Optimal combination therapy for advanced colorectal cancer

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Optimal combination therapy for advanced colorectal cancer: An examination of synergy and antagonism with EGFR inhibition.

Sub-category: Colorectal Cancer

Category: Gastrointestinal (Colorectal) Cancer

Meeting: 2012 ASCO Annual Meeting

Abstract No: e14075

Citation: J Clin Oncol 30, 2012 (suppl; abstr e14075)

Author(s): Nilesh Vora, Steven Evans, Paula J Bernard, Federico Francisco, Robert Alan Nagourney; Todd Cancer Institute, Long Beach, CA; Rational Therapeutics, Long Beach, CA

Abstract:

Background: While FOLFOX +/- Bevacizumab is the most widely used combination in colorectal cancer (CRC), the EGFr antagonists Cetuximab & Panitumumab have not further enhanced activity. On the contrary, the addition of EGFR inhibitors to Irinotecan-based regimens at 1st & 2nd line has improved response and both progression freel & overall survival (Van Cutsem. 2010; Peeters. 2010.)

Methods: We applied the ex vivo analysis of programmed cell death (EVA-PCD) (Nagourney, Curr Treat Opt Onc 2006) to examine interactions between EGFr antagonists and Irinotecan or FOLFOX in 534 human tumor primary culture microspheroids isolated from CRC surgical specimens or cytologically (+) fluids. Gefitinib was used as a surrogate for Cetuxima/Panitumumab activity. Tissue samples exposed to Oxaliplatin, 5FU, Irinotecan, and Oxaliplatin & 5FU (FOLFOX) provided dose response curves with and without Gefitinib for formal synergy analysis by median effect (Chou & Talalay).

Results: Shown in table below.

Conclusions: Results indicate superiority for Irinotecan combination with the EGFr antagonist Gefitinib. The percentage of synergistic interactions for Irinotecan & Gefitinib (41%) is demonstrably higher than that associated with FOLFOX & Gefitinib (4%). This suggests distinct modes of interaction between these classes of agents favoring Irinotecan and could have an impact upon future clinical trial designs. Recognizing the importance of Kras mutation, additional studies are underway to examine the impact of Kras mutation upon synergy. However, as wild-type and mutant samples would be expected to be equally distributed, subset analyses may reveal quantitative (higher % synergy) rather than qualitative differences (relative activity of Irinotecan vs FOLFOX). Results of these analyses will be reported. Supported in part by the Vanguard Cancer Foundation.

5FU & oxaliplatin: N=383 Synergy (%)=22% Antagonism (%)=19% Ratio=1.2

5FU & irinotecan: N=319 Synergy (%)=22% Antagonism (%)=25% Ratio=0.9

5FU & gefitinib: N=32 Synergy (%)=20% Antagonism (%)=33% Ratio=0.6

Oxaliplatin & gefitinib: N=6 Synergy (%)=0% Antagonism (%)=0% Ratio=0.0

Irinotecan & gefitinib: N=179 Synergy (%)=41% Antagonism (%)=12% Ratio=3.4

5FU & oxaliplatin & gefitinib: N=375 Synergy (%)=4% Antagonism (%)=39% Ratio=0.1

[url]http://abstract.asco.org/AbstView_114_97181.html

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The types of treatments recommended will depend on the stage of your cancer. The three primary treatment options are: Surgery, radiation and chemotherapy.

If your cancer is caught at an early stage it is probably confined to the polyp. In this case, your doctor may be able to remove it completely during a colonoscopy. If the pathology report confirms that the cancer didn’t extend into the base of the polyp (where it attaches to the bowel wall) the likelihood of cure is very good following surgery.

Larger polyps and invasive cancers might also require chemotherapeutic intervention. Currently, common treatment strategies are based upon standard chemotherapy protocols. For colorectal cancer patients the most widely used drugs are flourouracil (5-FU) plus leucovorin (FU/LV) and the closely related capecitabine. The addition of irinotecan and oxaliplatin can often demonstrably improve the effect of 5-FU based therapy and capecitabine. Monoclonal antibodies like Erbitux, Vectibix and Avastin are also often used in combination with chemotherapy.

