What Can You Do to Improve Your Odds Against Cancer?

I sometimes joke with my patients that a new diagnosis of cancer rarely provides them enough time to get an MD or PhD. Yet it is that level of preparation that may be required to answer the myriad questions that lie ahead.

Although it’s a joke, it is only partly in jest. Unlike buying a house or a car for which one’s life experiences can prepare you, medicine is opaque, complicated and ever changing. At the bleeding edge of medical complexity sits medical oncology and its dizzying array of genomics, transcriptomics, proteomics, epigenomics and metabolomics. Not only is it difficult for patients to keep up with all the changes, it is increasingly beyond the ken of their doctors who have spent entire careers training in the specialty, many of whom may have an MD and a PhD.

So how can patients improve their odds when the obstacles seem so daunting?

notebook-clipart-red-spiral-notebookMy first recommendation is that you develop a personal diary or record book of the procedures, staging studies, pathologic diagnosis, tumor markers, and physician recommendations. This can be accomplished by requesting that your doctors provide either electronic or physical copies of CT scans, pathology reports, blood tests and other clinically relevant information. While there has been some controversy surrounding their overuse, I am a believer in the simple blood tests used as barometers of your cancer with names like CEA, CA19.9, CA125, CA27.29, and CA 15.3. Although they are not perfect, they are easy to obtain, relatively inexpensive and can be repeated regularly to assess progress with therapy.

The second thing that I recommend is that you gain a working knowledge of your diagnosis. While there are no lung cancer search resultsperfect sources of information, the internet can provide useful basic information as a starting point. Begin by obtaining from your doctor the most accurate definition of the cancer. If it is breast cancer, is it infiltrating ductal or lobular? Are you ER positive? Is your tumor HER-2 positive? If it is stomach cancer, is it intestinal type or diffuse, etc? This will facilitate your searches, as well as your future conversations with consultants.

Once you know what you’ve got, the next thing you will need to know is where it is. That is what is known as your stage. The older classification used Roman Numerals I-IV with local disease (early) as stage I and metastatic (disseminated) as stage IV. The more modern system is known as TNM, where T stands for tumor size (1-4), N stands for lymph involvement(1-3), and M stands for metastatic involvement (0 or 1). Most contemporary pathology reports include TNM staging. With the diagnosis and stage established, you now know what you have and where it is.

This is where it gets interesting. Now, what do you do about it?

It is at this point that therapeutic choices must be made. Most physicians will rely upon standard established guidelines. Among the most widely used guidelines are those published by the National Comprehensive Cancer Network known as NCCN. While these guidelines can be useful, they can also be stultifying, limiting patients to what might be considered the lowest common denominator of care. While they may be better than haphazard treatment selection, they may very much miss the mark for your unique needs.

Here the process degenerates into a plethora of confusing choices.

Should you have genomic profiling? If so, should it be based on a tissue biopsy, circulating cell free tumor analysis, or even the newer urine tests that measure the presence or absence of abnormal genes? All of these technologies have merit and over the coming years the best ones will shake out. Despite these tests being widely touted (and profitable for the purveyors), none of these test have been put to formal trials that establish their capacity to influence survival. This is interesting because many of these tests have obtained insurance and Medicare coverage without even remotely rising to this standard. Nonetheless, these tests can be used for specific diseases like lung and leukemia where actionable targets are known to exist. Beyond that, caveat emptor (buyer beware).

One of the problems with genomic profiles is that they do very good job of telling you what the problem may be, but a very bad job at telling you the solution. It is a rare genomic mutation that comes with a drug to treat it. Most of the findings wind up asking more questions rather than providing more answers.

With the diagnosis established, the stage known and in certain circumstances molecular profiles complete, it is time for you to choose treatments and the centers that will provide them. Many seek the care of academic centers. These centers may offer clinical trials as a first line therapy for those who meet criteria.

NCI Clinical TrialsIt should be remembered that clinical trials are conducted in three principal formats. Phase I trials examine brand new drugs. These trials determine the safety of the drugs at different dose schedules. Phase II trials take the established safe doses and develop experience in each type of disease, e.g. lung versus colon versus breast. Phase III trials then compare the new drugs with existing treatments to see if there is any real improvement.

It is critical to recognize the functions of these different types of trials. Phase I studies classically have no therapeutic intent (your benefit is secondary to their measurement of your ability to tolerate the drug).

