A general pullback on cancer screening?

BY DEBU TRIPATHY | OCTOBER 28, 2009

A very interesting turn of events occurred this past week in the world of cancer prevention. It was not so much a major discovery or new drug trial result, but rather a political and communication phenomenon. It happened on a couple of fronts.

Noted breast surgeon Laura Esserman at USCF and urologist Ian Thompson at UT-San Antonio published an opinion piece in the widely read and influential Journal of the American Medical Association entitled "Rethinking Screening for Breast and Prostate Cancer." They argue that screening gained momentum as clear differences between the outcomes of early and more advanced stage cancers were noted a long time ago, supporting the importance of early detection of asymptomatic cancer. However, mortality rates attributable to screening have only modestly improved for breast cancer and have not even perceptibly changed for prostate cancer--this may be due to the fact that early detected cancers may never have affected the mortality, or even been clinically detected in the lifetime, of many of the screened cancer cases. Yet the diagnoses of early-stage breast and prostate cancers rose significantly with screening. So did the number of patients requiring therapies that have significant consequences, such as breast surgery effects and early menopause for women and urinary incontinence and erectile dysfunction for men.

Time to rethink screening? This would have been heresy a couple of years ago. In fact, when the National Cancer Institute developed consensus recommendations for mammography in 1993, the disharmony was anything but a consensus among the experts who debated like a hung jury. This culminated in an awkwardly written final statement that screening should begin at age 40, but that individual risks and benefits should be discussed with patients (and how many of you reading this blog who have had mammographic screening remember having this type of discussion with your doctor?)

The other big event was an admission by the American Cancer Society--who has steadfastly maintained the paramount importance of screening--that perhaps they have overstated the benefits of screening. Bravo to the ACS! This is an organization that depends politically and financially on such messages, yet they had the courage to recognize the emerging evidence and make an acknowledgment that is likely to confuse and possibly infuriate their constituency.

So what is the public to do now? They are getting used to contradictory statements on a weekly basis about the importance of a specific vitamins, food supplements, or physical activity. But cancer screening? Wasn't this based on the highest level of evidence and chiseled in stone?

Well, sort of.

No doubt that for cervical cancer, mortality has dropped 90% with Pap smears--an observation so dramatic that randomized trials were not ethical to even perform. Colon cancer is also reasonably secure--in fact just ONE colonoscopy in a lifetime can probably save many lives, and regular screening may lower the cancer death rate by nearly a third. Even mammographic screening for breast cancer does lower breast cancer deaths and should still be carried out as recommended (although interestingly, overall mortality decreases have not really been demonstrated). Prostate screening mortality benefits remain unproven, but clinical data suggests that more aggressive cancers in younger individuals or populations at higher risks (such as those with family history and of African descent) might benefit.

As Drs. Esserman and Thompson point out, the answer may lie in better selecting who and when we screen, and of course, by improving our screening technology to not just pick up ANY malignancy (because as we get older, cancers we harbor are less likely to kill us), but to detect the dangerous ones--based on the biology of the silent cancer as well as host risk factors such as age, family history, and maybe someday, gene testing. Until that time, cancer screening needs to be looked at just like all other medical decisions--a tradeoff between the potential benefits and the risks.

Even in the new era of "personalized screening," tradeoffs will have to be made, but should lead fewer people down the path of unnecessary treatment while still minimizing cancers that present at later and less curable stages.

For more on the recent controversy surrounding cancer screening, read CURE's "Life Preserver?" from the Fall 2009 issue.

A report from the 2009 ASCO Breast Cancer Symposium

BY DEBU TRIPATHY | OCTOBER 14, 2009

The Breast Cancer Symposium, organized by ASCO (American Society of Clinical Oncology) along with several organizations dedicated to breast cancer care and research, held its 3rd annual meeting on October 8-10, 2009. This meeting focuses on translating new information into clinical practice through analysis, discussion, and expert perspectives.

The session topics are a reflection of what is new and rapidly evolving--so this year they included bone health, genetic and other forms of risk for developing breast cancer, survivorship, how to assess lymph nodes at the time of surgery, and new drugs (as well as targets that the drugs attack).

Each topic deserves a separate summary, so I decided to address the first one--bone health, as I was a co-chair on this panel and helped select the speakers and topics.