Standard protocols are developed following lengthy and expensive Phase II and Phase III clinical trials. After so much time and money has been dedicated to this research, many patients (and physicians) believe that the recommended protocols are the best treatment. However, according to a published report, only 1 of 14 clinical trials improves survival by 50 percent or more (1). This is often days, sometimes weeks, rarely months and never years.

In a published review of more than 500 clinical experiences (2), cell death assays such as those offered by Rational Therapeutics, Inc. and Weisenthal Cancer Group, have shown a sensitivity of 94 percent, and a specificity of 71 percent. This means that drugs selected based on your assay results are more likely to provide a clinical response.

They understand that the same drugs that work for one patient may not work for another, even for those with the same diagnosis. To find the most effective treatment for you, living tumor cells are collected during biopsy or surgery. The scientists at Rational Therapeutics and Weisenthal Cancer Group perform the functional cytometric profiling platform on the cells, testing as many as 16 drugs and/or combinations of drugs to determine which is best to treat your cancer.

They recommend treatment regimens based upon the observed patterns of cell death in your cancer cells following exposure to drugs in the laboratory. As a colorectal cancer patient, you may be responsive to several different drugs or combinations. Selecting the most effective, least toxic drug regimen may offer an advantage to you as you confront this disease.

1. Djulbegovic A, et al. What is the probability that new cancer treatments are better than standard treatments? Proc ASCO, Abs. #6120, 2006.

2. Fruehauf JP, Bosanquet AG, Principles & Practices of Oncology, PPO Updates Vol 7, Dec 1993, Num 12.

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Just identifying molecular predisposing mechanisms still does not guarantee that a drug will be effective for an individual patient. Nor can it, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

The challenge is to identify which patients targeted treatment will be most effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone.

Molecular testing methods detect the presence or absence of selected gene or protein mutations which theoretically correlate with single agent drug activity. Cells are never exposed to anti-cancer agents.

What is needed is to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells (not cell lines) actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism?

Functional profiling assess the net effect of all inter-cellular and intra-cellular processes occurring in real time when cells are exposed to anti-cancer agents (targeted or conventional). Tests are performed using intact, living cancer cells plated in 3D microclusters. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

The core understanding is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any of these pathways, it is important to examine the effects of drug combinations within the context of the cell.

Both genomics and proteomics can identify potential therapeutic targets, but these targets require the determination of cellular endpoints. You still need to measure the net effect of all processes, not just the individual molecular targets.

Cell Function Analysis

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Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

I was consulted by a young man regarding the management of his heavily pre-treated, widely metastatic rectal carcinoma. Upon review of his records, it was evident that under the care of both community and academic oncologists he had already received most of the active drugs for his diagnosis. Although his liver involvement could easily provide tissue for analysis, I discouraged his pursuit of an assay. Despite this, he and his wife continued to pursue the option.

As I sat across from the patient, with his complicated treatment history in hand, I was forced to admit that he looked the picture of health. Wearing a pork pie hat rakishly tilted over his forehead, I could see few outward signs of the disease that ravaged his body. After a lengthy give and take, I offered to submit his CT scans to our gastrointestinal surgeon for his opinion on the ease with which a biopsy could be obtained. I then dropped a note to the patient’s local oncologist, an accomplished physician who I respected and admired for his practicality and patient advocacy.

A week later, I received a call from the patient’s physician. Though cordial, he was puzzled by my willingness to pursue a biopsy on this heavily treated individual. I explained to him that I was actually not highly motivated to pursue this biopsy, but instead had responded to the patient’s urging me to consider the option. I agreed with the physician that the conventional therapy options were limited but noted that several available drugs might yet have a role in his management including signal transduction inhibitors.

I further explained that some patients develop a process of collateral sensitivity, whereby resistance to one class of drugs (platins, for example) can enhance the efficacy of other class of drugs (such as, antimetabolite) Furthermore, patients may fail a drug, then be treated with several other classes of agents, only then a year of two later, manifest sensitivity to the original drug.

