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Surgery and adjuvant therapy may work for pancreatic cancer
By Dross at 2007-01-24 02:31
Surgery and adjuvant therapy may work for pancreatic cancer

 

In the largest single-institution retrospective study to date, researchers at Mayo Clinic Cancer Center have shown that giving patients both radiation and chemotherapyterm after completely removing invasive pancreatic cancer may improve overall survival rates. The study's lead author, a radiation oncology resident in Rochester, Michele Corsini, M.D., presented the findings Saturday, Jan. 20, at the 2007 Gastrointestinal Cancers Symposium. The American Cancer Society reports that while the incidence of pancreatic cancer has decreased over the last few years, it remains the fourth most common cause of cancer-related death. Pancreatic cancer, which has a very poor prognosis, killed more than 32,000 people in the United States last year. "We are constantly looking for ways to improve the prognosis of patients with cancers such as this," says Robert Miller, M.D., co-primary investigator and a radiation oncologist at Mayo Clinic. "Our findings show that surgery should be complemented by both radiation and chemotherapy for best results." In the study, the team of surgeons, oncologists and radiation oncologists from Mayo's Arizona and Minnesota campuses examined the records of 472 consecutively-treated patients. The patients all had surgery with negative margins (some healthy tissue cut out around the cancerous cells), between 1975 and 2005, to remove pancreatic adenocarcinomaterm. They excluded patients who had metastaticterm cancer, tumors that could not be removed or were not removed entirely (positive surgical margins), or indolent (slow growing) tumor types. Ultimately 454 patients were included in the final comparison of patients who received adjuvant therapyterm with those who had not. More than half (274) received concurrent radiation and chemotherapy following surgery and 50 percent survived two years, with 28 percent surviving at least five years. The researchers report more than one-third (180) received no additional therapy after surgery, and the comparative survival rates were significantly less, at 39 percent and 17 percent in two and five years, respectively. Additional chemotherapy after concurrent radiation and chemotherapy seemed to have an even greater effect on survival (61 percent and 34 percent survived two and five years), but only 28 patients received that combination, not enough for the researchers to draw a firm conclusion about its effectiveness. Drs. Miller and Corsini and their fellow researchers think these findings are important to clinicians worldwide. "While long-term outcomes with pancreatic cancer are generally poor," Dr. Corsini says, "our findings show that including both chemotherapy and radiation following surgery may significantly improve patient survival rates." Mayo currently uses a treatment strategy for most patients that includes a combination of radiation and chemotherapy after surgery.

 



11 comments | 4164 reads

by gdpawel on Sat, 2011-02-19 22:21
In this dawning era of molecular medicine, surgeons and pathologists are playing a more pivotal role in cancer medicine. They are the custodians of the specimens and therefore the molecules that represent the personalized part of personalized cancer medicine. Surgeons will continue to cure cancer with greater success rates through earlier detection and excision, but as the custodiams of the tissue, they will also be central to improving cancer management through molecularly targeted interventions.

Ann Surg Oncol. 2009 August; 16(8): 2079–2080.
Published online 2009 May 27. doi: 10.1245/s10434-009-0526-1. PMCID: PMC2711907

© Society of Surgical Oncology 2009

The Surgical Specimen Is the Personalized Part of Personalized Cancer Medicine

Carolyn C. Compton, MD, PhD

Office of Biorepositories and Biospecimen Research, National Cancer Institute, Bethesda, MD USA
Carolyn C. Compton, Email: [email]comptcar@mail.nih.gov[/email]

Received March 15, 2009

As a pathologist, I have been evaluating cancer resection specimens throughout my career and have come to have a deep appreciation of the challenges of surgical oncology. Happily for patients, surgeons cure cancer on a fairly regular basis by excising it with expert technique and detailed knowledge of human anatomy and tumor biology. The tissue resected by the surgeon and analyzed by the pathologist is the source of crucial information that, in turn, informs the decisions and actions of our medical oncology colleagues.

As cancer medicine looks forward to a new era of molecularly defined cancer subtypes and targeted therapies, however, the role of both surgeon and pathologist is evolving to require an ever greater degree of professional attention towards the surgical resection specimen. It is the surgically resected tissue that possesses the molecular information needed to define the specific molecular characteristics of the patient’s tumor, the specific therapies to which the tumor would be expected to respond, and even the specific risks of adverse reactions to given therapies predicted by the patient’s genetic make-up. This molecular information forms the basis of the “personalized” approaches envisioned for cancer patients in an age of molecular medicine. The professional responsibility to assure that the specimen’s molecular composition and integrity are safeguarded is shared by both the surgeon and the pathologist. Current momentum towards molecular medicine is rapidly elevating this professional responsibility to one of the most important aspects of cancer patient care.

Currently, however, safeguarding the molecular integrity or documenting surgical variables that impact the molecular composition of the resection specimen is not widely considered to be primary aspects of the surgeon’s professional responsibility. Manipulations of the tissue within the surgical procedure itself may have dramatic effects on the molecular make-up of that tissue. However, these manipulations are neither recorded nor controlled when and where possible. Variables such as anesthesia type and duration, drugs administered preoperatively and intraoperatively, and devascularization/ischemia time for the resected tissue may dramatically alter molecular profiles and/or molecular integrity. Once successfully resected, the specimen may spend varying amounts of time at room temperature in the surgical suite and/or holding unit before being delivered to Pathology, which may further alter the molecular composition and quality of the tissue.

