Health care reform -- Is there a Top 10 list?

BY DEBU TRIPATHY | MARCH 5, 2010

With all the political debate and drama regarding health care reform, the forgotten party, of course, is the general public - the consumer of health care. With a massive bill still in play, there appears to be an "all or nothing" mentality. Perhaps the public really deserves incremental improvements, starting with areas of consensus rather than seismic change in health care that carries a staggering price tag.

What, then, would be at the top of our list? I can give this a try:

> For one, people who already have insurance should count on coverage without worrying whether a disease was called pre-existing or not (fortunately, this is included in the House version of the bill).

> Second, if there is a public or minimal cost option, we should take advantage of a fresh start and offer coverage for a defined range of care that is clearly cost effective - for example, prenatal care, vaccinations, screening and treatment of hypertension and diabetes, and screening for cervical cancer. Of course, going down this path requires that comparative effectiveness research is carried out to serve as a basis for making these decisions.

> Third, waste and duplication should be addressed - starting with Medicare and other federally funded programs. This will require data systems and electronic medical records such that payment to hospitals and doctors would be contingent on electronic reporting (the government missed the boat years ago when it could have mandated this type of reporting for payment).

I could go on and on, but the point is that slow and steady progress with reform, starting with "low-hanging fruit" where there is agreement and a large impact from a small degree of change, is a much more preferable route than what we have now.

What will this mean for cancer care? Most likely it means that the emphasis will be on early detection and proper treatment for early-stage or curable cancers. Next would be strategies that improve survival and quality of life. Treatments that delay progression of cancer but do not impact survival or quality of life might not get covered - at least by lower cost insurance (or public options). Same for diagnostic tests that have not proven to improve outcome (there is a large list of these). However, as is the case with other technical fields, the avant-garde and unaffordable innovations would drift into greater availability and lower cost over time if the rules of the game were changed.

Whatever becomes of the health care bill, we must stay engaged with our lawmakers to press for the most important changes - one step at a time.

San Antonio Breast Cancer Symposium: What have we learned and where are we going?

BY DEBU TRIPATHY | DECEMBER 14, 2009

Any high-impact scientific meeting will end with a sense of new direction, priorities for research, and expectations for clinically meaningful advances in the coming years. Based on presentations over the last few days, we may see new candidate risk stratification or diagnostic markers, such as blood microRNA and optical imaging. The impact of MRI screening and diagnosis will be better understood. We could see further studies looking at the preventive nature of metformin and other strategies that affect energy balance.

The number of settings in which we use gene profiling tests and the number of assays available will likely grow. Hormonal therapy regimens will probably not change since key trials assessing oophorectomy will not be out for some time, but better guidance may arise from assays such as CYP2D6 which for now gives conflicting results in relationship to the effectiveness of tamoxifen --as well as factors that may tell us who is at most risk for toxicities and noncompliance of therapy.

The impact of bisphosphonates and newer bone-targeting agents on risk of cancer, risk of recurrence, as well as on bone metastases should all be better characterized, with results from a pivotal study in the adjuvant setting which will likely influence practice for a large proportion of patients. There is now more evidence to use Herceptin with chemotherapy instead of after it, and more confirmation that non-anthracyline regimens with Herceptin are safer on the heart and probably just as effective--so it is hoped that better clinical and biomarker factors will emerge to tailor therapy in this situation.

The line of therapy and the drugs which we combine with the anti-angiogenic antibody Avastin will probably change in the eyes of some oncologists but not others. Newer anti-HER2 therapies will be further expanded into clinical trials, with the possibility of some of the more effective and less toxic drugs even being approved for compassionate use. The same holds true for drugs like poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors. However, many other newer drugs like anti-angiogenic tyrosine kinase inhibitors face an uncertain future due to modest or negative results, and will need to further study. Fundamental discoveries about cancer progression and mechanisms of drug action and resistance are being translated into newer therapies--those expected to generate phase I or II trial data in the next year include PI3 kinase inhibitors, insulin-like growth factor receptor inhibitors along with Notch and other stem-cell pathway modulators.

Newer insights on meeting the needs of survivors and incorporating the needs of patients and advocates into research, clinical trial awareness/accrual, and public policy will continue to emerge as they have this year. This meeting will certainly continue its unique multi-disciplinary role in the breast cancer community through the inclusion and active participating of all its constituents in the presentation, interpretation, and the application of new data.

To read the rest of CURE's coverage of SABCS 2009, visit sabcs2009.curetoday.com

Updates on treatment for HER2-positive breast cancer

BY DEBU TRIPATHY | DECEMBER 13, 2009

In this morning's session, two updated results were presented on HER2-positive breast cancer.

