		Chief Innovations Officer, Professor, and Vice President of Cancer Services

		John Theurer Cancer Center at Hackensack University Medical Center

	Complementary! Sounds good, how could it hurt? When applied in cancer therapy, however, what sounds good may not always be good for patients. More than 65% of cancer survivors report using some form of “complementary“ or “alternative” medicine while receiving standard therapy, but strikingly, less than half of these patients inform their physicians even when asked. If something is considered complementary, why hide it from your physician? These questions are now facing significant scrutiny because what would seem to be an obvious—almost commonsense&mdash;notion of benefit has been found to be harmful in some circumstances.

	For example, it was once believed that beta carotene was capable of reducing the risk of lung cancer due to its antiproliferative properties.

 It turned out that people receiving beta carotene, as shown in several studies, had an average 20% increased incidence of developing lung cancer. Another example is vitamin E, which was once thought to help prevent many maladies, including cardiovascular disease, autoimmune disorders, and cancer.

 Here again the data did not bear out any benefit to patients. In fact, one study showed that patients who took vitamin E had a 17% increased risk of developing prostate cancer.

	Early research done in animals found that vitamin A- and vitamin E-deficient mice experienced less brain tumor progression than control animals that were not vitamin-deficient, possibly due to suppression of apoptosis by antioxidants.

 Other studies indicate that complementary medicines may reduce the side effects of chemotherapy and improve survival.

 In light of the conflicting studies and anecdotal evidence, most professionals agree that the data are just not clear enough to recommend complementary medicines, and yet most patients take them anyway. Why?

	Archeologists have found that from the beginning of humanity, man has demonstrated a need to understand and to control his environment. When something is a mystery, people will find an answer that brings them comfort and a sense of control, like early man burying tools with the remains of their loved ones for the afterlife. Early medicine is filled with remedies for a host of illnesses, including bloodletting and burr holes to let out the bad humors. These “remedies” were based on anecdotes and good intentions, but in the end were harmful to patients.

	More than 65% of cancer survivors report using some form of “complementary“ or “alternative” medicine while receiving standard therapy, but strikingly, less than half of these patients inform their physicians even when asked.

	This need to understand and control our health and our bodies has not changed or diminished. However, what has changed is our understanding of the causes of cancer and the ability to rationally target therapies. Well-designed clinical trials and molecular pathway elucidation should provide patients with a better insight into the causes and proper treatments of cancer. As oncologists become better equipped with the diagnostic tools and targeted therapies to treat cancer and personalize medicine, it is our hope that patients will feel less inclined to bring along “extra tools” on their journey.

			Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. 

			Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). 

			Albright CD, Salganik RI, Van Dyke T. Dietary depletion of vitamin E and vitamin A inhibits mammary tumor growth and metastasis in transgenic mice.

			Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?. 

			Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. 

Articles

Complementary! Sounds good, how could it hurt? When applied in cancer therapy, however, what sounds good may not always be good for patients.

What Patients Don't Know Might Hurt Them

	For more than 50 years, this country has funded our best scientists and clinicians to develop and test drugs that are proven to prolong and save the lives of patients with cancer. It seems incredulous that we are now running out of these life-saving medications. In 2011, the FDA reported 232 cancer therapies to be in limited supply. As a result, many patients have had therapies delayed or discontinued, and in some cases, patients have been left without access to appropriate alternatives. It appears that there is no single cause to this dangerous problem, but a common contributing factor seems to be an apparent lack of financial incentive for drug companies to continue to manufacture agents that are older and on generics lists, despite the needs of the patients. Further complicating the problem is the growing influence of the so called “Grey Market,” where products are bought and sold outside of the manufacturer’s authorized trading channels, creating an opportunity for secondary distributors to significantly mark up the cost of drugs.

	When we stop to consider the range of factors involved in maintaining appropriate supplies of these drugs, we must first look to the regulatory and market conditions that influence manufacturing. Drugs are created using current good manufacturing practices (cGMPs). cGMP manufacturing creates a standard, proscribed and regulated by the FDA, that is intended to assure the public that a drug is potent and free of contaminants. These standards, while assuring public safety, add considerably to the cost and time to manufacture and distribute a drug. When faced with the decision to manufacture a drug that is coming off patent protection and has a very limited ability to generate a profit, or to manufacture a newly patented drug with the profit margin intact, pharmaceutical companies would appear to have a duty to their shareholders and employees to cut their losses and switch over manufacturing capacity to the new drug. Companies that choose to continue to manufacture low-margin generic drugs will cut costs to drive a profit margin that limits their capacity to ensure quality. As a result, a number of manufacturers have been shut down for quality issues.

