Bevacizumab In Colon Cancer – “A Shot Across The Bowel”

Colon2 130320.01 lo resAn E-Publication article in the February Journal of Clinical Oncology analyzes the cost efficacy of Bevacizumab for colon cancer. Bevacizumab, sold commercially as Avastin, has become a standard in the treatment of patients with advanced colorectal cancer. Indeed, Bevacizumab plus FOLFOX or FOLFIRI, are supported by NCCN guidelines and patients who receive one of these regimens are usually switched to the other at progression.

A Markov computer model explored the cost and efficacy of Bevacizumab in the first and second line setting using a well-established metric known as a Quality-Adjusted Life Year (QALY). In today’s dollars $100,000 per QALY is considered a threshold for utility of any treatment. To put this bluntly, the medical system values a year of yavastinour life at $100,000. The authors confirmed that Bevacizumab prolongs survival but that it does so at significantly increased costs. By their most optimistic projections, Bevacizumab + FOLFOX come in at more than $200,000 per QALY. Similar results were reported for Canadian, British and Japanese costs. Though more favorable, the results with FOLFIRI + Bevacizumab still came in above the $100,000 threshold.

No one doubts that Bevacizumab provides improved outcomes. It’s the incremental costs that remain an issue. Society is now confronting an era where the majority of new cancer agents come in at a cost in excess of $10,000 per month. Where and how will we draw the line that designates some treatments unaffordable? On the one hand, clinical therapies could be made available only to the “highest bidder.” However, this is contrary to the western societal ethic that holds that medical care should be available to all regardless of ability to pay. Alternatively, increasingly narrow definitions could be applied to new drugs making these treatments available to a shrinking minority of those who might actually benefit; a form of “evidence-based” rationing. A much more appealing option would be to apply validated drug predication assays for the intelligent selection of treatment candidates.
In support of the latter, the authors state, “Bevacizumab potentially could be improved with the use of an effective biomarker to select patients most likely to benefit.” This is something that genomic (DNA) profiling has long sought to achieve but, so far, has been unable to do. This conceptual approach however is demonstrably more attractive in that all patients have equal access, futile care is avoided and the costs saved would immediately provide highly favorable QALY’s as the percentage of responders improved.

Similar to the recent reports from the National Health Service of England, the American public now confronts the challenge of meeting the needs of a growing population of cancer patients at ever-higher costs. It is only a matter of time before these same metrics described for colon cancer are applied to lung, ovarian and other cancers for which Avastin is currently approved.

At what point will the American medical system recognize the need for validated predictive platforms, like EVA-PCD analyses, that have the proven capacity to save both money and lives? We can only wonder.

Truly Personalized Cancer Care

In the mid 1980s, it became apparent to me that cancer did not result from uncontrolled cell proliferation, but instead from the lack of cell death. Yet, cancer research labored for almost a century under the erroneous belief that cancer represented dysregulation of cell proliferation. Today, we confront another falsehood: the complexities and redundancies of human tumor biology can be easily characterized based on genomic analyses.

The process of carcinogenesis reflects the accumulation of cellular changes that provide a selective survival advantage to transformed cells.  However, the intricate circuitry that provide these survival advantages, reflect harmonic osolations between DNA, RNA and protein. Put simply, Genotype does not equal Phenotype. It is the phenotype that determines biological behavior and clinical response in cancer. Thus, it is overly simplistic to imagine that a DNA profile by itself can provide more than a fraction of the information required to make individual patient treatment decisions.

Colon cancer

Colon cancer

When therapies are based on genomic analysis, only a portion of the patient’s profile is taken into consideration. These analyses disregard the environmental, epigenetic and proteomic factors that make each of us individuals. Though useful prognostically and applicable in select circumstances where a unique genetic perturbation leads to a clinical response (c-ABL and Imatinib response in CML), genomic analyses provide only a veneer of information.