The first one was a trial that compared the HER2 kinase inhibitor, Tykerb, alone or in combination with Herceptin in patients who had already progressed on Herceptin therapy. This strategy of "dual" blockade of the same target (HER2) is based on the notion that resistance to Herceptin might be overcome with Tykerb since it acts on a different part of the HER2 protein. This appears to be the case in the laboratory, and this study was reported earlier, showing an increase in the time to progression with both drugs compared to Tykerb alone.

This follow-up study was to look at survival, which was confounded by the fact that three-quarters of the patients who progressed on Tykerb had Herceptin added to their treatment, possibly diluting any survival difference. Still, this study showed an improvement in survival with dual blockade, about five months longer--this was statistically significant. Serious cardiac side effects were uncommon, 2 percent in the combination arm. This is the only study that has shown a survival advantage in patients who have progressed on Herceptin or with combination targeted therapy; therefore, the presenter, Dr. Kimberly Blackwell, felt that this all-biological regimen was a reasonable choice for patients in this setting, in addition to the approved Xeloda plus Tykerb regimen.

This study was followed by a presentation of the BCIRG 006 trial that examined Herceptin added to chemotherapy in the adjuvant setting. This study was unique among the four major adjuvant trials in that it tested a regimen (known as TCH, for Taxotere, carboplatin, and Herceptin) that did not include Adriamycin, a standard chemotherapy drug that can cause heart failure when used alone and can accentuate this side effect that is also caused by Herceptin.

The question that has not been fully answered is whether this regimen is equally as effective as the more standard combination of Adriamycin plus Cytoxan followed by a taxane plus Herceptin (AC/TH). The TCH regimen has already been adopted widely as it causes less heart side effects, and the final results of the update did indeed confirm that TCH was as good as AC/TH, with both these regimens being superior to the non-Herceptin comparator regimen of AC/T. While there were slightly more recurrences with TCH compared to AC/TH, this was not statistically significant. In addition, the small risk of leukemia that is known to occur with Adriamycin was not seen with TCH (except in one patient diagnosed with lymphoma after breast cancer and was treated with Adriamycin prior to developing leukemia).

According to the presenter, Dr. Dennis Slamon, who has spearheaded the scientific and clinical development of HER2-targeted therapy, TCH can now be considered as effective even for high-risk HER2-positive early stage breast cancer. The subgroup of higher risk patients with four or more nodes showed similar outcomes with either Herceptin-containing regimen. He also showed some controversial information about patients who exhibit gene amplification of topoisomerase II, a cell cycle-dependent gene that is also a target of Adriamycin, and is seen in about one third of HER2-positive cases. These patients appear to be sensitive to Adriamycin such that they do not even appear to benefit from adding Herceptin, with all three regimens being equivalent in this patient subset. He still favors TCH for this group given the absence of leukemia risk seen with the two other regimens (AC/T and AC/TH).

To read more articles from CURE's coverage of SABCS 2009, visit sabcs2009.curetoday.com

The importance of cellular pathways and updates on anti-angiogenic drugs

BY DEBU TRIPATHY | DECEMBER 11, 2009

Today's morning session started off with a heavy dose of basic science--two important pathways were discussed. One is a key driver of cell growth that originates from growth factor receptors and is transmitted through an enzyme called PI3 kinase. This pivotal enzyme is regulated (or turned off) by another enzyme called PTEN. It turns out that there are mutations in PI3 kinase as well as PTEN that can deregulate this pathway and lead to cell growth and also resistance to growth factor receptor antibody drugs. While we are years away from new therapies in the clinic, there are already PI3 kinase inhibitors in clinical trials.

Another pathway is less understood and leads to a cellular transformation termed epithelial-mesenchymal transition, whereby tumor cells may actually evolve into more difficult to treat cancer stem cells. Stem cells are thought to be responsible for recurrence and drug resistance, but newer drugs that target stem cells are now in clinical trials. Dr. Jenny Chang presented both animal and human clinical trial tissue-based data that preliminary shows effectiveness of these drugs at the cell level. Of course, the final proof of these drugs will be in later trials that will be ongoing over the next few years.

The afternoon session reviewed a follow-up of a trial of Avastin that showed an improvement in progression-free (but not overall) survival when added to the chemotherapy Taxotere for metastatic breast cancer--confirming early results. A newly presented trial, Ribbon II, examined Avastin in patients who had already received chemotherapy for advanced disease (second line) and showed that in this situation, Avastin can also delay progression when added to several types of chemotherapy (taxanes and capecitabine). This might expand the settings in which Avastin can be used, but several audience members questioned whether the lack of a survival benefit should justify the routine use of Avastin.

