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Colonoscopy isn't perfect

gdpawel's picture
Posts: 532
Joined: May 2001

[Dr. Herman Kattlove is a retired medical oncologist. For the last seven years, before he retired, he was a medical editor for the American Cancer Society where he helped develop much of the information about specific cancers that is posted on the website at [url]www.cancer.org[/url]. He trained in hematology and oncology at Montefiore Hospital and Medical Center in New York and then spent 5 years as an assistant professor at UCLA.]

I think of this when I see our friend Sarah. About five years ago her husband died of colon cancer even though he had a “negative” colonoscopy two years before. Everyone blamed the poor doc who did the procedure, but it turns out that he might not have been at fault. Colonoscopy reduces the chance of dying from this cancer, but doesn’t entirely eliminate it.

I was reminded of this by a recent report in the Journal of Clinical Oncology. The study, done in Germany, found that the chances of developing colon cancer within ten years of a negative colonoscopy were about one-fourth to one-third that of people who didn’t have the procedure. That is good, but not great.

Another study, this time from Canada, (Annals of Internal Medicine, January, 2009) came up with similar results. Only this study looked at the risk of dying from colorectal cancer after having a negative colonoscopy, like my friend Sarah’s husband. Their numbers were similar to the German group. The risk of dying from colorectal cancer, if you had a negative colonoscopy, was one-third that of people who never had a colonoscopy. Still good, but not great. And, if by any chance, the cancer started in the right side of the colon, the part of the colon farthest from the rectum, colonoscopy did not lower the chance of dying from colorectal cancer. People with cancers developing in the right side of the colon were not helped. This was the case with Sarah’s husband.

This is confusing, but let me explain. The colon is a fairly long tube that runs up the left side of the abdominal cavity and then crosses over to the right side. Cancers that develop on the left side are easy to spot. The colonoscopy tube has no problem getting there and the cancers generally start as polyps, which stand up and are easy to spot. But cancers on the right side are a problem. They are hard to find because they tend to be flat and not stand up like polyps. Also, it is hard to get that part of the colon really clean so that the colonoscopist can see everything that is there. And finally, snaking the colonoscope up that far is challenging.

Whatever the reason, the doctor who examined Sarah’s husband’s colon may have done a good job. But, since the tumor was on the right side, the odds were stacked against him. The procedure isn’t that good for cancers on the right side of the colon and perhaps gives people a false sense of security so when they have symptoms they ignore them.

This doesn’t help Sarah, but at least her husband’s death was not due to negligence, but rather to bad luck. His cancer started on the wrong side.

A colonoscopy is NOT a definitive procedure for a malignant tumor. It IS a definitive procedure for a benign polyp. If there is a malignancy, they'll probably do a segmental resection (regular operation).

gdpawel's picture
Posts: 532
Joined: May 2001

The AngioRx microvascular viability assay a laboratory test which identifies anti-angiogenic drug activity in live tumor microclusters. The test is capable of discriminating anti-tumor effect from anti-angiogenic effect in the same mixed-cell population. It is the only known technology which discriminates the effects of different types of anti-angiogenic drugs within the same class of drugs and within different classes of drugs, and is capable of identifying synergistic effects among different angiogenic and non-angiogenic drugs in specific drug combinations.

Drugs are tested against fresh human tumor microclusters, with 96 hour drug exposures and multiple functional profiling endpoints (MTT, DISC, resazurin and/or ATP). Functional Profiling consists of a combination of a morphologic (structure) endpoint (DISC) and two or more metabolic (cell metabolism) endpoints (MTT, resazurin, ATP) at the cell "population" level. Additional drug concentrations for the targeted/angiogenic agents, some of which have very steep dose response relationships.

A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and Sutent. The microvascular viability assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens.

The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect. The morphologic endpoint information is gathered by examining the state of hundreds of individual cells. The metabolic endpoints measure the combined metabolism of all cells present in the culture (whole cell population profiling). CD31 cytoplasmic staining confirms morphological identification of microcapillary cells in a tumor microcluster.

The principles and methods used in the microvascular viability assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.

It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.

Photomicrographs of the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The assay measures the net effect of everything which goes on (Functional Tumor Cell Profiling methodology). Are the cells ultimately killed, or aren't they?

This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first. After all, cutting-edge techniques can often provide superior results over tried-and true methods that have been around for many years.

Bibliography relevant to AngioRx/Microvascular Viability (MVV) assay

1. Weisenthal, L. M. Patel,N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264: 275-287, 2008. doi: 10.1111/j.1365-2796.2008.01955.x

2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166.

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010.

5. Eur J Clin Invest, Volume 37 (suppl. 1):60, 2007

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

7. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

gdpawel's picture
Posts: 532
Joined: May 2001

There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel).

However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.

This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy.

The FDA does not have the legal authority to regulate the practice of the medicine and the physician may prescribe a drug off-label. Some drugs are used more frequently off-label than for their original, FDA-approved indications. Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs.

The FDA wants to alter rules for cancer drug cocktails. Rather than mixing and matching approved drugs, scientists want to develop combinations designed to work in tandem to block cancer. Some have suggested to use assays to identify a potential targeted population of ovarian cancer patients that it thinks will benefit from any of the above drugs, singularly or in combination.

One can't remember phase I-II trials of combinations of drugs which had not received prior FDA approval. Cocktails tha mix drugs still in development wouldn't have been possible just five years ago.

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

The application of synergy analyses may represent one of the most important applications of the functional profiling platform; enabling clinicians to explore both anticipated and unanticipated favorable interactions. Equally important may be the platform's capacity to study drug antagonism wherein two effective drugs counteract each others’ benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs because they can.

These analyses are revolutionizing the way cell-based functional profiling applies newer classes of drugs and has the potential to accelerate drug development and clinical therapeutics. Good outcomes require good drugs, but better outcomes require good combinations. Intelligent combinations are a principle focus of functional tumor cell profiling.

Cell-based functional profiling assay labs have always tested new drugs in combination with each other, simultaneously measuring direct antitumor activity and antivascular activity.

Cocktails have become standard treatment in many oncological protocols: concoctions of two or more powerful cytotoxic agents which supposedly will attack the tumor in different ways. The ability of various agents to kill tumor and/or microvascular cells (anti-angiogenesis) in the same tumor specimen is highly variable among the different agents. There are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.

Data show conclusively that patients benefit both in terms of response and survival from drugs and drug combinations found to be 'active' in functional profiling assays even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents, but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

Source: Weisenthal Cancer Group, Huntington Beach, CA and Departments of Clinical Pharmacology and Oncology, Uppsala University, Uppsala, Sweden. Current Status of Cell Culture Drug Resistance Testing May, 2002.

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