI) would be a better predictor of such outcomes than the traditional Clavien-Dindo classification (CDC).

Methods: The study used a prospective database of 1296 patients with peritoneal metastases (PM) undergoing CRS-HIPEC between 2001 and 2016. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes. The Akaike information criterion and the Schwarz (Bayesian information) criterion were used to compare model fitting for CCI versus CDC.

Results: In this study, CRS-HIPEC was performed for malignant mesothelioma (12%) and PM from appendix (50%), colorectal (30%), and ovarian (8%) cancers. Major postoperative in-hospital complications (CDC grades 3-4) occurred for 24% of the patients. However, a range of CCI scores was calculated for each CDC grade because 36% of the patients experienced multiple complications. After a median follow-up period of 55 months, the median progression-free survival was 15 months, and the median overall survival was 39 months. In the multivariate Cox proportional hazards models, postoperative in-hospital complications (measured by CDC or CCI) were independent prognostic factors for 30-day post-discharge morbidity and readmission, as well as for survival. The CCI scores demonstrated higher prognostic sensitivity for these outcomes than CDC grades.

Conclusions: Reduction of postoperative complications after CRS-HIPEC is essential for optimal short- and long-term outcomes. For assessing total burden of postoperative complications per patient, CCI is superior to CDC and more sensitive for assessing surgery- and cancer-related outcomes after CRS-HIPEC.
Preoperative Circulating Tumor DNA in Patients with Peritoneal Carcinomatosis is an Independent Predictor of Progression-Free Survival. J.M. Baumgartner, V.M. Raymond, R.B. Lanman, et al. 2018;25(8):2400-2408. PubMed · Publisher · Free full text

Abstract

Background: Next-generation sequencing (NGS) is a useful tool for detecting genomic alterations in circulating tumor DNA (ctDNA). To date, most ctDNA tests have been performed on patients with widely metastatic disease. Patients with peritoneal carcinomatosis (metastases) present unique prognostic and therapeutic challenges. We therefore explored preoperative ctDNA in patients with peritoneal metastases undergoing surgery.

Methods: Patients referred for surgical resection of peritoneal metastases underwent preoperative blood-derived ctDNA analysis (clinical-grade NGS [68-73 genes]). ctDNA was quantified as the percentage of altered circulating cell-free DNA (% cfDNA).

Results: Eighty patients had ctDNA testing: 46 (57.5%) women; median age 55.5 years. The following diagnoses were included: 59 patients (73.8%), appendix cancer; 11 (13.8%), colorectal; five (6.3%), peritoneal mesothelioma; two (2.5%), small bowel; one (1.3%) each of cholangiocarcinoma, ovarian, and testicular cancer. Thirty-one patients (38.8%) had detectable preoperative ctDNA alterations, most frequently in the following genes: TP53 (25.8% of all alterations detected) and KRAS (11.3%). Among 15 patients with tissue DNA NGS, 33.3% also had ctDNA alterations (overall concordance = 96.7%). Patients with high ctDNA quantities (≥ 0.25% cfDNA, n = 25) had a shorter progression-free survival (PFS) than those with lower ctDNA quantities (n = 55; 7.8 vs. 15.0 months; hazard ratio 3.23, 95% confidence interval 1.43-7.28, p = 0.005 univariate, p = 0.044 multivariate).

Conclusions: A significant proportion of patients with peritoneal metastases referred for surgical intervention have detectable ctDNA alterations preoperatively. Patients with high levels of ctDNA have a worse prognosis independent of histologic grade.
The C-Reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma: A Retrospective Multi-institutional Study. S. Takamori, G. Toyokawa, M. Shimokawa, et al. 2018;25(6):1555-1563. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown.

Methods: The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival.

Results: Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p < 0.001) and chemotherapy alone (p = 0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p < 0.001) and disease- or progression-free survival (DFS/PFS) (p < 0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p = 0.003 and p = 0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS.

Conclusions: CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings.
The C-Reactive Protein/Albumin Ratio May Predict the Long-Term Outcome in Patients with Malignant Pleural Mesothelioma. N. Yoshida, H. Baba. 2018;25(6):1471-1472. Editorial · Comment PubMed · Publisher

Summary

This editorial, by two surgeons at Kumamoto University, Japan, commented on a study by Takamori et al. of the serum C-reactive protein/albumin ratio (CAR) as a prognostic marker in malignant pleural mesothelioma (MPM). The authors first outlined the background. MPM is one of the most lethal neoplasms, and long-term outcomes remain insufficient despite multimodal treatment with extrapleural pneumonectomy, chemotherapy and radiotherapy. They noted that various markers of inflammation and nutrition had been suggested as prognostic indicators. Takamori et al. had retrospectively studied 100 MPM patients treated with chemotherapy alone, neoadjuvant chemotherapy followed by surgery, or surgery alone. They used propensity score matching for clinical stage, histopathology, performance status and treatment type, and concluded that CAR was an independent prognostic factor for overall survival and disease-free/progression-free survival. The editorialists described this as the first study to show the importance of CAR in MPM. They noted that CAR can be calculated easily from routine blood tests, and they considered the proposed mechanisms reasonable. However, they said it was unclear how CAR should be used in practice and how patients with elevated CAR should be treated. They identified limitations: the number of patients was not large, only 35 underwent surgery, and recruitment spanned 1995–2015, which raised the possibility of historical biases. They concluded that larger multi-institutional studies were desirable.

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Conversion to Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma After Bidirectional Chemotherapy. F. Le Roy, M. Gelli, A. Hollebecque, et al. 2017;24(12):3640-3646. PubMed · Publisher

Abstract

Background: This report aims to describe preliminary results concerning secondary resectability after bidirectional chemotherapy for initially unresectable malignant peritoneal mesothelioma (MPM).

Methods: Between January 2013 and January 2016, 20 consecutive patients treated for diffuse MPM not suitable for upfront surgery received bidirectional chemotherapy associating intraperitoneal and systemic chemotherapy. Evaluation of the response to chemotherapy was assessed clinically and by laparoscopy.

Results: The median peritoneal cancer index (PCI) score at staging laparoscopy was 27 (range 15-39). Altogether, 118 intraperitoneal chemotherapy cycles were administered without any specific adverse catheter-related event. Concerning tolerance, 85% of the patients experienced no pain or mild pain during chemotherapy administration. The clinical response rate was 60% after a median of three chemotherapy cycles. At laparoscopic reevaluation, the median PCI was 18 (range 0-35), and a secondary resectability was considered for 55% of the patients. Complete cytoreduction surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) was finally achieved for 10 patients (50%), with a median intraoperative PCI score of 14 (range 6-30). After a median follow-up period of 18 months, the 2-year overall survival rate was 83.3% for the patients treated by CRS followed by HIPEC and 44% for the patients treated by bidirectional chemotherapy.

Conclusion: Bidirectional chemotherapy is a promising, well-tolerated treatment capable of increasing the resection rate for selected patients with diffuse MPM initially considered as unresectable or borderline resectable. For patients with definitively unresectable disease, bidirectional chemotherapy achieves a higher clinical response rate.
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Adolescent and Young Adults with Peritoneal Metastases. M. Dhir, L. Ramalingam, Y. Shuai, et al. 2017;24(4):875-883. PubMed · Publisher

Abstract

Background: Several studies suggest that young patients may derive less oncologic benefit from surgical resection of cancers compared with older patients. We hypothesized that young patients may have worse outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) for peritoneal metastases.

Methods: Perioperative and oncologic outcomes in adolescent and young adults (AYA), defined as younger than age 40 years (n = 135), undergoing CRS/HIPEC between 2001 and 2015 were reviewed and compared with middle-aged adults, defined as aged 40-65 years (n = 684).

Results: The two groups were similar with regards to perioperative characteristics except that AYA were more likely to be symptomatic at presentation (65.2 vs. 50.9%, p = 0.003), had lower Charleson comorbidity index (median 6 vs. 8, p < 0.001), were less likely to receive neoadjuvant chemotherapy (32.8 vs. 42.5%, p = 0.042), and had longer operative times (median 543 vs. 493 min, p = 0.010). Postoperative Clavien-Dindo grade 3-4 morbidity was lower in AYA (17 vs. 26%, p = 0.029), and they required fewer reoperations for complications (3.7 vs. 10.4%, p = 0.014). AYA had longer median overall survival (103.6 vs. 73.2 months, p = 0.053). In a multivariate Cox regression analysis, age was an independent predictor of improved overall survival [hazard ratio 0.705; 0.516-0.963, p = 0.028].

Conclusions: Young patients with peritoneal metastases derive similar benefits from CRS/HIPEC as middle-aged patients. Young age should not be a deterrent to consideration of CRS/HIPEC for peritoneal metastases.
Preoperative Thrombocytosis Predicts Shortened Survival in Patients with Malignant Peritoneal Mesothelioma Undergoing Operative Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy. Y.C. Li, T. Khashab, J. Terhune, et al. 2017;24(8):2259-2265. PubMed · Publisher

Abstract

Background: This study was designed to determine the clinical significance of preoperative thrombocytosis in patients with malignant peritoneal mesothelioma (MPM) undergoing operative cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). CRS and HIPEC have been associated with prolonged survival in patients with MPM and is the preferred treatment in select patients. However, patient selection criteria remain ill-defined for this operation that is also associated with significant morbidity and mortality. Preoperative thrombocytosis has been associated with poor outcomes in various malignancies but never studied in MPM.

Methods: Between January 2006 and December 2015, 100 patients with high-grade epithelioid MPM were evaluated and selected for CRS and HIPEC at our center (M: 53, F: 47; mean age: 54 years [range 17-81 years]). We analyzed various patient and treatment related factors potentially associated with overall survival (OS).

Results: The median actuarial overall survival was 32.8 months; the actuarial 1-, 3-, 5-year survivals were 70, 49, and 36%, respectively. On multivariate analysis, suboptimal resection (CCR > 1), high tumor burden (PCI > 20), and elevated preoperative platelet count (>367,000/mm3) were independently associated with shortened OS (P < 0.05). Median OS in patients with elevated versus normal platelet counts were 13 and 58 months, respectively (P < 0.001). Compared with patients with normal platelet counts, patients with elevated counts had significantly greater residual disease after operation (P = 0.008).

Conclusions: Elevated preoperative platelet count is independently associated with poor outcome. Notably, thrombocytosis reflects aggressive tumor biology and should be considered a factor in patient selection for CRS and HIPEC.
Recurrence of Optimally Treated Malignant Peritoneal Mesothelioma with Cytoreduction and Heated Intraperitoneal Chemotherapy. D.R. Heller, C. Chiuzan, R.N. Taub, et al. 2017;24(13):3818-3824. PubMed · Publisher

Abstract

Background: The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients.

Methods: We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan-Meier method.

Results: Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Group B). Forty-two percent of patients developed disease recurrence with a median recurrence-free survival of 38.5 months for the cohort; 79% of these received a form of iterative treatment. There was no statistically significant difference in recurrence-free survival between Group A (median RFS: 44.6 months) and B (median RFS: 35.5 months) (log-rank test, p = 0.06). Additionally, the only variable significantly associated with RFS was male gender (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.16-3.38).

Conclusions: Absence of gross disease at the second operation was not statistically protective against recurrence compared with presence of quantifiable residual disease (Group B) that was effectively cytoreduced. Long-term disease surveillance is recommended, because recurrence continues years after treatment. Where a question of recurrence arises on surveillance, males may benefit from a higher degree of suspicion.
A Novel Tool for Predicting Major Complications After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy. J.M. Baumgartner, T.G. Kwong, G.L. Ma, et al. 2016;23(5):1609-17. PubMed · Publisher · Free full text

Abstract

Background: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has an emerging role in the treatment of peritoneal malignancies. The CRS-HIPEC approach has known treatment-related toxicities. This study sought to determine the predictors of major postoperative complications after CRS-HIPEC in a high-volume center.

Methods: From a single-institution database, this study investigated complications experienced by patients undergoing CRS-HIPEC. Multiple preoperative and operative factors were analyzed for their ability to predict 60-day Clavien grade 3 and greater (major) complications by logistic regression. A predictive model was created from preoperative factors using multivariate logistic regression. The model was tested by Akaike's information criterion, the Hosmer and Lemeshow Goodness-of-Fit Test, the receiver operating characteristic, and the Youden Index.