	In 2011, the FDA reported 232 cancer therapies to be in limited supply. As a result, many patients have had therapies delayed or discontinued, and in some cases, patients have been left without access to appropriate alternatives.”

	So, let’s do the math. As a nation, we have invested untold billions of dollars to develop drugs that prolong and save lives. However, we have decided that the cost of healthcare is too expensive, and therefore have demanded substantial reductions in what we pay for the very drugs that we invested billions to develop. In essence, we are asking a segment of our market to forget free-market capitalism, and demanding that these companies produce drugs at low margins because we need them.

	When all is said and done, we are left with 232 cancer therapies in limited supplies. Hmm, that’s a shocker.

	In limiting the cost of drugs, it appears that we have created drug shortages, lower-quality manufacturing, and “Grey Markets” that substantially increase the cost of the limited supply of available drugs.

	Perhaps we should consider paying fair-market value for drugs that really work and less for those that do not. Or even better, why not extend patent expirations on efficacious drugs until a more effective replacement is available?

	We learn early on in life that there are no “free lunches.” In this case, not only are patients left hungry, but they’re also in jeopardy of having their lives unnecessarily cut short from our own efforts to limit free-market enterprise.

In 2011, the FDA reported 232 cancer therapies to be in limited supply. As a result, many patients have had therapies delayed or discontinued, and in some cases, patients have been left without access to appropriate alternatives.

Where Are the Drugs?

	Much has been made of the difficulties companies, investigators, and patient advocates have in providing access to novel therapies. These difficulties are due, in part, to the complexities of the regulatory approval process. There are clear examples of where the regulatory approval process has slowed the approval of potentially life-extending medications (eg, Provenge). Largely, delays have been due to questions regarding efficacy or safety. However, until recently, drug approvals have languished when the usual standards by which efficacy is measured were not achieved despite a clear benefit to patients. This has changed in a positive direction with the recent approval of the JAK inhibitor ruxolitinib, for treatment of myelofibrosis.

	JAK1 and JAK2 enzymes regulate blood production, and at times when these enzymes are aberrant, as in myelofibrosis, there is uncontrolled hematopoiesis leading to splenomegaly. In addition to the discomfort caused by splenomegaly, other and more troubling symptoms can occur, including fatigue, fever, night sweats, pruritis, and bone pain. Evolving cachexia, deterioration in blood counts, and ultimate organ failure and death follow after years of suffering. Agents such as thalidomide and, more recently, lenalidomide have been used in conjunction with hydroxyurea to control blood counts and lessen splenomegaly. But efficacy of these agents has been mixed and short term. With the discovery that a mutation of JAK2 was present in some patients with myelofibrosis, the new agent ruxolitinib was tested in clinical trials. Ruxolitinib was found to have a biologic effect in most patients with myelofibrosis, regardless of the JAK2 mutation, but a question arose: Was the effect, although clinically meaningful, adequate for regulatory approval?

	Ruxolitinib was found to have a biologic effect in most patients with myelofibrosis, regardless of the JAK2 mutation, but a question arose: Was the effect, although clinically meaningful, adequate for regulatory approval?”

	Two phase II trials (COMFORT I and II) presented at the 2011 ASCO meeting had unusual endpoints for a cancer drug. Nevertheless, these endpoints were clinically meaningful for patients with myelofibrosis. The studies demonstrated a ≥35% reduction in spleen size and, equally important, significant symptom alleviation. Symptom alleviation as part of a registration endpoint of efficacy of a cancer drug was somewhat surprising to the industry. The decision to include symptom alleviation as an endpoint arose from pre-agreed specifications negotiated with the FDA using a myelofibrosis symptom assessment form that was developed through a collaboration between the FDA and industry. Nearly all patients had a reduction in spleen size, and 42% met criteria for a 35% reduction. Moreover, 46% of patients had at least a 50% decrease in total symptom score. The drug was largely nontoxic and showed evidence, although not extensive, that drug administration may lead to longer survival.

