Ann's NOTE: There are some strategies that may protect the heart during chemotherapy. Look at L-carnitine, CoQ10, Traditional Chinese Medicine (herbs and acupuncture) and more. A new retrospective analysis of phase 1/2 clinical-trial data with a novel cancer drug, the tyrosine kinase inhibitor sunitinib (Sutent, Pfizer), has revealed that it could be cardiotoxic [1]. Until further studies can clearly define the nature and rate of any sunitinib-associated cardiovascular events, close monitoring of patients taking this drug is warranted, say Tammy F Chu (Children's Hospital Boston and Harvard Medical School, MA) and colleagues in their paper in the December 15, 2007 issue of the Lancet. These findings come as somewhat of a surprise, because sunitinib was originally thought to be relatively free of cardiac side effects. The new research found that six of 75 patients developed symptoms consistent with moderate to severe heart failure and that those with a history of hypertension and/or coronary artery disease were at increased risk for heart failure. In addition, almost half of the patients developed high blood pressure, and animal studies performed by the same research group suggest that hypertension might contribute to sunitinib-associated heart failure. Senior author Dr Ming Hui Chen (Children's Hospital Boston and Harvard Medical School)--a cardiologist who specializes in the cardiac health of cancer patients--told heartwire that doctors "need to pay close attention to the triad of dyspnea, fatigue, and peripheral edema in their patients, because this may be the presentation of heart failure, and they need to be aware that there are cardiac effects of this drug." Unfortunately, "these are also the symptoms of metastatic cancer," she notes, adding, "It's not that it's always heart failure, but doctors need to be vigilant." In addition, "it's important that physicians recognize the frequency and magnitude of blood-pressure increases that sunitinib can cause, that they institute blood-pressure control where necessary, and that patients are adherent to antihypertensive medications," she noted, because of the possibility that hypertension contributes to the heart failure seen with sunitinib. Fortunately, says Chen, five of the six patients who developed congestive heart failure were able to go back on sunitinib after the drug was withheld temporarily, cardiovascular medications were administered, and the dose of sunitinib was adjusted. "Patients should be encouraged that with cardioprotective measures, they can stay on their lifesaving therapy longer," she notes. As a cardiologist who spends her life dealing with cancer patients, she says the psychological effects of this on patients can never be underestimated. "They are so focused on their cancer. But as you are curing the cancer, it's important to care for the heart." A Study From Bedside to Bench Sunitinib is currently approved as first-line therapy for metastatic renal-cell carcinoma, and it is the only treatment for GI stromal tumors that have become resistant to imatinib (Gleevec, Novartis). Chen explained to heartwire that phase 3 trials of sunitinib for approval "were primarily designed to assess tumor efficacy and general safety and did not find the degree of cardiotoxicity we did." Importantly, she noted, patients with hypertension were excluded from the phase 3 trials, and at least one of the trials also ruled out those previously treated with other anticancer drugs, such as anthracyclines, that are known to cause cardiotoxicity. In this new retrospective analysis, she and her colleagues reviewed the phase 1/2 data on the drug--which, she noted, Pfizer was "very collaborative in providing, they gave me access to all the phase 1/2 data they could"--but this time, the researchers focused on cardiovascular end points and gathered additional data from patients' medical records. "This is a sensitive way to detect side effects that may not have previously been anticipated," she notes. In their analysis, which included 75 patients with imatinib-resistant metastatic GI stromal tumors receiving sunitinib at FDA-approved or lower doses, they looked at a composite end point of cardiac death, MI, and congestive heart failure. They also examined the effect of sunitinib on left ventricular ejection fraction (LVEF) and blood pressure. Separately, coauthors Drs Tom Force (Jefferson Medical College, Philadelphia, PA) and Maria Rupnick (Children’s Hospital Boston) investigated potential mechanisms of sunitinib-associated cardiac effects in isolated rat cardiomyocytes and in mice. "This is one of the few papers that spans from observations of the patient at the bedside all the way back to the basic science to try to figure out why we see what we do," Chen observed. Chen believes the population in the phase 1/2 studies that her team analyzed "may more closely mirror the people that will be taking this drug now that it is FDA and EU approved. The 'real-world' patients will have other cardiac comorbidities and risk factors, and that's why we