I remember when it was very common to hospitalize patients with metastatic breast cancer due to bone pain, or high blood calcium, a dangerous complication of bone metastases that causes major metabolic disturbances and affects the brain, kidney, and other organs. Drugs to treat high calcium levels, particularly a class of drugs called bisphosphonates, were developed in the 80s and 90s, rendering these complications very rare indeed.

Then bisphosphonates were also found to prevent other bone problems, such as fractures, and the need for surgery or radiation therapy. They were also found to slow osteoporosis in general and are now widely used for that indication. The most recent finding is that they may even help prevent metastases after early-stage breast cancer, presumably by making the bone less able to harbor microscopic deposits of cancer cells, a potential stepping stone to spread to other parts of the body as well. We will not know for sure until larger and more definitive trials are completed sometime in the next year and beyond. However, bisphosphonates can cause rare side effects such as kidney injury and damage to the jawbone.

Against this backdrop, three lectures were presented that reviewed the state of the art in monitoring the bone in patients with early-stage breast cancer. It turns out that bone thinning (osteopenia) and more marked thinning (osteoporosis), which increase the risk of fractures, are rather common in breast cancer patients, and even made worse over time with early menopause brought on by chemotherapy and anti-hormonal therapy.

Guidelines for monitoring the general population and breast cancer patients were presented--this involves not only measuring bone density with a DEXA scan, bit also looking for risk factors such as slender body shape, history of smoking, or a personal or family history of bone fracture. Physical activity, along with calcium and vitamin D replacement, are the first line of defense and, in fact, should be adopted for all women (and men, who are also susceptible in general, albeit at an older age). However, if the bone density is in the osteopenic range with additional risk factors, or in the osteoporotic range, some form of "antiresorptive therapy," primarily bisphosphonates in patients with breast cancer, should be used.

It is not clear for how long patients should be treated, since some of the more serious side effects, including spontaneous fractures of the femur, might be seen after many years of therapy, justifying a "holiday," or a break for months or even one to two years.

For patients with bone metastases, new surgical and radiation techniques are evolving along with the already established role of bisphosphonates, and these were reviewed in the second lecture.

The third lecture focused on newer drugs that may have fewer side effects. Denosumab is an antibody that, like bisphosphonates, inhibits osteoclasts (cells that break down and remove bone calcium), but through a different mechanism. When compared with the bisphosphonate Zometa (zoledronate) in patients with bone metastases, it was recently found to have a greater reduction in bone complications with fewer kidney side effects. However, osteonecrosis of the jaw was seen equally with either drug, at a rate of 1.5-2.

Denosumab is being reviewed by the FDA for osteoporosis (not related to cancer) on the basis of other clinical trials and may eventually also be approved for bone metastases. This series of studies demonstrates the evolution of bone protection initially for metastases, then osteoporosis, and even lowering the risks of metastases--so bone health has clearly become an important theme in the overall management of breast cancer.

Clearly, the standards of care have rapidly evolved in this area--so efforts to make every oncologist fluent in this field are critical.

Pushing your doctor for a survivorship care plan

BY DEBU TRIPATHY | OCTOBER 2, 2009

We have received several comments about the new trend and recommended practice of survivorship plans for patients following cancer treatment. By way of background, there has been a widening recognition that cancer patients are lost in the shuffle after a diagnosis of cancer and when they go back to their regular life and routine medical care.

Given the growing number of cancer survivors and more awareness of the need for special types of monitoring for long-term side effects, several organizations like the Institute of Medicine and the American Society of Clinical Oncology have made recommendations to develop treatment summaries and survivorship plans for patients and their primary care providers.

Several contributors to the CURE Message Board have weighed in that while they believe survivorship plans are good ideas, they are not getting a welcome reception from their doctors. Others have commented that their own research and thoughts about cancer treatments are dismissed by their oncologists.

It turns out that doctors and the medical field in general are vulnerable to the same inertia that we all experience when it comes to change. Two decades ago, it was unheard of for doctors to explain the pros and cons of their treatment recommendations in detail or to solicit opinions from their patients regarding alternative approaches.

Centering care around the patient is a welcome trend, but it is still young. The field of survivorship has matured in part due to the growing voice of patient advocates who pressured the government and other agencies to increase research funding and services for those living with or after cancer. The fruits of awareness and research are now being evidenced by new guidelines for survivorship. But change in physicians' attitudes can be slow, but I suspect that survivorship plans, even with input from patients themselves, will soon become routine.

