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.

Aspirin -- The Drug of the Day

BY DEBU TRIPATHY | FEBRUARY 19, 2010

A recent article showing that users of aspirin had a better survival rate after they were diagnosed with breast cancer received a lot of press, but what does it really mean?

I think that this is an example of a very preliminary observation that resonates with both the public and the medical world, but is fraught with uncertainty. On one hand, there is a lot of evidence that inflammation and clotting are both related to cancer, so it stands to reason that a drug which can affect both, could also be a cancer treatment. However, this article illustrates the problems of using a retrospective design--in this case from the Harvard Nurse's Health Study, a cohort of over 120,000 nurses with many years of detailed personal and clinical information gathered since 1976.

This cohort has generated hundreds of important articles, and since about 4,000 individuals have developed early-stage breast cancer, findings--such as a protective effect of exercise on breast cancer recurrence--have been reported earlier.

Participants with stage I, II, or III breast cancer were asked about aspirin use and then rates of breast cancer in these women were examined. Those who used 1 aspirin a week had no difference in breast cancer deaths rates compared to non-users, but those who took more than 1 aspirin a week, had two-thirds fewer deaths--a rather dramatic "effect." But is this really an effect, or just an association?

The researchers involved used statistical tools to correct for other factors, such as age, weight, diet, physical activity, and reproductive factors, but it is not possible to consider every subtle association with aspirin use. This is why we have to do prospective trials to confirm these findings, and even the authors of this article concede that such a trial would be needed before we could recommend aspirin to patients with breast cancer routinely.

Unfortunately, such trials require upward of 3,000 subjects and five or more years of follow-up time. So, given the multi-million dollar price tag, there is tremendous competition as to what strategies should be tested. This is why we are left with many clues but few answers about these types of reports.

So, my answer for now is--do not take aspirin automatically if you have breast cancer. But do lobby your congressmen and others to develop an efficient and comprehensive clinical trial system that is broadly inclusive of patients and centers and is efficiently run using innovations in information technology. This is one solution to rapidly confirm the findings you see on an almost daily basis in these types of press releases. Hopefully, we will be able to chase more leads in the near future than we do now.

Quality Assurance: How can you make sure you are not a victim of error?

BY DEBU TRIPATHY | FEBRUARY 2, 2010

I read with interest a recent article in The New York Times that exposed examples of errors in the administration of radiation therapy to patients at numerous facilities (As Technology Surges, Radiation Safeguards Lag). The stories on an individual level raised sadness, sorrow, and anger at the consequences of over-radiation, but also raised a more general concern about the lack of quality controls and reporting of errors or complications in the medical system in general.

It turns out that the procedures and the laws in this area are inadequate--they do not, in many cases, require that a system be in place or even that errors be reported. This coupled with overworked and undertrained staff as well as a lack of oversight has exposed areas of weakness in the system. Even though this led to quick changes in the institutions where these events occurred, many centers are vulnerable to rare but potentially serious mistakes.

When I look at this from a patient's perspective, it appears to add yet another concern to the many worries that are already on the patient's horizon regarding the diagnosis and treatment plan. I believe that most centers have good quality-control systems, but most of them are home-made and specific to that one facility, so it is nearly impossible for a patient to "grade" a center.

There are some plans by different societies and organizations to establish the definitions of good care, but very few actually detail the systems that should be implemented to make sure these plans are followed correctly. For example, in many centers, chemotherapy orders are reviewed independently by a pharmacist to make sure the drug, the dose, and the route of administration are all within the accepted norms. This is again rechecked by an experienced oncology nurse, at the time of administration who then documents the details. Finally, a periodic chart review should ensure that documentation and follow-up of patients reveals no problems. Inspections of the chemotherapy storage and mixing areas are also required periodically. This common sense set of procedures is rather typical, although I would guess that the thoroughness of this process varies considerably.

In general, a formalized set of independent checks and balances for all procedures should be in place. This should be aided by automated technology but ultimately overseen by a human being with a clear line of accountability. There are many ways to accomplish this general scheme and each center needs a written protocol for this. All physicians and staff need to feel free to report deviations from this plan, problems or errors in confidence; therefore, whistleblowers need to be protected. Investigations to such concerns must be done independently and swiftly, with a final report made to the proper authorities (hospital and governmental) and, of course, the patient needs to notified.

So perhaps the next time you see your cancer specialist, you can innocently ask how their center undertakes the mission of quality control.

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.

Mammographic screening: More heat than light

BY DEBU TRIPATHY | NOVEMBER 23, 2009

The saga of the new breast cancer screening guidelines issued by the US Health Preventive Services Task Force continues to evolve and has now polarized the public as well as professional fields. Many radiologists and surgeons, along with their patients and the public, feel betrayed by what they perceive as a reversal in public policy and a denial of service.

Some sense a plot by the government to ration health care (the USPST denies that cost was entered into their analysis and they are in fact an independent body even though appointed by the Department of Health and Human Services). The other side of the argument (and one that the USPST is now maintaining as they have slightly backpedaled) is that the recommendations all along were for women ages 40-50 to have an individualized decision about the pros and cons of screening, and not to abandon screening altogether. They did sneak in the every 2 years recommendation based on the fact that numerous trials looking at either yearly or every other year screening show about the same impact on lowering mortality due to breast cancer.

OK, so where is the reasoning in this heated debate? Is it possible that there is one truth, but just divergent interpretations of the data, in part driven by emotion? I propose that the answer to this is yes. Most experts agree that screening does lead to early detection for some but not all breast cancers. They also agree that most positive finding in mammograms are in fact benign and in many cases lead to unnecessary additional imaging, biopsy, and even surgery. They also agree that many cancers that are picked up would never have affected the patient over their lifetime. Finally, false positive results and unneeded tests are more common in the 40-50 year old group.

So in fact, these dramatic guideline "changes" are essentially nothing new. In my opinion, most women who are 40-50 should be offered screening because even though mammograms are not as effective in this in this group, the age distribution of breast cancer indicates that this age group is clearly susceptible (data from Surveillance Research Program, Cancer Statistics Branch, 2007. http://www.seer.cancer.gov ).

However, this age group needs to be clearly informed of the consequences of screening, including going to surgery for a false positive result, and also how their risk of dying of breast cancer is being impacted (essentially going from about 1 in 28 to 1 in 37 based on the 25% reduction in breast cancer mortality). The USPST estimates that in the 40-49 year old range, about 1900 women have to be screened for 10 years to save one life, but at the risk of over 100 false positives that require additional imaging with some going on to biopsy. For age 50-59, 1300 women have to be screened, but this number is only 380 for women aged 60-69. Americans are accustomed to saving life at all cost and sparing no expense for a medical beneficial procedure. In fact, many states have legislated coverage for mammograms for women beginning at age 40. At the current time, policy by the FDA, Medicare and most insurance companies is set based on benefit traded off against health risk but not cost. Since women do not die from false positive results, it would seem logical that beginning at age 40, women should be screened provided they are informed, in a numerical sense) about the risks.

However, stay tuned for my next blog as I discuss what may be in store for the new realities of health care reform where cost does enter into the picture, and what this may mean in the cancer field. But I will tell you in advance that there should not be cause for alarm – especially when one looks at the alternative of continuing to do business as usual.