wanted to call attention to this." Also, 20% of the patients they looked at had previously been treated with anthracyclines, which, Chen notes, "might have contributed to the higher rate of sunitinib-associated CHF." They found that eight of the 75 patients (11%) given repeating cycles of sunitinib in the phase 1/2 trial had a cardiovascular event, with CHF recorded in six of the 75 (8%) and two having MIs. Ten of 36 patients (28%) treated at the approved dose of sunitinib had absolute reductions in LVEF of at least 10%, and seven of these had reductions of 15% or more. Sunitinib also induced increases in mean systolic and diastolic blood pressure, and 35 of the 75 patients (47%) developed hypertension (>150/100 mm Hg). "The degree and rapid onset of hypertension associated with sunitinib in our study were unexpected," the researchers note. Sunitinib Patients Require Monitoring, Like Those On Trastuzumab In an accompanying editorial [2], Dr Heikki Joensuu (Helsinki University Hospital, Finland) says, "Chu and colleagues can be congratulated for vigilance and for careful documentation of their cases." Joensuu says their findings parallel those of another research group in Austria, so far only presented as an abstract. The Austrian scientists looked at patients taking sunitinib or another anticancer drug, sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals). Joensuu notes that "cardiac adverse events with sorafenib seem similar to those related to sunitinib." "Patients treated with sunitinib need careful monitoring for . . . cardiac function. Although data are limited and more research is needed, sunitinib might be at least as cardiotoxic as [the breast cancer drug] trastuzumab [Herceptin, Genentech]," the Finnish oncologist notes. "Longitudinal monitoring of LVEF is standard practice in breast-cancer patients treated with trastuzumab. Such monitoring and an electrocardiogram also seem indicated in patients treated with sunitinib. Patients with coronary artery disease, severe heart disease, or previous treatment with anthracyclines may be at particularly high risk of cardiac failure and possibly cardiac infarction during sunitinib therapy and will need close follow-up. Sunitinib-related hypertension should be treated promptly," Joensuu concludes. Hypertension Not Always Associated with Heart Failure Importantly, Chen told heartwire, that while mice experiments showed them that hypertension might play a role in the injury to the heart, "some people without high blood pressure also ended up with heart failure, so it is important for doctors to pay attention to both of these issues, which are of equal importance. "The contribution of hypertension to sunitinib-associated problems with heart muscle need to be closely examined, and I hope ongoing studies will give us an opportunity to further define the nature and rate of events." In the meantime, it's important to aggressively identify and treat blood pressure, she notes. Also, further investigation is warranted to assess the effect of previous anticancer drug therapy on cardiovascular susceptibility to sunitinib, she says. "This type of rigorous interdisciplinary assessment of trial data is important as we develop new targeted therapies for cancer," Chen told heartwire, adding there are about 150 tyrosine kinase inhibitors currently in development. "The model of collaboration here between oncology and cardiology was instrumental to making these observations." Cardiologists Need to Catch Up on Cancer Field But in general, cardiologists require education in this rapidly evolving field of oncology therapy, she notes. "Most of us cardiologists are familiar with the cardiotoxicity seen with older anthracyclines, but we need to understand that the field of oncology now requires us to learn and to reexamine our own assumptions. Many of these patients are not as sick as we think they are." By way of illustration, she says that even in the metastatic setting for which sunitinib is currently approved, she has patients who have been taking the drug for up to four years. "And what's important to note is that as you take drugs that were tested in the metastatic setting that then become considered for use as adjuvant therapy, the whole safety/efficacy ratio may shift. As cardiologists get more involved in the oncology field, we will gain a better understanding of this. However, the paradigm for cardiologists still remains to treat the cancer while caring for the heart." Conflicts of interest for the authors are listed in the paper. Joensuu has received honoraria for speaking and advisory board meetings for Novartis and Bayer Schering Pharma and has received payment for one testimony from Pfizer. 1. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370:2011-2019. 2. Joensuu H. Cardiotoxicity of sunitinib. Lancet 2007; 370:1978-1979. The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals. Posted December 2007 Source: www.medscape.com Heart failure associated with sunitinibCancer, 2008 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.