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Drug Sensitivity Testing in Cytoreductive Surgery and Intraperitoneal Chemotherapy of Pseudomyxoma Peritonei
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktiv hälsa/Sundström Poromaa)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
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2015 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 22, p. S810-S816Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an established therapy for pseudomyxoma peritonei (PMP). However, the role of IPC is unclear. By ex vivo assessment of PMP tumor cell sensitivity to cytotoxic drugs, we investigated the basis for IPC drug selection and the role of IPC in the management of PMP.

METHODS: Tumor cells were prepared by collagenase digestion of tumor tissue from 133 PMP patients planned for CRS and IPC. Tumor cell sensitivity to oxaliplatin, 5FU, mitomycin C, doxorubicin, irinotecan, and cisplatin was assessed in a 72-h cell-viability assay. Drug sensitivity was correlated to progression-free survival (PFS) and overall survival (OS).

RESULTS: Samples from 92 patients were analyzed successfully. Drug sensitivity varied considerably between samples. Peritoneal mucinous carcinomatosis (PMCA), compared with PMCA intermediate or disseminated peritoneal adenomucinosis, was slightly more resistant to platinum and 5FU and tumor cells from patients previously treated with chemotherapy were generally less sensitive than those from untreated patients. Multivariate analysis showed patient performance status and completeness of CRS to be prognostic for OS. Among patients with complete CRS (n = 61), PFS tended to be associated with sensitivity to mitomycin C and cisplatin (p ≈ 0.06). At the highest drug concentration tested, the hazard ratio for disease relapse increased stepwise with drug resistance for all drugs.

CONCLUSIONS: Ex vivo assessment of drug sensitivity in PMP provides prognostic information. The results suggest a role for IPC as therapeutic adjunct to CRS and for individualization of IPC by pretreatment assessment of drug sensitivity.

Place, publisher, year, edition, pages
2015. Vol. 22, p. S810-S816
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-265752DOI: 10.1245/s10434-015-4675-0ISI: 000367288100072PubMedID: 26193962OAI: oai:DiVA.org:uu-265752DiVA, id: diva2:866493
Funder
Swedish Cancer Society
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-04-23Bibliographically approved
In thesis
1. Predictive and prognostic factors of epithelial ovarian cancer and pseudomyxoma peritonei
Open this publication in new window or tab >>Predictive and prognostic factors of epithelial ovarian cancer and pseudomyxoma peritonei
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The overall aim of my thesis was to investigate potential prognostic and predictive factors associated with the tumor cells of epithelial ovarian cancer (EOC) and the gastrointestinal tumor pseudomyxoma peritonei (PMP) to improve and individualize cancer therapy. Both PMP and EOC can develop into peritoneal carcinomatosis (PC), which is characterized by widespread metastasis of cancer tumors in the peritoneal cavity. Major improvements in the management of PC, such as cytoreductive surgery in combination with chemotherapy, have dramatically changed the prognosis.

To further optimize and tailor treatment, increased knowledge on tumor biology and pathogenesis is needed. Today’s choice of treatment is mainly based on clinical trials and standard protocols that have not taken individual differences in drug sensitivity into consideration. With ex vivo testing of tumor drug sensitivity, individuals at risk of side effects only (and no treatment benefit) could potentially be identified prior to treatment.

Napsin A is an anti-apoptotic protein that promotes platinum resistance by degradation of the cell cycle regulator and tumor suppressor TP53. Immunohistochemical stainings of 131 early EOC tumors in study I showed that expression of Napsin A was associated with expression of the apoptosis regulators p21 and p53 and with histological subtype. Positivity of Napsin A in an epithelial ovarian tumor strengthens the morphological diagnosis of clear cell carcinoma and should be useful in diagnostics. In study II, the relevance of the proteins HRNPM and SLC1A5 as prognostic factors for recurrent disease, survival and impact on clinical or pathological features was evaluated in 123 patients with early EOC. Our results support concomitant positivity of HRMPM and PUMA/p21 in ovarian cancer and indicate that HRNPM may trigger activity in systems of cell cycle regulation and apoptosis. In subgroup analyses of tumors from patients with non-serous EOC histology, expression of SLC1A5 was shown to be a prognostic factor in terms of prolonged disease-free survival. In studies III and VI, we investigated the ex vivo drug sensitivity of tumor cells from EOC and PMP with the 72-h cell viability assay fluorometric microculture cytotoxicity assay (FMCA). The two studies confirm that drug sensitivity varies considerably between tumor samples from patients within the same diagnostic group. In ovarian cancer, ex vivo results show that type I tumors were generally less sensitive to cytotoxic agents than type II tumors. Samples from patients previously exposed to cytotoxic drugs generally tended to be more resistant to most drugs than samples from unexposed patients in both EOC and PMP. This observation is in line with clinical experience and findings supporting that exposure to cytotoxic treatments contribute to development of chemo-resistance mechanisms. In ovarian cancer, resistance to the kinase inhibitors after exposure varied but was less pronounced than that for standard cytotoxic drugs. In PMP patients, ex vivo drug sensitivity provided prognostic information for progression-free survival, and this is in line with earlier findings.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1462
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-349159 (URN)978-91-513-0326-0 (ISBN)
Public defence
2018-06-08, Gustavianum, auditorium minus, Akademigatan 3, Uppsala, 09:15 (Swedish)
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Supervisors
Available from: 2018-05-17 Created: 2018-04-22 Last updated: 2018-05-17

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Bjersand, KathrineMahteme, HaileSundström Poromaa, IngerAndreasson, HåkanGraf, WilhelmLarsson, RolfNygren, Peter

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Obstetrics and GynaecologyColorectal SurgeryDepartment of Women's and Children's HealthDepartment of Medical SciencesDepartment of Immunology, Genetics and Pathology
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