Our conversation then took a surprising turn. First, he told me of his attendance at a dinner meeting, some 25 years earlier, where Dan Von Hoff, MD, had described his experiences with the clonogenic assay. He went on to tell me how that technique had been proven unsuccessful finding a very limited role in the elimination of “inactive” drugs with no capacity to identify “active “drugs. He finished by explaining that these shortcomings were the reason why our studies would be unlikely to provide useful information.

I found myself grasping for a handle on the moment. Here was a colleague, and collaborator, who had heard me speak on the topic a dozen times. I had personally intervened and identified active treatments for several of his patients, treatments that he would have never considered without me. He had invited me to speak at his medical center and spoke glowingly of my skills. And yet, he had no real understanding of what I do. It made me pause and wonder whether the patients and physicians with whom I interact on a daily basis understand the principles of our work. For clarity, in particular for those who may be new to my work, I provide a brief overview.

1. Cancer patients are highly individual in their response to chemotherapies. This is why each patient must be tested to select the most effective drug regimen.

2. Today we realize that cancer doesn’t grow too much it dies too little. This is why older growth-based assays didn’t work and why cell-death-based assays do.

3. Cancer must be tested in their native state with the stromal, vascular and inflammatory elements intact. This is why we use microspheroids isolated directly from patients and do not grow or subculture our specimens.

4. Predictions of response are not based on arbitrary drug concentrations but instead reflect the careful calibration of in vitro findings against patient outcomes – the all-important clinical database.

5. We do not conduct drug resistance assays. We conduct drug sensitivity assays. These drug sensitivity assays have been shown statistically significantly to correlate with response, time to progression and survival.

6. We do not conduct genomic analyses for there are no genomic platforms available today that are capable of reproducing the complexity, cross-talk, redundancy or promiscuity of human tumor biology.

7. Tumors manifest plasticity that requires iterative studies. Large biopsies and sometimes multiple biopsies must be done to construct effective treatment programs.

8. With chemotherapy, very often more is not better.

9. New drugs are not always better drugs.

10. And finally, cancer drugs do not know what diseases they were invented for.

While we could continue to enumerate the principles that guide our practice, one of the more important principles is humility. Medicine is a humbling experience and cancer medicine even more so. Patients often know more than their doctors give them credit for. Failing to incorporate a patient’s input, experience and wishes into the treatment programs that we design, limits our capacity to provide them the best outcome.

With regard to my colleague who seemed so utterly unfamiliar with these concepts, indeed for a large swath of the oncologic community as a whole, I am reminded of the saying “There’s none so blind as those who will not see.”

Assay Results and Bayes' Theorem

[url]http://cancerfocus.org/forum/showthread.php?t=3754

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The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells.

Endothelial cells line the entire circulatory system, from the heart to the smallest capillary. These cells reduce turbulence of the flow of blood, allowing the fluid to be pumped farther.

Endothelial tissue is a specialized type of mesenchymal tissue, and not an epithelial tissue. Mesenchymal cells do not bind to each other, forming more disorganized tissues in which the cells move around. Both blood and lymphatic capillaries are composed of a single layer of endothelial cells called a monolayer.

Blood samples for assay-testing are good for ALL, ANLL, CLL, CML Blast Crisis, Non-Hodgkin's Lymphoma (leukemic phase only) Plasma Cell Leukemia, and Hairy Cell Leukemia. Hematologic neoplasms (leukemia, lymphoma and myeloma) are single cell, discohesive neoplasms which can not be tested in monolayers, because the cells don't attach to the culture dish. They are tested in suspension (floating cell) culture.

There is a problem with "growing" or "manipulating" tumor cells in any way. When looking for cell-death-related events, which mirror the effect of drugs on living tumors, cells are generally not "grown" or "amplified" in any way. The object is occurrence of programmed cell death in cells that come into contact with therapeutic agents.

Labs that perform chemo sensitivity without a surgical specimen usually proliferate (grow) cancer cells from a smaller sample obtained by a blood or needle biopsy and subject those cells to chemo. Because they test on subcultured cells (as opposed to 'fresh' tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cells grown in the lab will not behave the same way as the actual cancer cells do in your body's own environment.