Results: The study evaluated 247 patients undergoing CRS-HIPEC. The primary tumor site was the appendix in 166 cases (67.2 %), the colorectal area in 51 cases (20.6 %), the peritoneum (mesothelioma) in 22 cases (8.9 %), the ovary in 5 cases (2 %), and the small bowel in 3 cases (1.2 %). The median peritoneal cancer index was 14 (range 0-29), and 235 patients (95.1 %) had a complete (CC-0/1) cytoreduction. Major complications occurred for 41 patients (16.6 %), classified as grade 3 in 33 cases (13.4 %), grade 4 in 5 cases (2 %), and grade 5 (deaths) in 3 cases (1.2 %). The factors predictive of major complications in the multivariate analysis were a Charlson Comorbidity Index (CCI) score higher than 0 [odds ratio (OR), 2.505; p = 0.035], presence of preoperative symptoms (OR 1.951; p = 0.064), and prior resection status [no resection or prior CRS-HIPEC (OR 2.087) vs. prior resection without CRS-HIPEC (OR 3.209); p = 0.046]. These variables were used to create a tool predictive of postoperative complications.

Conclusion: Presence of symptoms, CCI, and prior resection status predict major complications and define a low-risk population after CRS-HIPEC.
Impact of Major Complications on Patients' Quality of Life After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. T.D. Hamilton, E.L. Taylor, A.J. Cannell, et al. 2016;23(9):2946-52. PubMed · Publisher

Abstract

Introduction: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for selected patients with peritoneal surface malignancies (PSM). Although it can have significant morbidity, perioperative mortality is low. Little is known about whether major complications after CRS/HIPEC have a lasting impact on patients' quality of life (QOL).

Methods: We retrospectively reviewed data from a prospectively collected database on patients treated with CRS/HIPEC for PSM (2011-2014). Patients with CRS/HIPEC and 6-month QOL evaluation were included. Major perioperative complications (Clavien-Dindo grade 3/4) were the primary independent variable. QOL was evaluated using the validated EORTC QLQ-C30 score. The primary outcome was 6-month global health score. Secondary outcomes were individual functional and symptom domains.

Results: Forty-two patients were analyzed. Median age was 57.5; 64 % were female. Origin of PSM was appendix (55 %), colorectal (38 %), mesothelioma (5 %), and small bowel (2 %). Fourteen patients (33 %) had major (grade 3/4) complications. Median length of stay was 16 days; patients experiencing major complications had significantly increased length of stay (35.5 vs. 13 days, p < 0.01). Major complications included intra-abdominal abscess (9.5 %), bleeding (9.5 %), symptomatic pleural effusion (7.1 %), anastomotic leaks (7.1 %), and renal failure (2.4 %). The average global health score at 6 months was 68.1. The worst-rated symptom scores at 6 months were diarrhea (39.8) and fatigue (35.4). There were no significant differences in 6-month QOL scores between patients with and without major complications, globally or in specific domains.

Conclusions: Although major complications are common after CRS/HIPEC, QOL at 6 months recovers and is similar to those without major complications.
Laparoscopy is Safe and Accurate to Evaluate Peritoneal Surface Metastasis Prior to Cytoreductive Surgery. R.A. Marmor, K.J. Kelly, A.M. Lowy, et al. 2016;23(5):1461-7. PubMed · Publisher

Abstract

Background: Completeness of cytoreduction is a significant predictor of long-term outcome after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Imaging has limited sensitivity to identify peritoneal metastases and therefore predict whether complete cytoreduction is possible. We reviewed our experience using laparoscopy to determine candidates for complete cytoreduction and HIPEC.

Methods: This single-center, retrospective study examined patients from 2007 to 2014 who underwent laparoscopy to determine complete cytoreduction (CC-0/1)/HIPEC candidacy. Preoperative, intraoperative, and postoperative data were collected.

Results: A total of 145 laparoscopies were performed on 141 patients, 72 (51.1 %) of whom were female, with a median age of 53 years (range 20-79). The primary site was appendiceal in 67 (47.5 %) patients, colorectal in 43 (30.5 %), mesothelioma in 17 (12.1 %), unknown in 9 (6.4 %), small bowel in 3 (2.1 %), gastric in 1, and ovarian in 1 (0.7 % each). Overall, 115 (81.6 %) patients had prior abdominal surgery, 111 (76.6 %) had evidence of disease on imaging, and 117 (80.7 %) underwent prior chemotherapy, with a median of 5.9 weeks between the last treatment and laparoscopy (0.9-498.9 weeks). Four (2.8 %) intraoperative complications were observed (one liver laceration, two enterotomies, and one air embolus), and nine (6.2 %) postoperative complications [four (2.8 %) Clavien grade (CG) I, three (2.8 %) CG II, one (0.7 %) CG III (return to operating room) and one (0.7 %) CG IV (transient ischemic attack)]. Forty-eight patients deemed candidates by laparoscopy underwent CRS/HIPEC (positive predictive value 82.8 %).

Conclusion: Diagnostic laparoscopy is a safe, feasible, and accurate staging tool in patients with suspected peritoneal metastases being considered for CRS.
Malignant Peritoneal Mesothelioma: Characterization of the Inflammatory Response in the Tumor Microenvironment. S. Judge, P. Thomas, V. Govindarajan, et al. 2016;23(5):1496-500. PubMed · Publisher

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare cancer arising from mesothelial cells lining the peritoneal surface. Little is known about the tumor microenvironment in regulating MPM oncogenesis. The current study defined the chemokine/cytokine expression profile and inflammatory responses within the MPM microenvironment.

Methods: Levels of 10 cytokines (Fractalkine, IFNγ, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, TNFα, VEGF) in matched ascites and sera from 15 MPM patients were measured using Milliplex immunoassays. Sera from six normal control sera were included. Statistical analyses included the Wilcoxon signed-rank test, the Mann-Whitney U test, bivariate analysis, and the R (2) coefficient of correlation.

Results: The median levels of IL-6 (3190 vs 3.18 ng/ml; p < 0.001), IL-8 (118 vs 4.93 ng/ml; p < 0.001), IP-10 (3923 vs 384 ng/ml; p < 0.001), and MCP-1 (2886 vs 544 ng/ml; p = 0.005) were significantly higher in the MPM ascites than in the matched MPM serum. In the MPM serum samples, the levels of IL-8 (4.93 vs 1.52 ng/ml; p = 0.002), MIP-1β (53.8 vs 22.3; p = 0.016), TNFα (9.97 vs 4.5 ng/ml; p = 0.013), and VEGF (277 vs 105.4 ng/ml; p = 0.036) were significantly higher than in the control sera.

Conclusion: The chemokines/cytokines in the MPM tumor microenvironment are distinct from those associated with inflammatory responses to infection or injury (e.g., IL-1, IL-2, TNFα, IFNγ). These local changes reflect active reciprocal communication between tumor and associated stroma, which the authors predict is integral to MPM oncogenesis. Future studies will test this hypothesis and identify potential serum biomarkers for MPM.
The Role of Ki-67 and Pre-cytoreduction Parameters in Selecting Diffuse Malignant Peritoneal Mesothelioma (DMPM) Patients for Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). S. Kusamura, P.A. Torres Mesa, A. Cabras, et al. 2016;23(5):1468-73. PubMed · Publisher

Abstract

Background: We conducted a prognostic analysis of preoperative parameters and Ki-67 determination to develop selection criteria for cytoreductive surgery (CRS) and HIPEC in patients with diffuse malignant peritoneal mesothelioma (DMPM).

Methods: DMPM patients treated with CRS and HIPEC at NCI of Milan participated in this study. Multivariate analysis was conducted using Cox proportional hazard model and conditional inference tree method to select independent predictors of overall survival (OS) from the followings pre-cytoreduction parameters: age, sex, ECOG performance status, Charlson comorbidity index, previous systemic chemotherapy, CA-125, histological subtype (epithelioid vs. biphasic/sarcomatoid), Ki-67 (determined with immunohistochemistry), and peritoneal cancer index (PCI).

Results: A total of 117 patients (male/female: 67/50) with median age of 60.5 (range 22-75) years were included. Eighty-three patients had ECOG performance status = 0, median Charlson comorbidity index was 4 (range 2-9), and 102 cases had epithelioid subtype. Median Ki-67 was 5 % (range 1-60). Ninety-four (80.3 %) cases were optimally cytoreduced. The Cox analysis identified Ki-67, PCI, and histological subtype as independent prognosticators of OS. Conditional inference tree method identified three prognostic subsets: (I) Ki-67 ≤ 9 %; (II) Ki-67 > 9 % and PCI ≤ 17; and (III) Ki-67 > 9 % and PCI > 17. The median OS for subsets I, II, and III were, 86.6, 63.2, and 10.3 months, respectively.

Conclusions: Ki-67 is a powerful prognosticator that allows, along with PCI, and histological subtype, a good prediction of OS in patients with DMPM. Patients with Ki-67 > 9 % and PCI > 17 are unlikely to benefit from the procedure and should be considered for other treatment protocols.
Association between hospital finances, payer mix, and complications after hyperthermic intraperitoneal chemotherapy: deficiencies in the current healthcare reimbursement system and future implications. M.H. Squires, C.A. Staley, W. Knechtle, et al. 2015;22(5):1739-45. PubMed · Publisher

Abstract

Background: Despite increasing implementation of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), there are little data on its financial implications. We analyzed hospital cost and reimbursement data within the context of insurance provider type and postoperative complications.

Methods: Clinicopathologic variables, hospital costs, and reimbursement for all patients undergoing CRS/HIPEC at a single institution from 2009 to 2013 were analyzed.

Results: A total of 64 patients underwent CRS/HIPEC. Median PCI score was 19, and average operative time was 550 min. Tumor histology included appendiceal (n = 40; 62 %), colorectal (n = 16; 25 %), goblet cell (n = 5; 8 %), and mesothelioma (n = 3; 5 %). Median length-of-stay was 13 days. Complications occurred in 42 patients (66 %), including 13 (20 %) with major (Clavien grade III-IV) complications. Payer mix included 42 private insurance and 22 Medicare/Medicaid. Financial data was available for 56 patients: average total hospital cost was $49,248 and reimbursement was $63,771, for a hospital profit of $14,523/patient. Despite similar costs between Medicare/Medicaid and private-insurance patients, Medicare/Medicaid reimbursed much less ($30,713 vs $80,747; p < 0.001), resulting in a net loss of $17,342 per patient. For private-insured patients, major complications were associated with increased cost and increased reimbursement, resulting in a net profit of $36,285, compared with a net loss of $54,274 in Medicare/Medicaid patients.

Conclusions: CRS/HIPEC is profitable in privately insured patients, even for those with major complications, but loses money in patients with Medicare/Medicaid. Under a future bundled-reimbursement system, complications will be negatively associated with profit. With these impending changes, hospitals must place emphasis on value, recalculate the reimbursement necessary for financial viability, and focus on decreasing costs and minimizing complications.
Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for children, adolescents, and young adults: the first 50 cases. A. Hayes-Jordan, H. Green, H. Lin, et al. 2015;22(5):1726-32. PubMed · Publisher

Abstract

Background: Extensive peritoneal metastatic disease is rare in children. Although usually manifested as carcinomatosis in adults, sarcomatosis is more common in children. The authors began a pediatric hyperthermic intraperitoneal chemotherapy (HIPEC) program, and this report describes their initial results from the first 50 pediatric, adolescent, and young adult patients.

Methods: A single-institution, retrospective study investigated the first 50 cytoreductive surgeries and HIPEC by one surgeon for patients 3-21 years of age. The HIPEC was added to chemotherapy and radiotherapy treatment. Demographics, outcome, and complications were recorded.

Results: The median follow-up period for the surviving patients was 21.9 months. The most common diagnoses were desmoplastic small round cell tumor (n = 21), rhabdomyosarcoma (n = 7), mesothelioma (n = 4), and other carcinoma (n = 17). Multivariate analysis showed that patients treated with HIPEC and an incomplete cytoreduction had a greater risk for recurrence than those who had a complete cytoreduction (p = 0.0002). The patients with a higher peritoneal cancer index (PCI) (i.e., a large tumor burden) had a median overall survival (OS) time of 19.9 months relative to the patients with a lower PCI score, who had a median OS of 34 months (p = 0.049). The patients without complete cytoreduction had a median OS of 7.1 months compared with 31.4 months for the patients with complete cytoreduction (p = 0.012). No perioperative mortalities occurred. The incidence of major complications was 28 %.