Phase II trials seek evidence of clinical activity by disease, but your specific disease may not be right for that drug.

Finally, Phase III allows a comparison of standard treatment to the new one. Many of these drugs do not make the grade and fall off the development wagon. In addition, you must be willing to be randomly assigned.

It is here that my approach diverges from those outlined. I have long maintained that each patient is unique and that their cancers must be treated individually. Recognizing that no genomic, proteomic or transcriptomic platform can answer the very complex questions of therapeutic response, we at Rational Therapeutics have developed functional analyses through the use of the EVA-PCA assay, which studies each patient’s tumor by exposing it to the drugs of interest. The most active, least toxic combinations are then recommended. In a report at the American Society of Clinical Oncology meeting of 2013, we showed a 2.02 higher response rate (P < 0.001) and a 1.44 improvement in one year survival (P < 0.02) for patients who received assay-guided therapy. This established the predicative validity of the functional approach.

It is important for patients to realize that cancer is an unbalanced system, not just an abnormal cell. Cancer as a disease goes beyond the cell or even the tumor to affect the body itself. Alterations in immunity, metabolism and physiology contribute to the good or bad outcomes of every patient. Patients should seek to normalize their lifestyle, improve their diets, maintain an active exercise program, reduce their weight to lean body weight, and may in some circumstances consider nutritional supplements and/or appropriately selected natural products that may augment their wellbeing.

The human body is a complicated machine and each part resonates with every other part. A good diet, a good night’s sleep and avoidance of an unhealthy lifestyle, as much as they may sound like your mother’s advice, is indeed very good advice.

Every cancer patient has the right to get better. As a patient, you should take charge of your cancer and make smart decisions. Afterall, no one is more interested in saving your life than you.

In Cancer Research: An Awakening?

In 2005, as the Iraq War reached a low point with casualties mounting and public support dwindling, Sunni tribesman in the Anbar Province arose to confront the enemy. Joining together as an ad hoc army these fighters turned the tide of the war and achieved victories in the face of what had appeared at the time, to be overwhelming odds.

I am reminded of this by an article in The Wall Street Journal by Peter Huber and Paul Howard of the Manhattan Institute that examined the bureaucracy of drug development. It raised the question: Are new cancer treatments failures or is the process by which they are approved a failure? They describe “exceptional responders” defined as patients who show unexpected benefits from drug treatments. Using molecular profiles, they opine, scientists will unravel the mysteries of these individuals and usher in an era of personalized medicine. Thus, rigid protocols that use drugs based upon tumor type e.g. lung vs. colon fail because they do not incorporate the features that make each patient unique – an awakening.

The example cited is from Memorial Sloan-Kettering where a patient with bladder cancer had an unexpected response to the drug Everolimus (approved for kidney cancer). Subsequent deep sequencing identified a genetic signature associated with sensitivity to this drug. While it is a nice story, I already knew it very well because it had been repeated many times before and would in the past have been dismissed as an “anecdote.” It is precisely because of its rarity that it has been repeated so many times.

The WSJ analysis strikes a familiar chord. For decades, we have decried the failure of rigid clinical trials that underestimate a patient’s unique biology yet cost millions, even billions of dollars, while denying worthy candidates new treatments under stultifying disease-specific designs.

Well Tray Closeup2 smallWe pioneered phenotypic (functional) analyses (the EVA-PCD platform) to examine whole cell models as we explored drug response profiles, novel combinations and new targets. It is regrettable that these WSJ authors, having raised such important issues, then stumble into the same tantalizing trap of molecular diagnostics, and call for bigger, better, faster genomic analyses.

Cancer patients need to receive treatments that work. They do not particularly care why or how they work, just that they work. These authors seem to perpetuate the myth that we must first understand why a patient responds before we can treat them. Nothing could be further from the truth.

Alexander Fleming knew little about bacterial cell wall physiology when he discovered penicillin in 1928, and William Withering knew nothing about the role of muscle enzymes in congestive heart failure when he discovered digoxin extracts in 1785. Would anyone argue that we should have waited decades, even centuries to apply manifestly effective therapies to patients because we did not have the “genes sequenced?’

We may be witness to an awakening in cancer drug development. It may be that a new understanding of individualized patient response will someday provide better outcomes, but platforms with the proven capacity to connect patients to available treatments should be promoted and applied today.