Without the surgeon’s extension of professional responsibility to the resected tissue to control, when feasible, and track such variables, the advantages of personalized adjuvant approaches may be lost to the patient. In molecular medicine, the resected tissue becomes the major determinant of all downstream therapy. Therefore, the care of the specimen must be addressed co-equally with the care of the patient. This elevated bar for ensuring tissue integrity and molecular quality also must be addressed by pathologists. The fresh specimen will need to be overseen by the pathologist with the same immediacy and professional attention. More than ever, surgeons and pathologists will be required to work together closely to achieve the goal of meeting the new standards of “specimen care” required for molecular analysis.

Our knowledge about the affects of iatrogenic variables such as surgical manipulation, intraoperative drug delivery, and pathological handling on the molecular profiles that reflect the biology in resected tissues is growing rapidly.1–5 Postoperative tissue ischemia time, for example, has been shown to alter gene and protein expression profiles within minutes following surgical excision in colectomy specimens and prostatectomy specimens.1–3 Not surprisingly, even before resection has been completed, intraoperative manipulations have been shown to markedly alter gene transcription levels during radical prostatectomies.4 The effects of different peri- and intraoperative variables on molecular profiles in different types of tissues are just beginning to be understood, but it is clear that surgeons and pathologists alike contribute significantly to the final molecular composition and integrity of the resected tissue.5

Procedures that maximize specimen quality respect the fact that resected tissues are vital and biologically reactive. Until they are fixed or frozen, biospecimens are viable and capable of reacting to physiological stress. They are a living part of the patient from which they come and are responsive to changes in temperature, perfusion, oxygenation, and other physiological and biochemical variables, both pre- and intraoperatively as well as postoperatively. Typically, once a tumor is successfully resected, the surgeon’s attention turns to patient and relatively little is directed towards the specimen. Unless an intraoperative consultation such as a frozen section is requested and the specimen is immediately addressed for this purpose, it may sit unattended for varying periods of time before being prepared for delivery to the pathology laboratory. The conditions of delivery itself may vary, as may the immediacy of the specimen handling once it has arrived in the pathology laboratory. Furthermore, some of the newer surgical techniques, such as robotically assisted prostate resections, may further compromise the quality of the resection specimen if it is allowed to remain in the operative site at body temperature for significant amounts of time after devascularization.

In this emerging age of molecular medicine, a new level of awareness of and attention to “the state of the specimen” will be required by surgeons, operating room staff, pathologists, and pathology staff. All play essential roles in the series of events leading up to stabilization of the tissue that impact its molecular make-up and molecular integrity. Surgeons are the initiators and controllers of many of these events and therefore represent the “gatekeepers.” The powerful molecular analysis technologies now at our disposal and the increasingly sensitive and specific analysis platforms under development provide us with unprecedented abilities to define the molecular features of cells and tissues. However, they also pose new risks by providing us with the ability to derive the wrong answer with even greater speed and accuracy unless the analytes are of high quality and are derived from high-quality specimens. It is our joint professional responsibility to follow procedures that will ensure the quality of the biospecimen and to document the specimen handling history for the patient’s record.

In this dawning era of molecular medicine, where a hard-won understanding of the molecular details of cancer is leading to more powerful and accurate diagnostics and therapeutics, I foresee surgeons and pathologists playing a new and more pivotal role in cancer medicine. They are the custodians of the specimens and therefore the molecules that represent the personalized part of personalized medicine. Surgeons will continue to cure cancer with greater success rates through earlier detection and excision; but as the custodians of the tissue, they will also be central to improving cancer management through molecularly targeted interventions.

References

1. Spruessel A, Steimenn G, Jung M, Lee SA, Carr T, Fentz A-K, et al. Tissue ischemia time affects gene and protein expression patterns within minutes following surgical excision. BioTechniques. 2004;30:1030–7.

2. Dash A, Maine IP, Varambally S, Shen R, Chinnaiyan AM, Rubin MA. Changes in differential gene expression because of warm ischemia time of radical prostatectomy specimens. Am J Pathol. 2002;161:1743–8.

3. Lin DW, Coleman IM, Hawley S, Huang CY, Dumpit R, Gifford D, et al. Influence of surgical manipulation on prostate gene expression: implications for molecular correlates of treatment effects and disease prognosis. J Clin Oncol. 2006;23:3763–70.

4. Schlomm T, Näkel E, Lübke A, Buness A, Chun FK-H, Steuber T, et al. Marked gene transcript level alterations occur early during radical protatectomy. Eur Urol. 2008;53:333–46.

5. Signoretti S, Bratslavsky G, Waldman FM, Reuter VE, Haaga J, Merino M, et al. Tissue-based research in kidney cancer: current challenges and future directions. Clin Cancer Res. 2008;14:3699–705.

by gdpawel on Sat, 2011-02-19 22:22
As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis is needed matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.

Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden and the Annual Meeting of the American Assoication for Cancer Research (AACR) in San Diego, CA concluded that "functional profiling" with cell-based assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity) in primary cultures of "fresh" human tumors.

Cell-based Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.

Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.

There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell-based assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).

Funtional profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead.

For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.

The funtional profiling technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.

This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a pre-test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.

Literature Citation:

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

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