Conclusion: Cytoreductive surgery and HIPEC with a programmatic approach for patients 3-21 years of age is unique. The best outcome was experienced by patients with desmoplastic small round cell tumor and those with complete cytoreduction. Complete cytoreduction for patients without disease outside the abdominal cavity at the time of surgery affords the best outcome.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis. J.H. Helm, J.T. Miura, J.A. Glenn, et al. 2015;22(5):1686-93. Meta-analysis · Systematic review PubMed · Publisher

Abstract

Background: Due to the increased adoption of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients with malignant peritoneal mesothelioma (MPM) have seen improved outcomes. We aimed to evaluate and synthesize the recent published literature.

Methods: The review was conducted according to the recommendation of the Meta-Analysis of Observational Studies in Epidemiology group with prespecified inclusion and exclusion criteria. The DEALE method was used to combine mortality rates, and imputation techniques were used to calculate standard errors. Meta-regression techniques were used to synthesize data. Publication bias was assessed using funnel plots.

Results: Of 6,528 citations collected, 20 articles reporting on 1,047 patients were included in the analysis. The median age was 51 years (interquartile range 49-55), with 59 % (54-67) female. The median peritoneal carcinomatosis index score was 19 (16-23). Complete cytoreduction (CC0, 1) was performed in 67 % (46-93 %) of patients. Pooled estimates of survival yielded a 1-, 3- and 5-year survival of 84, 59, and 42 %, respectively. Patients receiving early postoperative intraperitoneal chemotherapy [EPIC] (44 %) and those receiving cisplatin intraperitoneal chemotherapy alone (48 %) or in combination (44 %) had an improved 5-year survival.

Conclusions: While CRS + HIPEC has led to an improved survival for patients with MPM compared to historic data, heterogeneity of studies precludes generalizable inferences. EPIC chemotherapy and cisplatin chemoperfusion may infer survival benefit.
Immunohistochemical Evaluation of Minichromosome Maintenance Protein 7 (MCM7), Topoisomerase IIα, and Ki-67 in Diffuse Malignant Peritoneal Mesothelioma Patients Using Tissue Microarray. M. Deraco, A. Cabras, D. Baratti, et al. 2015;22(13):4344-51. PubMed · Publisher

Abstract

Purpose: Immunohistochemistry and tissue microarray (TMA) were used to perform a prognostic analysis of markers related to cell proliferation in diffuse malignant peritoneal mesothelioma (DMPM).

Methods: Clinicopathologic data were extracted from a prospectively collected database containing cases of peritoneal mesothelioma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the National Cancer Institute of Milan from 1995 to 2013. Eighty-one DMPM patients were recruited and their tissue samples were used to construct TMAs. We evaluated the immunoexpressions of markers related to cell proliferation-topoisomerase IIα, minichromosome maintenance protein 7 (MCM7), and Ki-67-and then conducted a multivariate Cox model to identify the predictors of overall survival (OS) and progression-free survival (PFS) among the following parameters: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, baseline serum albumin, Charlson Comorbidity Index, previous systemic chemotherapy, histological subtype (epithelioid vs. biphasic/sarcomatoid), peritoneal cancer index, completeness of cytoreduction (CC), and proliferative biological markers.

Results: The rates of high/intermediate immunoreactivity were 95 % for topoisomerase IIα and 90 % for MCM7, and the median Ki-67 labeling index was 5 %. The independent predictors of OS were baseline serum albumin >3.5 g/dl, CC, and Ki-67 >5 %, whereas those for PFS were an ECOG performance status of 0, baseline serum albumin >3.5 g/dl, Charlson Comorbidity Index >3, previous systemic chemotherapy, morbidity G3-5, and Ki-67 >5 %. The remaining biological markers were not associated with outcome.

Conclusions: Ki-67 was found to be a new powerful determinant of outcome. Patients with a Ki-67 labeling index >5 % carry a very poor prognosis and do not benefit from the combined procedure. Further studies should be conducted to confirm the present data.
Institutional learning curve of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for peritoneal malignancies. P.M. Polanco, Y. Ding, J.M. Knox, et al. 2015;22(5):1673-9. PubMed · Publisher

Abstract

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is routinely used to treat certain peritoneal carcinomatoses (PC), but it can be associated with relatively high complication rates, prolonged hospital length of stay, and potential mortality. Our objective was to determine the learning curve (LC) of CRS/HIPEC in our high-volume institution.

Methods: A total of 370 patients with PC from mucinous appendiceal neoplasms (MAN = 282), malignant peritoneal mesothelioma (MPM = 60), and gastric cancer (GC = 24) were studied. Outcomes analyzed included incomplete cytoreduction (IC), severe morbidity (SM), 60-day mortality, progression-free survival (PFS), and overall survival (OS). Risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of CRS/HIPEC for IC and SM using prespecified odds ratio (OR) boundaries derived from previously published data. Risk adjusted-cumulative average probability (RA-CAP) was used to analyze 1-year PFS and 2-year OS.

Results: Complete cytoreduction, severe morbidity, and 60-day mortality were 84.2, 30, and 1.9 % respectively. Higher simplified peritoneal cancer index was the major independent risk factor for IC, whereas high-grade histology, IC, and diagnosis of MPM and GC (compared with MAN) were predictors of SM after CRS/HIPEC (p < 0.05). RA-SPRT showed that approximately 180 cases are needed to achieve the lowest risk of IC and SM. Ninety cases were needed to achieve a steady 1-year PFS and 2-year OS in RA-CAP plots.

Conclusions: The completeness of cytoreduction, morbidity, and mortality rates for CRS/HIPEC at our institution are comparable to previously reported data. Approximately 180 and 90 procedures are required to improve operative and oncologic outcomes respectively.
Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent or progressive diffuse malignant peritoneal mesothelioma: clinicopathologic characteristics and survival outcome. C. Ihemelandu, L. Bijelic, P.H. Sugarbaker. 2015;22(5):1680-5. PubMed · Publisher

Abstract

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive disease for which cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been used with remarkable survival benefits. Our aim was to analyze the clinicopathologic characteristics and prognosis of recurrent DMPM managed with iterative CRS and HIPEC.

Methods: A retrospective analysis of a prospectively maintained database for all patients treated for DMPM from 1989 to 2012.

Results: Of 205 consecutive CRS and HIPEC procedures, 44 (21.5 %) patients underwent an iterative procedure-22 (50.0 %) males versus 22 (50.0 %) females. Mean age at recurrence was 51.5 years. There was no 30-day mortality following an iterative procedure, and the grade III-V morbidity was 2.3 %. The median overall survival of patients undergoing an iterative CRS and HIPEC was 54 months versus 77 months following an initial CRS and HIPEC (p = 0.96). Patients undergoing an iterative surgery had a 3- and 5-year survival of 61 and 46 %, respectively, versus 60 and 52 % following an initial CRS and HIPEC. Amongst the iterative group, the achieved complete cytoreduction (CC) score was 15.9, 18.2, 22.7, and 43.2 % for CC0, CC1, CC2 and CC3, respectively, versus 3.1, 43.5, 28.6 and 24.8 %, respectively, following initial CRS (p = 0.000). Significant predictors of an improved survival in multivariate analysis were an epithelioid subtype, female sex, complete or near CC (CC0 or CC1), HIPEC regimen utilized, absence of postoperative complication, and age at diagnosis.

Conclusion: Iterative CRS and HIPEC can be performed safely and appear to have benefits with this group of patients showing an improved median survival.
Morbidity of the abdominal wall resection and reconstruction after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). M.F. Nunez, A. Sardi, C. Nieroda, et al. 2015;22(5):1658-63. PubMed · Publisher

Abstract

Background: CRS/HIPEC has evolved as a therapeutic option for selected patients with peritoneal surface malignancies. To achieve complete cytoreduction (CC), some patients require extensive abdominal-wall resection (AWR) and subsequent complex reconstructions, which may be associated with wound complications (WC) and delay of postoperative cancer therapy.

Methods: Review of a prospective database of 350 patients revealed 213 patients with peritoneal carcinomatosis who underwent AWR due to suspected or proven wound/port site metastases during CRS/HIPEC. Tumor origin included: appendix, colon, ovarian, peritoneal mesothelioma, primary peritoneal, and others. WC were related to peritoneal carcinomatosis index (PCI), CC score, length of surgery, type of AWR and closure, blood transfusion, and albumin levels using binary logistic regression (odds ratios (OR) and 95 % CIs) analysis.

Results: PCI ≥ 20 was found in 151 (71 %), CC was achieved in 178 (84 %). Mean length of surgery was 613 min. Postoperative WC were detected in 49 of 213 (23 %) patients, 13 (6 %) had Grade III (according to Clavien-Dindo's classification) WC, and led to delay of postoperative chemotherapy. WC occurred in 21 of 64 (32.8 %) patients with excision of port sites (odds ratio [OR] = 2.11, confidence interval [CI] = 1.09-4.10, p = 0.026). Primary fascial closure was performed in 191 of 213 (89.7 %) patients, 40 (21 %) of whom had WC. Mesh-assisted abdominal wall reconstruction was required in 22 of 213 (10.3 %) patients, of whom 9 (40.9 %) had WC (OR = 2.61, CI = 1.04-6.55, p = 0.035).

Conclusions: Port-site excision and mesh-assisted abdominal wall reconstruction were associated with higher incidence of postoperative WC following CRS/HIPEC. The implications of these preliminary findings may need to be considered during surgical planning for these patients.
Tumoral CD10 expression correlates with aggressive histology and prognosis in patients with malignant pleural mesothelioma. K. Kadota, J. Villena-Vargas, J. Nitadori, et al. 2015;22(9):3136-43. PubMed · Publisher · Free full text

Abstract

Background: Currently, tumor-node-metastasis stage and histologic type are the established prognostic factors for malignant pleural mesothelioma, whereas no prognostic markers have been established for clinical practice. We investigated the prognostic value of CD10, a metalloproteinase that can promote cancer aggressiveness through enzymatic degradation and intracellular signaling crosstalk, in malignant pleural mesothelioma.

Methods: CD10 immunostaining was performed for 176 cases of malignant pleural mesothelioma (epithelioid, 148; biphasic, 14; sarcomatoid, 14), and its expression was dichotomized as negative (no staining) or positive (any staining). Epithelioid tumors were classified as pleomorphic subtype when cytologic pleomorphism was ≥10 % of the tumor. Overall survival (OS) was analyzed by log-rank tests and Cox proportional hazard models.

Results: Tumoral CD10 expression was identified in 42 % of epithelioid non-pleomorphic tumors, 57 % of epithelioid pleomorphic tumors, 79 % of biphasic tumors, and 93 % of sarcomatoid tumors (p < 0.001). Positive CD10 expression was correlated with higher mitotic count (p = 0.002). Overall survival for patients with positive CD10 expression was significantly shorter than that for patients with negative CD10 expression in all patients (p = 0.001) and in patients with epithelioid tumor (p = 0.04). On multivariate analysis, CD10 expression was an independent prognostic factor for all patients (hazard ratio 1.48; p = 0.019).

Conclusions: Tumoral CD10 expression correlated with aggressive histologic types and higher mitotic activity and is an independent prognostic factor for patients with malignant pleural mesothelioma.
Utility of Chemoresponse Assay in Patients Undergoing Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy. S. Bhagwandin, S. Naffouje, G. Salti. 2015;22(8):2573-7. PubMed · Publisher

Abstract

Purpose: Our aim was to evaluate the utility of in vitro drug sensitivity testing in patients with peritoneal surface malignancies undergoing cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods: We found data for 27 patients who underwent CRS plus HIPEC from September 2009 to May 2012 and whose tumors were submitted for in vitro drug sensitivity (ChemoFx(®)). Intraperitoneal chemotherapy agents included mitomycin C, cisplatin + doxorubicin, or cisplatin alone.