Rationed or Rational: The Future of Cancer Medicine

Disturbing news from Britain’s Health Service on Monday, January 12, described the National Health Services’ decision to “delist” 25 of the nation’s 84 currently available chemotherapy drugs from their formulary. Citing the rising cost of cancer therapy Professor Peter Clark, chair of the Cancer Drug Fund said that the CDF, originally established in 2011, had already exceeded its annual budget. From ₤280 million in 2014 the costs for 2015 are projected to rise to ₤340 million. In defense of the policy Dr. Clark said the delisted drugs “did not offer sufficient clinical benefit.”

avastinAn examination of the delisted drug should raise concern for medical oncologists. Among those delisted are Bevacizumab (Avastin) for colorectal cancer, Eribulin (Haloven) and Lapatinib (Tykerb) for breast cancer and Pemetrexed (Alimta) for advanced lung cancer. Additionalhalaven deletions include Bendamustine (Treanda) for some non-Hodgkin’s lymphoma, Bortezomib (Velcade) for relapsed mantle cell lymphoma and Waldenström’s macroglobulinemia. Bortezomib will also be limitedvelcade_MP_thumb in some cases of myeloma, while Cetuximab will be unavailable as second or third line treatment in colorectal cancer. For American oncologists these agents have become standards of care.

Many physicians in England are outraged. Mark Flannagan, executive chief of the Beating Bowel Cancer Fund described this as “bad news for bowel cancer patients” suggesting that 65% of patients with advanced colorectal cancers will confront the risk of an earlier death. Despite these draconian measures physicians may still have the opportunity to request delisted drugs under what is described as “exceptional cases.”

The breadth and scope of the drug restrictions are surprising. After all, Pemetrexed is one of the most widely used treatments for advanced lung cancer, Bevacizumab has become an established part of colorectal cancer management and Eribulin is a favored salvage regimen in recurrent breast. The withdrawal of Bortezomib, an active agent in mantle cell, Waldenström’s and myeloma, will not be suffered lightly by patients in need.

Are the problems confronting the UK an early harbinger of the same for the American medical system?

With aging populations in western societies and increasingly sophisticated medical technologies, the cost of medical care, particularly cancer care may soon become unmanageable. UK’s centralized medical care delivery through the National Health Service, a single payer system, was designed to save money. Despite its high-minded intentions, the NHS appears to be failing. While spending more money each year the dissatisfaction with medical delivery only grows. A nearly 12% increase in health care per person expenditures in England between 2009 and 2013 (₤1712 to ₤1912) was met with an 18% increase in patient complaints.

Among the problems are progressive layers of middle management that add cost without providing care.  Physicians find it more difficult to do their jobs while people inexpert in the delivery of medical care have been given decision-making power. As the English population has come to look upon health care as a right, some overuse medical services, even ER’s, for non-serious conditions. Reformers have suggested the solution may lie in charging fees for appointments or requiring an annual membership fee. In today’s political milieu however, few elected officials are likely to relish policies that end “free health care” in England.

What might solve this dilemma for medical oncology? An obvious solution is to apply resources where they are most likely to benefit patients, e.g. personalized care. While this seemed a pipe dream 20 years ago when we first introduced the concept, a growing chorus of scientists now embraces the idea. With their focus almost exclusively on genomics this new cadre of clinical investigators describe a future where each patient gets exactly the right treatment.

We applaud this thinking and fully agree. However, we must be prepared to use all platforms to achieve this worthy goal. To fill the current void phenotypic analyses offer substantive benefits. By capturing cancer biology at a functional level, these studies identify true “driver mutations,” and have the capacity to examine synergy and sequence-dependence, both beyond the scope of genomic analyses.

As human tumor primary culture analyses (such as EVA-PCD) have already been shown to double objective response rates and improve one-year survival, it is time for government officials and policymakers to re-examine the benefits of drug selection technologies that are available today.

Will the future of cancer medicine in the UK and the US be rationed under the duress of rising costs, or rational, through the application of available technologies capable of making intelligent cost- and life-saving decisions? That remains to be seen.

Cancer Centers and Advertising: The Truth Be Told

Screen shot 2014-08-06 at 5.08.23 PMSome of the most interesting literature on cancer comes from journals that are not directly involved in the field. I was reminded of this by an article that appeared in the June 17, 2014 Annals of Internal Medicine entitled “What Are Cancer Centers Advertising to the Public?”

