ANTICOAGULANTS USE INCREASE PROSTATE CANCER SURVIVAL

Anticoagulant use may be a predictor of overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel, retrospective data suggest.

The information, presented in a poster at the 2013 American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium in Orlando, Florida, "adds to the growing body of evidence that anticoagulants, including aspirin although not studied here, improve outcome following treatment for prostate cancer," Dr. Mark Buyyounouski, from Fox Chase Cancer Center, Philadelphia, who moderated the poster session, told Reuters Health.

Presenting author Caroline Pratz, a nurse practitioner from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD, told Reuters Health, "We had an interest in collecting data on these patients who had deep vein thrombosis or pulmonary embolism because we see them frequently in the clinic and we were curious as to how this would affect their overall survival."

Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting, she said.

Pratz and her team reviewed the records of 247 consecutive mCRPC patients who received first-line docetaxel chemotherapy from 1998 through 2009, and noted whether anticoagulation was used and if so, the type, indication, and duration.

Twenty-nine men (11.7%) received anticoagulation; 15 for deep vein thrombosis (DVT), nine for pulmonary embolism (PE), and five for both DVT and PE.

Compared to men who received no anticoagulation, those who did had a significant increase in overall survival (hazard ratio for death 0.61; p=0.024). But when types of anticoagulants were analyzed separately, only low molecular weight (LMW) appeared to show a benefit (HR 0.58; p=0.048). The improvement with warfarin was not statistically significant (HR 0.82; p=0.23).

Patients who received any anticoagulant lived a median of 3.8 months longer (median overall survival 20.9 months with any anticoagulant versus 17.1 months with no anticoagulant).

After controlling for a number of other prognostic factors, including alkaline phosphatase, albumin, hemoglobin, prostate specific antigen, number of chemo cycles, and Eastern Cooperative Oncology Group status, anticoagulant use remained a significant predictor of overall survival (HR 0.63; p=0.038).

Pratz said she and her group were surprised by the study results. "It is counter-intuitive to what you think of when you think of blood clots. Typically they can be life threatening, so it was a surprise to us, although it has been reported in some other solid tumor cancers, that this was also the case."

Dr. Buyyounouski added: "These results are particularly compelling given the advanced nature of the disease in the study population."

"We've known for a long time that cancer and blood clots are related, that patients with cancer are more likely to have clotting and that patients with unexplained clotting disorders are more likely to get cancer. So in looking at whether using drugs that inhibit clotting will improve cancer outcomes Pratz and her group found that yes, it looks that way," he said.

Dr. Buyyounouski, a radiation oncologist, cautioned that the study is observational and sheds no light on the possible mechanism by which anticoagulation might benefit cancer outcomes.

"It may interfere with the cancer cells' ability to grow, that is one possibility. Another is that it perhaps interferes with the cancer's ability to stick in blood vessels, and this is one that people think is likely."

The ideal method of anticoagulation, dose, timing, and associated risks all need to be better defined and require further study, he added.

The 2013 Genitourinary Cancers Symposium is co-sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO).

CRITICAL ROLE OF TIME TO REPERFUSION AFTER STROKE

Watson, the IBM supercomputer that grabbed headlines after beating human contestants on Jeopardy!, has commercial applications in healthcare. And its developers have chosen to debut it in oncology.

Watson's first application in cancer is highly focused: recommending the best drug treatment options for patients with stage IV adenocarcinomas, said Mark Kris, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, which is developing the tool with IBM and WellPoint, the managed care company.

"It's the biggest decision in lung cancer treatment," Dr. Kris toldMedscape Medical News. He explained that systemic therapies are the most common form of treatment, and adenocarcinomas are the most common form of lung cancer.

The supercomputer has synthesized an array of data gleaned from thousands of sources, including journal articles, national guidelines, individual-hospital best practices, clinical trials, and even textbooks.

Programming Watson for clinical decision-making in lung cancer "is not an easy task," said Dr. Kris. He pointed out that it took 4 years to program the computer so that it could participate in the game show.

Although Watson is a work in progress, it is currently being used at the Maine Center for Cancer Medicine and Blood Disorders, according to an IBM press statement.