Results: There were 12 (44.4 %) appendiceal adenocarcinomas, 5 (18.5 %) colon cancers, 4 (14.8 %) sarcomas, 3 (11.1 %) ovarian cancers, 2 (7.4 %) mesotheliomas, and one (3.7 %) gastric cancer. In all, 15 patients (55.5 %) underwent complete cytoreduction (CC ≤ 1). Seventeen tumors (63 %) displayed in vitro sensitivity to the agents used. Mean overall (OS) and progression-free (PFS) survivals for the entire group were 34.4 ± 4.5 months (median 41 months) and 12.5 ± 2.1 months (median 8 months), respectively. There were no significant differences in OS and PFS for patients whose tumors displayed in vitro drug sensitivity versus those whose tumors did not (p = 0.101 and p = 0.403, respectively). These results also did not differ when evaluating only the patients who underwent complete cytoreduction. In vitro, the drug sensitivity did not correlate with primary tumor pathology or preoperative systemic chemotherapy administration. In vitro drug sensitivity correlated with the drug used at the time of HIPEC (p = 0.003). None of the tumors tested showed in vitro sensitivity to cisplatin and/or doxorubicin. Eight nonresponsive tumors, however, showed in vitro activity to other agents.

Conclusions: Data indicate a high rate of in vitro resistance to the intraperitoneal chemotherapeutic agents used. In vitro drug sensitivity is not useful in patients undergoing CRS plus HIPEC.
Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM). K. Yoneda, F. Tanaka, N. Kondo, et al. 2014;21 Suppl 4:S472-80. PubMed · Publisher

Abstract

Purpose: To investigate the diagnostic and prognostic value of circulating tumor cells (CTCs), a potential surrogate of micrometastasis, in malignant pleural mesothelioma (MPM).

Methods: We prospectively evaluated CTCs in 7.5 mL of peripheral blood sampled from patients with a suspicion of MPM. A semiautomated system was used to capture CTCs with an antibody against the epithelial cell adhesion molecule.

Results: Of 136 eligible patients, 32 were finally diagnosed with nonmalignant diseases (NM), and 104 had MPM. CTCs were detected in 32.7 % (34 of 104) of MPM patients but in only 9.4 % (3 of 32) of NM patients (P = 0.011). The CTC count was significantly higher in MPM patients than in NM patients (P = 0.007), and a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between MPM and NM, with an area under ROC curve of 0.623 (95 % confidence interval, 0.523-0.723; P = 0.036). Among MPM patients, CTCs were more frequently detected in patients with epithelioid subtype (39.7 %, 31 of 78) than in those with nonepithelioid subtypes (11.5 %, 3 of 26; P = 0.016). Positive CTCs (CTC count ≥ 1) were a significant factor to predict a poor prognosis among epithelioid patients (median overall survival, 22.3 months for positive CTCs vs. 12.6 months for negative CTCs; P = 0.004) and not in nonepithelioid patients (P = 0.649). A multivariate analysis showed that positive CTCs were a significant and independent factor to predict a poor prognosis (hazard ratio, 2.904; 95 % confidence interval, 1.530-5.511; P = 0.001) for epithelioid MPM patients.

Conclusions: CTC was a promising marker in diagnosis and prediction of prognosis in MPM, especially in epithelioid MPM.
Current trends in the management of malignant peritoneal mesothelioma. J.T. Miura, F.M. Johnston, T.C. Gamblin, et al. 2014;21(12):3947-53. PubMed · Publisher

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 survival with surgical therapy is lost in a significant number of MPM patients.
Efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in the management of malignant ascites. R.W. Randle, K.R. Swett, D.S. Swords, et al. 2014;21(5):1474-9. PubMed · Publisher · Free full text

Abstract

Background: In peritoneal surface disease, accumulation of malignant ascites represents a difficult problem to treat, with adverse impact on quality of life. The role of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites is not well defined.

Methods: A retrospective analysis of a prospectively maintained database of 1,000 procedures was performed. Type of malignancy, resolution of ascites, duration and agent of chemoperfusion, performance status, resection status, morbidity, mortality, and survival were reviewed.

Results: Ascites was found in 299 patients (310 procedures) either before or during exploration. A total of 142 (46 %) procedures were performed for appendiceal primary disease, 53 (17 %) colorectal, 20 (6 %) gastric, 45 (15 %) mesothelioma, and 26 (8 %) ovarian. A total of 288 (93 %) patients had resolution of ascites by 3 months' follow-up. In patients with ascites, complete cytoreduction was obtained in 15 versus 59 % when ascites was not present (p < 0.001). In the group of patients who had their ascites controlled, 243 of 288 (84 %) had resection with residual macroscopic disease (R2 status). Twenty-two patients (7 %) had persistent ascites at 3 months' follow-up, 19 (86 %) of whom had an R2 resection. Univariate analysis revealed that type of primary disease, resection status, duration or agent of chemoperfusion, and performance status did not predict failure.

Conclusions: CRS-HIPEC is effective in controlling ascites in 93 % of patients with malignant ascites, even when a complete cytoreduction is not feasible. Ascites is predictive of incomplete cytoreduction and worse overall survival. Although complete cytoreduction remains the goal of this procedure, HIPEC can provide palliative value in selected patients with malignant ascites.
Malignant peritoneal mesothelioma: prognostic factors and oncologic outcome analysis. D. Magge, M.S. Zenati, F. Austin, et al. 2014;21(4):1159-65. PubMed · Publisher · Free full text

Abstract

Background: Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM.

Methods: We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes.

Results: Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p = 0.00001).

Conclusions: Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC.
Oncolytic vaccinia virus as an adjuvant treatment to cytoreductive surgery for malignant peritoneal mesothelioma. S.A. Acuna, K. Ottolino-Perry, B. Çako, et al. 2014;21(7):2259-66. PubMed · Publisher

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Oncolytic viruses are a promising new therapy for cancer because of their ability to kill tumor cells with minimal toxicity to normal tissues. This experimental study aimed to examine the potential of modified vaccinia virus (VV) to treat MPM when administered alone or as an adjuvant treatment to surgery.

Methods: Two aggressive murine mesothelioma cell lines (AC29, AB12), were used. Cell viability and viral cytopathic effects were assessed using MTS and crystal violet assays. Immunocompetent mice were injected intraperitoneally with MPM cells and treated with intraperitoneal VV. Tumor-bearing mice also underwent cytoreductive surgery (CRS) followed by VV (or control) therapy.

Results: The cytotoxic effects of VV on MPM cell lines was significantly increased compared with the control non-cancer cell line. In both orthotopic models, VV induced tumor regression, prolonging median and long-term survival. VV treatment after incomplete CRS was not superior to VV alone; however, when mice with microscopic disease were treated with VV, further prolongation of median and long-term survivals was observed.

Conclusions: VV selectively kills MPM cells in vitro and leads to improved survival and cures in immunocompetent murine models. Higher efficacy of the virus in the microscopic disease context suggests the use of the virus as an adjuvant treatment to complete surgical resection. These promising results justify further studies of VV in humans as a novel treatment for MPM.
Regional delivery of oncolytic vaccinia virus: it's time for clinical trials. S. Downs-Canner, D.L. Bartlett. 2014;21(7):2127-8. Editorial · Comment PubMed · Publisher · Free full text
Repeat cytoreductive surgery and heated intraperitoneal chemotherapy may offer survival benefit for intraperitoneal mesothelioma: a single institution experience. J. Wong, A.L. Koch, J.L. Deneve, et al. 2014;21(5):1480-6. PubMed · Publisher

Abstract

Introduction: Cytoreduction with heated intraperitoneal chemotherapy (HIPEC) has demonstrated improved overall survival (OS) in malignant peritoneal mesothelioma (MPM). The role of repeated HIPEC for MPM is less clear.

Methods: An institutional review board-approved database of MPM patients was analyzed for clinical factors and outcomes.

Results: From June 2004 to March 2012, 29 patients underwent surgical treatment for mesothelioma. HIPEC was aborted in 3 and completed in 26; 8 underwent additional repeat HIPEC. The majority was male (62 %), median age 66 years. There was no significant difference in surgery duration, blood loss, or hospital-stay-duration between initial and repeat HIPEC. Cisplatin was the chemotherapy used. Complications occurred in 17 (65 %) initial and 6 (50 %) repeat HIPEC, with wound complications being most common. Reoperation was less common (4 % initial and 25 % repeat), and perioperative death was rare (4 % initial, 0 % repeat). Fourteen (54 %) initial and seven (58 %) repeat HIPEC patients received adjuvant chemotherapy. Median time from HIPEC to initiation of chemotherapy was not different between initial and repeat HIPEC (8.8 and 4.6 months, respectively, p = 0.68). Median treatment-free time (time from initial to repeat HIPEC or chemotherapy) also was not different between initial and repeat HIPEC (8.8 and 6.3 months, respectively, p = 0.92). Median OS for the cohort was 41.2 months. Patients who underwent repeat HIPEC had improved median OS (80 months) versus single HIPEC (27.2 months; p = 0.007). A lower peritoneal carcinoma index and complete cytoreduction were associated positively with OS.

Conclusions: Cytoreduction and HIPEC for MPM are associated with longer OS. Patients who are candidates for repeat HIPEC may derive an even greater OS advantage.
A new policy regarding ovarian resection in young women treated for peritoneal carcinomatosis. D. Elias, E. Duchalais, P. Dartigues, et al. 2013;20(6):1837-42. PubMed · Publisher

Abstract

Objective: To appreciate if the ovaries can be preserved in selected young women with peritoneal carcinomatosis (PC).

Background: The traditional rule is to resect the ovaries systematically when PC is found at surgery.

Methods: A new policy was developed to preserve the ovaries when they were macroscopically normal in young women with PC of different origin who expressed a strong desire for future pregnancy.

Results: A total of 106 women younger than age 41 years underwent complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. At least one ovary was preserved in 29 % of them (and in 44 % of those who strongly wished future pregnancy). Among resected "normal" ovaries, 17 % were involved by tumor at the final pathologic examination. Among the resected "suspicious" ovaries, 38 % were involved. Among the 29 preserved ovaries (in 21 women), after a median follow-up of 32 months, 4 (14 %) developed ovarian recurrence, in 3 of them associated with other metastases. Two women became pregnant. In five women with partially normal ovary, egg harvesting and cryopreservation was performed.

Conclusions: This new policy allowed ovarian preservation in 44 % of the young women wishing childbearing and allowed two births. Recurrence in the preserved ovary was 14 % with our criteria of selection. This policy is promising but can be further improved.
A novel nomogram for peritoneal mesothelioma predicts survival. N.P. Schaub, M. Alimchandani, M. Quezado, et al. 2013;20(2):555-61. PubMed · Publisher · Free full text

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Estimation of personalized survival times can potentially guide treatment and surveillance.

Methods: We analyzed 104 patients who underwent CRS and cisplatin-based HIPEC for MPM. By means of 25 demographic, laboratory, operative, and histopathological variables, we developed a novel nomogram using machine-learned Bayesian belief networks with stepwise training, testing, and cross-validation.

Results: The mean peritoneal carcinomatosis index (PCI) was 15, and 66 % of patients had a completeness of cytoreduction (CC) score of 0 or 1. Eighty-seven percent of patients had epithelioid histology. The median follow-up time was 49 (1-195) months. The 3- and 5-year overall survivals (OS) were 58 and 46 %, respectively. The histological subtype, pre-CRS PCI, and preoperative serum CA-125 had the greatest impact on OS and were included in the nomogram. The mean areas under the receiver operating characteristic curve for the 10-fold cross-validation of the 3- and 5-year models were 0.77 and 0.74, respectively. The graphical calculator or nomogram uses color coding to assist the clinician in quickly estimating individualized patient-specific survival before surgery.

Conclusions: Machine-learned Bayesian belief network analysis generated a novel nomogram predicting 3- and 5-year OS in patients treated with CRS and HIPEC for MPM. Pre-CRS estimation of survival times may potentially individualize patient care by influencing the use of systemic therapy and frequency of diagnostic imaging, and might prevent CRS in patients unlikely to achieve favorable outcomes despite surgical intervention.
Body surface area predicts plasma oxaliplatin and pharmacokinetic advantage in hyperthermic intraoperative intraperitoneal chemotherapy. J.C. Leinwand, G.E. Bates, J.D. Allendorf, et al. 2013;20(4):1101-4. PubMed · Publisher · Free full text

Abstract

Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface-spreading malignancies to maximize local drug concentrations while minimizing systemic effects. The pharmacokinetic advantage of HIPEC is defined as the intraperitoneal to intravascular ratio of drug concentrations. We hypothesized that body surface area (BSA) would correlate with the pharmacokinetic advantage of HIPEC. Because oxaliplatin is administered in 5 % dextrose, we hypothesized that BSA would correlate with glycemia.