The authors examined the types of clinical services that are promoted by commercial advertising. They reviewed advertisements that appeared in the top media markets during the year 2012, including both television and magazine ads. They excluded duplicates, public service announcements, fund raising and research subject recruitment. Of 1,427 total advertisements, 409 were considered to be unique ads that promoted clinical programs at 102 different cancer centers.

Screen shot 2014-08-06 at 5.13.29 PMTo analyze the content, the investigators developed a “code book” that included four domains; the types of clinical services, information provided, the use of emotional advertising appeals and the use of patient testimonials. Among the centers analyzed, 59% were for profit and the same percent were accredited by the Commission on Cancer. Sixteen percent were NCI designated centers. Advertising was also characterized by region of the United States. The results are interesting and instructive.

Of the 409 unique clinical advertisements, 88% promoted treatment. This was demonstrably higher than the percentage promoting cancer screening at 18% or supportive services at only 13%. While the benefits of therapies were described in 27% of the ads, the risks were only mentioned in 2%. Emotional appeals were frequent with 85% of the ads evoking hope for survival. Cancer was often described as a fight or battle, and the use of fear (of death, etc.) was found in fully 30% of the advertisements.

Screen shot 2014-08-06 at 5.15.28 PMIn their discussion, the authors pointed out several interesting findings. Among them, the “frequent use of emotional appeals and scarce mention of risk of services or quantification of benefit.” They also found “that NCI designated centers more frequently used emotional appeals related to survival or potential for cure.” These same centers “omitted information about risks, benefits and alternatives with similar frequency as non-NCI designated centers.” They concluded that “emotional appeals coupled with incomplete information are being widely used to promote services even among the nation’s most prestigious cancer centers.” Interestingly while only 5% of cancer centers in the United States are NCI designated, fully 16% of the clinical cancer advertising in 2012 was conducted by NCI-designated centers, a three-fold higher use.

What are we to gather from this analysis? First a journal like the Annals of Internal Medicine, removed from the direct delivery of cancer care, has the gravity to review processes that would rarely be reported in the oncology literature. Second, NCI designated (academic) cancer centers, who claim to eschew dissemination of unsScreen shot 2014-08-06 at 5.23.56 PMubstantiated information, appear to be the very centers that engage in such promotion. As the authors note, “clinical advertisements that use emotional appeal uncoupled with information about indications, benefits, risks, or alternatives may lead patients to pursue care that is either unnecessary or unsupported by scientific evidence.”

We applaud the authors of this Annals of Internal Medicine article for their unbiased and informative analysis. We must all strive to provide patients practical and actionable information about cancer and its treatment. It appears from this study that the practice of self-promotion crosses all lines of cancer care delivery from the most august academic institutions to the for-profit cancer centers. As with all activities in life, cancer patients are to be reminded of the ancient Roman admonition “Caveat Emptor” (Buyer Beware!).

Cancer Patients Take Heart: The Power of Public Opinion

A January 27, 2014, report on National Public Radio brought recent discussions into sharper focus. Though the story was unrelated to cancer, the lessons learned provide a road map for cancer patients in their pursuit of the most effective, least toxic treatments.

The condition known as “clubfoot” (talipes equinovarus) is a congenital deformity that afflicts one of every 1,000 births in the US. The abnormal internal rotation of the ankle is highly debilitating if not corrected shortly after birth. For decades, orthopedic surgeons used complex surgical procedures that disrupted the ankle structure and realigned the bones. Despite numerous surgeries, this rarely corrected the deformity resulting in chronic arthritis and gait disturbances. The costs were significant and the loss of productivity for those afflicted even greater, yet the dilemma remained unresolved.