Watson's hardware is physically located in Raleigh, North Carolina, and it uses cloud computing to interface with electronic medical records, Dr. Kris explained.

A clinician enters case notes into an electronic medical record and Watson immediately provides evidence-based and individualized treatment recommendations.

Individual treatment recommendations are updated as case notes become more detailed over time. The "natural language processing," which is the capability of the computer to read and comprehend case notes (in all their variety), is "the heart of Watson," he said.

IBM has produced an 8-minute video, entitled IBM Watson Demo: Oncology Diagnosis and Treatment, that illustrates a clinician interacting with Watson to receive treatment recommendations about a patient with lung cancer.

Watson can help human beings to do the increasingly complex job of being an oncologist, said H. Jack West, MD, from the Swedish Cancer Center in Seattle, Washington, and the author of the Blowing Smoke Medscape blog. He has been following the development of Watson and has commented onlineabout its potential usefulness.

"A computer can incorporate a nearly infinite amount of new data coming out, whereas the human brain can't attend to as much and integrate it," he told Medscape Medical News in an email.

Replacing Doctors?

Dr. West, who is not involved with Watson, sees 2 problems with its use in oncology: first, cancer is "defined by its variability"; and second, clinical decisions are often, in the end, matters of "judgement."

Even the most complex algorithms rely, to some degree, on "classic presentation," he said. Medical practice is less orderly, he noted. "The truth is that just about every cancer case is special and has some unique aspects to it, or at least there are so many extenuating factors that it's hard to be rigidly rule-based," he said.

Ideally, Dr. West would like to see a randomized controlled trial comparing clinical outcomes for patients treated with and without Watson. At the very least, he would like to see Watson's recommendations compared with those from several cancer experts to clarify its value over currently available second opinion.

Dr. West tips his hat to Watson's developers who have admitted that "there is no substitute for the most expert input when it is available." In other words, computers will never replace doctors, both Dr. West and the IBM team assert.

But a high-profile technology pioneer disagrees.

At the 2012 Health Innovation Summit in San Francisco California, Vinod Khosla, a cofounder of Sun Microsystems, reportedly said that computers could replace 80% of doctors. "Healthcare is like witchcraft and just based on tradition," he said. The solution? Data-based, computer-generated decision making.

Watson is "not a replacement" for physicians, according to Dr. Kris. In fact, it will take a "long, long time" to fully develop clinically, he said. However, he added Watson can improve on current oncology resources, such as the National Comprehensive Cancer Network guideline on nonsmall-cell lung cancer.

Dr. Kris, who is one of the authors of this guideline, pointed out that, for stage IV adenocarcinomas, bevacizumab and/or chemotherapy are recommended for patients with a performance status of 0 or 1. The advice is fairly nonspecific for chemotherapy. Two-drug chemotherapy regimens are "preferred," according to the guideline, but it does not specify which of the many of potential chemotherapies are best, nor does it address dosing or length of treatment, Dr. Kris notes.

"Guidelines are a scaffolding...but you've got to finish the building," he explained, referring to the relatively increased "granularity" of detail that Watson will provide and then improve upon as it is further developed.

Dr. Kris, commented on Watson in his Kris on Oncology Medscape blog last year when Memorial-Sloan Kettering entered into its partnership with IBM to develop the technology.

Watson is not the only electronic medical record-mediated computing initiative aimed at facilitating healthcare delivery. Major healthcare players, including McKesson, the American Society of Clinical Oncology, and Aetna, are developing clinical decision-making tools, said Dr. Kris.

In this study, they aimed to test that hypothesis in the much larger IMS-III trial.

IMS-III was a phase 3, randomized, open-label international trial comparing a combined intravenous and intraarterial approach to stroke treatment to standard intravenous tPA alone. The planned target for patient enrollment was 900 patients, randomly assigned in a 2:1 ratio to combined vs standard therapy within 3 hours of stroke onset.

Endovascular therapy included a choice of catheters and devices or intra-arterial tPA based on the lesion characteristics, the experience and training of the investigator, and the specified use of devices.