New anti-angiogenic kinase inhibitors are being tested in addition to chemotherapy and two trials of the drug Nexevar, already approved for kidney cancer, were tested in addition to Xeloda or Taxol in two separate studies, compared to chemotherapy alone. The Taxol study showed a very slight benefit, but the Xeloda study showed a clear improvement in progression-free survival. Both of these were smaller trials and not the type that the FDA would review for approval, but will probably lead to more definitive studies. In both cases, side effects were rather prominent, especially with hand/foot syndrome seen in the Xeloda study--although the presenting investigator, Dr. Jose Baselga, felt that these could be lessened with closer monitoring and more rapid dose adjustments. The general theme of how small of a benefit is worthwhile was again brought up--especially in light of the side effects. The larger trials will have formal quality of life analyses. Another anti-angiogenic kinase inhibitor, sunitinib, also already approved in kidney cancer was compared to Xeloda, both drugs given by themselves, and somewhat surprisingly, Xeloda was better than sunitinib. So this drug will probably not be further developed for breast cancer, at least not as a single agent.

To read more articles from CURE's coverage of SABCS 2009, visit sabcs2009.curetoday.com

Bisphosphonates and breast cancer risk

BY DEBU TRIPATHY | DECEMBER 11, 2009

Breast cancer prevention can be accomplished with tamoxifen, and this cuts the risk by about one-third to one-half, but very few women actually choose to go this route--in part, due to side effects. Dietary prevention studies have been negative as well, although with longer follow-up, we may find some benefit with very low-fat and high-vegetable diets.

But what about bisphosphonates? These drugs are already approved for osteoporosis as well as for patients with bone metastases. There is now some evidence that these drugs might prevent recurrence in patients with early stage breast cancer and definitive studies examining this will be out soon. Dr. Rowan Chlebowski presented data from a series of studies in 151,000 postmenopausal women that were studying diet, hormonal replacement, vitamin D, and calcium replacement. He looked at the small fraction of women who happened to be taking bisphosphonates for low-bone mineral density, and using the appropriate statistical adjustments, he found that the risk of breast cancer was lowered by about one-third.

This is very intriguing information about a completely new way to lower breast cancer risk, but this type of analysis cannot fully assure that other factors might account for the lowered risk. For example, these patients also weighed less than average, and while the analysis attempted to correct for many such factors, it is impossible to fully correct for unknown factors that may also be associated with bisphosphonate use. Still, this is a very compelling analysis and needs to be studied formally in a prospective trial, as a separate case-control study of patients in Northern Israel presented at the same session showed similar results.

Individuals carrying BRCA1 or BRCA2 mutations are at very high risk of breast cancer, and MRI screening appears to be more sensitive in picking up cancers compared to mammogram in this population. During an SABCS session on Thursday, Dr. Ellen Warner reported on a large group of such patients who underwent regular MRI screening at Sunnybrook Regional Cancer Center in Toronto who were compared to a group of similar patients at several centers who only had mammographic screening. The purpose of this study was to verify that patients screened by MRI and mammography would be picked up at lower stages of cancer compared to mammography alone.

This study did indeed show that the average tumor size with MRI screening was 9 compared to 18 millimeters and that more patients had in situ (pre-invasive) or stage 1 cancers with MRI screening, whereas those who had mammographic-only screening had more stage 2 and 3 cancers. While this study does not definitely prove that MRI screening will lead to better curability of cancer in the setting of BRCA mutations, it does provide more support for this approach--one that is already recommended by the American Cancer Society as well as other organizations.

To read more articles from CURE's coverage of SABCS 2009, visit sabcs2009.curetoday.com

New insights on hormonal therapies

BY DEBU TRIPATHY | DECEMBER 10, 2009

The theme of this morning's SABCS session was adjuvant hormonal therapy--an important topic given the fact that 70 percent of all women with early stage breast cancer receive this. Aromatase inhibitors (AIs) have become the preferred type of hormonal therapy over tamoxifen for postmenopausal women as this leads to fewer recurrences.

The TEAM trial looked at the "switching" strategy of tamoxifen for two to three years followed by the AI Aromasin (exemestane) for two to three years compared to Aromasin for five years and found this to be equivalent. It was nice to hear very educated questions from a breast cancer advocate at the end of this session inquiring as to whether genetic variations that affect tamoxifen metabolism were examined, and the response was that this relevant issue will be examined in the near future.