	The debate will continue about how we can and should accelerate drug approval in the United States. Regardless, this is a specific example where industry and the FDA collaborated to create criteria that went beyond the traditional efficacy metric and resulted in a clinically meaningful drug approval.

Much has been made of the difficulties companies, investigators, and patient advocates have in providing access to novel therapies.

Taking Comfort

	The US Food and Drug Administration (FDA), an agency of the US Department of Health and Human Services, has broad authority to regulate food safety, as well as the safety, efficacy, and utilization of drugs and medical devices. A concern for public safety is at the core of the FDA’s mission. The cornerstone of the agency and its longstanding mission was laid in the passing of the Pure Food and Drug Act, also deemed the “Wiley Act,” which was signed into law by President Theodore Roosevelt in 1906. A chemist, Harvey Washington Wiley, MD, ran the predecessor agency, the Bureau of Chemistry from 1883 to 1902, and was responsible for the original effort to regulate drug products through the enactment of the Biologics Control Act in 1902, after a horse serum that was used to treat tetanus caused the deaths of 13 children.

	From its beginning, actions by the agency have sparked considerable political battle and debate over the reach and authority initially held by the Bureau of Chemistry, and later by the newly organized FDA.

	Between 1938 and 1962, the FDA reviewed 13,000 new drug applications. However, it was not until 1962 and the passing of the Kefauver-Harris Amendments (a consequence of the teratogenic effects of thalidomide) that the FDA received the power to decide the fate of drugs using a new standard that required all new drugs to demonstrate “substantial evidence” of efficacy for approval. The Kefauver-Harris Amendments have been at the root of controversy that has led to public challenges of the reach and authority of the FDA.

	The methods by which the FDA approves new drugs have led to several positive changes, including expedited reviews of drugs for life-threatening illnesses (eg, AIDS, cancer) and the new critical path initiative. However, the cardiac fatalities associated with Vioxx use led to increased scrutiny of FDA approval procedures, prompting many to call for more restrictions of the FDA’s authority. In turn, these restrictions have slowed the efforts by some to provide patients with access to unapproved drugs that pass through phase I safety testing.

	This month, FDA Commissioner Margaret A. Hamburg, MD, revoked approval of the antiangiogenic agent bevacizumab (Avastin) for use in patients with metastatic breast cancer. The basis of this decision is embodied in the Kefauver-Harris Amendments because, according to FDA, Avastin did not show “substantial evidence” of efficacy and had substantive associated toxicity. Many critics believe that the decision was made partly due to the cost of drug. However, the FDA has no current authority to approve or revoke a drug based on its cost. Others believe that because the drug works for some but not all patients, it should remain approved until a biomarker can be developed to predict efficacy or futility.

	Because patient safety is one of the FDA’s primary responsibilities, the agency decided to remove approval until “substantial evidence” of efficacy is evident in a prospective, well-defined group. Many women feel betrayed by this decision, and yet others like Frances M. Visco, president of the National Breast Cancer Coalition, appear to support it. The topic is now being discussed among presidential candidates and many state authorities who are once again questioning the role of the FDA.

	In the end, when any agency has the authority to decide what constitutes the appropriate use of a drug or device that others want to use, there will be friction. Add to this our current economic crisis, the soaring cost of healthcare, and our apparent aversion to any level of risk, and you have a volatile list of competing priorities.

	The one thing I am sure about is that Dr Harvey Washington Wiley would be quite pleased that his endeavor to create and impose regulations to keep the public safe marches swiftly on.

The FDA has broad authority to regulate food safety, as well as the safety, efficacy, and utilization of drugs and medical devices.

The FDA Revokes

	When you look up the definition of the word “virus,” several interesting facets of the word emerge: “A corrupting influence;” “a poison produced in a person or animal suffering from an infectious disease;” or the even more clinically descriptive “any of a group of disease-producing agents smaller than bacteria and dependent on living tissue of a host for their reproduction and growth.”