The trial was halted early for futility after enrollment of 656 patients. Full results were presented here by principal investigator Joseph P. Broderick, MD, from the University of Cincinnati at a session dedicated just to this trial. They were published online simultaneously in the New England Journal of Medicine, and reported by Medscape Medical News.

In the overall analysis, there was no statistically significant difference between the interventions on the primary endpoint, a modified Rankin Scale score of 2 or less at 90 days, indicating functional independence. The absolute difference between groups was 1.5% (95% confidence interval [CI], -6.1% to 9.1%), adjusted for stroke severity by National Institutes of Health Stroke Scale (NIHSS) score. A score of 8 to 19 indicates moderate to severe strokes, and a score of 20 or more indicates the most severe strokes.

In this new time analysis, Dr. Khatri and colleagues used the same methods as in their previous report, excluding patients with very large clots to make a more homogeneous population. Included were patients with M1, M2, or internal carotid artery terminus occlusions who were treated with endovascular therapy and in whom reperfusion was technically successful, defined as a Thrombolysis in Cerebral Infarction (TICI) score of 2 to 3.

Time to successful reperfusion was considered the time from symptom onset to the time the procedure ended, Dr. Khatri noted. Good clinical outcome was defined as a modified Rankin Scale score of 0 to 2, also the primary endpoint of IMS-III.

Of the 656 patients in the overall study, 240 had a qualifying occlusion for this analysis, among whom operators achieved TICI 2/3 reperfusion in 182 (76%). The mean time from symptom onset to reperfusion was 325 minutes (range, 180 to 418 minutes). The longest period was time from symptom onset to start of intravenous tPA, at 121 ± 34 minutes.

After adjustment for baseline variables (such as a baseline Alberta Stroke Program Early CT Score [ASPECTS] of 5 to 10, indicating a favorable computed tomographic scan; lack of disability prior to stroke; and an NIHSS score of 8 to 19 vs 20 or higher, indicating a less severe stroke among these moderately severe strokes), Dr. Khatri said, "we still had a relationship between time to reperfusion and outcome. Every 30-minute delay in reperfusion was associated with a 10% relative reduction in good outcome."

Table. IMS III: Predictors of Favorable Outcome (Modified Rankin Scale Score, 0 to 2)

Variable	Risk Ratio (95% Confidence Interval)	P Value
Time to reperfusion (every 30-min delay)	0.90 (0.82 - 0.99)	.02
Baseline ASPECTS of 5 to 10	3.70 (1.25 - 11.00)	.01
Lack of premorbid disability	2.61 (1.05 - 6.50)	.01
NIHSS score ≤19 vs ≥20	1.64 (1.07 - 2.51)	.01

They found the time relationship was maintained across ASPECTS groups, NIHSS strata, TICI score achieved, and type of occlusion.

One limitation is that by using the time to the end of the procedure as a surrogate for time to reperfusion, they may have overestimated the actual time to reperfusion, she noted.

Going forward, Dr. Khatri said, they plan to carry out more statistical analyses to help define any "point of no clinical return," where no benefit will be seen even if reperfusion is achieved, probably around the 7-hour mark after symptom onset.

Finally, she showed another analysis plotting the IMS-III results on their previous graph showing probability of good outcome against time to reperfusion, "just raising the possibility that if we had opened up clots faster, transitioned patients faster to IA [intraarterial] therapy, perhaps we would have had a positive trial."

IMS-III was funded by the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Khatri reports significant support from NINDS as part of the IMS-III trial executive committee, significant support from Penumbra as neurology principal investigator for the THERAPY trial and from Genentech as the overall principal investigator for the PRISMS trial in planning stages, and modest support from Travek for Genentech as an unpaid consultant.

CARDIOVASCULAR TOXICITIES WITH TARGETED TREATMENT OF RENAL CANCER

 Agents that target the mTOR axis, which have become particularly important in treating advanced renal cell carcinoma (RCC), have significant adverse cardiovascular effects, a Stanford University team reports.

"The main finding of our study is that cardiovascular side effects of targeted cancer therapies -- particularly the ever-growing class of tyrosine kinase inhibitors -- are extremely common, and far more common than most practitioners appreciate," Dr. Ronald Witteles commented in an email to Reuters Health.