PonsetiInto the fray came Dr. Ignacio Ponseti. Ponseti, the son of a Spanish watchmaker, had gained a unique perspective on structural integrity working in his father’s shop. Fleeing the Spanish Civil War he came to the US to practice orthopedic surgery at the University of Iowa. Recognizing the poor outcomes for clubfoot surgery, he took it upon himself to rethink the problem. After all, newborns have flexible ligaments. These ligaments, he reasoned, could be re-trained through a series of casts that were replaced serially over months after birth. Once the foot was in better alignment, the children were placed in a boot to retrain the joint into its normal alignment. Not surprisingly, this simple, noninvasive, inexpensive method was eschewed by the orthopedic professionals. Undaunted, he continued to practice his art, with excellent results year after year. Dr. John Herzenberg, a Baltimore-based practitioner of the Ponseti method was quoted: “People were falling over themselves to do fancy invasive surgery, and this one strange old guy, who speaks softly with a Spanish accent in Iowa, was getting sort of ignored by the drumbeat of people who were in favor of surgery.” Despite its obvious appeal and its manifest successes, this technique remained largely in Iowa for 50 years.

And then came the Internet. When a child born with clubfoot in 2000 was recommended for standard surgery, her mother went online to examine all the options and came across Dr. Ponseti. She traveled to Iowa for an opinion. Convinced that Dr. Ponseti’s approach was superior, this brave mother took the leap and undertook the Ponseti method. Dr. Ponseti completely corrected the child’s foot. Horrified that her daughter would have suffered a life of misery without this brilliant breakthrough, this young mother took it upon herself to get the word out. Using the Internet, she created a Yahoo Support Group called “No Surgery 4 Clubfoot.”  Families with afflicted children could now find out about this technique and identify practitioners who used it.

Voting with their feet, parents took their children to centers that applied this simple, relatively noninvasive approach. Over time, the academic community and their adherents to invasive surgery found themselves on the wrong side of patient referrals. Demanding better outcomes for their children, parents charted a new course for their medical care and forced their doctors to agree or be left behind. With a 97% success rate today, virtually every orthopedic surgeon in America practices the Ponseti method. Indeed, it is now recommended by the American Academy of Orthopedic Surgeons.

I relate this story to cancer patients as they confront similar resistance. While marginally effective therapies are promoted by many academic centers, simple, comparatively easy techniques are available that can empower patients in treatment selection. Just like the clubfoot parents, cancer patients must demand access to treatment options and explore every lead.

The Internet has offered an entirely new platform for cancer patients to communicate their experiences, recommend physicians, educate friends and family members and change referral patterns. The power to change the way cancer is treated in America today is within the grasp of the patients themselves. Just like Dr. Ponseti, who knew that his method worked and just like his patients who avoided the pain and suffering they would have otherwise endured, patients enlightened about better ways to treat cancer need to communicate and take charge of their disease.

Rallying the Troops to Confront Cancer

The recent blog “Stand Up To Cancer Research!” described some of the pitfalls of modern cancer research and the clinical trial process. It has engendered an active discussion. It may be helpful to address some of issues raised. For those of you who did not have the opportunity to read that blog, it defined the difficulty that many patients encounter when they seek experimental treatments. Clinical trials are often only available at select centers, sometimes at great distances from patient’s homes. There can be rigid inclusionary and exclusionary criteria, and the pre-entry evaluations e.g. re-biopsy, CT/PET, etc. can be daunting, time consuming and inconvenient. Travel and accommodations may come at great personal expense.

I penned the blog, in part, to remind patients that they are ultimately in control of the process. One patient asked how can “we stand up to the system” describing herself a consumer while “they’ve got the goods.” This is the frustration many people feel. It should be remembered, however, that a substantial portion of research support comes from tax dollars and charitable donations. These are your dollars. If the system is not working, then those responsible must be held accountable. The American public has the power of the vote. Patient advocates can approach and lobby their representatives and demand improvements in the clinical trial process. To wit, the level of scrutiny and restriction upon access to new drugs must be re-examined. There is an army of well-trained clinical oncologists capable of delivering experimental drugs today. Not just the fully vetted, just-about-ready-for-prime-time agents currently found in phase III trials, but the really new exciting drugs. Once a drug has passed Phase I and found to be safe in patients, open up the accrual process. “Compassionate use” has virtually disappeared from the lexicon of cancer research. Twenty years ago I made a discovery in the laboratory. Working with the pharmaceutical company and the FDA, we were almost immediately granted access to a yet-to-be approved agent. The combination proved so effective that today it is one of the most widely used regimens in the world. That would not happen today. We simply cannot get access to the best drugs for our patients.

