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Detection of Micrometastases in Peritoneal Washings of Pancreatic Cancer Patients by the Reverse Transcriptase Polymerase Chain Reaction

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Objective

Pancreatic cancer patients with positive (+) peritoneal cytology have a prognosis similar to stage IV patients. We studied the ability of quantitative real time-polymerase chain reaction (RT-PCR) to detect micrometastases in patients undergoing staging laparoscopy.

Methods

Peritoneal washes were obtained prospectively from 35 consecutive patients with pancreatic adenocarcinoma undergoing staging laparoscopy and 16 patients undergoing laparoscopy for benign disease. Each sample was assessed by cytologic examination and RT-PCR analysis for tumor markers: CEA, CK7, Kras2, and MUC1. Markers and their combinations were evaluated on the basis of their deviance from the ideal marker.

Results

Pathologic stages for pancreatic cancer patients were: 1A-1 (3%), IB-1 (3%), IIA-5 (15%), IIB-13 (38%), III-5 (15%), IV-9 (26%). Eight patients were cytology (+) and stages IIA-1, IIB-2, IV-5. Twenty-five patients were RT-PCR (+). The optimal threshold for cycle amplification was 35 based on a receiver operating characteristic curve. CEA had the best profile of sensitivity, specificity, PPV, NPV, and the smallest deviance.

Conclusion

RT-PCR using a panel of tumor markers, including CEA, was comparable in sensitivity, specificity, PPV, and NPV to cytology. RT-PCR could represent a more sensitive method for detection of subclinical peritoneal tumor dissemination; this may be useful in patient selection for operative management and clinical trials.

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Acknowledgments

We would like to acknowledge members of the Fong Laboratory, Yun Shin Chun, MD, and David Eisenberg, MD, as well as research study assistants Judy Fong and Maria Janakos.

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Authors and Affiliations

  1. Department of Surgery, Memorial-Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Yanghee Woo, Charles Galanis, Peter Allen, Ronald DeMatteo, Yuman Fong & Daniel G. Coit

  2. Department of Surgery, David Grant U.S. Air Force Medical Center, Travis AFB, CA, USA

    Kimberly Moore Dalal

  3. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mithat Gonen

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Laura Tang

Authors
  1. Kimberly Moore Dalal
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  2. Yanghee Woo
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  3. Charles Galanis
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  4. Mithat Gonen
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  5. Laura Tang
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  6. Peter Allen
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  7. Ronald DeMatteo
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  8. Yuman Fong
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  9. Daniel G. Coit
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Corresponding author

Correspondence to Daniel G. Coit.

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DISCUSSION

Keith D. Lillemoe, M.D. (Indianapolis, IN): Kim, that was a very nice presentation. Seeing you up there in uniform reminds me that I think both myself and immediate Past President Dr. Bass had our first SSAT presentations in uniform too. So I think your future looks bright in this organization, as we all knew it would be.

I have a few questions. I guess the first thing is, really, what value is this? If I am not correct, you do your laparoscopic staging at the time that you plan to explore the patients for resection. In other words, you are really not using this information at all for clinical decision-making. So I guess the first question is, when are you going to believe your cytology data to start doing it as a planned procedure, a day, a week or whatever it takes, before you can plan exploration for resection? A lot of groups talk about the value of peritoneal cytology, but when the rubber hits the road, in their clinical practice, they do not really practice the use of it that much.

Let us just assume that this analysis was of value. What is the cost associated with this analysis? In the end, we will be adding not only this, but a separate laparoscopic procedure with general anesthesia, some time in the hospital, or at least in the recovery room. Is this really going to have a cost/benefit ratio in helping the small number of patients where it is going to be of benefit?

Obviously you alluded to it, but we obviously want to see a second paper showing the follow-up of these people with a “false positive” RT-PCR positivity to see if indeed their survival is affected.

Finally, where I think this analysis might be of value are those patients who we see in follow-up after pancreatic resection who develop ascites. Many times we do not know the cause of that ascites. If we could tap the ascites and find out definitely if they have malignant disease, it may help us better direct their therapy.

It is a beautiful study. I am not sure if it is quite ready for prime time application to all those people who are doing pancreatic surgery, but I think it adds to our knowledge of the disease. Nice presentation.

Kimberly M. Dalal, M.D. (Travis AFB, CA): Thank you for your comments and for your support. When will we believe the data and actually apply them to our patients? Well, that is probably not for at least 5 years. Now that this pilot study has established the feasibility and optimized the primers and parameters for RT-PCR, Drs. Fong and Coit and a couple of current surgical oncology fellows have taken on a prospective study looking at 200 patients with pancreatic adenocarcinoma. To accrue 200 patients and to obtain 2 years of follow-up will take about 5 years. I agree; actually using this information to make treatment decisions is not something we can do immediately.

With regard to your second question about the cost benefit of RT-PCR, I will say that to perform laparoscopy under general anesthesia at a separate setting and to process the peritoneal wash samples for RNA isolation and RT-PCR for the panel of tumor markers will cost several hundred to a thousand dollars. However, if we could identify patients who would not benefit from surgery, this would provide a tremendous benefit that may outweigh that initial cost by preventing the potential morbidity that can be associated with pancreatic resections, decrease in quality of life, and additional costs that may result from an operation that ultimately would not lead to a curative resection. This procedure may, in fact, come out to have a definite cost benefit. But again, we will not know this for at least 5 years.

Craig P. Fischer, M.D. (Houston, TX): How about the use for malignant ascites, do you think that that has some utility?

Dr. Dalal: I think it does. We have not pursued that ourselves, but I think that it is definitely something to consider investigating in future studies.

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Dalal, K.M., Woo, Y., Galanis, C. et al. Detection of Micrometastases in Peritoneal Washings of Pancreatic Cancer Patients by the Reverse Transcriptase Polymerase Chain Reaction. J Gastrointest Surg 11, 1598–1606 (2007). https://doi.org/10.1007/s11605-007-0283-z

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