In a paper this month in JACC: Heart Failure, Dr. Witteles and colleagues note that in the last six years, the U.S. Food and Drug Administration has approved the tyrosine kinase inhibitors (TKI) sunitinib, axitinib, sorafenib, and pazopanib; the anti-VEGF (vascular endothelial growth factor) agent bevacizumab; and the mTOR (mammalian target of rapamycin) inhibitors everolimus and temsirolimus for various malignancies.

Among these agents available for the treatment of RCC, sunitinib has been linked most often to cardiovascular toxicity - but not in the phase III trials that led to FDA approval. Instead, the researchers say, "subsequent retrospective and prospective studies have since illuminated the significantly elevated risk of heart failure."

To look into this issue, the team assessed the incidence and severity of adverse cardiovascular effects in 159 patients with advanced metastatic RCC who received targeted therapies at the Stanford Cancer Institute in Stanford, California between 2004 and 2011. Since 2007, most of these patients underwent regular, prospective cardiac monitoring.

TKIs were used in 92% of patients, and sunitinib was the most commonly used agent (64% of patients). Some form of cardiovascular toxicity occurred in 116 (73%) of the patients, most often related to hypertension requiring antihypertensive therapy.

Excluding hypertension, 52 patients (33%) experienced some other cardiotoxicity, ranging from asymptomatic increases in levels of NT-proBNP (N-terminal prohormone of brain natriuretic peptide) to severe heart failure, the investigators report.

Among the 41 patients who received mTOR inhibitors, 17% of those treated with everolimus developed grade 1 heart failure, and 24% of temsirolimus recipients developed grade 3 hypertension, the report indicates.

So how does Dr. Witteles view the benefit-risk balance with use of the targeted therapies? "I certainly don't believe that these agents shouldn't be used, as they often have tremendous efficacy as cancer therapy," he responded, "but patients and physicians need to be aware of the likelihood of cardiovascular side effects so that early treatment can be initiated."

In fact, the team found a very high rate of asymptomatic cardiotoxicity. "In our study," the authors said, "asymptomatic cardiotoxicity, as defined by an elevated NT-proBNP level and/or a decrease in systolic function as estimated by left ventricular ejection fraction, was identified in 43 patients (27%). Given their asymptomatic status, these patients would likely not have been identified without screening."

Screening often allowed for asymptomatic cases to be referred to a heart failure specialist and to begin medical therapy with beta blockers and renin-angiotensin inhibitors. "Accordingly," Dr. Witteles and colleagues conclude, "we propose guidelines for monitoring therapy in this population to potentially improve detection and guide treatment."

BIRTH RATE FALLS IN USA

The crude birth rate in 2011 was "the lowest rate ever reported for the United States," according to the authors of the Annual Summary of Vital Statistics, published online February 11 inPediatrics.

Expressed as live births per 1000 women, the 2011 crude birth rate was 12.7, down from 13.0 in 2010, 14.4 in 2000, and 24.1 in 1950. Overall, there were 1% fewer children born in the United States in 2011 than in 2010, and 4% fewer than in 2009, lead author Brady E. Hamilton, PhD, from the Division of Vital Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland, and colleagues report. The data come from birth and death certificates for residents of the 50 states and the District of Columbia.

The decline in birth rate among mothers aged between 15 and 19 years was especially dramatic, with an 8% relative decrease between 2010 and 2011 to reach a historic low of 31.3 births per 1000 women in 2011. This represents a 25% relative decrease in birth rate since 2007 and a 49% relative decrease since 1991, the authors say. "If the 1991 rates had continued to prevail from 1992 through 2011, an estimated 3.6 million additional births to women aged 15 to 19 years would have occurred in the United States (with >1 million of those additional births occurring between 2008 and 2011)."

Birth rates among women in the 20- to 24-year age category also decreased, from 90.0 per 1000 women in 2010 to 85.3 per 1000 in 2011, another record low in the United States. In contrast, women aged 40 to 44 years saw a 1% increase in birth rates, going from 10.2 per 1000 in 2010 to 10.3 per 1000 in 2011. There was no change in rate among women aged 45 to 49 years during that period.