 In the nonclinical realm, viruses can have a profound corrupting influence on software, and often, as a consequence on the functioning of “hardware.” The commonality of the corrupting influence—clinical or not&mdash;is the insertion of information (eg, new code) that alters the otherwise normal functioning of the infected entity, and in the usual case, it is rarely to the benefit of the entity (ie, a cell) or the host in which the entity resides.

	In a recent article in Nature, Breitbach and colleagues

 embrace the corrupting influence of a specific virus (poxvirus), and have been able to tweak the information code of the virus to selectively corrupt cancer cells while sparing (normal) cells that do not have a specific cancer phenotype. The genetically altered virus, JX-594, is a smallpox vaccine derivative of the Wyeth strain of vaccinia virus. To obtain tumor selectivity, the researchers successfully inserted an inactivated thymidine kinase gene together with 2 transgenes: a granulocytemacrophage colony-stimulating factor (GM-CSF)- producing gene to stimulate an immune response and a gene to allow for detection (β-galactosidase).

	In a specific solid tumor type where there is excessive epidermal growth factor receptor-induced Ras signaling, thymidine kinase is produced in large quantities. The engineered virus is able to replicate in the tumor cell somewhat exclusively because the tumor cells provide the thymidine kinase at levels not present in nonmalignant cells. The term oncolytic virus was coined to describe the ability of the virus to target and kill cancer cells.

	In a phase I clinical trial, the JX-594 oncolytic virus resulted in dose-related antitumor activity. Much like the results of the trial of an oncolytic Newcastle disease virus (PV701) that I conducted in 2002

, the JX-594 oncolytic virus selectively infects and replicates in tumor tissue, but not in adjacent healthy tissue or blood mononuclear cells. As in my PV701 study, the greatest clinical effects were observed after dosing of the JX-594 oncolytic virus in the 109 plaqueforming unit range (PFU; 1 virion creates 1 plaque). However, unique to the JX-594 oncolytic virus was the demonstrated ability to insert additional code (ie, GM-CSF production) to enhance the clinical effect.

	It would be fair to say that no one looks forward to having a virus infect them or their computer. However, nature has its wisdom, and the viral transfer of information has contributed significantly to evolution. As we begin to tap that wisdom to our advantage, therapeutics like PV701 and JX-594 may become as ubiquitous as common viruses.

			Breitbach CJ, Burke J, Jonker D, et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. 

			Pecora AL, Rizvi N, Cohen GI, et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. 

A look at tweaking the corruptive influence of the virus information code to selectively corrupt cancer cells while sparing (normal) cells that do not have a specific cancer phenotype.

Not All Viruses Are the Same

	Each of us consists of some 10 to 100 trillion cells and, amazingly, we each start with a single cell. One single cell is capable of reproducing over and over, and also of differentiating (with the help of a few ham sandwiches along the way) to create an adult human able to live over 100 years. With differentiation, cells were thought to lose their ability to replicate or go back to a “de-differentiated” state. However, in vitro laboratory manipulations have shown that this is not the case. In fact, direct manipulation or indirect changes of the cell’s genetic code—read out through changes in methylation patterns or insertion of neoproteins&mdash; can render cells capable of new functions. Thus, in vitro cell manipulation has unleashed the therapeutic potential of human cells.

	Recent news of the potential of cell-based therapy has garnered international attention.

 Researchers from the University of Pennsylvania published results of a gene-modified autologous T-cell therapy for advanced chronic lymphocytic leukemia (CLL). The modified T cells were engineered in vitro to express a chimeric antigen receptor that enabled the T cells to bind to a specific antigen (CD19) on the surface of CLL cells and signal other T cells to multiply and kill CLL cells. The approach resulted in a 1000-fold increase in circulating modified T cells, all capable of killing CLL cells. In the clinical trial, all 3 patients treated had dramatic reductions in their CLL burden and experienced prolonged responses. Equally compelling was the authors’ conclusion that this approach will likely be applicable to a variety of cancer types.

	Another cell therapy story also made recent news, but here the emphasis was not on the cell, but the sell. Dendreon Corporation lost two-thirds of its market value after significantly downgrading its sales forecast of Provenge, a cell therapy for prostate cancer. Once equally heralded as a breakthrough therapy, the issues of limited efficacy relative to cost, reimbursement, and, according to some analysts, poor logistical execution by Dendreon management have resulted in limited utilization of Provenge to date. Dendreon has been in search of a corporate partner, but so far has been unsuccessful, which is thought by some to be due to a fundamental flaw in its business model.