Methods: We collected blood and peritoneal perfusate samples from ten patients undergoing HIPEC with a BSA-based dose of 250 mg/m(2) oxaliplatin, and measured drug concentrations by inductively coupled plasma mass spectrophotometry. We monitored blood glucose for 24 h postoperatively. Areas under concentration-time curves (AUC) were calculated by trapezoidal rule. Pharmacokinetic advantage was calculated by (AUC[peritoneal fluid]/AUC[plasma]). We used linear regression to test for statistical significance.

Results: Higher BSA was associated with lower plasma oxaliplatin AUC (p = 0.0075) and with a greater pharmacokinetic advantage (p = 0.0198) over the 60-minute duration of HIPEC. No statistically significant relationships were found between BSA and blood glucose AUC or peak blood glucose levels.

Conclusions: Higher BSA is correlated with lower plasma drug levels and greater pharmacokinetic advantage in HIPEC, likely because of increased circulating blood volume with inadequate time for equilibration. Plasma glucose levels after oxaliplatin HIPEC were not clearly related to BSA.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Asian patients: 100 consecutive patients in a single institution. M.C. Teo, G.H. Tan, C.K. Tham, et al. 2013;20(9):2968-74. PubMed · Publisher

Abstract

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been shown to improve survival in selected patients with peritoneal carcinomatosis. We review our institutional experience with the procedure and evaluate the overall survival (OS) and disease-free survival (DFS) rates in 100 consecutive patients.

Methods: Data were prospectively collected from 100 consecutive patients with peritoneal carcinomatosis treated by CRS and HIPEC at the National Cancer Centre Singapore between April 2001 and May 2012. Our primary end points were OS and DFS.

Results: Of the 100 patients, 84 were of Chinese ethnicity, 3 were Malay, 6 were Indian, and 7 were of other ethnicities. Primary tumors were ovarian cancer (n=39), colorectal cancer (n=28), primary peritoneal (n=6), appendiceal cancer (n=20), and mesothelioma (n=7). Median follow-up duration was 21 months. At 5 years, the DFS was 26.3% and OS was 50.9%. Factors influencing OS and DFS were cytoreductive score, primary cancer, and disease-free interval of more than 12 months on univariate analysis. The only factors that remained significant for prognosis after multivariate analysis were primary cancer and cytoreductive score. Thirty-day morbidity was 56%, and there were no 30-day mortalities.

Conclusions: CRS and HIPEC can be safely carried out in Asian patients with peritoneal carcinomatosis from ovarian, colorectal, appendiceal, mesothelioma, and primary peritoneal origins. Overall, the ovarian, appendiceal, mesothelioma, and primary peritoneal cancer patients tended to do better than the colorectal patients, but careful patient selection ensuring that optimal cytoreduction can be achieved is essential for the success of this procedure.
Intraperitoneal cytokine level in patients with peritoneal surface malignancies. A study of the RENAPE (French Network for Rare Peritoneal Malignancies). V. Vlaeminck-Guillem, J. Bienvenu, S. Isaac, et al. 2013;20(8):2655-62. PubMed · Publisher

Abstract

Background: Prognosis of peritoneal surface malignancies is influenced by the adequacy of surgical and chemotherapeutic treatment and by tumor spread at the time of diagnosis. By promoting morphological changes in the mesothelium, inflammatory cytokines reflect tumor biology and could be evaluated as biomarkers. Our objective was to evaluate intraperitoneal levels of IL-6, IL-8, IL-10, TNF-alpha, and sICAM in patients with pseudomyxoma peritonei and peritoneal mesothelioma.

Methods: Serum and peritoneal fluid samples were prospectively collected in patients managed for peritoneal surface malignancies including pseudomyxoma peritonei (PMP), mesotheliomas, and other rare primitive peritoneal cancers (cancer group) and patients who underwent intraperitoneal laparoscopic surgical procedures for benign diseases (noncancer group). Samples were analyzed for IL-6, IL-8, IL-10, TNF-alpha, and sICAM concentrations. Correlations were assessed with tumor spread related clinical scores.

Results: In both patient groups, intraperitoneal cytokine levels were higher than serum levels. Cancer patients had significantly higher intraperitoneal cytokine levels than noncancer patients. Peritoneal levels tended to increase in cancer patients with free tumor cells in peritoneal fluid. They were significantly higher in patients with tumor implants ≥2 cm and/or patients with peritoneal carcinomatosis index (PCI) >19. Furthermore, patients with malignant pseudomyxoma peritonei (grades II and III) had higher levels than patients with nonmalignant disease (grade I).

Conclusions: Assessment of intraperitoneal IL-6, IL-8, IL-10, TNF-alpha, and sICAM levels can be performed in patients with peritoneal surface malignancies. They can be considered as both diagnostic and prognostic biomarkers that could be used as useful adjuncts for therapeutic decision making.
Malignant peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is GLUT1 expression a major prognostic factor? A preliminary study. J. Hommell-Fontaine, S. Isaac, G. Passot, et al. 2013;20(12):3892-8. PubMed · Publisher

Abstract

Purpose: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare primary peritoneal malignancy. Its prognosis has been improved by an aggressive locoregional treatment combining extensive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prognostic factors are currently poorly defined for this disease but are essential if treatment is to be standardized.

Methods: Twenty-eight patients with DMPM, who were considered preoperatively to be candidates for CRS and HIPEC between June 1998 and August 2010 at our institution, were selected for this study. Medical records and histopathological features were retrospectively reviewed and 24 clinical, histological, and immunohistochemical parameters were assessed for their association with overall survival by univariate and multivariate analyses.

Results: The following factors were significantly associated with overall survival by univariate analysis: predominant histological growth pattern in the epithelioid areas, nuclear grooves in the epithelioid areas, atypical mitoses, and calretinin and GLUT1 expression by immunohistochemistry in the epithelioid areas. Expression of the facilitative glucose transporter protein GLUT1 in the epithelioid areas was the only factor independently associated with overall survival by multivariate analysis.

Conclusions: GLUT1 expression appears to be an indicator of poor prognosis in DMPM. Standard histological classification of DMPM may not be adequate to select patients for aggressive locoregional treatments, such as CRS and HIPEC. Multicenter validation of the prognostic factors identified in this preliminary study is needed to refine patient selection for potential cure.
Outcomes of Cytoreductive Surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients older than 70 years; survival benefit at considerable morbidity and mortality. K.I. Votanopoulos, N.A. Newman, G. Russell, et al. 2013;20(11):3497-503. PubMed · Publisher · Free full text

Abstract

Background: Cytoreductive surgery (CRS)/Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is associated with prolonged survival in selected patients with peritoneal surface disease. Yet, for elderly patients (older than 70 years of age) CRS/HIPEC is controversial, due to associated morbidity.

Methods: A retrospective analysis of a prospective database of 950 procedures was performed. Type of malignancy, demographics, performance and resection status, hospitalization, morbidity, mortality, and survival were reviewed.

Results: A total of 81 patients (median age 73, range 70-87) underwent CRS/HIPEC between 1991 and 2011. Median follow-up was 48.1 months. Complete cytoreduction was achieved in 44 %. Median survival was 31.8 months for appendiceal cancer, 41.5 for mesothelioma, 54.0 for ovarian cancer, 13.2 for colon cancer, and 7.6 for gastric cancer. The 30-day mortality was 13.6 %. The combined grade III and IV morbidity was 38 %. Median ICU and hospital stay for uncomplicated patients was 1 and 8 days, respectively. The 3-month mortality was 27.4 %. There were no deaths in the octogenarian group. In stepwise multivariate analysis, type of primary (p = 0.03), albumin (p = 0.02), and R status (p = 0.007) were predictive of survival only in the absence of complications. Splitting the data at the midpoint of surgical experience, there was a drop in 1- and 3-month mortality over time to 9.5 and 19.3 %, respectively, while the median survival increased from 11.2 (N = 39) to 46.9 months (N = 42).

Conclusions: HIPEC in the elderly is associated with a steep learning curve and considerable morbidity and mortality. However, age alone is not a contraindication for the procedure. Institutional experience and stringent patient selection are key factors for prolonged survival.
Quality of life in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is it worth the risk?. N. Tsilimparis, C. Bockelmann, W. Raue, et al. 2013;20(1):226-32. PubMed · Publisher

Abstract

Objective: To investigate the course of health-related quality of life (HQL) over time in patients with peritoneal carcinomatosis (PC) after complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods: Prospective, single-center, nonrandomized cohort study using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.

Results: Ninety patients who underwent CRS and HIPEC for PC in our institution were enrolled in the study. Mean age was 56 years (range 27-77 years) (61% female). Primary tumor was colorectal in 21%, ovarian in 19%, pseudomyxoma peritonei in 16%, an appendix tumor in 16%, gastric cancer in 10%, and peritoneal mesothelioma in 13% of cases. Mean peritoneal carcinomatosis index was 22 (range 2-39). Mean global health status score was 69±25 preoperatively and 55±20, 66±22, 66±23, 71±23, and 78±21 at months 1, 6, 12, 24, and 36, respectively. Physical and role function recovered significantly at 6 months and were close to baseline at the 24-month measurement. Emotional function starting from a low baseline recovered to baseline by month 12. Cognitive and social function had slow recovery on follow-up. Fatigue, diarrhea, dyspnea, and sleep disturbance were symptoms persistent at 6-month follow-up, improving later on in survivors.

Conclusions: Survivors after CRS and HIPEC have postoperative quality of life similar to preoperatively, with most of the reduced elements recovering after 6-12 months. We conclude that reduced quality of life of patients after CRS and HIPEC should not be used as an argument to deny surgical therapy to these patients.
Quantitative X-ray computed tomography peritoneography in malignant peritoneal mesothelioma patients receiving intraperitoneal chemotherapy. J.C. Leinwand, B. Zhao, X. Guo, et al. 2013;20 Suppl 3(Suppl 3):S553-9. PubMed · Publisher · Free full text

Abstract

Background: Intraperitoneal chemotherapy is used to treat peritoneal surface-spreading malignancies. We sought to determine whether volume and surface area of the intraperitoneal chemotherapy compartments are associated with overall survival and posttreatment glomerular filtration rate (GFR) in malignant peritoneal mesothelioma (MPM) patients.

Methods: Thirty-eight MPM patients underwent X-ray computed tomography peritoneograms during outpatient intraperitoneal chemotherapy. We calculated volume and surface area of contrast-filled compartments by semiautomated computer algorithm. We tested whether these were associated with overall survival and posttreatment GFR.

Results: Decreased likelihood of mortality was associated with larger surface areas (p = 0.0201) and smaller contrast-filled compartment volumes (p = 0.0341), controlling for age, sex, histologic subtype, and presence of residual disease >0.5 cm postoperatively. Larger volumes were associated with higher posttreatment GFR, controlling for pretreatment GFR, body surface area, surface area, and the interaction between body surface area and volume (p = 0.0167).

Discussion: Computed tomography peritoneography is an appropriate modality to assess for maldistribution of intraperitoneal chemotherapy. In addition to identifying catheter failure and frank loculation, quantitative analysis of the contrast-filled compartment's surface area and volume may predict overall survival and cisplatin-induced nephrotoxicity. Prospective studies should be undertaken to confirm and extend these findings to other diseases, including advanced ovarian carcinoma.
The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. M. Deraco, D. Baratti, I. Hutanu, et al. 2013;20(4):1093-100. PubMed · Publisher

Abstract

Background: The aim of this study was to evaluate the effects of perioperative systemic chemotherapy (CT) on short-term surgical and long-term oncologic results in diffuse malignant peritoneal mesothelioma (DMPM) patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Patients And Methods: We retrospectively analyzed data obtained from an institutional prospective database at NCI of Milan. The study group comprised 116 DMPM patients treated with CRS + HIPEC from August 1995 to October 2011. A total of 60 cases underwent preoperative CT (PRECT), 30 underwent postoperative CT (POSTCT), and 26 did not undergo any CT (NOCT). Also, 55 cases used the perioperative combination of platinum and pemetrexed. We tested whether covariates related to clinical, histologic, PRECT, and surgical treatment were correlated with completeness of cytoreduction (CC), postoperative G3-5 morbidity, and progression-free survival and overall survival (OS). Univariate and multivariate analyses were performed.