There are well over 10 million survivors in the U.S. so every physician needs to have knowledge on monitoring and addressing problems that can arise. Oncologists will not be able to follow all their patients long-term with the looming shortage of cancer specialists and increasing complexity of cancer treatments. So the movement toward survivorship wellness will clearly continue and will be further refined not only by the medical field, but also by patients and the public--perhaps even through CURE's message board.

What do we look for in new drugs?

BY DEBU TRIPATHY | SEPTEMBER 18, 2009

Amid all the hoopla about a new drug approval, we sometimes lose sight of what we are actually gaining. Words like "significant improvement," "benefit," and "new treatment option" all sound like important milestones and lead to the logical conclusion that if the situation applies, the new drug should now be used.

The technical term for what we measure that tells us how well a drug works is called an "endpoint." Different endpoints are used for different trials. Most companies that develop a new drug are primarily interested in getting approval by the Food and Drug Administration and in getting it as quickly as possible. The FDA does not have firm rules on what endpoint is required for drug approval, although they do have guidelines for what is used.

The endpoint of survival--measured as how long patients live after being started on a drug--is the gold standard. But this is the hardest to prove because it requires the most patients and the most time (and expense) to conduct. However, time-to-disease progression (the time from the start of treatment to when scans show the cancer has grown by a specified amount) is another endpoint that will sometimes lead to an approval, especially if the available treatment options have more side effects, or if there is no effective standard therapy.

The flimsiest endpoint is response rate--the percentage of patients who experience shrinkage of tumor. Some argue that time to progression and response rate are "surrogates" for survival, since many studies show that all these endpoints seem to go in the same direction for a given trial. However, this is not always the case.

For less common cancers, it is not possible to enroll enough patients to demonstrate a survival difference attributable to a new drug, so the FDA must use other endpoints. In early-stage cancers that are highly curable (like hormone receptor-positive breast cancer), the number of deaths is so low that, again, time to recurrence must be used as a surrogate. For common cancers, survival advantages must usually be proven, especially for first-line therapy (the first treatment given for advanced disease).

However, this was not the case when Avastin was approved for breast cancer, in part because time to disease progression was nearly doubled even though no survival difference was seen.

There is no clear answer to this debate. One solution is to streamline the research process and increase the number of centers that are able to do trials, such that large numbers of patients can be enrolled quickly and the gold standard of survival improvement can be proven or disproven. The downside is that the "quick and dirty" approach might overlook important safety issues.

The other technological solution is to "validate" surrogate markers, even lab tests, such as one that measures the number of circulating tumor cells that can be determined within weeks of giving experimental therapy. Such studies are ongoing and these may represent the best route, although the validation studies themselves can be time consuming, difficult to interpret, and not generalizeable to different types of cancers or stages of disease.

In this day and age of personalized therapies and new drugs given for smaller subsets of patients, the challenge to enroll high numbers is even greater, but at the same time, the hope is that the differences in outcome will be more striking, such that survival differences can be shown with fewer patients (for example as was the case with PARP inhibitors in "triple-negative" breast cancer (see the "Targeting the Triple Threat" in the Fall issue of CURE).

The argument for what endpoint is best will continue for some time from the halls of academia to the corporate boardrooms to the FDA hearing rooms.

Rationing health care: More heat than light

BY DEBU TRIPATHY | SEPTEMBER 1, 2009

It is hard to avoid blogging about health care reform in the world of cancer at the present moment. It is a bright flashing light on our radar screen.

Cancer care is so complex and typically a long-term process, so it will obviously be affected by any change in health care, let alone massive reform. One of the more contentious aspects of reform is the rationing of health care, particularly in cases where overall outcomes are not good and therapy is often futile. The recent flap about "death panels" has brought up an important point--to what extent should doctors be encouraged (or mandated) to address end-of-life issues and what exactly should their advice and actions be in this regard?

There is no doubt that oncologists in many cases do not adequately discuss issues of curability, probabilities of successful therapy, or prognosis--especially for incurable cancer. This is also true of non-malignant but life-threatening diseases like advanced congestive heart failure or chronic pulmonary disease. At the same time, doctors should not impart their values on the patients' decisions. One potential health plan attempts to level the playing field by providing templates for doctors and allowing multiple constituents (not the government, as rumor has it) to develop and continually improve these templates, which are meant to serve as guides, not absolute mandates.