[url]http://cancerfocus.org/forum/showthread.php?t=3566

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Susan Jenks

Imagine taking a snapshot of a tumor in action as it overwhelms healthy cells to survive—and then using that information in the clinic to monitor which drugs best kill cancer cells. In vitro chemosensitivity assays promise to do that, using proprietary screening tests for clues about each individual’s cancer.

But more than two decades after these assays debuted, oncologists remain divided: those who support such laboratory analyses and those who maintain that they unduly raise patients’ hopes, often at considerable expense, while not improving survival. “Predicting what doesn’t work [as opposed to what will] is not seen by most as an advance,” said Jeffrey Abrams, M.D., associate director of the National Cancer Institute’s Cancer Therapy and Evaluation Program.

Last year, the American Society of Clinical Oncology (ASCO) performed a literature review of data published between December 1, 2003, and May 31, 2010, on chemosensitivity testing. ASCO concluded, as it had in 2004, that this “in vitro analytic strategy has potential importance” but should be confined to patients participating in clinical trials. The National Cancer Comprehensive Network holds a similar view.

“In vitro testing is an old oncologist’s dream,” said Alain Hendlisz, M.D., chief of gastroenterology in the medical oncology clinic at the Jules Bordet Institute in Brussels, where researchers are using metabolic imaging to evaluate colorectal cancer treatments after an initial round of therapy.

“In an ideal world, we should know what will be the effect of a treatment before its very beginning. That’s the purpose of in vitro testing, and that’s the philosophical reason why people are attracted by tests with a high positive predictive value,” Hendlisz wrote in an e-mail. “However, that’s a philosophical point of view, not a scientific one.”

Still, in certain circumstances, where no standard of care exists, chemosensitivity testing may be useful to determine how best to treat some patients, according to Robert Holloway, M.D., co–medical director of Florida Hospital’s gynecologic oncology program in Orlando. Holloway routinely recommends such tests for his ovarian cancer patients, at a cost of $3,500–$4,000.

Although insurance coverage tends to be spotty, Medicare does cover the cost for ovarian cancers, because these tumors account for most of chemosensitivity testing’s use today, Holloway said.

His decision to use the assays is based on “strong retrospective data” in at least two recent studies in ovarian cancers, including one by Julian Schink, M.D., and Larry J. Copeland, M.D., of the Comprehensive Cancer Center of Northwestern University, showing that chemosensitivity assay testing closely predicted patients’ responses and "accurately predicted progression-free and overall survival.” The study was published in the September 2011 Journal of the National Comprehensive Cancer Network.

Also, the development in recent years of several drugs for ovarian cancer, which has a high recurrence rate, makes selecting the right drug problematic for clinicians and the field ripe for this type of testing, Holloway said.

“Through chemosensitivity testing, we try to narrow down the selection,” he said. “Our feeling is it can’t be any worse than random selection, and there is logic behind it. I would caution, however, it’s not something that makes an absolute decision for you. You still weigh toxicities and other risks, such as how readily accessible the tissue is, but it provides another piece of information.”

Laura Shawver, Ph.D., an ovarian cancer survivor and founder of a nonprofit for ovarian cancer patients called the Clearity Foundation in San Diego, takes a nuanced view of chemosensitivity’s clinical value for ovarian and other cancers. Her main concern: the lack of standardization in these tests.

“Unfortunately, with chemosensitivity testing, it’s not done in a standardized format,” she said. “Some labs use apoptosis, some use cell growth, and still others use 3-D assays where they grow cells in clusters so the assay more closely resembles a tumor.” Even how a tumor is removed from the body can adversely affect the reliability of an assay’s results, she added.

Shawver favors genomic analysis, and her nonprofit helps women diagnosed with ovarian cancer gain access to molecular profiling to find the best treatment options at recurrence. She views genomics as potentially “a way to supplement or even replace chemotherapy” someday and a technique far better poised to capture tumors’ heterogeneity than chemosensitivity testing.

“People need to realize tumors change over time; they are highly mutable," she said. "There's heterogeneity at diagnosis, so chemosensitivity testing will test a portion of those tumor cells only, and not wipe them all out."