	On its own, with no help from scientists, clinicians, or investors, a single cell can accomplish a lot and lead to a long and healthy life. We are probably some ways off from efficiently tapping the power of cells therapeutically and commercially. Nonetheless, the ability of an autologous dendritic cell (ie, Provenge) or gene-modified T cell to significantly alter the natural history of a cancer in favor of the host is no less remarkable. Over 100 years ago people wondered what would come of tapping into the power of the atom. Just think what they will be saying 100 years from now about the power of cells.

	1. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor—modified T cells in chronic lymphoid leukemia. 

. 2011;365:725-733. doi:10.1056/NEJMoa1103849.

In vitro cell manipulation has unleashed the therapeutic potential of human cells.

Cell or Sell: That Is the Question

	Time is a funny thing to think about. It is finite when it comes to living beings, yet seemingly infinite when it comes to the universe we live in. In the context of caring for cancer patients, all physicians and nurses trained in oncology receive education in quality-of-life issues; however, prolonging quantity of life remains our ultimate goal. In many situations, we are not yet able to prolong quantity of life, but can profoundly affect the quality of life of the patients we treat. People and societies have long accepted the paradox of spending a very brief period of time alive relative to time itself. Until recently, cancer care specialists were not primarily focused on quality-of-life issues; we accepted toxicities of therapy in exchange for prolongation of survival. By adapting the life-prolonging skills they have acquired over the years, oncologists are now conducting research to improve quality of life even when quantity of life is brief and unalterable.

 conducted a study of 823 patients receiving chemotherapy and found that 37% had insomnia and an additional 43% had difficulty falling asleep. Surprisingly, the researchers found that younger patients (aged <55 y) were more likely to have insomnia. In addition, breast cancer and lung cancer patients had the greatest incidence of insomnia, which was highly correlated with depression and fatigue. Thus, the vast majority of patients treated with chemotherapy experience difficulty sleeping and many develop corresponding depression. Similar to new molecular-targeted therapies, efforts are now underway to intervene early with quality-of-life targeted therapies for patients with cancer, particularly if they have incurable disease.

	The power of these quality-of-life initiatives was underscored when oncologists added palliative care to patients with lung cancer before they received chemotherapy. In a study of lung cancer patients receiving chemotherapy, 151 patients were randomized to receive chemotherapy with or without palliative supportive care, including pain management.

 Those receiving the palliative intervention not only had better quality-of-life scores, but surprisingly better overall survival (11.6 mo vs 8.9 mo). Only 16% of patients receiving palliative care with chemotherapy had reported depression compared to 38% who had chemotherapy alone.

	Yoga is another example of a targeted quality-of-life intervention that is getting increased attention due to recent study results. Researchers assessed the benefit of yoga for 410 cancer survivors who reported sleeping problems between 2 and 22 months after completing chemotherapy. Patients received routine medical management for sleep disorder either with or without yoga. Patients receiving yoga had greater improvement in quality of sleep, greater reductions in sleep medication use, and most striking, a 42% reduction in fatigue.

	There is little doubt that we are highly unlikely to change the time paradox anytime soon. Our profession continues to make great strides in preventing premature death and prolonging the lives of our patients. Knowing that death is inevitable, trying simply to prevent it would seem shortsighted and incomplete. As studies indicate, we can provide our patients with great benefit even if we cannot prolong life, through greater application of quality-of-life targeted therapies.

			Palesh OG, Roscoe JA, Mustian KM, et al. Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. 

			Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. 

			Mustian KM, Sprod L, Peppone LJ, et al. Effect of YOCAS yoga on circadian rhythm, anxiety, and mood: A URCC CCOP randomized, controlled clinical trial among 410 cancer survivors. 

In the context of caring for cancer patients, all physicians and nurses trained in oncology receive education in quality-of-life issues; however, prolonging quantity of life remains our ultimate goal.