Microscope Detail2-lo resWith the industrialization of medical care, growth of mega-medical systems and the increasing role of government, medicine must be viewed through a different lens. Changes in cancer research will require changes in cancer policy, and policy comes from political power. Cancer patients will need to identify legitimate spokespeople to take their concerns forward to their elected officials. While the current clinical trial process slowly grinds out new development, even the smartest, fastest trials take years to change practice. Every day, more than 1,500 cancer patients die in the United States alone. Cancer patients do not have time for clever doctors to pose interesting questions while they suffer the slings and arrows of ignoble, ineffective therapy. It is time for a change in cancer research, and patients must be the instrument for that change.

Gastric Cancer: A Call for Patient Selection

Gastric cancer is the fourth most common cancer worldwide with more than 930,000 diagnoses and 800,000 deaths attributed to this disease each year. Although relatively uncommon in the U.S., constituting only 2 percent of new cancers, in countries like Korea it makes up 20 percent of all new malignancies.

Among the causes are Helicobacter pylori infection, diets rich in smoked food, a high intake of nitrates and nitrites and cigarette smoking. A rare but aggressive form of the disease is associated with a gene mutation known as CDH1. The high frequency of metastatic disease at the time of initial diagnosis often precludes surgery, leaving systemic chemotherapy as the principal treatment option.

Annals of Oncology coverA recent report in The Annals of Oncology (No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy: Bernards N. et al, Annals of Oncology. November, 2013) describes a retrospective analysis by Dutch investigators who examined the use of chemotherapy in patients with inoperable gastric cancer.

In total, 4,797 cases were examined from 1990 to 2011. Over this time, the proportion of patients presenting with metastatic disease increased from 24 percent in 1990 to 44 percent in 2011. At the same time, palliative chemotherapy use increased from 5 percent to 36 percent. Younger patients and those of higher socioeconomic status had the largest increase in chemotherapy use, while older patients, those with linitis plastica and those with multiple metastases had lower chemotherapy use. Despite the significant increase in the use of chemotherapy, the median survival for patients was unchanged at 15 weeks in 1990 and 17 weeks in 2011 (P = 0.1).

Over this period, early treatment regimens like 5-fluorouracil (5FU) and FAM were largely replaced by combinations like Docetaxel/Cisplatin/5-FU (DCF), Cisplatin/Irinotecan, Epirubicin/Oxaliplatin/Capecitabine (EOX) and Carboplatin/Taxol. While response rates and palliative benefits have continued to improve, this has not translated into improved overall survival. This reflects a dilemma that has confronted medical oncologists for decades.

For many years, clinical trialists have held that one cannot assess the benefit of a treatment by comparing responders to non-responders. That is, time to progression and survival must compare all patients on a given treatment arm to those on the control arm. Their rationale was that “one must treat all patients to obtain the benefit seen in some.”  Put differently you cannot “cherry pick” your winners and losers. It was said that this proscription was needed to avoid selection bias. But as any medical or nonmedical person would recognize, people who respond to treatment do better than those who do not. Lacking the ability to identify responders upfront, these trialists have insisted upon a one-size-fits-all approach to the detriment of clinical therapeutics and drug development.

With the dawn of the molecular era we see chinks in the armor of these trial designs as investigators now question why everyone should receive a treatment if only a small percentage will benefit. In gastric cancer, HER2 over-expression, found in 20-25 percent of patients, is now routinely used to identify patients who will respond to trastuzumab. But what of the other 75-80 percent of patients who do not carry HER2 and for whom there are no widely used determinants of clinical response? Do the results of Bernard article suggest that these patients should not receive therapy?

The Bernard article offers an interesting insight into what may be the future of medical oncology. As cancer therapy is increasingly scrutinized, not only for response or palliation but also for overall survival, patients may soon be denied treatments unless the results of the therapy rise to this, the highest level of evidence, for the entire population of treated patients.

Would it not be preferable to use laboratory analyses, like the EVA-PCD®, to select among treatment candidates before subjecting all patients to the risk and expense of toxic chemotherapy? In this regard, the author’s comments are poignant: “Identification of the subgroup of patients which benefit from palliative chemotherapy is of the utmost importance to avoid unnecessary treatment.” As a laboratory investigator engaged in the field of drug selection science (functional profiling), I couldn’t agree more.