Results: Factors independently associated with CC were ECOG performance status (PF) of 0, and PCI <20. Factors independently associated with postoperative G3-5 morbidity were ECOG >1, bowel anastomosis, and number of peritonectomy procedures. Preoperative platelet count >400 × 103/mm(3), histological subtype (biphasic and sarcomatoid vs epithelial), CC, and G3-5 morbidity were independent prognostic factors. PRECT was not associated with CC or G3-5 morbidity. There was no significant difference in terms of survival between the PRECT, POSTCT, and NOCT groups.

Conclusions: The CC, G3-5, and OS were not influenced by aspects related to perioperative CT. The present data warrants confirmation reconducting the comparative analysis in a larger multi-institutional series preferably using matching control techniques.
Anesthetic management and renal function in pediatric patients undergoing cytoreductive surgery with continuous hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin. P. Owusu-Agyemang, R. Arunkumar, H. Green, et al. 2012;19(8):2652-6. PubMed · Publisher

Abstract

Background: Extensive tumor implants secondary to sarcoma, sarcomatosis, or mesothelioma in children is rare. We conducted the first phase 1 trial of escalating doses of cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) in children with sarcomatosis. The most devastating complication of cisplatin therapy is nephrotoxicity. Here we present the anesthetic management and analysis of the impact of intraoperative fluid management on the incidence of renal failure.

Methods: Of the 10 patients under 18 years of age who underwent HIPEC in the context of our phase 1 trial, six patients were under the age of 10 years. We reviewed the anesthetic management, intraoperative fluid and blood administration, and postoperative renal function in these patients.

Results: The average age and weight were 6 years and 20.9 kg, respectively. To avoid renal toxicity, urine output was maintained at an average of 3 ml/kg/h. Crystalloid and colloid were transfused at an average rate of 9 ml/kg/h. Percentage increase in creatinine postoperatively varied from 33 to 500 %. Volume of fluid administered did not correlate with percentage increase in creatinine. All patients had a temporary increase in their serum creatinine, but none required dialysis.

Conclusions: Fluid administration at an average rate of 9 ml/kg/h was required to maintain satisfactory urine output. This rate of intraoperative fluid administration is similar to what is provided to adult HIPEC patients. There was no significant correlation in the volume or type of fluid delivered and the increase in serum creatinine. More studies are needed to determine optimal fluid management in children undergoing HIPEC with cisplatin.
Bioluminescence imaging serves as a dynamic marker for guiding and assessing thermal treatment of cancer in a preclinical model. J.T. Au, L. Gonzalez, C.H. Chen, et al. 2012;19(9):3116-22. PubMed · Publisher

Abstract

Background: Bioluminescence has been harnessed as a dynamic imaging technique in research. This is a proof of principle study examining feasibility of using bioluminescent proteins as a marker to guide therapeutic ablation.

Methods: Mesothelioma cancer cells (MSTO-Td) were transfected with a retroviral vector bearing firefly luciferase gene, plated in serial dilutions, and imaged to compare bioluminescence signal to cell number, determining threshold of bioluminescence detection. MSTO-Td cells were subjected to thermal treatment in a heated chamber; the bioluminescence signal and number of remaining live cancer cells were determined. Mice with MSTO-Td xenografts underwent electrocautery tumor ablation guided by bioluminescence imaging; bioluminescence signal and tumor size were monitored for 3 weeks.

Results: MSTO-Td cells emitted a bright, clear, bioluminescence signal that amplified with the cell number (P < .001) and was detectable with as few as 10 cells in cell culture. Bioluminescence decreased in a dose-dependent fashion upon thermal treatment as temperature increased from 37 to 70 °C (P < .001) and as treatment duration increased from 5 to 20 min (P < .001). This correlated with the number of remaining live MSTO-Td cells (Pearson coefficient = 0.865; P < .001). In mice, the bioluminescence signal correlated with tumor size posttreatment and effectively guided the ablation procedure to completion, achieving 0 % tumor recurrence.

Conclusions: Bioluminescence imaging is a sensitive, real-time imaging approach; bioluminescence reporters such as firefly luciferase can assess and guide thermal treatment of cancer. This encourages research into bioluminescence imaging as a molecular technique with potential to target tumors via biomarkers and optimize thermal treatment procedures in a clinical setting.
Circulating endothelial cell (CEC) as a diagnostic and prognostic marker in malignant pleural mesothelioma (MPM). K. Yoneda, F. Tanaka, N. Kondo, et al. 2012;19(13):4229-37. PubMed · Publisher

Abstract

Background: The purpose of this study was to investigate the diagnostic and prognostic value of circulating endothelial cell (CEC), a potential surrogate of tumor angiogenesis, in malignant pleural mesothelioma (MPM).

Methods: We prospectively evaluated CEC count in 4.0 mL of peripheral blood sampled from patients with a suspicion of MPM. An automated system was used to capture CECs with an anti-CD146 antibody.

Results: Of 109 eligible patients, 30 were finally diagnosed with non-malignant diseases, and 79 were with MPM. CEC count was significantly higher in MPM patients than in NM patients (mean CEC count, 120.3 and 39.9, respectively; P = 0.001), and a receiver operating characteristic (ROC) curve analysis showed that CEC provided a significant diagnostic performance in discrimination between MPM and nonmalignant diseases with an area under curve (AUC-ROC) of 0.700 (95 % confidence interval [95 % CI], 0.595-0.806; P = 0.001). Among MPM patients, CEC count was positively correlated with intratumoral microvessel density (MVD), a measurement of tumor angiogenesis (Spearman correlation coefficiency [r] = 0.444; P = 0.001). Higher CEC count (>50) was significantly associated with a poor prognosis (median overall survival, 11.4 months [95 % CI, 7.6-15.2] for higher CEC count patients versus 20.1 months [95 % CI, 16.0-24.2] for lower CEC count patients; P = 0.028). A multivariate analysis showed that higher CEC count was a significant and independent factor to predict a poor prognosis (hazard ratio [HR], 2.24, [95 % CI, 1.24-4.43]; P = 0.009).

Conclusions: CEC, as a surrogate of tumor angiogenesis, was a promising marker in diagnosis and prediction of prognosis in MPM.
Clinical impact of extrapleural pneumonectomy for malignant pleural mesothelioma. V. Ambrogi, A. Baldi, O. Schillaci, et al. 2012;19(5):1692-9. PubMed · Publisher

Abstract

Background: The clinical impact of extrapleural pneumonectomy in malignant pleural mesothelioma is poorly investigated.

Methods: Between 1997 and 2007, 29 consecutive patients underwent extrapleural pneumonectomy for mesothelioma and adjuvant chemoradiotherapy. Function (spirometry, arterial blood gas analysis, 6-min walk test, and echocardiographic fraction ejection estimation), symptoms (quantification of pain, dyspnea, cough, fever, weight loss, and Karnofsky performance status) and quality of life [Medical Outcomes Study Short Form, 36 item (SF-36) and St. George's Respiratory Questionnaire] were timely evaluated. Data were prospectively collected and retrospectively reviewed.

Results: Only one postoperative death occurred. 30-day postoperative morbidity was 41%. Median survival was 19.5 months with 17 patients still alive at 1 year and 10 at 2 years, respectively. At 3 months, the expected decrement of forced expiratory volume in 1 s (P = 0.06) and forced vital capacity (P = 0.09) was not significant. Conversely, arterial blood gas, 6-min walk test, cardiac fraction ejection, pain (P < 0.05), dyspnea (P < 0.01), cough (P < 0.05), fever (P < 0.01), weight loss (P < 0.01), performance status (P < 0.01), SF-36 physical (P < 0.01), SF-36 mental (P < 0.05), St. George's Respiratory Questionnaire symptom (P < 0.01), activity (P < 0.05), and impact on mood (P < 0.05) improved. At 12 months, the amelioration of pain, dyspnea, performance status, and physical-related quality of life parameters remained stable. Thereafter, all parameters progressively deteriorated, although pain and dyspnea still persisted above the baseline values even after 24 months in all survivors. Postoperative improvement of pain (P = 0.04), dyspnea (P = 0.04), 6-min walk test (P = 0.03), and SF-36 physical (P = 0.04) and mental (P = 0.03) components were positive prognosticators.

Conclusions: Extrapleural pneumonectomy has a significant and durable impact on function and symptoms as well as on physical and mental components of quality of life in patients with malignant pleural mesothelioma.
Combined diffusion-weighted and gadolinium-enhanced MRI can accurately predict the peritoneal cancer index preoperatively in patients being considered for cytoreductive surgical procedures. R.N. Low, R.M. Barone. 2012;19(5):1394-1401. PubMed · Publisher

Abstract

Purpose: To determine whether abdominal and pelvic magnetic resonance imaging (MRI) with diffusion-weighted and dynamic gadolinium-enhanced imaging can be used to accurately calculate the peritoneal cancer index (PCI) before surgery compared to the PCI tabulated at surgery.

Methods: Thirty-three patients underwent preoperative MRI followed by cytoreductive surgery for primary tumors of the appendix (n = 25), ovary (n = 5), colon (n = 2), and mesothelioma (n = 1). MRIs were retrospectively reviewed to determine the MRI PCI. These scores were then compared to PCI tabulated at surgery. Patients were categorized as having small-volume tumors (PCI 0–9), moderate-volume tumors (PCI 10–20), and large-volume tumors (PCI > 20). The respective anatomic site scores for both MRI and surgery were compared.

Results: There was no significant difference between the MRI PCI and surgical PCI for the 33 patients (P = 0.12). MRI correctly predicted the PCI category in 29 (0.88) of 33 patients. Compared to surgical findings, MRI correctly predicted small-volume tumor in 6 of 7 patients, moderate-volume tumor in 3 of 4 patients, and large-volume tumor in 20 of 22 patients. MRI and surgical PCI scores were identical in 8 patients (24%). A difference of <5 was noted in 16 patients (49%) and of 5–10 in 9 patients (27%). Compared to surgical-site findings, MRI depicted 258 truly positive sites of peritoneal tumor, 35 falsely negative sites, 35 falsely positive sites, and 101 truly negative sites, with a corresponding sensitivity of 0.88, specificity of 0.74, and accuracy of 0.84.

Conclusions: Combined diffusion-weighted and gadolinium-enhanced peritoneal MRI accurately predicts the PCI before surgery in patients undergoing evaluation for cytoreductive surgery.
Cytoreductive surgery with selective versus complete parietal peritonectomy followed by hyperthermic intraperitoneal chemotherapy in patients with diffuse malignant peritoneal mesothelioma: a controlled study. D. Baratti, S. Kusamura, A.D. Cabras, et al. 2012;19(5):1416-24. PubMed · Publisher

Abstract

Background: Combined treatment involving peritonectomy procedures, multivisceral resections, and hyperthermic intraperitoneal chemotherapy (HIPEC) has reportedly resulted in survival benefit for peritoneal surface malignancies, including diffuse malignant peritoneal mesothelioma (DMPM). Many unanswered questions remain regarding the surgical options in the management of DMPM. The aim of this case–control study was to assess the impact of the type and extent of parietal peritonectomy on survival and operative outcomes.

Methods: Thirty patients with DMPM undergoing selective parietal peritonectomy (SPP) of macroscopically involved regions, and 30 matched patients undergoing routine complete parietal peritonectomy (CPP), regardless of disease distribution, were retrospectively identified from a prospective database.

Results: Groups were comparable for all characteristics, except for a higher proportion of patients treated before July 2003 and undergoing preoperative systemic chemotherapy in the SPP group. Median follow-up was 86.2 months in the SPP group and 50.3 months in the CPP group. Median overall survival was 29.6 months in the SPP group and not reached in the CPP group; 5-year overall survival was 40.0% and 63.9%, respectively (P = 0.0269). At multivariate analysis, CPP versus SPP was recognized as an independent predictor of better prognosis, along with complete cytoreduction, negative lymph nodes, epithelial histology, and lower MIB-1 labelling index. Morbidity and reoperation rates were not different between groups. No operative mortality occurred. In 12 of 24 patients undergoing CPP, pathologic examination detected disease involvement on parietal surfaces with no evident tumor at surgical exploration.