The Rational Therapeutics Ex Vivo Analysis – Programmed Cell Death™ (EVA-PCD) assay focuses upon the complexity of human tumors by measuring cell death, the end result of all cellular mechanisms of response and resistance acting in concert. By incorporating cell-cell, vascular, stromal and inflammatory elements into the tumor response assessment, the EVA-PCD platform provides a robust surrogate for human tumor response. While much of modern cancer research pursues the question of “Why” cancer arises, the clinical oncologist must confront the more practical question of “How” the best outcome can be achieved.

Assay-directed therapy is truly personalized cancer care providing treatments unique to the individual.


Reblogged from February 2010.

Best Chance for Colon Cancer Survival – Don’t Let It Start

Two papers in the February 23, 2012, New England Journal of Medicine reported important findings in the fight against colon cancer. The first paper (Zuber, AG et al; Colonoscopic Polypectomy and Long-Term Prevention of Colorectal Cancer Deaths) conducted by American investigators establishes the benefit of polyp removal in the prevention of death from colorectal cancer. The study conducted upon 2,602 patients who had adenomas removed reveals a 53 percent reduction in mortality from colon cancer compared with the expected death rate from the disease in this population.

To put this into perspective – virtually no intervention in the advanced disease setting provides a survival advantage. The best we can usually do once the disease is established is an improvement in time to progression. When we do observe a true survival advantage it is usually in the range of a few percentage points and never of this magnitude. How might we explain this astonishingly positive result?

One way to view this finding is to reexamine the biology of cancer. One of the leading experts in the field, Bert Vogelstein, MD, from Johns Hopkins, explained colon carcinogenesis as a pattern of gene perturbations starting at atypia, progressing to carcinoma in situ and ending with invasive, metastatic disease. According to Dr. Vogelstein, the average colon cancer found in a patient at the time of colonoscopy has been present in that person’s colon for 27 years. From there it is only a hop, skip and a jump from one-centimeter adenomatous polyp to metastatic (lethal) disease, all playing out over the last three years in the natural history of the disease. Thus, cancer truly is a disease that doesn’t grow too much, but dies too little and interrupting this process while it is still slumbering can, it would seem, lead to cures.

What I find surprising is the success of the strategy. Since it is now well established that cancer can metastasize when it has achieved the rather diminutive proportions of 0.125 cubic centimeters or less and the average polyp can only be detected at one or more cubic centimeters, it is our good fortune that so many cancers chose not to (or could not) metastasize prior to detection. Reading between the lines, those 12 patients who died of colon cancer as opposed to the expected 25.4 are presumably those with early metastasizing disease. The next frontier will be the detection of these cancers when they are teenagers and not 20-somethings. It may be that proteomic analyses will provide an avenue for earlier detection in the future.

The second article is a European study (Quintero, E et al; Colonoscopy versus Fecal Immunohistochemical Testing in Colorectal-Cancer Screening) that compared colonoscopy with fecal blood testing in a large cohort of patients. While the rates of detection for colorectal cancer were similar, the rates of detecting both advanced and early adenomas, favored colonoscopy (p < .001). This study represents an interesting adjunct to the American study described above. Specifically, if the early detection (and removal) of adenomas can confer a survival advantage then it could be argued that colonoscopy by its virtue of it’s higher detection rate of these precancerous adenomas, is the preferred “screening” modality. With over 50,000 deaths attributed to colorectal cancer in the U.S. each year, the public health benefit of colonoscopies becomes an intersecting point of discussion. Until now, fecal occult blood testing yearly or sigmoidoscopies every several years has been considered equivalent to colonoscopies every 10 years starting at age 50. Do we need to move colonoscopies to the front of the line?

What is most interesting about both these reports is the low-tech nature of the study modalities – and the astonishing efficacy of their application. Colonoscopies have been conducted for decades. They are comparatively simple, do not require affymetrix chips, and yet provide demonstrable benefit that appears to exceed anything offered, to date, by the “genomic revolution.” Perhaps we should all keep an open mind about other comparatively low-tech methodologies that can provide survival advantages.