For this plan to work, the public needs to educate itself and take some responsibility, just as they did with deciphering the complicated Medicare drug coverage plans or changes in the tax code, for that matter. However, at the crux of the argument is whether physicians should primarily advocate for the patient or whether they are also wardens of society-at-large. In our current system, the "have-nots" cannot get even basic care, whereas those with insurance and the means to cover co-payments and other expenses can receive very costly treatment even for questionable or marginal benefits.

Should physicians adopt agreed-upon cost/benefit lines and apply them consistently for all patients? The recent town hall meetings were dominated by those who have something to lose and not those who have something to gain, and the idea of denying care either due to cost-effectiveness or other factors, such as the co-morbidities, age, and likelihood of survival has been roundly criticized in these forums. It appears that, for now, there is an impasse between the need to distribute care resources equitably and the desire by most individuals to keep medical decisions between doctors and their patients. Not the best recipe for cost containment, but perhaps a slight recalibration in everyone's thinking as to how we measure quality health care and innovation.

In the cancer field, this means a continuation of the trend to personalize medicine--that is, to avoid diagnostic and therapeutic treatments that do not clearly improve outcome (see CURE's article on CA125 level measurements for ovarian cancer recurrence, "CA-125 Monitoring Not Helpful for Ovarian Cancer Survivors"), and to develop more effective therapies for biologically defined subsets of disease.

A new career trajectory combines medicine, research, education, and advocacy

BY DEBU TRIPATHY | JULY 31, 2009

I am privileged to be in a field that is constantly changing and to have the opportunity to help those with cancer live a healthier and long life. Like many of my colleagues I struggle to find how to best use my knowledge and abilities to advance cancer care and to strike a personal balance.

What has worked best for me is to continually evolve, but to keep a part of each phase of my career active as I move forward. Two years ago, I left academic life full time to run a medical education company, Physicians' Education Resource (PER), that focuses in oncology, and to serve as editor-in-chief of CURE magazine that is published by PER's sister company.

I chose to focus on peer education--after all, what good are all the fruits of laboratory research and clinical trials if they are not applied properly in patient care? Through my work at CURE, I was able to address another important educational mission--the empowerment of patients and their loved ones with useful information.

I am now embarking on yet another direction as I return to academia full time as co-leader of the Women's Cancer Program and Professor of Medicine at the University of Southern California and Norris Comprehensive Cancer Center.

I will stay involved with PER as the Chair of the Medical Advisory Committee--a group of oncologists that will provide clinical input in the myriad of continuing medical education programs that span the different types of malignancies. And thankfully, I will continue in my role as editor-in-chief of CURE magazine. I missed the discovery from the frontiers of biological science--the chance to link what we know of the genomic and protein drivers of cancer toward meaningful solutions for patients.

My prior research at the University of Texas Southwestern Medical Center focused on understanding why cancer cells could start out or become resistant to Herceptin and other newer drugs targeting the HER2 gene. At USC, I plan to continue to ask these and other questions that address tumor evolution--through the study of tumor tissue from patients undergoing treatment.

This field of translational medicine offers insights that cannot be gained in the laboratory. The challenge is designing the trials and the analysis in such a way that candidate genes and proteins emerge--new targets to which drugs can be made to reverse resistance and inform us about rational combinations of "synergistic" treatments, whereby two or more agents are much more effective than the sum of their individual activities. The problem with most advanced cancers is that available therapies do not wipe them out sufficiently and the few cells that are left are resistant because the tiny fraction that may have had less responsiveness to treatment initially now multiply and take over the tumor.

Translational work is exciting, but moves slowly and requires not only large teams of specialists in different fields, but cooperation across universities, medical centers, pharmaceutical companies, and governmental agencies. I look forward to building more bridges and exploring innovative ways to crack to code of resistance to different therapies for breast cancer.

At the same time, I honor my duty to keep my colleagues abreast of how new advances are best applied, and hearing back from them the regarding challenges and uncertainties they face in the clinic. Learning is a two-way street and I always gain knowledge from the medical education process whether I am the "teacher" or the "learner." The same holds true about communicating with patients and the public at large.