But whenever chemosensitivity assays are available (Shawver does not recommend them), she does compare their results with molecular profiling. “We should think of these assays as a way of prioritizing drugs, not as a yes or no,” she said.

David Alberts, M.D., an Arizona Board of Regents professor and director of the University of Arizona Cancer Center, takes an equally pragmatic view, suggesting a limited role for chemosensitivity testing, at least in patients with uncommon tumors, where no "gold standard" of treatment exists. In such cases, he said, "I want as much information as I can get."

And though he concedes a lack of clinical data, Alberts also sees a similar lack of “adequate clinical testing” of genomic assays. “These tests don’t tell you what proteins are expressed . . . or about drug interactions during treatment.”

In several cases where patients received dire diagnoses, Alberts sent their tumor samples for functional/chemosensitivity testing and to an international genomics center in Tucson for expression profiling. The two assays yielded similar results and helped guide the patients' successful treatments. "There's no question from my point of view that there's a national need for randomized well-designed clinical studies, comparing all these assays," Alberts said.

Jonathan Lancaster, M.D., Ph.D., chairman of the department of women’s oncology at Moffitt Cancer Center in Tampa, Fla., agreed. But with the expense and the difficult risk–reward balance of proving that an assay works, he said, such studies will probably not be conducted anytime soon. At Moffitt, he said, oncologists rarely use chemosensitivity testing, except when patients’ cancers prove so intractable that, like Alberts, “we feel as if we’re stumbling in the dark.”

Over the years, chemosensitivity tests have become more refined, evolving from detecting only drug resistance to more sophisticated biomarkers that yield better information about a tumor’s biology, Lancaster said. But in his view, two fundamental questions remain: (1) the science of prediction, or whether a bio- marker predicts what it’s supposed to predict, and (2) what happens to a patient when you use the information gleaned from these tests.

No studies have shown that chemosensitivity testing improves overall survival. The 2011 literature review by ASCO’s working group found that of 11,313 new articles on chemosensitivity testing within the 7-year window assessed, only 21 met predefined inclusion criteria. Of these, five were randomized clinical trials, none of which supported chemosensitivity testing in oncology practice, given the few patients involved.

Such studies are incredibly difficult to do, Lancaster said. Moreover, many tests in medicine today don’t categorically improve survival, he said, such as weekly blood count monitoring after chemotherapy or even some widely used cancer drugs. “We can delay growth of a tumor or increase the time of stable disease, but does it improve survival? Are we holding these assays to a higher standard than we do other tests?”

One practitioner, Robert Nagourney, M.D., Ph.D., medical and laboratory director of a company in California, who has been doing chemosensitivity testing for more than two decades, thinks so. From his perspective, the scientific elegance of genomics testing has obscured research interest in chemosensitivity assays, which were "not well done for a long time, so they were dismissed."

But new tests can better capture the microenvironment of tumor cells inside the body, he contends, enabling technicians to isolate cancer cells into clusters that include even some of their vasculature.

Still, doctors generally prefer to follow treatment results from clinical trials rather than from the laboratory. According to Richard Levine, M.D., president of Space Coast Cancer Center in Titusville, Fla., and a member of ASCO’s National Quality Care Committee, “If you have a standard regimen for a particular cancer, but chemosensitivity testing says don’t give a certain drug, there’s no article that shows a patient will do better. We have to go with the known data."

Although genomic testing already carries storied data (including advances with Her2/neu, ALK inhibitors, and BCR– ABL gene mutations in chronic myeloid leukemia) that have influenced patient care, chemosensitivity assays have not yet attained the same level of success, Levine said.

But a recent ASCO initiative called CancerLinQ might change that. The mul- timillion-dollar massive electronic database will record, track, and collate chemosensitivity and molecular profiling testing results for clinicians to access.

“This system should help guide treatment and help us be current,” Levine said. “It will have all the toxicities, response rates, and survival, so doctors can mine the data for the best care for their patients.”