Quality-of-Life Targeted Therapies

	George W. Sledge Jr, MD, the outgoing president of the American Society of Clinical Oncology (ASCO), gave a forward-looking talk during the recent annual ASCO meeting that he concluded by stating, “Oncologists need to prepare for a new era in which rapidly advancing genetic technology will change the way cancer is treated.” He added, “Physicians are entering an era of genomic chaos—a phrase that describes both the genetic madness that makes healthy cells turn into deadly cancers and the instability that incorporating rapidly advancing genetic technology into cancer care will bring.” Sledge acknowledged that the way clinical trials are run will need to change, and he encouraged physicians to face the onslaught of new technology head-on.

	The elucidation of a specific BRAF gene mutational status (v600E), present in approximately half of patients with advanced life-threatening melanoma, is one example of the potential benefit of harnessing genomic chaos. B-Raf protein, a member of the Raf kinase family of serine/threonine-specific protein kinases, plays a central role in regulating the MAP kinase/ERK signaling pathways that affect cell growth and differentiation. B-Raf protein transcribed from mutated BRAF is capable of stimulation of downstream pathways, independent of upstream receptor signaling. As a result, several drugs have been developed that specifically target the mutation, shutting off mutated BRAF-driven pro-survival and growth. In one trial presented at ASCO (abstract LBA4; see page 17 in this issue), a BRAF inhibitor (vemurafenib) demonstrated unprecedented clinical outcomes, including a 63% reduction in the risk of dying at 6 months (84% alive) when compared with chemotherapy (ie, dacarbazine, 64% alive). Clinical responses usually are delayed, if observed at all, when treating advanced melanoma with chemotherapy. However, responses were observed within 2 to 3 days of starting vemurafenib.

	Another “genomic” targeted therapy, crizotinib, has been in development for patients with anaplastic lymphoma kinase-positive (ALK ) advanced non— small cell lung cancer and is now showing promise. ALK, a member of the insulin receptor superfamily, is a membrane-associated tyrosine kinase receptor. A dependence receptor, ALK fuels the growth and survival of malignant cells and can be blocked by targeted agents such as crizotinib. In a trial presented at ASCO of 82 ALK  patients treated with crizotinib (abstract 7507), 1- and 2-year overall survival (OS) was 77% and 64%, respectively, without yet reaching median overall survival. These data compared favorably with the 37 ALK  control patients not treated with crizotinib (73% and 33%; median OS at 20 months) and 253 ALK-negative patients (49% and 33%; median OS at 11 months).

	The pace of discovery is accelerating. Our healthcare delivery and payer systems need to remain flexible enough to accommodate rapid, significant changes in diagnostic and treatment paradigms as new genomic results mature into validated pathways to guide therapy development and choice. The so-called “black box” that hid the mechanisms of cancer from plain view is slowly but surely being dismantled through a genomic lens. Sledge’s call to arms is well-founded, and if heeded, we will be poised to turn genomic chaos into multiple genomic-guided treatment successes.

Oncologists need to prepare for a new era in which rapidly advancing genetic technology will change the way cancer is treated.

Genomic Chaos

	I am far from unique as a physician whose love for physics is limited only by my inability to “do the math.” I deeply enjoy reading the latest theories “of everything” that try to tie together all of nature’s forces with matter. Recently, significant attention has been focused on dark energy, despite our inability to directly detect it, because it represents 72% of everything in the universe, with regular matter representing only 5% and dark matter filling in the rest at 23%. Adam Riess, an astrophysicist from Johns Hopkins University, received the 2011 Einstein Medal for his confirmation of the effect of dark energy, which was deemed by Science Magazine as the “breakthrough discovery of the year” in 1998. Using the Hubble telescope, Riess and his team discovered that the expansion rate of the known universe is accelerating due to dark energy. Einstein himself thought the so-called cosmologic constant (now called dark energy) that pushed galaxies apart in the face of gravity was his greatest error in judgment. He would be happy today to know he was correct all along and probably amused that his biology colleagues are coming to an analogous conclusion regarding the inner workings of the human cell.