As I move into my new position, I marvel at the community of which I am a part. Medicine, research, education, and advocacy are inseparable in my mind and I am fortunate to merge my prior experiences in my new career trajectory.

Comparative effectiveness: rationing health care or reforming it?

BY DEBU TRIPATHY | JULY 22, 2009

"Comparative effectiveness" has become a buzzword in the health field and a political powder keg--a big ticket item to be financed by the federal stimulus package and endorsed by the Institute of Medicine. Opponents of this discipline say that it is the first step toward rationing health care, while proponents say this is necessary to save our health system from total collapse. What exactly does this term mean and why is it so polarizing?

Comparative effectiveness basically means the study of how much cost and resources a given medical test, procedure, or treatment consumes in relationship to how much it improves health, which is usually measured by how long someone lives and with what quality of life and ability to function. In essence, it is the "bang for the buck" you get from health care dollars, for which we all pay for one way or another.

The reason that it has negative connotations is in part due to the fact that in England the National Institute for Health and Clinical Excellence (NICE) has used cost calculations per "quality adjusted life-year (QALY)" saved as an index for what the National Health Service (the nationalized health program) will and will not cover anything that costs more than 30,000 British pounds per QALY saved. While there are exceptions to this rule, many have considered this to represent health care rationing. Not only might this disallow a potentially life-saving treatment, but it might discourage the private sector from investing in medical technology and stymie the advances we have enjoyed over the recent years.

However, research in comparative effectiveness might not be such a bad thing after all. For one, we know that spending more money on tests and treatment can improve health, but only to a certain point. Many health strategies, particularly those that prevent disease in the first place (exercise, smoking cessation, vaccines, hypertension treatment), improve longevity at lower costs, but you get diminishing returns for every extra dollar spent (see figure below). It only makes sense that the line has to be drawn somewhere since we have finite health care dollars to spend. As you can in the figure, the difference between the two dashed lines represents a very large outlay for a small potential benefit.

On the other hand, the problem with benefit-cost curves is that they represent the average of all patients in the analysis. They hide the fact that a few people who get a "low yield" therapy might actually see spectacular results. Of course, when you or your loved one has cancer, you may roundly object if the treatment plan your oncologist outlines is beyond the threshold for payment. The mindset changes to wanting to take the gamble when it applies to you. As we develop better tools to personalize therapy and better identify more precisely who benefits from low yield therapies, we can take less gambles and make more informed decisions.

Comparative effectiveness research allows us to know the shape of the curve, but it does not force us to adopt rules. It can help us make more informed decisions as to how to spend health dollars for the best collective health of the population--these decisions cannot rest with just lawmakers, policy wonks, or even physicians and scientists. They must be made with representation from all who pay into health care, so a broad consortium must deliberate on what to do with the data. This is much better than many of today's arbitrary coverage rules made in the dark.

What we need in addition to comparative research is more study on biomarkers and predictive tests that will focus expensive therapies where they are most effective, significantly lowering the cost per QALY saved and thereby lowering overall health care costs. One compromise could be that a new expensive technology or drug could be conditionally approved if the sponsor agrees to conduct further studies to define subsets of patients who benefit the most--otherwise, the cost (or covered amount) would then have to fall in line with an agreed-upon cost per QALY saved. This might give us the best of both worlds--an environment that supports the development and availability of new technology, but also requires efforts to ensure the costs (and side effects) be applied in cases where the chances of success are reasonably good.

Additional information on comparative effectiveness can be found in the New England Journal of Medicine:

A Time for Revolutions -- The Role of Clinicians in Health Care Reform July 22, 2009

Comparative Effectiveness -- Thinking beyond Medication A versus Medication B July 23, 2009

Prioritizing Comparative-Effectiveness Research -- IOM Recommendations July 30, 2009