[url]http://www.asco.org/ASCOv2/Practice+%26+Guidelines/Quality+Care/CancerLinQ+-+Building+a+Transformation+in+Cancer+Care

Oxford University Press 2012. DOI:10.1093/jnci/djs499

[url]http://cancerfocus.org/forum/showthread.php?t=3490

[url]http://cancerfocus.org/forum/showthread.php?t=3692

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Avastin (bevacizumab) is already approved for use in combination with chemotherapy as a first-line treatment for metastatic colorectal cancer, but the drug now has an extended indication. The US Food and Drug Administration has approved new labeling, which allows the use of bevacizumab to be continued after disease progression. The European product labeling has also been updated.

"The majority of people diagnosed with metastatic colorectal cancer receive bevacizumab (Avastin) plus chemotherapy as their initial treatment," said Hal Barron, MD, chief medical officer at Genentech, in a press release. "These people now have the option to continue with bevacizumab (Avastin) plus a new chemotherapy after their cancer worsens, which may help them live longer than changing to a new chemotherapy alone," he explained.

The clinical data to support this indication come from the phase 3 ML18147 study, which was presented last year at the American Society of Clinical Oncology trade show, and reported at the time by Medscape Medical News.

Many oncologists in the United States are already extending Avastin (bevacizumab) beyond first progression; this study gives justification for that, said Bruce J. Roth, MD, professor of medicine in the division of oncology at Washington University School of Medicine in St. Louis, Missouri.

At the ASCO trade show last year, Dr. Roth explained that the trial was well designed and demonstrated the benefit of continuation, but didn't address the magnitude of that benefit. "That's...for individual physicians and their patients to decide," he added.

One issue is the high cost of the drug, and the question of "whether it is worth these months of second-line therapy," Dr. Roth said. "It's hard to know where that breakpoint is, but this study provides a scientific benefit for that strategy."

Improved Survival

The ML18147 study involved 820 patients with metastatic colorectal cancer whose disease had progressed after Avastin (bevacizumab) plus standard first-line chemotherapy (fluoropyrimidine plus either irinotecan or oxaliplatin). All patients were then treated with a chemotherapy different than their first-line regimen, and half continued on Avastin (bevacizumab).

The results, calculated from the initiation of this second-line treatment, show significantly better median overall survival with Avastin (bevacizumab) continuation than with chemotherapy alone (11.2 vs 9.8 months; hazard ratio [HR], 0.81; P = .0057), and significantly better median progression-free survival (5.7 vs 4.1 months; HR, 0.68; P < .0001).

Citation: Bevacizumab's Indication Extended in Colorectal Cancer. Medscape. Jan 24, 2013.

The U.S. FDA approved the use of Avastin for patients whose colon cancer has worsened despite previous treatment with the drug. The new use will allow patients first treated with Avastin plus chemotherapy to be treated again with the drug in combination with a different chemotherapy regimen. A clinical trial showed that such a treatment strategy improved survival.

According to Genentech's chief medical officer, the majority of people diagnosed with metastatic colon cancer receive Avastin plus chemotherapy as their initial treatment. These patients now have the option to continue with Avastin plus a new chemotherapy after their cancer worsens, which may help them live longer than changing to a new chemotherapy alone.

In "Curing Cancer: Running on Vapor" (May 1, 2007 edition of Genetic Engineering and Biotechnology News), the cancer research arena has reached a sorry state of affairs. The tiniest increase in the survival time or median time to progression of drug-treated cancer patients is touted as a cure.

One example of this is the clinical reality for metastatic colon cancer. The FDA-approved combination regimen of chemotherapy (irinotecan, bolus fluorouracil, and leucovorin) plus Avastin increases median overall survival by 4.7 months.

This small increase comes with a host of side effects, which impinge upon the quality of life, as well as placing a burden on the patient, as well as the healthcare system.

The much-vaunted blockbuster drug Avastin is simply an antibody supplement incorporated into an already complex chemotherapeutic drug regimen that may slow down the cancer process depending on the genetic constitution of that individual.

When the front-line treatment for solid tumors is still chemotherapy (cytotoxic and/or targeted) and radiation, and the best that blockbuster drugs can achieve is to prolong the inevitable by either a few months or not at all, then it’s surely time to stop the delusion.

[url]http://cancerfocus.org/forum/showthread.php?t=3566