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Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery. (Peritoneal Carcinomatos Forskargrupp)
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 Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2013 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, 435- p.Article in journal (Refereed) Published
Abstract [en]

Background: The optimal choice of cytotoxic drugs for intraperitoneal chemotherapy (IPC) in conjunction with cytoreductive surgery (CRS) for treatment of peritoneal carcinomatosis(PC) is poorly defined. We investigated drug sensitivity ex vivo in patient samples of various PC tumor types and correlated clinical outcome to drug sensitivity within the subset of PC fromcolorectal cancer (CRC). 

Methods: PC tissue samples (n = 174) from mesothelioma, pseudomyxoma peritonei (PMP), ovarian cancer, CRC or appendix cancer were analyzed ex vivo for sensitivity to oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan, docetaxel, doxorubicin and 5-FU. Clinicopathological variables and outcome data were collected for the CRC subset. 

Results: Mesothelioma and ovarian cancer were generally more drug sensitive than CRC, appendix cancer and PMP. Oxaliplatin showed the most favorable ratio between achievable IPC concentration and ex vivo drug sensitivity. Drug sensitivity in CRC varied considerably between individual samples. Ex vivo drug sensitivity did not obviously correlate to time-to-progression (TTP) in individual patients. 

Conclusions: Drug-sensitivity varies considerably between PC diagnoses and individual patients arguing for individualized therapy in IPC rather than standard diagnosis-specific therapy. However, in the current paradigm of treatment according to diagnosis, oxaliplatin is seemingly the preferred drug for IPC from a drug sensitivity and concentration perspective. Inthe CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was inconclusive due to the heterogeneous nature of the data.

Place, publisher, year, edition, pages
2013. Vol. 13, 435- p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-172441DOI: 10.1186/1471-2407-13-435ISI: 000325079100001OAI: oai:DiVA.org:uu-172441DiVA: diva2:514680
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Cytoreductive Surgery and Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Colorectal Cancer: Aspects of loco-regional treatment outcome, patient selection, and chemo-sensitivity
Open this publication in new window or tab >>Cytoreductive Surgery and Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Colorectal Cancer: Aspects of loco-regional treatment outcome, patient selection, and chemo-sensitivity
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Previously, peritoneal metastases(PM) from colorectal cancer(CRC) have been considered a terminal and generalised form of cancer. A new treatment strategy combining cytoreductive surgery(CRS) and intraperitoneal chemotherapy(IPC) has recently shown promising results. The aim of this thesis was to investigate different aspects of this treatment in order to optimise the treatment and to clarify its potential as a new treatment option. Treatment outcome, patient selection, method of IPC (hyperthermic intraperitoneal chemotherapy-HIPEC vs. sequential postoperative intraperitoneal chemotherapy-SPIC) and choice of drugs for IPC were the aspects covered in this thesis.

The treatment outcome of CRS and IPC according to the median overall survival ranged from 24 to 34 months with 5-year overall survival ranging from 20 to 40% depending on the IPC treatment administered. Furthermore, the 5-year disease-free survival was impressive at 32% for patients receiving HIPEC. This establishes the curative potential of this treatment. Due to current inadequacies of radiological imaging, a score (Corep score) was developed for patient selection purposes. This score had a sensitivity of 80% and specificity of 100% in identifying patients with short cancer-specific survival after the treatment (<12 months). Further studies are needed to elucidate the clinical usefulness of the Corep score. HIPEC was associated with better survival than the SPIC method at similar morbidity and mortality rates, suggesting that HIPEC be the method of preference. Concerning the choice of drugs, the last study investigated the chemo-sensitivity of different PM tumour-types with a special focus on CRC. While CRC samples were generally more resistant, the ratio of the in vivo concentration compared to the ex vivo concentration giving a 50% tumour cell death showed that oxaliplatin had the best profile across all PM tumour types as well as for CRC. This needs further confirmation in a clinical trial.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 75 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 765
National Category
Surgery Cancer and Oncology
Research subject
Surgery; Oncology
Identifiers
urn:nbn:se:uu:diva-172443 (URN)978-91-554-8347-0 (ISBN)
Public defence
2012-05-25, Auditorium minus, Gustavianum, Akademigatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-04 Created: 2012-04-10 Last updated: 2012-08-01Bibliographically approved

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Cashin, Peter HMahteme, HaileGraf, WilhelmKarlsson, HenningLarsson, RolfNygren, Peter

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