Vitamin D and Cancer

A report issued earlier this year (available on Medscape once you register) on Vitamin D levels in breast cancer, identified low levels of this nutritional factor as a risk for breast cancer. Dr. Kristin Skinner reported at the American Association of Breast Surgeons, that the most aggressive forms of breast cancer (i.e. ER negative, triple negative or basal-like) were associated with lower blood levels of vitamin D.

This is one of many reports associating vitamin D levels with disease. Indeed, so many reports on this topic have been published that vitamin D consumption in the U.S. has exploded. While some physicians have made careers promoting the concept, the science of vitamin D is indeed credible and very interesting.

What is vitamin D? Well, although we refer to it as a vitamin, it is, in fact, a hormone. It is obtained from the diet or from exposure to sun. The most potent form of vitamin D is that associated with sunlight exposure. Once in the body, vitamin D interacts with cells at very specific receptors. The term receptor reflects the role of these “landing sites” contained within the cell’s nucleus. As the vitamin D molecule traverses the cell membrane and enters the cell nucleus, it binds with the vitamin D receptor, which connects to the chromosome at a hormone response element and drives the cell machinery forward.

The vitamin D receptor is part of a large collection of genes called the steroid super gene family. These include receptors for estrogen, progesterone, testosterone, and, yes, vitamin D.

What makes the field so interesting is the interaction between these factors. Inside the nucleus are a large variety of receptors. Vitamin D and the other molecules are known as ligands. When the ligands enter the nucleus, they must compete for receptors. This leads to a complicated collection of down-stream events that are unique to the individual. If, for example, your nucleus has a number of orphan receptors (receptors with unclear ligand associations) and these orphan receptors have some binding affinity for the vitamin D, then the down-stream signaling will reflect this new biology.

Many studies have associated vitamin D levels with disease. Prostate cancer, colon cancer, even blood-born tumors may, in part, arise in vitamin D deficient states. But, the most compelling evidence in several analyses supports its protective effect against colon cancer. In one study there was a 15 percent risk reduction for every 10 ug/ml increase in circulating blood levels of calciferol (Gandini S, Int J Cancer. March 11, 2011). What is interesting about the report from the University of Rochester is that it was the most aggressive forms of breast cancer that were found to be associated with Vitamin D deficiency. To date, the correlations with the more common forms of breast cancer have been less positive.

Cardiovascular disease and musculoskeletal diseases are also associated with vitamin D levels. So critical is vitamin D to the well-being of the human that mankind could not easily migrate far north from the equator until he found a source of vitamin D unrelated to the skin synthesis. This source proved to be fish and animals that survived by eating fish. Older readers will remember cod liver oil as a remedy doled out by grandparents. It is ironic that cod liver oil is an excellent source of vitamin D.

While deficiencies of vitamin D are likely to be deleterious, substantially exceeding the normal levels of 30 micrograms/ml have not been shown to further enhance health. It is prudent for patients to monitor their vitamin D levels and highly appropriate for physicians to recommend replacement. Interestingly, a scientific colleague recently commented that sun exposure, by providing active vitamin D, is greatly under appreciated as a healthful activity. He wondered whether the broad use of sunscreens would ultimately save or cost more lives when the aggregate impact of vitamin D levels upon cancer and health is finally understood.

An Ounce of Prevention

Colorectal cancer is among the leading causes of cancer death in the United States. While most patients develop this disease over a period of decades, associated with an accumulation of genetic mutations (elegantly described by Burt Vogelstein, PhD at Johns Hopkins), a small percentage of patients have a genetic predisposition for this cancer. Among these are those people that carry the familial adenomatous polyp syndrome (FAPS) and those who carry mismatch repair mutations know as Lynch syndrome.

It is the latter group who are the subject of a report in the October issue of the English journal Lancet. In this study, known as the CAPP2 trial, patients with Lynch syndrome received either placebo or 600mg of aspirin per day (the equivalent of two tablets). The results reveal a statistically significant reduction of colon cancer that clearly favored the aspirin group.