Cancer Survival and Matrimony: A Marriage Made In Heaven

JCO coverThe November 1, 2013 issue of the Journal of Clinical Oncology (Marital Status and Survival in Patients with Cancer, Aizer, A. et al J Clin Oncol, 2013), reports a study by investigators from Harvard University. Using the Surveillance, Epidemiology and End Results (SEER) data they examined more than 1.2 million cancer patients diagnosed between 2004 and 2008 to measure the impact of marital status on overall survival. Results reveal a statistically significant impact of marriage on cancer survival. The benefit slightly favored males over female, but remained significant across different diseases and for never married, separated, divorced or widowed. The authors note, “The survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.”

Epidemiologic studies that correlate disease states with socioeconomic status, level of education, geographic location, lifestyle or diet are fraught with confounding variables. Nonetheless, well-done studies can open a wealth of interesting questions regarding non-treatment related aspects of our health and well-being. This study is provocative for it identifies the interaction between marital status and stage at diagnosis, as well as overall survival.

There are many ways one might interpret the findings. The accompanying editorial (Marriage Is as Protective as Chemotherapy in Cancer Care, Kissane, D) notes that non-married status may reflect “reduced adherence to state-of-the-art treatment.” That, we presume, would include such variables as regular physicals, frequency of mammograms, PSA evaluations, willingness to undergo surgery or the use of adjuvant treatments. The role of depression is also noted. While all of these may apply, they have a self-serving ring, whereby good health, it would seem, can only be attributed to good doctoring. Controversies surrounding PSA screening or the impact of “annual physicals” on general health are but a few examples where more may not necessarily be better.

While it may be argued that unmarried individuals fail to obtain adequate medical care, the data may reflect somethinAA010368g more profound, the psychoneuroimmunology of cancer survivorship. That is, each patient’s capacity to will-themselves better. The will-to-live is enhanced by close human relationships. We are all witness to patients who survive against all odds. They are usually filled with zeal, willing to go to whatever lengths are required to overcome their illness and most have close interpersonal relationships, nurturing environments, loving families or husbands and wives who dote on them.

Norman Cousins spoke at length about the healing force of one’s emotional and spiritual belief systems in his own battle with ankylosing spondylitis (Anatomy of An Illness, As Perceived by the Patient, 1979). Might his experience reflect a similar dynamic to that described in the current study? My patient Alan Kapuler’s excellent outcome over Non-Hodgkin’s lymphoma, described in my book (Outliving Cancer, 2013, chapter 12) exemplifies this same mind-over-matter dedication, characteristic of many of our long-term survivors.

I applaud Dr. Aizer and his co- investigators for examining this aspect of cancer survivorship. I am impressed that such a report would find its way onto the pages of the Journal of Clinical Oncology. However, I am less certain that these good outcomes reflect state-of-the-art treatment and more of the opinion that married patients may be part of a happier, healthier, better adjusted and more humanly connected population. Interpersonal relationships are not devices. They cannot be patented or sold. However, as can be seen from this study, they may be among the most powerful interventions at our disposal in the management of advanced cancer.

Of Prostate Cancer, Glucose, Metabolism and Metformin

A study conducted by Canadian investigators and reported in the September 1, 2013 issue of the Journal of Clinical Oncology examined the impact of Metformin use on mortality in men with diabetes and prostate cancer (Margel D. Urbach DR., Lipscombe LL, Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men with Diabetes, Journal of Clinical Oncology, volume 31, #25, pgs 3069-3075, 2013). The investigators examined 3837 patient with a median age of 75 years. They conducted a retrospective analysis examining the Ontario Province heath care records. The intent was to examine duration of exposure to Metformin as a diabetes management in patients with prostate cancer to assess the impact on all-cause and prostate cancer-specific mortality.

The results are impressive and instructive. There was a significant decrease in the risk of prostate cancer-specific and all-cause mortality, which related to the dose and duration of exposure to Metformin. The adjusted hazard ratio for the study of 0.76 indicates that there is a 24% reduction in mortality for prostate cancer-specific events with the use of Metformin. This study was not perfect, as it was retrospective, there was no randomization and it was impossible to control for all other variables such as exercise, smoking history and clinical parameters of prostate cancer. Nonetheless, there is a clear and important trend toward reduced prostate cancer and even overall mortality. This is but one of a series of clinical studies that have examined the impact of Metformin upon not only prostate cancer but also breast cancer. Much of this work was originally pioneered by Dr. Michael Pollack from McGill University in Montreal.