Conclusions: CPP improved survival in patients with DMPM undergoing combined treatment. This information may contribute to standardize surgical options for DMPM and other peritoneal malignancies.
Parietal peritonectomy. P.H. Sugarbaker. 2012;19(4):1250. PubMed · Publisher

Abstract

Parietal peritonectomy is an initial part of cytoreductive surgery in patients with peritoneal surface malignancy. After this dissection, the necessary visceral resections, other peritonectomy procedures, and perioperative hyperthermic chemotherapy are administered. The parietal peritoneum is an immobile portion of the abdominal and pelvic surface area that is often involved by cancer implants in patients with carcinomatosis or peritoneal mesothelioma. The dependent peritoneal surfaces, such as the right retrohepatic space, paracolic sulcus, and pelvis, are involved as a result of gravitational forces. The undersurfaces of the diaphragm and omentums are involved because of major peritoneal fluid resorption at these anatomic sites. Before the parietal peritonectomy is initiated, a peritoneal window is created to digitally and visually inspect the undersurface of the anterior abdominal wall, small bowel, and small bowel mesentery. This inspection is frequently repeated so that parietal peritoneum is removed only where there is visible evidence of cancer implants. Electrosurgery is used as a dissection tool. The dissection proceeds in a centripetal fashion starting at the edges of the large midline abdominal incision and proceeding to the attachments of the peritoneum to the viscera. Initially, exposure is maintained with traction sutures from the skin edge to the fixed retractor. As the dissection deepens, a self-retaining retractor is positioned. Generally, the parietal peritonectomy takes approximately 2½ h and does not require blood replacement. After the parietal peritonectomy, additional cytoreductive surgical procedures and then perioperative chemotherapy are performed.
Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. M. Horio, M. Sato, Y. Takeyama, et al. 2012;19 Suppl 3(Suppl 3):S634-45. PubMed · Publisher · Free full text

Abstract

Background: The role of ZEB1, a master epithelial-to-mesenchymal transition gene, in malignant pleural mesothelioma (MPM) is unclear.

Methods: The expression of ZEB1, E-cadherin, vimentin, and epithelial cell adhesion molecule (EpCAM) in 18 MPM cell lines and a normal pleural mesothelial cell line MeT-5A was determined by quantitative real-time polymerase chain reaction and Western blot testing. RNA interference-mediated transient and/or stable knockdown of ZEB1 and EpCAM was performed. Microarray expression analysis was performed with a TORAY-3D gene chip. Growth was evaluated by colorimetric proliferation and colony formation assays. Luciferase reporter assay was performed to access the effects of ZEB1 knockdown on EpCAM promoter activity.

Results: Most MPM cell lines exhibited mesenchymal phenotype and expressed ZEB1. Transient ZEB1 knockdown suppressed growth in all four cell lines studied (ACC-MESO-1, H2052, Y-MESO-8A, Y-MESO-29) while stable ZEB1 knockdown suppressed growth only in Y-MESO-29. Genome-wide gene expression analysis revealed that EpCAM was the most prominently up-regulated gene by both transient and stable ZEB1 knockdown in ACC-MESO-1, with more marked up-regulation in stable knockdown. We hypothesized that EpCAM up-regulation counteracts the stable ZEB1 knockdown-induced growth inhibition in ACC-MESO-1. Transient EpCAM knockdown suppressed growth dramatically in ACC-MESO-1 cells expressing shZEB1 but only modestly in those expressing shGFP, supporting our hypothesis. Luciferase reporter assay showed that ZEB1 knockdown resulted in increased EpCAM promoter activity. EpCAM was also up-regulated in Y-MESO-29 expressing shZEB1, but this EpCAM up-regulation did not counteract ZEB1knockdown-induced growth suppression, suggesting that the counteracting effects of EpCAM may be cellular context dependent.

Conclusions: RNA interference-mediated ZEB1 knockdown may be a promising therapeutic strategy for MPM, but one has to consider the possibility of diminished growth inhibitory effects of long-term ZEB1 knockdown, possibly as a result of EpCAM up-regulation and/or other gene expression changes resulting from ZEB1 knockdown.
Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C. N.M. Rueth, S.E. Murray, S.J. Huddleston, et al. 2011;18(1):174-80. PubMed · Publisher

Abstract

Background: Oxaliplatin (OX) is increasingly used for hyperthermic intraperitoneal chemotherapy (HIPC) for patients with peritoneal metastases. Our aim was to review electrolyte disturbances and complications after HIPC with oxaliplatin (OX) versus mitomycin C (MMC).

Materials And Methods: We included patients enrolled in single-institution prospective clinical trials who underwent cytoreductive surgery and HIPC with MMC or OX. We reviewed patient demographics, pathology, perioperative course, HIPC administration, and postoperative electrolyte disturbances. Measured postoperative sodium values were corrected for systemic hyperglycemia using the formula: (measured Na(+)) × [(glucose - 100/100) × 1.6].

Results: From January 2002 to April 2009 we performed 80 HIPC procedures. A total of 60 patients (75%) received MMC (dose range 12.5-50 mg/m(2)) carried in lactated ringers solution. There were 20 patients (25%) who received OX (dose range 300 × 400 mg/m(2)) carried in 5% dextrose solution. For patients receiving HIPC with OX, electrolyte disturbances were the most common complication. Compared with MMC, patients receiving OX had significant 24-h postoperative uncorrected hyponatremia (P < 0.001), corrected hyponatremia (P < 0.001), hyperglycemia (P < 0.001), and metabolic acidosis (P < 0.001). In the OX group, corrected (mean 130.5) and uncorrected (mean 127.4) sodium levels were significantly lower than preoperatively (mean 139.9, P < 0.001). The overall nonelectrolyte complication rate was 56.2%. (MMC n = 33, 55.0%; OX n = 12, 60%); the 30-day mortality rate was 0% in both groups.

Conclusions: Compared with MMC, HIPC with OX was associated with significant but predictable electrolyte disturbances; however, these electrolyte disturbances were not associated with higher overall complication rates. Close monitoring with early correction is imperative to maximize perioperative care. Further studies are needed to provide mechanistic insight.
Summary of prognostic factors and patient selection for extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. C. Cao, T.D. Yan, P.G. Bannon, et al. 2011;18(10):2973-9. Systematic review PubMed · Publisher

Abstract

Background: Extrapleural pneumonectomy (EPP) has been shown to improve long-term survival outcomes in selected patients with malignant pleural mesothelioma (MPM). The present study aimed to evaluate potential prognostic factors on overall survival for patients who underwent EPP for MPM and to examine the patient selection process in major referral centers that perform EPP.

Methods: A systematic review of the current literature was performed using 5 electronic databases. Relevant studies with prognostic data on overall survival for patients with MPM treated by EPP were included for review. Two reviewers independently assessed each included study.

Results: A total of 17 studies from 13 institutions containing the most updated and complete data on prognostic factors for patients with MPM who underwent EPP were included for review. A number of quantitative, clinical, and treatment-related factors were identified to have significant impact on overall survival.

Conclusions: Patients with nonepithelial MPM and nodal involvement have consistently demonstrated to have a worse prognosis after EPP. Their eligibility as candidates for EPP should be questioned. The preoperative patient selection process currently differs greatly between institutions and should focus on identifying patients with nonepithelial histologic subtypes and nodal involvement to exclude them as EPP surgical candidates in the future.
Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for malignant peritoneal mesothelioma: mitomycin versus cisplatin. A.U. Blackham, P. Shen, J.H. Stewart, et al. 2010;17(10):2720-7. PubMed · Publisher

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare, rapidly fatal disease. Because traditional treatments offer little benefit, there has been increasing interest in cytoreductive surgery (CS) with intraperitoneal hyperthermic chemotherapy (IPHC). The most efficacious chemotherapy regimen is not established. Herein we report clinical outcomes of MPM patients treated with CS and IPHC and contrast results using two chemoperfusates: mitomycin and cisplatin.

Methods: Thirty-four patients were treated for MPM. Following CS, 19 patients underwent IPHC with mitomycin and 15 received cisplatin. Overall survival, disease-free survival, and progression-free survival were compared between the two groups.

Results: Overall survival was 56 and 17% at 3 and 5 years, with median survival of 40.8 months. Those perfused with cisplatin were more likely to be alive at 1, 2, and 3 years (P < 0.05, 0.05, and 0.04, respectively). Median survival for mitomycin and cisplatin was 10.8 and 40.8 months, respectively (P = 0.22). Median disease-free survival and progression-free survival were 10.3 and 9.1 months, respectively. There was a trend toward improved disease-free and progression-free survival using cisplatin.

Conclusions: CS with IPHC is a promising modality for patients with MPM, and clinical outcomes appear to be improved using cisplatin. We recommend using high-dose intraperitoneal cisplatin following cytoreductive surgery when treating malignant peritoneal mesothelioma.
Five reasons why cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy must be regarded as the new standard of care for diffuse malignant peritoneal mesotheliomia [corrected]. P.H. Sugarbaker. 2010;17(6):1710-2; author reply 1713-4. Comment · Letter PubMed · Publisher

Summary

In this letter to the editor, the author responded to an article by Baratti and colleagues from the Istituto Tumori, Milan, on lymph node metastases in diffuse malignant peritoneal mesothelioma, and to an accompanying editorial by Dr. Alexander. He agreed that careful lymph node sampling was an important part of surgical cytoreduction. He argued, however, that the article's conclusions and the editorial did not go far enough. He gave five reasons why cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) should be regarded as the new standard of care. First, no alternative existed: a review reported a median survival of 12 months with systemic chemotherapy, while published series of CRS and HIPEC reported median survivals of 29 to 100 months. A table listed seven phase II reports, ranging from 15 to 405 patients. Second, natural history studies showed that patients die mainly from local-regional progression. Third, selection factors had been established, including extent of disease, lymph node status and preoperative CT findings. Fourth, drugs suited to intraperitoneal delivery, such as cisplatin and doxorubicin, had been identified. Fifth, the goals of treatment were established. The author argued that a phase III trial against systemic chemotherapy was neither likely nor ethical. He called for treatment centers worldwide, noting that the UK National Health Service did not treat CRS and HIPEC as standard care. He also called for international collaborative research.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Lymph node metastases in diffuse malignant peritoneal mesothelioma. D. Baratti, S. Kusamura, A.D. Cabras, et al. 2010;17(1):45-53. PubMed · Publisher

Abstract

Background: Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The significance of lymph node involvement in this disease is still poorly understood.

Methods: Prospectively collected clinical data on 83 consecutive patients with DMPM undergoing surgical cytoreduction and closed-abdomen HIPEC with cisplatin and doxorubicin were reviewed. Clinically suspicious lymph nodes were submitted to pathological examination. The impact of nodal involvement on survival was assessed by multivariate analysis; 14 clinicopathological control variables were tested.

Results: For the overall series, median follow-up was 52 months (range 1-126 months) and 5-year overall survival (OS) was 49.5%. Lymph nodes were submitted to pathological examination in 38 patients, being positive in 11 and negative in 27. Lymph nodes were not clinically suspicious and not sampled in 45 patients. Iliac (n = 7) and paracolic (n = 2) nodes were the most commonly involved nodes. OS was 18.0% for patients with pathologically positive nodes and 82.5% for those with pathologically negative nodes (P = 0.0024). On multivariate analysis, pathologically negative (versus positive/not assessed) nodes [hazard ratio (HR) = 2.81; 95% confidence interval (CI) = 1.12-7.05; P = 0.027], epithelial subtype (HR = 2.93; CI = 1.24-6.95; P = 0.015), mitotic count <or=5/50 high-power microscopic fields (HPF) (HR = 5.34; CI = 1.96-14.54; P = 0.001), and completeness of cytoreduction (HR = 2.06; CI = 1.19-3.56; P = 0.001) correlated with increased OS. Positive nodes (versus negative/not assessed) did not significantly correlate with survival.

