Harbenger of the Future

Following are excerpts from Dr. Guy B. Faguet's book, The War on Cancer An Anatomy of Failure, A Blueprint for the Future. This book can be located at Amazon.com as mentioned in a previous post.

I feel compelled to share this. I suspect none of what Dr. Faguet has to say will come as much of a surprise to some in the medical community. However, to me, it is like someone living today going back in time trying to explain what the interstate highway system will be like to someone living one hundred years ago. The concepts would be so foreign they would almost not be comprehensible. The concept of cell-kill vs. pharmacogenomics is a huge paradigm shift and is discussed in depth in the excerpts that follow. It is interesting to note the post about Mayo Clinic researching the possibility of wood mold to kill myeloma cells is of the cell-kill paradigm. Cancer knowledge has come a long way and has a long way to go yet as discussed below.

Note: This is a very lengthy post. If you are interested in learning more about the concept but don't particularly want to invest the time to read the complete post at this time, you can cut to the chase by scrolling down to the bold print where Dr. Faguet sums it all up in one sentence.
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Chapter 12

A VISION FOR THE FUTURE

Predicting the next revolution in cancer care is admittedly an uncertain undertaking but cumulative evidence of a system gone astray and nascent trends for correction are unmistakable. Until recently, researchers and their sponsors focused their efforts, and clinicians and their patients centered their hope more on the eradication of advanced cancer than on its prevention or detection in surgically curable early stages. This arose from the belief that cancer represents a seldom preventable, deadly tissue growth that is difficult to diagnose in early stages, is distinct from the host and, as such, must be eradicated. However, while surgery is adept at eradicating early-stage cancer, the types of cancer drugs fostered by the notion of non-self are inefficacious in altering patients' outcome, and the notion itself was proven obsolete by recent advances in cancer genetics. Additionally, it is increasingly clear that translational application of cancer genetics data is the foundation for the emerging pharmacogenomics of the future that will replace the trial-and-error approach of the past. Thus, the time has come to develop a new approach to cancer control based not on eradication at any cost but on comprehensive, stepwise, and evidence-based measures. They include prevention, early diagnosis, and, when these fail, on controlling the aberrant molecular genetic pathways underlying the development, growth, and dissemination of cancer (the caveat "when these fail" underscores the difficulties of controlling complex genetic abnormalities often associated with advanced cancer). Adoption of such broad-based cancer control measures requires a fundamental paradigm shift of such a magnitude and reach that its adoption and implementation is likely to be resisted by supporters of the old, cell-kill paradigm. Indeed, as Max Planck the physicist who postulated the quantum theory observed, "An important scientific innovation rarely makes its way by gradually winning over and converting its opponents ... Instead, opponents gradually die out and the new generation adopts the idea from the beginning". It might be argued that old hypotheses about the nature of cancer and theories about its treatment seemed cogent when first proposed and were proven wrong only in retrospect, and that the new paradigm might also lead us adrift. However, the inability of the old paradigm to explain most of the recent scientific tenets regarding the nature of cancer and its inadequacy as a foundation for spawning efficacious treatments can be neither redeemed, redressed, nor improved by any future discoveries potentially on its path. In contrast, the new paradigm is anchored on new scientific information regarding the nature, development, and progression of cancer and is supported by clinical studies that provide proof of concept of each of its component parts. Indeed, the crucial role played by prevention and screening on declining of cancer incidence rates recorded since 1992 was underscored in NCI' s 2001 Cancer Progress Report. It acknowledged, "Behind the numbers are declines in certain behaviors that cause cancer, especially cigarette smoking by adults. More people are getting screened for breast, cervical, and colorectal cancers". Likewise, the success of Imatinib mesylate, a drug developed to harness the molecular defect that causes chronic myelocytic leukemia rather than to kill the leukemic cells, and its success in the clinical arena provide proof of concept in support of molecularly targeted agents of the future. Thus, because it is sound in conception, based on scientific and clinical evidence, and of plausible implementation, the proposed new paradigm is likely to succeed in controlling cancer. Nevertheless, cognizant of the enormity of the task at hand and of the difficulties lying ahead my purpose is not to impose my vision for the future but to encourage a long overdue paradigm shift that is necessary to ultimately control cancer, whether or not it follows my proposal. The fate of over one million Americans who develop cancer each year, and millions more around the World, depend on it.


CONCLUSIONS

The War on Cancer was given impetus by the National Cancer Act of 1971, which tapped the vast resources of the Federal government to confront the growing cancer challenge. As a result, all cancer initiatives funded by Federal dollars have been channeled through the NCI; itself remade by the National Cancer Act. While proponents who anticipated the conquest of cancer by the nation's bicentennial were overly optimistic and patently unrealistic, this book reviews the achievements and failures of the War on Cancer in an objective and dispassionate manner, based on factual data published in mainstream scientific journals and other reliable sources. Over four hundred pertinent, easily retrievable, and verifiable references are cited in support of the author's core argument that the War on Cancer has been lost, and of his proposed three-part approach to cancer control as an alternative to the failed cell-kill dogma that dominated clinical research and patient care for decades.

