Guest guest Posted May 23, 2005 Report Share Posted May 23, 2005 22 May 2005 21:05:07 -0000 " Cancer Decisions " < THE MOSS REPORTS Newsletter (05/22/05) ---------------------- Ralph W. Moss, Ph.D. Weekly CancerDecisions.com Newsletter #185 05/22/05 ---------------------- THE MOSS REPORTS When physicians reporting the results of a major clinical trial announce a 23 percent improvement in survival for lung cancer patients taking a new drug, it would be hard to see this as anything less than a breakthrough. But examine this claim a little more closely and you will discover that the 23 percent improvement in survival actually translates into patients living for 12.5 months, rather than 10.2 months. Furthermore, a significant proportion – 4.5 percent - of patients receiving the new wonder drug can be expected to die as a direct result of the treatment itself, a mortality rate which, according to one of the lead researchers involved, is " well within accepted limits. " There seems to be a vast and widening gulf between the way in which therapeutic advances of this sort are perceived and reported by the medical profession, and the real-world benefit that patients can expect to receive from submitting to such treatments. This week and next, I report on my visit to the annual meeting of the American Society of Clincal Oncology, a forum in which, as you will see, announcements of this sort are plentiful. My goal, as always, is to be an objective observer, and if it seems to me that the Emperor has no clothes, I see it as my duty to say so. The most important thing I, in my capacity as a science journalist, can accomplish is to give my readers the tools they need in order to make up their own minds and come to their own conclusions. This has also been my hope and my aim in writing The Moss Reports, a series of detailed summaries of the best available conventional and alternative treatments for almost 200 different cancer diagnoses. If you would like to order a Moss Report for yourself or someone you love, you can do so from our website, www.cancerdecisions.com, or by calling Diane at 1-800-980-1234 (814-238-3367 from outside the US). We look forward to helping you. NOTE: Readers who have high-speed Internet connections as well as the program QuickTime on their computers are encouraged to look at our first venture into homemade film journalism. I have made a little 5-minute movie showing some of the highlights of the ASCO meeting. The movie can be found at: http://www.cancerdecisions.com/ASCO2005.mov You may also view the movie at a later time from our archive page on our site by going to: http://www.cancerdecisions.com/mossmovies.html If you do not have the QuickTime plug-in on your computer (Mac or PC), you can download it for free at: http://www.apple.com/quicktime/download REFLECTIONS ON ASCO 2005 I have just returned from the 41st annual meeting of the American Society of Clinical Oncology (ASCO). Twenty-five thousand oncologists converged on Orlando, Florida, to present their latest work and to learn about the progress that has been made over the past year in treating various types of cancer. There were nearly 10,000 abstracts presented at this meeting, as well as numerous commercial displays in the vast and towering exhibition hall. Some of these were masterpieces of advertising design, although not necessarily of hard science. Like the blind men in the fable trying to describe an elephant, every observer of a meeting this complex comes away with his or her own, somewhat subjective, impression. In future issues of this newsletter I shall comment on particular studies that I consider most promising. But right now I would like to give you my personal observations on the state of oncology as revealed by this ASCO meeting. I first attended an ASCO meeting in the 1970s, when the organization was relatively small and unknown. The first thing that strikes me, as I look back, is the dramatic shift from a chemotherapy-based model of cancer treatment to the new paradigm based around molecularly `targeted' therapies. Such a change should in fact be welcomed by people who are sympathetic to complementary and alternative medicine (CAM). The great philosophical debate over the excess toxicity of standard chemotherapy has been won by those favoring a " kinder, gentler " approach to cancer treatment. Indeed, almost every speech and most of the poster sessions featured targeted drugs of one description or another. At the same time, I find little in the actual practice of targeted therapy to kindle much enthusiasm. In this, I am at odds with most leaders of oncology. For instance, in his 2005 Karnofsky Memorial Lecture (the highest honor given by ASCO), Charles L. Sawyers, MD, of the University of California at Los Angeles (UCLA), spoke for many of his colleagues when he said that the age of molecularly targeted cancer therapy had unquestionably arrived. As he saw it, the fact that so many presentations focused on the use of so-called tyrosine kinase inhibitors such as imatinib (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva) validated the basic concepts of targeted therapy. Since it has been seven years since the Food and Drug Administration (FDA) approved Herceptin (trastuzumab), one of the very first targeted drugs, to treat breast cancer, and four years since it approved Gleevec for chronic myelogenous leukemia (CML), one could certainly expect to see some definitive proof of the targeted treatment philosophy. But while such agents have undoubtedly scored some successes over the years—Gleevec in particular is a very worthwhile agent—the field as a whole has run into many unanticipated obstacles as it tries to tackle the common tumors of adults. In particular, it has turned out that these agents have more side effects than was predicted initially by advocates of molecular targeting. For example, take the surprisingly widespread occurrence of potentially fatal bleeding episodes with the drug Avastin (bevacizumab). According to the manufacturer's own website: " Serious, and in some cases fatal, hemoptysis [the coughing of blood from the lungs, ed.] has occurred in patients with non-small cell lung cancer treated with chemotherapy and Avastin. In a small study, the incidence of serious or fatal hemoptysis was 31 percent in patients with squamous histology and 4 percent in patients with adenocarcinoma receiving Avastin as compared to no cases in patients treated with chemotherapy alone. Patients with recent hemoptysis should not receive Avastin. " In addition, when given as stand-alone treatments, most of these agents have demonstrated surprisingly poor results in various clinical trials. As was seen recently with the phase III clinical trials of Iressa, they sometimes do not actually extend overall survival at all. In April, 2005, the US National Cancer Institute (NCI) decided to discontinue all further clinical trials with Iressa, once a front-runner in the targeted therapy movement. " Iressa Clinical Trials Squashed Like a Nasty Cigarette Butt, " is how one former pharmaceutical developer (Stacey Lloyd) graphically summed up NCI's action. Plenary Session Disappointments At the ASCO plenary session held on Saturday afternoon (May 14, 2005), there was a discussion of three different combinations of chemotherapy with targeted drugs, in this case antiangiogenic agents. Such agents are designed to stop the formation of new blood vessels that can promote the growth of tumors. This session illustrated the complex obstacles that researchers in this field have encountered. Two of the speakers reported that the targeted drug bevacizumab (Avastin) provided what they called a significant survival advantage in patients with metastatic colorectal cancer and advanced non-small cell lung cancer, respectively. However, a third study, using the up-and-coming antiangiogenic drug PTK/ZK, failed to show that this drug significantly improved progression-free survival when given in combination with chemotherapy as a first-line treatment for advanced colorectal cancer. At first sight, you might think that two positive trials out of three is not bad. However, what the survival numbers actually show is something quite different. Thus, when Avastin was given alone to patients with metastatic colorectal cancer, their median overall survival was just 10.2 months. A standard chemo regimen of 5-FU, leucovorin and oxaliplatin, called FOLFOX 4, yielded a very similar 10.8 months. Only when the two treatments were administered together did survival rise to 12.9 months. Thus there was a gain of two months through the use of this intensive - and expensive - regimen. How much of this increased survival time was spent by patients feeling sick because of toxicity remains to be discovered. NOTE: The median is the middle number in a set of ordered data. Thus, the median of the numbers 1,1,1,2,4,6,6 is 2 since 2 is the middle number when all of the numbers are placed in order. In statistics, the median is considered a more reliable measure than the mean, which is more commonly what is meant by the word " average. " Another figure that oncologists frequently look at is median progression-free survival (PFS). This refers to the time that elapses between administration of the treatment and the time that progression of the disease is detected in a living patient. Here the figures were even less encouraging. With Avastin alone, this period of remission was just 2.7 months. With FOLFOX 4 alone it was 4.8 months. When the two were given together it was 7.2 months. At that point, the cancer was detected to be once again on the march. So, again, we're talking about a gain of a few months. In the second reported trial, the standard regimen FOLFOX4 was given with PTK/ZK, a new orally administered, targeted antiangiogenic agent. The effects of this combination were then compared to FOLFOX 4 given with a placebo pill. No figures on median overall survival will be available until 2006. But the combination that included PTK/ZK yielded an average (median) progression-free survival of 7.7 months. This was nearly identical to the 7.6 months experienced by the FOLFOX 4 group. It seems therefore that in this group of patients the new drug had no effect on the progression of their cancer. In a third trial, a standard regimen of two drugs, paclitaxel and carboplatin (PC), was compared to PC + bevacizumab (Avastin) in the treatment of metastatic non-small cell lung cancer. The median overall survival here was 10.2 months for PC alone vs. 12.5 months when Avastin was added. The median progression free survival was 4.5 months for PC alone vs. 6.4 months for the combination. These studies support the idea that Avastin (at least in clinical trials) adds around two months to disease free and to overall survival when it is added to standard chemotherapy for some advanced solid tumors of adults. TO BE CONCLUDED, WITH REFERENCES, NEXT WEEK. --Ralph W. Moss, PhD --------------- IMPORTANT DISCLAIMERS The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice. Copyright © The Internet Society (2004). This document is subject to the rights, licenses and restrictions contained in BCP 78, and except as set forth therein, the authors retain all their rights. This document and the information contained herein are provided on an " AS IS " basis and THE CONTRIBUTOR, THE ORGANIZATION HE/SHE REPRESENTS OR IS SPONSORED BY (IF ANY), THE INTERNET SOCIETY AND THE INTERNET ENGINEERING TASK FORCE DISCLAIM ALL WARRANTIES, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTY THAT THE USE OF THE INFORMATION HEREIN WILL NOT INFRINGE ANY RIGHTS OR ANY IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. This document may not be modified, and derivative works of it may not be created. -------------- IMPORTANT NOTICE: If you have questions or concerns, please use our form at http://www.cancerdecisions.com/contact.html Thank you. 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