	The symphony of life embodied in each cell of our body is finally coming into focus through systems biology. No longer are we limited to assessing cause and effect through a single pathway. Now, using systems biology, we are able to assess the effect of an external natural stimulus or drug on the entirety of the cellular pathways. Until recently, the understanding of the relationship between stimuli and effect at the cellular level was discernible only in small part, with most intracellular events occurring as a consequence of an amalgam of unknown pathways or “dark energy.” Biology remains an observational science due to the near limitless permutations of possible outcomes for any given stimulus. Nonetheless, there is probably a finite number of outcomes, albeit a large number, that defines a cellular phenotype, including malignant outcomes. Advances and synergies in computational sciences, genomics, epigenomics, transcriptomics, and metabolomics are beginning to enlighten biologists in discerning the pathways to and maintenance of the malignant cell phenotype.

	It is common knowledge that our country and others are on an unsustainable path of increasing healthcare expenditures, particularly in oncology. The cost of drug discovery and ultimate FDA approval is staggering, exceeding $1 billion on average. Most of us realize that it will not be one drug but combinations of drugs that will significantly improve outcomes for our patients and hopefully reduce the overall cost of care. We can no longer support nor wait for the traditional approach of phase I-III in vivo clinical trials to get answers. Instead, using well-designed cellular models and systems biology readouts, drug combinations, sequencing, and dosing can be worked out for a fraction of the cost and time in vitro before time and money is wasted in vivo. In physics and biology, change is heralded by advances in technology. The time has come in biology to shine a bright light on intracellular “dark energy” and help to create a desirable cellular phenotype to improve outcomes for our patients living with cancer.

Recently, significant attention has been focused on dark energy, despite our inability to directly detect it, because it represents 72% of everything in the universe

'Dark Energy' Within the Human Cell

	The explosion of knowledge emanating from laboratories and clinics across the globe is steadily clearing the “haze” that shrouds the molecular basis of malignant cell transformation, growth, and spread. It was first thought to be of limited clinical value to understand expressions of aberrant molecular pathways conferring a malignant phenotype. This began to change with the remarkable yet singular clinical success of identifying aberrant 

—induced tyrosine kinase activity as the cause of chronic myelogenous leukemia (CML). This led to development of a highly effective therapy, imatinib (Gleevec), that transformed the treatment of CML from an allogeneic transplant to a single pill taken daily

	Now, with more recent approvals of other tyrosine kinase inhibitors (sunitinib), mTOR inhibitors (everolimus), histone deacetylase inhibitors (vorinostat), and hypomethylating agents (decitabine), the clinical value of clearing the haze is no longer in question.

	As our patients benefit from the growing clarity of the molecular drivers of cancer, a new haze is blowing in with a ferocity driven by current economics. The federal deficit this year will exceed $1.5 trillion, adding to an already staggering national debt of approximately $14 trillion. Our aging population, compounded by medical breakthroughs that keep patients with disease alive longer, are poised to significantly add to our national financial burden.

	The current proposed solution to limit the rate of growth of healthcare expenditures and improve quality of care is the so-called accountable care organization (ACO). At first blush, ACOs seem fairly straightforward: They allow healthcare providers to organize to deliver higher-quality care at a lower cost, and reward them for doing so. Similar to the early presumed understanding of the cause of cancer that turned out to be woefully superficial and inadequate, when one takes a careful look at the details of the presented inner workings of an ACO, it is not at all clear how it will affect the discovery and delivery of cancer care in the United States.

	As currently planned, ACOs will consist solely of primary care doctors in partnership with other primary care doctors and/or hospitals. A primary care doctor can belong only to one ACO while specialists can belong to multiple ACOs. Is the delivery of cancer care a primary or specialty service? If ACOs are rewarded for cost savings, what will be the effect on delivery of effective but expensive cancer care in the context of overall cost of care in an ACO? How will clinical trials be integrated into the new system? What will become of cancer hospitals that do not employ primary care doctors?

	These are but a few of the many questions facing cancer care delivery. Add to this the growing chorus of the need to eliminate wasteful care, which potentially includes life-extending cancer therapies that may not meet the current economic “value lens.”

	For now it would appear that leaders in cancer care need to remain vigilant so that the investment of time, lives, and capital that resulted in clearing the “cancer haze” is not replaced with a new “economic haze” that again will cloud over the significant advances we have made in cancer discovery and care delivery.

The explosion of knowledge emanating from laboratories and clinics across the globe is steadily clearing the "haze" that shrouds the molecular basis of malignant cell transformation, growth, and spread

Andrew L. Pecora, MD