PARP inhibitors create buzz at ASCO

BY DEBU TRIPATHY | JUNE 8, 2009

What happens when a preliminary study that was not designed for drug approval ends up showing dramatic results? A study in patients with advanced "triple negative" breast cancer (defined as being negative for estrogen, progesterone, and HER2 receptors) compared chemotherapy (Gemzar and carboplatin) with or without BSI-201, a poly ADP-ribose polymerase (PARP) inhibitor. PARP inhibitors have been shown to work exceptionally well in the laboratory against cancers that have defects in DNA repair – this is an abnormality that is prominent in cancers that derive from patients who have inherited mutations in the breast and ovarian cancer predisposing genes BRCA1 and 2. It turns out that BRCA1-associated tumors tend to be triple negative (although not all triple negative tumors have abnormalities of the BRCA pathways). This was a preliminary phase II study, so even though it was randomized, it did not have enough patients to qualify as an FDA-approval trial. But it nevertheless showed unprecedented effects on inducing tumor responses, delaying time to progression, and improving survival – even greater than hormonal therapy and Herceptin have. We all know that smaller studies can sometimes be irreproducible and overestimate real benefits, but given the paucity of therapies and the aggressive nature of refractory triple negative advanced breast cancer, we might see some unusual developments as a result of this study – such as the establishment of a compassionate trial that is made widely available while more definitive trials are being pursued. These results have created quite a buzz among my colleagues in the breast cancer research arena. Many of us wonder whether it would even be possible to randomize patients with this type of cancer to a non-PARP containing arm in a clinical trial. At the same time, these results must be confirmed in a larger and more reliable study. A trial design that allows patients to cross over to the active drug if they progress on the placebo arm is a strategy that might address some of the concerns, but this trial design tends to obscure survival benefits. The trials will also need to be able to explore different biological subsets to pin down exactly what type of patient benefits most. Still, we prefer to have all these dilemmas to address when a potentially new important drug can be added to our armamentarium.

Update from ASCO: Personalizing breast cancer treatment

BY DEBU TRIPATHY | JUNE 8, 2009

At ASCO's breast cancer oral abstract session, several findings that highlight this year's overall ASCO theme of personalized medicine were presented.

It has been postulated that differences we inherit in genes that metabolize drugs might make a difference in how we react to them. Tamoxifen, a hormonal agent that has been used for three decades and shown to lower the risk of recurrence of hormone responsive breast, has recently been shown to be made more active when it is metabolized, or chemically changed into a more active compound called endoxifen. Studies have shown that those who inherited "weak" versions of the enzymes (particularly one called CYP2D6) that metabolize tamoxifen may have a higher risk of recurrence, presumably because they are not able to form the most active form of hormonal therapy.

Certain drugs, like some antidepressants, can also inhibit this enzyme. Two large "real life" studies taken from pharmacy services that were used over a period of several years to look at the relationship between the outcomes of patients on tamoxifen and whether they also took drugs that inhibit CYP2D6 were presented. One showed more recurrences in those that took inhibiting drugs, while the other smaller study did not. So, the jury is still out as to whether this theory still holds water. However, since we know a lot about what drugs inhibit CYP2D6, it makes sense to avoid these when one is taking tamoxifen.

The trickier question, not addressed in this study, is whether we should be doing gene testing on everyone for whom tamoxifen is recommended. These tests are already available, but we are not sure what to do. For example, in a premenopausal woman with early-stage estrogen receptor-positive cancer who has a "slow metabolizer" genetic variant of CYP2D, should we then block or remove the ovaries and use an aromatase inhibitor? This is a more complicated therapy with more potential side effects, but we do not yet have enough information to make this a standard of care.

Other lectures in this session reviewed markers that predict recurrence risk and help with therapy decisions for early-stage breast cancer. Over the last few years, sophisticated tumor studies that measure the activity of multiple genes have been developed, but they have not been tested in what is called a prospective fashion. That is, the test is used for making a decision, and then the performance of the test is measured based on how patients actually do over time.

One older biochemical test called uPA/PAI-1 (urokinase plasminogen activator and plasminogen activator inhibitor-1) developed over 10 years ago was actually tested in this fashion and the updated results do confirm that this test can segregate those at low versus higher risk of recurrence and also showed that the higher risk group benefited from chemotherapy compared to no treatment. This test never really caught on in the U.S. because of the inconvenience of requiring fresh tissue to be submitted. Now that more sophisticated multi-gene tests are used for prognostication, we are awaiting prospective trials which are years away from completion, but already these assays are being used based on retrospective data. The most important prerequisite to deciding what test to use is that the oncologist and the patient review how the risk/benefit analysis and subsequent treatment decisions would be affected the results of the test prior to ordering it.