To put this in perspective, this dramatic improvement in the highest risk population didn’t come about as the result of a new signal transduction inhibitor or a monoclonal antibody. Instead, it came from the simple administration of one of mankind’s earliest medicinal substances. I applaud these English investigators in conducting this study of 861 patients.

What is most laudatory is that the intervention, while highly effective, is so inexpensive. In an era of proprietary medications and the promotion of expensive new interventions, it is indeed refreshing to read the results of a well-conducted study using an intervention available to all.

Data generated more than two decades ago established the benefit of non-steroidal anti-inflammatory drugs like aspirin for the prevention of colorectal cancer. It is gratifying that this simple intervention has additional scientific support both for those with high-risk predisposition, as well as other patients at risk for this relatively common, yet potentially lethal, malignancy.

What’s the Best Treatment for Metastatic Colorectal Cancer?

The answer is: nobody knows.

We have previously described a patient with a small bowel cancer for whom a treatment regimen contrary to the most widely used triplet was recommended. While it is arguable that small bowel adenocarcinoma is rare enough that no one really has a favorite regimen, colorectal management has become somewhat rigidly focused on FOLFOX. Yet, this popular combination may not be right for every patient with colon cancer.

We know, for example, that FOLFOX combined with Avastin provided no advantage in the adjuvant setting. We also know that the random addition of Erbitux to FOLFOX similarly failed to provide an advantage. As the modes of action differ between drugs, it is not surprising that subsets of colon cancer patients may do better with Irinotecan based therapies. Indeed, clinical trials combining the new monoclonal antibodies with Irinotecan have proven quite favorable, including the 2007 BOND-2 trial reported by investigators at Memorial Sloan Kettering in New York.

With this in mind, patients who present with both untreated colon cancer and a favorable profile for Irinotecan based combinations always interest us. One such patient presented to our attention in the last few weeks. This patient, in his mid 30s, was found to have inoperable, widely metastatic disease with extensive liver involvement. Confirmatory biopsies provided tissue for analysis and revealed no evidence of mismatch repair.

The results of the EVA-PCD platform were interesting on many levels. First, the EGFr active drugs provided a uniquely favorable profile, as did the down-stream inhibition of the MEK-ERK inhibitor we studied. These findings strongly suggested that the patient was RAS wild type (i.e. non-mutated). It is known that RAS mutation confers resistance to the EGFr active drugs. By inference, his sensitivity to the EGFr active drugs was prima facie evidence of RAS wild type, a finding that was confirmed later by molecular analysis. There was also a favorable profile for VEGF active drugs. Most favorable of all was the combination of Irinotecan with inhibitors of both VEGF and EGFr. This was the regimen that we selected.

We wait with interest the results of the therapy, as re-staging for response will be conducted in the coming months.

Why do People get Cancer?

While there are a lot of reasons why people develop cancer, there is a growing recognition that a subset of patients carries genetic predispositions for the disease. Some of these genetic syndromes result in childhood cancers like the retinoblastoma gene or mutations in P53. These abnormalities are so profound that virtually all patients develop aggressive cancers at an early age. However, there is a second group of genetically driven cancers that are being encountered in young and middle aged adult patients. One of the best described is the ovarian/breast cancer syndrome associated with the BRCA 1 and 2 genes. Another group of patients carry a DNA repair deficiency known as mismatch repair or Lynch Syndrome.

Not unlike the BRCA patients, people with mismatch repair have an inability to respond to DNA damage. This failure leads to mutational events that, over the course of a lifetime, can result in cancer. We now know that the BRCA genes may provide therapeutic opportunities as the new class of drugs known as PARP inhibitors can target them. What we are now learning is that the Lynch Syndrome patients may have a similar attribute that can, in some circumstances, render them “hypersensitive” to chemotherapeutics. One such patient has been under my care for the last two years.