The biguanide class of antidiabetic drugs, originates from the French lilac or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries.  (Wikipedia)

The biguanide class of antidiabetic drugs, originates from the French lilac or goat’s rue (Galega officinalis). (Wikipedia)

Metformin and the closely related Phenformin are members of the class of drugs known as biguanides. While the exact mode of action of the biguanides is not fully understood, they are known to disrupt mitochondrial respiration at complex I. This upregulates an enzyme known as adenosine monophosphate kinase (AMPK) thereby altering energy metabolism within the cell and down regulating mTOR. In diabetics, this drives down blood glucose to control the disease. However, in cancer patients, a profound effect is observed that suppresses synthetic pathways necessary for energy metabolism, cellular survival and cellular proliferation. These effects appear responsible for the impact upon prostate cancer. Interestingly, these drugs are more effective in controlling already transformed cells and less effective in the prevention of cancer. This is consistent with the observation that malignantly transformed cells change their state of metabolism.

This article is interesting on many levels. The first and most obvious is that this relatively inexpensive and well-tolerated drug can have an impact on prostate cancer.

Secondly, these effects appear to cross the lines of different cancer types, such that breast cancer and other forms of cancer might also be successfully treated.

The third note of interest shows that even patients without diabetes can tolerate Metformin, suggesting this as an adjunct to many different treatments. Finally and most importantly this represents the new and important recognition that cancer is not a genomic disorder, but a metabolic disorder. Cancer may utilize normal genetic elements to its own advantage. AMP kinase, LKB1 and mTOR are not unique to cancer, but instead, are found in every cell. These normal proteins are simply altered in their function in malignantly transformed cells. Metformin is one of what will soon be a large number of metabolomic agents entering the clinical arena as cancer research moves from the nucleus to the mitochondrion.

Is There a Role for Maintenance Therapy in Cancer Treatment?

There is a long tradition of maintenance therapy in pediatric oncology. Children with acute lymphoblastic leukemia uniformly receive three stages of therapy: induction, consolidation, and finally maintenance. The maintenance stage consists of weekly, or even daily therapies.

The historical experiences of relapse in this population lead investigators to consistently expose these patients to drugs for a period of years. Despite the apparent success of this approach in childhood cancers, long-term maintenance therapy did not gain popularity in adult oncology. Why?

There are probably several reasons. One reason is that childhood leukemia is among the most chemo-responsive diseases in medicine. As such, there are many active drugs available for treatment and many non-cross-resistant maintenance schedules that can be employed.

A second reason is the relative tolerability of drugs like oral thioguanine or mercaptopurine that are used in chronic maintenance therapy. By contrast adult tumors rarely achieve complete remissions. The number of active drugs has historically been very limited and the tolerance of long-term treatments characteristically poor.

Despite this, there is an appealing rational for maintenance therapy. Once we recognized and incorporated the tenents of apoptosis and programmed cell death into cancer management, we were forced to reconsider many of the principles of older treatment protocols.

Conceptually, maintenance allows for a cytotoxic exposure when the cell enters a “chemosensitive” period in its life cycle.  Cancer cells that are “out surviving” their normal counterparts often do so in a quiescent stage (G0 Gx). In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy. As we have now achieved increasingly durable remissions in diseases like breast cancer, small cell lung and ovarian, we are confronting patients in long-term complete remission. When you add to this newfound population the availability of comparably mild agents, like the low dose Gemcitabine/Cisplatin doublet, we now have at our disposal active drugs that can be safely continued for long periods of time.

Using laboratory selection to identify first line (induction), second line (consolidation) and finally third line (maintenance) schedules, we can now offer our patients well-tolerated combinations that offer the hope of more durable remissions.

The GOG 178, in which continued taxol dosing provided more durable remission in ovarian cancer, provided the first inklings of this. Unfortunately, taxol is toxic. And the more durable remissions came at an increasingly high price: neuropathy, myelosuppression, alopecia, fatigue and malaise, which greatly limited the utility of this approach. Yet it does not limit its theoretical attractiveness as we continue to develop targeted agents with more selective activity and modified toxicity profiles. We anticipate maintenance therapies will become more widespread.

Based upon our experiences to date, we are successfully using this approach with our patients who achieve good clinical remissions.

Outliving Cancer

You can find more information about our use of maintenance therapy, in Chapter 14 of the book Outliving Cancer.

This blog was originally posted in August 2011.