Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer

Our plain-English summary of Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer, by P.H. Cashin, H. Mahteme, W. Graf, et al (BMC Cancer, 2013).

The study

• Authors: P.H. Cashin, H. Mahteme, W. Graf, H. Karlsson, R. Larsson, P. Nygren
• Journal: BMC Cancer
• Published: 2013;13:435
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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 from colorectal 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. In the CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was inconclusive due to the heterogeneous nature of the data.

In plain English

This Swedish laboratory study tested eight chemotherapy drugs on tumor cells taken during surgery from patients with cancer spread across the abdominal lining (peritoneal carcinomatosis). It analyzed 174 samples: pseudomyxoma peritonei (72), colorectal cancer (52), ovarian cancer (19), appendix cancer (16) and mesothelioma (15). The article does not discuss asbestos. In the authors' words, mesothelioma samples were surprisingly sensitive across the drugs, much like ovarian cancer. Colorectal, appendix and pseudomyxoma samples were generally more resistant. The authors compared drug concentrations reached in the abdomen, as reported in earlier studies, with the concentrations that halved measured cell viability relative to untreated control cultures. Oxaliplatin had the most favorable ratio for every diagnosis. Sensitivity varied widely between individual colorectal samples. Among 23 colorectal patients with complete surgery, time to progression did not differ statistically significantly between those classed as drug-sensitive (15) and drug-resistant (8). The authors concluded that sensitivity varies by diagnosis and by patient, which argues for individualized treatment. They also concluded that, under current practice, oxaliplatin seemed the preferred drug from a drug-sensitivity and concentration perspective. They judged the colorectal outcome analysis inconclusive.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (ex vivo) drug-sensitivity testing of fresh patient tumor samples, with an analysis of clinical outcome in the colorectal cancer subgroup
• Who was studied: 174 tumor samples taken during cytoreductive surgery at Uppsala, Sweden, from patients with peritoneal carcinomatosis: pseudomyxoma peritonei 72, colorectal cancer 52, ovarian cancer 19, appendix cancer 16, mesothelioma 15 (7 previously treated with chemotherapy, 8 not). Leukemia samples and blood mononuclear cells were tested for comparison. Study dates are not given.
• Exposure: Eight chemotherapy drugs (oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan, docetaxel, doxorubicin and 5-FU) applied to the tumor cells in the laboratory. Effect was measured as a fluorescence-based survival index relative to untreated control cultures. No asbestos or fiber exposure was studied.
• Main results:
  • Colorectal, appendix cancer and pseudomyxoma samples generally had higher IC50 values (were more resistant) than the other groups, except for 5-FU. Mesothelioma samples were sensitive across the drug panel, similar to ovarian cancer.
  • The authors divided the abdominal drug concentrations reported in the literature by the IC50 (the concentration giving a survival index of 50% of control). Oxaliplatin had the most favorable ratio in every diagnosis: 47.7 for mesothelioma, 38.2 for ovarian cancer, 19.9 for pseudomyxoma, 18.5 for colorectal cancer and 16.4 for appendix cancer.
  • Drug sensitivity varied widely between individual samples. Cross-resistance between drugs was modest to high, but many individual samples were resistant to one drug and sensitive to another.
  • In the colorectal subgroup, mucinous tumors were generally less sensitive than non-mucinous tumors. For cisplatin the difference was 30 vs. 14 μM (p = 0.05), and for irinotecan it was 184 vs. 81 μM (p = 0.07). Prior chemotherapy made essentially no difference to drug sensitivity.
  • In a multivariable analysis of the colorectal subgroup (n = 47), three factors were independently associated with longer time to progression: sensitivity to doxorubicin (median 12 vs. 1 months), synchronous peritoneal carcinomatosis, and macroscopically radical surgery.
  • Among 23 colorectal patients with complete cytoreduction (CC 0), time to progression did not differ statistically significantly between ex vivo 'sensitive' (n = 15) and 'resistant' (n = 8) patients (p = 0.4). At three years, 3 patients in the sensitive group and none in the resistant group were disease free.
• The authors' conclusion: The authors concluded that drug sensitivity varies considerably between diagnoses and individual patients, which argues for individualized rather than diagnosis-specific intraperitoneal chemotherapy. They also concluded that, under current diagnosis-based practice, oxaliplatin seemed the preferred drug from a drug-sensitivity and concentration perspective. They judged the colorectal analysis of sensitivity versus time to progression inconclusive.
• Limitations the authors state:
  • Only 23 colorectal patients could be analyzed for the link between laboratory sensitivity and outcome, and the drug regimens they received varied.
  • Longer follow-up and more patients are needed for a conclusive analysis.
  • The doxorubicin finding might be due to chance.
  • The laboratory assay differs from conditions inside the patient, including drug exposure time.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer.

Medical terms in this study, explained in our Lexicon: Colorectal Cancer, Chemotherapy, Cytoreductive Surgery, Mesothelioma, Ovarian Cancer, Cisplatin, Mitomycin C, Doxorubicin.

Related studies

• Repeat Cytoreductive Surgery and HIPEC for Peritoneal Surface Malignancy and Peritoneal Carcinomatosis — J.F. Wong, G.H. Tan, et al. (2015)
• A new policy regarding ovarian resection in young women treated for peritoneal carcinomatosis — D. Elias, E. Duchalais, et al. (2013)
• Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Adolescent and Young Adults with Peritoneal Metastases — M. Dhir, L. Ramalingam, et al. (2017)
• The Role of Hyperthermic Intraperitoneal Chemotherapy for Non-colorectal Peritoneal Surface Malignancies — M.C. Morris, J.M. Cloyd, et al. (2021)
• Evolution of locoregional treatment for peritoneal carcinomatosis: single-center experience of 308 procedures of cytoreductive surgery and perioperative intraperitoneal chemotherapy — T.C. Chua, W. Liauw, et al. (2011)
• Value of laparoscopy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis — L.H. Iversen, P.C. Rasmussen, et al. (2013)

Browse more research in BMC Cancer, or return to medical research.