The 2011 crude death rate, at 8.1 per 1000 population, was up slightly from 8.0 in 2010 and 7.9 in 2009, although it remains lower than the 8.5 and 9.6 deaths per 1000 population reported in 2000 and 1950, respectively.

However, age-adjusted death rates, which control for variations in age distribution and are considered a better indicator of mortality risk over time than crude death rates, decreased from 7.5 deaths per 1000 US standard population in 2010 to 7.4 in 2011, a relative change of 1.3% and another record low. Deaths among children aged 1 to 19 years accounted for 20,192 of the 2,513,171 total deaths recorded in the United States in 2011. Accidents, homicide, and suicide were the 3 leading causes of death in this age group.

Life expectancy for children born in 2011 was 78.7 years, the same as in 2010. It was highest for Hispanic females, at 83.7 years, and lowest for non-Hispanic black males, at 71.6 years.

MOLECULAR CLASSIFICATION OF COLORECTAL CANCER

A new diagnostic classification system categorizes colorectal cancers into 3 "completely different subtypes" on the basis of tumor gene-expression patterns, according to a researcher who helped develop the tool.

The tumor subtypes are associated with different prognoses and responses to adjuvant chemotherapy, said study coauthor Josep Tabernero, MD, director of clinical research at Vall d'Hebron Institute of Oncology in Barcelona, Spain.

He spoke at a presscast in advance of the American Society of Clinical Oncology (ASCO) 2013 Gastrointestinal Cancers Symposium, being held January 24 to 26 in San Francisco, California.

"Although several treatments exist, we do not have a good way to select treatments for individual patients," Dr. Tabernero told reporters. Only KRAS status has been established as a predictor of response to anti-EGFR therapy, he explained.

For colorectal cancer, a broad molecular classification is "still missing," the authors note in their study abstract.

This is in contrast to breast cancer, for which "unbiased genome-wide analyses of gene-expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans," they write.

The hope for the colorectal cancer classification system is that it will eventually aid in treatment decisions, including those related to chemotherapy and targeted therapies, according to ASCO press materials.

In their study, Dr. Tabernero and his fellow European researchers used gene-expression data from 188 patients with stage I to IV colorectal cancer to develop their molecular subtype classification system.

They found 3 major intrinsic subtypes of colorectal cancer (A, B, and C).

The classification system was subsequently validated in tumor samples from 543 patients with stage II or III disease. Of those, 21.5% were subtype A, 62.0% were subtype B, and 16.5% were subtype C.

The heterogeneity of the subtypes is "largely based" on 3 biologic hallmarks of the tumors, the authors report: an epithelial-to-mesenchymal transition; a deficiency in mismatch repair genes that results in a high frequency of mutation associated with microsatellite instability; and cellular proliferation. These features are known to independently affect outcomes in patients with cancer, they state.

Ten-year follow-up data show that patients with subtype C tumors have the worst outcome, a mesenchymal gene-expression phenotype, and receive no benefit from adjuvant chemotherapy treatment with fluorouracil (5-FU).

Patients with subtype A or B tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant 5-FU chemotherapy.

Subtype B tumors have a low overall kinome mutation frequency (1.6%), whereas subtype A and C tumors have a higher mutation frequency (4.2% and 6.2%, respectively), "in agreement with their mismatch repair deficiency," the authors report.

Compared with subtype B tumors, subtype A and C tumors have higher rates of gene alterations, including genes that play a role in the development and growth of colorectal cancer, such as KRAS,BRAF, and PI3KCA, according to ASCO press materials.

"These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and, consequently, require different treatment strategies," the authors write in their abstract.

As a next step, the researchers are validating the system in patients with stage IV disease.

This study reflects the direction that diagnostic medicine is headed, said Neal J. Meropol, MD, who moderated the presscast. "Tumors that all look the same...at the level of their molecular make-up may actually fit into several different categories," said Dr. Meropol, who is chief of the division of hematology and oncology at the Case Western Reserve University School of Medicine in Cleveland, Ohio.