First, we must acknowledge that the National Cancer Act of 1971 has had a profound and multifaceted positive impact on basic cancer research. However, translational application of our growing understanding of the nature of cancer to patient care has lagged far behind. Indeed, while our knowledge in molecular biology and genetics of cancer has grown exponentially in the last 20 years, patient care has improved only marginally despite the National Cancer Act. This is mainly due to neglecting prevention, undervaluing screening, and to our over reliance on inefficacious non­specific cancer drugs stumbled upon by serendipity or developed by a process of trial-and-error favored by the NCI, the main drug development funding source until recently. For example, molecular genetics is now poised to uncover the genetic defects underlying the emergence, growth, and dissemination of each of the more than 200 human cancers. In contrast, the 17 drugs identified by the World Health Organization as "essentiaf' to manage cancer were developed between 1953 and 1983. Less than a handful of drugs developed since then is having a meaningful impact on cancer care. As a result, in 2003 fewer than 24,000 Americans with mostly advanced hematologic or embryonal cancers, representing approximately 2% of all cancers, were cured of their disease by chemotherapy used alone or in combination with surgery or radiation therapy. In contrast, over 550,000 Americans died of cancer that same year despite receiving a variety of cytotoxic drugs, often to the very end. Of these, over 150,000 or 28% of all cancer deaths died of tobacco-induced lung cancer, the most lethal though preventable malignancy in the US and worldwide, after an average survival of 7 to 8 months; a figure virtually unchanged since 1973.

Thus, how are we to interpret reports of declining cancer incidence and death rates in the US after 1992 and of increased survival over decades? Is progress finally being made in cancer treatment? Unfortunately, the fall in incidence and mortality rates after 1992 did not extend beyond 1995 and 2000, respectively. Moreover, in 1997 fewer patients died of cancers with decreasing mortality rates (39% of total cancer deaths) rather than with increasing mortality rates (51 % of total cancer deaths), and 86% of the decline was due to reduced death rates in only 5 cancers. Additionally, factors other than treatment have contributed to lower mortality rates after 1992, and to increased survival over several decades. While the latter is due mostly to improvements in overall health care over time, the former resulted from public education campaigns that foster prevention via reduction in environmental and behavioral risk exposure, and early stage diagnosis via screening programs. Overall, fifty years of cytotoxic chemotherapy contributed minimally to the modest improvements in mortality rates or survival. This is because the faulty cell-kill paradigm, that views cancer as a "new growth" distinct from the host that must be eradicated at any cost, has misguided drug development and patient care for decades. From a treatment standpoint, surgery can satisfy this overriding principle because of its ability to remove early-stage cancer visually discernible from neighboring normal tissues, but current cancer drugs cannot given their non-specific mechanism of action unrelated to the cancerous process. This, in large measure, explains why innumerable attempts to enhance the efficacy of cytotoxic drugs, mainly via drug combinations and dose escalation with or without bone marrow transplantation, have failed to substantially increase cure rates or prolong survival for most cancer patients. That being the case, why does this failed system endure? The answer is multifaceted but can be summarized in one sentence. The information pipeline, generated by clinical researchers and supported by their sponsors and publishers, fosters standards of care that are reinforced by financial incentives and the extraordinary capacity of physicians for self-delusion, and by unrealistic expectations of consumers nurtured by the media.

Thus, the time has come to abandon the cell-kill paradigm and to anchor cancer control on an incremental, three-tier approach that incorporates prevention, early diagnosis, and when these fail, on controlling the aberrant genetic defects that lead to the development, growth, and dissemination of cancer. Is this approach likely to succeed where the cell-kill paradigm failed? It could be argued that, while found flawed in retrospect, past cancer control strategies seemed sound when first advocated, suggesting that the new paradigm I propose might also lead us astray. However, in contrast to hypothesis-driven past strategies the present proposal is solidly anchored on proof of concept for each of its components. Prevention has been validated by the success of anti-smoking campaigns in reducing the incidence of lung cancer in American males and by hepatitis B immunization programs in reducing the incidence of liver cancer in Taiwan. Screening programs to uncover cervical, prostate, and breast cancer in surgically curable early stages are saving lives, though screening tools at our disposable today are insensitive, non-specific, and confined to only a few cancers. Finally, the feasibility of controlling aberrant genetic defects underlying cancer rather than killing the affected cells has been amply demonstrated by the efficacy of Imatinib mesylate, the first specific, molecularly targeted anti-cancer agent of the post-genomic era. However, treatment of advanced cancer will remain at a disadvantage relative to prevention and early-stage diagnosis given the sheer size and greater genetic deregulation of such tumors. Ultimately, the success of the proposed measures will require a strategic shift from reliance on the conceptually faulty and implementally failed cell­kill notion of cancer treatment to a post-genomic cancer control paradigm. The new paradigm calls upon medical researchers to design means to identify and prevent cancer-causing agents, to develop simple, specific, and cost-effective screening tools for the early detection of all cancers, and to exploit the vast genomic database towards translational therapies for patients with advanced or progressive malignancies. It also calls upon policy makers to enact enlightened public policies towards cancer prevention and screening programs of national scope and achievable goals, and for the Nel to playa pivotal role in steering funding towards prevention, screening, and translational research. At the community level, it urges practitioners to focus on patient- rather than tumor-outcomes, to ensure that potential treatment risks are justified by the probability and magnitude of expected benefits, and to provide maximum pain reliefand comfort to terminal patients.