The older IES study that compared the switching regimen to tamoxifen for five years continues to show lowered recurrence, now with a slight survival. Therefore, we have solid evidence to show that an AI, whether used for the full five years, or for three years after two years of tamoxifen is better than tamoxifen alone. The big question now is whether more than five years of an AI (or more than three years if you took tamoxifen for two years prior to the AI) will be even better, and this is currently being studied.

Another study called MA.17 had already shown that five years of the AI Femara (letrozole) given after five years of tamoxifen is better than just five years of tamoxifen. Today, a sub-analysis was presented on the few patients who were premenopausal at the time of diagnosis and either had their ovaries removed or went through menopause during chemotherapy, but before hormonal therapy started. This showed a more pronounced effect of letrozole, so it will be interesting to see if this can be confirmed in other trials.

Finally, in this and other studies, analysis of inherited genes showed that a specific variation in a gene, involved in inflammation and immunity, might be responsible for some of the side effects seen with AIs. Understanding this mechanism might lead to understanding who might be at risk for these side effects and might even lead to treatment for the few patients in which these side effects are disabling.

Alcohol has been shown to be a mild risk factor for breast cancer in numerous studies, but we do not know if women already diagnosed with breast cancer might have a higher risk of recurrence based on alcohol use. The research group at Kaiser reported a large series of nearly 2,000 patients with breast cancer who were given extensive questionnaires on diet, alcohol, and other lifestyle factors. With about eight years of follow-up, patients who consumed three to four drinks a week or more had approximately one-third more recurrences and about one-half more breast cancer deaths. However, alcohol might protect against heart disease, which might explain the fact that deaths from other causes were lower, although this was not statistically significant. This adds more reason to suggest a comprehensive lifestyle approach to moderate or minimize alcohol use as well as to follow a heart-healthy diet and a physical activity regimen for everyone.

To read more articles from CURE's coverage of SABCS 2009, visit sabcs2009.curetoday.com

What to expect in 2009 at SABCS

BY DEBU TRIPATHY | DECEMBER 9, 2009

The 32nd San Antonio Breast Cancer Symposium has a slightly different flavor this year--more definitive trial data that will influence how we take care of breast cancer. Last year happened to be a time when few major trials with immediate implications were presented. But many preliminary findings from the laboratory and from early phase clinical trials were presented that set the stage for this year. Of course, we could not have more high-impact results without all the preliminary studies--they are all important in the grand scheme. This year, the timing was such that several trials now have complete data to report. Keep in mind that we cannot predict when the information from a clinical trial will be presented--that depends on the number of "events" as defined by the trial, such as the number of patients that recur. When this happens, all the data is gathered and the biostatistical team pours over the results. Then, along with the other investigators, the team presents their findings and their conclusions.

This is not the end of the story, since the results are then critiqued by the scientific and clinical community, and again, when the final results are published in final form. Of course, for trials that lead to new drug approvals, the FDA and its advisers also have a say. Over the next few days, you will hear our first takes on key data from San Antonio and some of the early feedback from other attendees.

New information about the use of Herceptin in early stage breast cancer exhibiting the HER2 protein will come from updated analyses of two major trials--one looking at giving Herceptin after chemo compared with the Taxol part of the chemotherapy regimen, and another that is looking at a regimen that omits the chemotherapy Adriamycin, which has been a staple drug for the last two decades. The risk of cardiac side effects is lower with these strategies, so if we can get the same benefit with lower risk of heart problems, that will be an important advance.

For patient with bone metastases, a completely new drug is being tested in comparison to the current standard, Zometa. Denosumab works on a different pathway and may be superior to Zometa based on a trial recently reported initially in Berlin a few months ago. We will see the final results of this study and this is likely to be submitted to the FDA. The critical questions will be: Is it really better and how do the side effects compare? New trials on the anti-angiogenic drug Avastin, currently approved as first-line therapy for advanced breast cancer (HER2-negative), will be presented in the second-line setting, and this will have implications as to whether this drug might be used later in the course of treatment. We will also hear different approaches to breast cancer screening and whether ultrasound has a role in addition to mammography. There will be more on special tumor tests to individualize therapy and even preliminary information about using diabetes drugs in breast cancer as well as the reasons behind this.

Despite the weather around the country, we expect about 10,000 to register for this meeting as it begins this afternoon. So stay with us for the next few days to keep up with the latest from San Antonio.

To read more articles from CURE's coverage of SABCS 2009, visit sabcs2009.curetoday.com.

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.