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

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.

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.