This charming 43-year-old patient presented with cancer of the uterus. She was managed by a gynecologic oncology service and received a combination of surgery, radiation and chemotherapy. One year later, she revealed recurrent disease in the right, lower abdomen with involvement in the liver. Impending bowel obstruction lead to surgical exploration, providing my laboratory with tissue for analysis. When I first received the tissue specimen, I was expecting recurrent uterine cancer, the same diagnosis for which she had been treated the year earlier. But, to my surprise, the patient was actually diagnosed with colon cancer. This triggered an analysis of her mismatch repair gene and provided confirmation of Lynch Syndrome.

What I found amazing was that this patient’s colon cancer was sensitive to a two-drug combination that I had never in my career administered for colon cancer. Indeed, in my published work I had consistently identified colon cancer as a bad target for this doublet. Yet, this patient’s tumor was unequivocally sensitive to the combination. Her response was as prompt as it was dramatic — a complete remission within a scant few months. And then, in follow up, her PET/CT revealed a small focus of abnormality, seemingly associated with the colon. With a negative colonoscopy, we waited an additional several months and repeated the study. This time, it was even more evident; there was clearly an abnormality in the left pelvis.

A biopsy provided an unexpected finding. It was cancer, but it wasn’t colon cancer. The patient’s original uterine cancer from two years earlier had recurred, most likely as a residual vestige of tumor from an incomplete resection two years before. The drug response profile was distinctly different, but highly consistent with a profile one might find in a patient with mismatch repair. As we prepared to treat the patient, she developed gastrointestinal bleeding, a workup for which confirmed erosion by the uterine cancer into the bowel wall. We decided to use our findings to treat the patient and initiated a three-drug combination. The patient’s tolerance was excellent and gastrointestinal bleeding stopped immediately.

She is now receiving additional courses of therapy and will be evaluated for response in the coming months. While it is too early to know how well she’ll respond, we are optimistic regarding her outcome. Among the most interesting feature of this and related cases is the fact that the genetic mutation that caused her cancer may be the same genetic mutation that makes it possible for us to treat her.

Is Metastatic Colon Cancer Curable?

Following the introduction of 5FU in 1958, response rates for metastatic colon cancer remained in the range of 12-14 percent. After several decades, the addition of Leucovorin to 5FU improved these response rates to 20 percent. Optimal infusion schedules further enhanced responses providing objective benefits in 20-30 percent of patients. Subsequent to the introduction of Irinotecan and later Oxaliplatin, colon cancer response rates are now observed in 40-50 percent of patients — even higher in some series.

This has spawned a new interest in post-chemotherapy surgical cytoreduction. Under these circumstances, patients who present with Stage 4 disease (most often metastatic to liver) undergo aggressive combination therapy — usually Folfox-based. Those achieving substantial response (complete or partial) are then considered for partial hepatectomy to reduce residual tumor burden. In a series of trials conducted by large institutions like MD Anderson, a subset of patients is now achieving durable complete remissions using this multi-modality approach.

One example of this approach represents a novel opportunity to explore the biology of this disease.

Case Report
A 44-year-old previously healthy male presents with T3, N2, M1 colon cancer with multiple positive lymph nodes and a liver metastases. Despite the primacy of Folfox-based therapies in this setting, functional profiling of his tumor revealed superior activity for the dual modulation of Irinotecan activity with Erbitux and Avastin After several cycles of therapy, all disease had disappeared with the exception of a small residual focus in the liver.

The patient underwent a partial hepatectomy and tissue removed at the time of surgery was re-examined in the laboratory. The Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) functional profile results had completely changed, now favoring Folfox over Irinotecan-based therapy. Following surgical recovery, the patient was provided post-operative adjuvant Folfox.

Today, more than two years since diagnosis, all biochemical and radiographic restaging reveals no evidence of disease. While the patient will require continued surveillance, he represents a genuine advance in the management of this disease and may escape recurrence. This allows him to continue a normal life, despite a diagnosis that a decade earlier would have been considered a death sentence. Cases like this will ultimately enable us to answer the question: Is metastatic colon cancer curable?