Conclusion: Pathologically negative nodes (as compared with pathological positive and not assessed), along with pathological and biological features, independently correlated with increased survival following comprehensive treatment. This suggests the need for careful node sampling when performing surgical cytoreduction for DMPM patients.
Surgical treatment of malignant peritoneal mesothelioma: past, present, and future. H.R. Alexander. 2010;17(1):21-2. Comment · Editorial PubMed · Publisher · Free full text

Summary

In this editorial, the author discussed the surgical treatment of malignant peritoneal mesothelioma (MPM) and commented on a study by Baratti and colleagues published in the same issue. He noted that only 10–15% of patients with mesothelioma have the peritoneal form, about 300–400 cases a year in the USA, and that many trials of systemic agents had not separated peritoneal from pleural disease. He reviewed early reports. These included Borow's report of the association between asbestos exposure and mesothelioma, and a 1973 report of four patients treated with cytoreduction and whole-abdominal radiotherapy, two of whom survived more than 5 years. He also cited a series of 37 patients treated at the Dana Farber Cancer Institute and Brigham and Women's Hospital between 1965 and 1984. He described the rationale for cytoreduction combined with hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC). Summarizing the Baratti study of 83 patients, he reported that nodal metastases were found in 20% of 15 patients whose nodes were routinely sampled and in 40% of a group with enlarged, suspicious nodes. Epithelioid histology, low mitotic count, complete gross cytoreduction and pathologically negative nodes were independent factors associated with increased survival. He stated that the predictive value of nodal status needed validation in additional studies. He concluded that meaningful progress required collective and cooperative efforts rather than single-institution reports.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Volume-based parameter of 18)F-FDG PET/CT in malignant pleural mesothelioma: prediction of therapeutic response and prognostic implications. H.Y. Lee, S.H. Hyun, K.S. Lee, et al. 2010;17(10):2787-94. PubMed · Publisher

Abstract

Background: To evaluate the importance of assessing volume-based parameter of (18)F-FDG PET/CT in patients with malignant pleural mesothelioma (MPM) for the prediction of response and patient outcome early in the course of treatment.

Materials And Methods: Patients (n = 13; M:F = 9:4, mean age, 54 years) with histopathologically proven MPM, all of whom were scheduled to undergo curative extrapleural pneumonectomy (EPP) or palliative chemotherapy, were included in this study. They were evaluated using integrated (18)F-FDG PET/CT at baseline. Maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured using PET/CT data. Relationships between tumor progression and PET parameters were statistically analyzed.

Results: Of the 13 patients, 8 (62%) developed disease recurrence after surgery or tumor progression after chemotherapy (median follow-up, 329 days; range, 28-536 days). Between subgroups with and without tumor progression, significant differences were noted in MTV (P = 0.045). On ROC curve analysis, MTV (AUC = 0.850, 95% confidence interval [95% CI] 0.550-0.977) and TLG (AUC = 0.800, 95% CI 0.494-0.960) showed good predictive performance for tumor progression. Multivariate analysis adjusted for treatment modality showed that MTV (HR 1.003, P = 0.025) and TLG (HR 1.001, P = 0.031) were independent factors associated with tumor progression. Time to tumor progression was shorter in patients with a high volume-based parameter of PET than in those with a low value.

Conclusions: Volume-based parameters of (18)F-FDG PET/CT have the potential to provide prognostic information in MPM patients who are receiving surgery or palliative chemotherapy.

2000s

Cytoreductive surgery and continuous hyperthermic peritoneal perfusion in patients with mesothelioma and peritoneal carcinomatosis: hemodynamic, metabolic, and anesthetic considerations. N. Miao, J.F. Pingpank, H.R. Alexander, et al. 2009;16(2):334-44. PubMed · Publisher · Free full text

Abstract

Cytoreductive surgery and continuous hyperthermic peritoneal perfusion (CHPP) involve the conduct of a complex surgical procedure and delivery of high-dose hyperthermic chemotherapy to the peritoneum. This therapeutic modality has been shown to benefit patients with peritoneal carcinomatosis resulting from gastrointestinal and ovarian tumors and mesothelioma. However, it is unknown whether the primary disease (mesothelioma versus peritoneal carcinomatosis) affects hemodynamic and metabolic perturbations during the course of CHPP with cisplatin. We examined the perioperative course of patients undergoing CHPP with cisplatin and evaluated the effect of primary diagnosis (mesothelioma versus peritoneal carcinomatosis) on hemodynamic and metabolic parameters in response to peritoneal perfusion. Sixty-nine mesothelioma and 100 peritoneal carcinomatosis patients underwent 169 consecutive cytoreduction and CHPP procedures with general anesthesia. During CHPP, patients from both groups developed significant increases in central venous pressure, and heart rate, decreases in mean arterial pressure (all P < 0.0001), metabolic acidosis with significant decreases in pH and bicarbonate (P < 0.0001), deterioration of gas exchange with significant increases in PaCO(2) and oxygen alveolar-arterial gradient (P < 0.0001), and significant increases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) and decreases in hematocrit and platelet counts (all P < 0.0001). However, patients with mesothelioma had lesser increases in temperature (P < 0.01) and heart rate (P < 0.0001) and lesser decreases in hematocrit (P = 0.0013) during CHPP and greater decreases in sodium bicarbonate (P = 0.0082) after completion of CHPP compared with patients with peritoneal carcinomatosis. We conclude that the transient hemodynamic and metabolic perturbations associated with cytoreductive surgery and CHPP with cisplatin can vary according to the primary diagnosis (mesothelioma versus peritoneal carcinomatosis) warranting this therapy.

1990s

Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. P.H. Sugarbaker, D. Chang. 1999;6(8):727-31. PubMed · Publisher

Abstract

Introduction: In the past, peritoneal carcinomatosis, regardless of primary tumor type, has always been a lethal condition. Recently, special treatments using cytoreductive surgery with peritonectomy procedures combined with perioperative intraperitoneal chemotherapy have resulted in long-term survival. Appendiceal malignancy with a low incidence of liver and lymph node metastases may be especially appropriate for these aggressive local regional treatments.

Methods: All patients treated with surgery before January 1999 are included. Patients left with gross residual disease after surgery were not given intraperitoneal chemotherapy, but were later treated with intravenous chemotherapy. The intraperitoneal chemotherapy was given in the perioperative period, starting with mitomycin C at 12.5 mg/m2 for males and 10 mg/m2 for females. For patients whose pathology showed adenomucinosis, intraperitoneal chemotherapy was limited to treatment in the operating theater with heated mitomycin C. Patients with mucinous adenocarcinoma or pseudomyxoma/adenocarcinoma hybrid had, in addition to mitomycin C, five consecutive days of intraperitoneal 5-fluorouracil at 650 mg/m2 instilled in 1-1.5 liters of 1.5% dextrose peritoneal dialysis solution. A complete cytoreduction was defined as tumor nodules <2.5 mm in diameter remaining after surgery. The histopathology categorized the patients as having adenomucinosis, adenomucinosis/carcinomatosis hybrid, or mucinous carcinomatosis. A previous surgical score was used to estimate the extent of previous surgical procedures.

Results: The morbidity of treated patients was 27% and the mortality was 2.7%. In a multivariate analysis, prognostic factors for survival included the completeness of cytoreduction (P < .0001), the histopathological character of the appendix malignancy (P < .0001), and the extent of previous surgical interventions (P = .001). Patients with a complete cytoreduction and adenomucinosis by pathology had a 5-year survival of 86%; with hybrid pathology, survival at 5 years was 50%. Incomplete cytoreduction had a 5-year survival of 20% and 0% at 10 years.

Conclusions: Cytoreductive surgery and perioperative intraperitoneal chemotherapy can be used to salvage selected patients with peritoneal surface spread of appendiceal primary tumors. Similar strategies for other patients with peritoneal surface malignancy such as peritoneal carcinomatosis from colon or gastric cancer, peritoneal sarcomatosis, or peritoneal mesothelioma should be pursued.
Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP). B.J. Park, H.R. Alexander, S.K. Libutti, et al. 1999;6(6):582-90. PubMed · Publisher

Abstract

Background: Primary peritoneal mesothelioma is a locally aggressive disease that is difficult to treat or even palliate. Continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin (CDDP) allows uniform, high regional delivery of chemotherapeutics and hyperthermia to the peritoneal surface for the treatment of peritoneal tumors. This article summarizes the results of 18 patients with peritoneal mesothelioma treated with CHPP.

Methods: From June 1993 through April 1998, 18 patients with primary peritoneal mesothelioma (13 male, 5 female; median age, 51 years) underwent surgical exploration and tumor debulking followed by a 90-minute CHPP with CDDP and hyperthermia as part of three consecutive phase I trials conducted at the National Cancer Institute. Seventeen of 18 patients had malignant peritoneal mesothelioma, 13 with associated ascites. One patient had a symptomatic, multiply recurrent, benign, cystic peritoneal mesothelioma. Three patients who had a recurrence after a prolonged progression-free interval (>6 months) after CHPP underwent re-treatment. CHPP parameters included median cisplatin dose of 530 mg (range, 187-816), perfusate volume 6.0 liter (range, 4-9), flow 1.5 liter/min (range, 1-2), intraperitoneal temperature 41 degrees C (range, 38.7-43.2), and central temperature 38.6 degrees C (range, 36.8-39.7).

Results: Median follow-up after CHPP is 19 months (range, 2-56) with no operative or treatment-related mortality. Overall operative morbidity was 24% and included two patients with superficial wound infection and one patient each with atrial fibrillation, pancreatitis, fascial dehiscence, ileus, line sepsis, and clostridium difficile colitis. The major treatment-related toxicity was systemic renal toxicity at doses above what was defined as the maximum tolerated dose of cisplatin. Nine of 10 patients had resolution of their ascites postoperatively. Three patients who developed recurrent ascites (27, 22, and 10 months after initial treatment) were re-treated and had resolution of their ascites with ongoing responses at 24, 6, and 4 months after the second perfusion. The median progression-free survival was 26 months, and the overall 2-year survival was 80%. The median overall survival has not been reached.

Conclusions: CHPP with cisplatin can be performed safely with no mortality and minimal morbidity. In selected patients, successful palliation in the abdomen and long-term survival, compared with historical controls, can be achieved with aggressive surgical debulking and CHPP. Re-treatment after initial response can result in a second long-term response.
Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. H.I. Pass, B.K. Temeck, K. Kranda, et al. 1997;4(8):628-33. Randomized trial PubMed · Publisher

Abstract

Background: Patients with malignant pleural mesothelioma (MPM) usually die of progressive local disease. This report describes the results of a Phase III trial comparing maximum debulking surgery and postoperative cisplatin, interferon alpha-2b, and tamoxifen (CIT) immunochemotherapy with and without intraoperative photodynamic therapy (PDT) to determine (1) whether such a multimodal approach can be performed with minimum morbidity and mortality in malignant pleural mesothelioma (MPM), and (2) whether first-generation (i.e., 630-nm laser light, Photofrin II) intrapleural PDT impacts on local recurrence of survival.

Methods: From July 1993 to June 1996, 63 patients with localized MPM were randomized to either PDT or no PDT. The tumors of 15 patients could not be debulked to 5 mm. Patients assigned to PDT (n = 25) and no PDT (n = 23) were similar with respect to age, sex, tumor volume, and histology.

Results: The type of resection (11 pleurectomies and 14 pneumonectomies vs. 12 pleurectomies and 11 pneumonectomies), length postoperative stay, and ICU time were comparable (PDT vs. no PDT). There was one operative death (hemorrhage), and each group had two bronchopleural fistulas. Postoperative staging divided patients into the following categories: stage I: PDT, 2, no PDT, 2; stage II: PDT, 2, no PDT, 2; stage III, PDT, 21; no PDT, 17; stage IV, PDT, 0; no PDT, 2. Comparable numbers of CIT cycles were delivered. Median survival for the 15 non-debulked patients was 7.2 months, compared to 14 months for the 48 patients on protocol. There were no differences in median survival (14.4 vs. 14.1 months) or median progression-free time (8.5 vs. 7.7 months), and sites of first recurrence were similar.

Conclusions: Aggressive multimodal therapy can be delivered for patients with higher stage MPM. First-generation PDT does not prolong survival or increase local control for MPM.

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