ESMO 2012-SIGLE OR COMBINATION CHEMOTHERAPY IN SARCOMA?

A large trial comparing single and combination chemotherapy in the first-line treatment of soft tissue sarcoma failed to meet its primary overall survival end point. However, the results were of borderline significance, and secondary end points favored the combination, so was the trial really negative?

This was the question raised here at the 2012 European Society for Medical Oncology Congress by one commentator.

Speaking at a Best of ESMO summary session, Alessandro Gronchi, MD, a surgical oncologist from the Instituto Nazionale Tumori in Milan, Italy, suggested that the results can be interpreted as providing evidence for both treatment options.

In the palliative setting, single-agent chemotherapy with doxorubicin should be used, he said. However, if there is a chance of cure or if a reduction of tumor size is needed to improve symptoms and quality of life, then the combination of doxorubicin plus ifosfamide should be used, he said.

Although there have been several previous trials comparing single and combination chemotherapy, none have given a definitive answer, he noted.

There has been a lot of transatlantic and transcultural debate about which is the best first-line option, explained study author Winette van der Graaf, MD, from Radboud University Medical Center in Nijmegen, the Netherlands. This is the reason her team conducted this large randomized phase 3 study.

The trial, conducted by the European Organization for Research and Treatment of Cancer (EORTC), involved 455 patients recruited from 9 countries. Patients had grade 2 or 3 advanced or metastatic soft tissue sarcoma, and were 18 to 60 years of age.

Both of these factors are notable, said George Demetri, MD, from the Dana-Farber Cancer Center in Boston, Massachusetts, who was not involved with the study. He noted that sarcoma is disproportionately common in children, and in adults sarcoma is more common in the elderly. He explained that all sarcomas are of mesenchymal origin but that they cover a very broad range of different histologic subtypes.

Single vs Combo Chemotherapy

Patients were randomized to receive doxorubicin (75 mg/m² as a bolus or 72-hour infusion) either alone or in combination with ifosfamide (10 g/m² over 4 days with the colony-stimulating factor pegfilgrastim), and were treated every 3 weeks until disease progression or the completion of 6 cycles of therapy.

After a median follow-up of 56 months, there was no significant difference in median overall survival, the primary end point, between the combination and single-agent groups (14.3 vs 12.8; hazard ratio [HR], 0.83; P = .0076).

Secondary end points were significantly better with the combination. Median progression-free survival was 7.4 months with the combination and 4.6 months with the single agent (HR, 0.74; P = .003). Most of this effect was seen in patients 40 to 50 years of age, Dr. van der Graaf noted. In addition, the overall response rate with the combination was double that with doxorubicin alone (26.5% vs 13.6%).

However, the combination was "considerably more toxic," Dr. van der Graaf said. Grade 3 or higher adverse events reported in the combination and single-agent groups included febrile neutropenia (45.9% vs 13.5%), leucopenia (43.3% vs 17.9%), anemia (34.9% vs 19.7%), and thrombocytopenia (33.5% vs 0.4%).

The lack of significant survival results means that single-agent doxorubicin remains the standard treatment for first-line use, Dr. van der Graaf concluded.

However, she noted that "if surgery for unresectable tumors or (curative) metastasectomy is foreseen, combination therapy can be considered."

"In highly symptomatic disease in patients without comorbidity, combination treatment is optional. The pros and cons should, as always, be discussed with the patients," she said, adding that "this is easier now that we have the results of this study."

Poor Prognosis

Dr. Demetri reminded the audience that metastatic soft tissue sarcomas have variable clinical behaviors, but they are nearly all incurable. "Therefore, our intention is to palliate and prolong life with the highest possible quality," he explained.

The median survival for these patients is about 1 year, he said. In this study, after 1 year, 60% of patients in the combination group were still alive, compared with 51% in the single-agent group. During the first year of the study, there was some divergence between the 2 curves, he noted; disease control was longer with the combination than with doxorubicin alone (7.4 vs 5.0 months). For a patient who may have only 1 year to live, there is a chance that more of that time will be disease-free when treated with the combination, he said.

Dr. Demetri concluded that, in his opinion, if a patient is asymptomatic, the best first-line therapy remains single-agent doxorubicin. However, if a patient is symptomatic or if tumor shrinkage is required because the tumor is causing pain, then he would suggest using the combination of doxorubicin plus ifosfamide.

But there is another option, he reminded the audience; the targeted agent pazopanib (Votrient) was approved for use in sarcoma in April in the United States and in August in Europe.

"This is an important step," Dr. Demetri explained in a previous interview, because it offers an alternative to chemotherapy. Pazopanib is an oral drug with a milder adverse-effect profile, and might be preferable for patients who have small asymptomatic tumors, he said.

Can it! Soda studies cite stronger link to obesity

As Americans debate what is most to blame for the nation's obesity epidemic, researchers say they have the strongest evidence yet that sugary drinks play a leading role and that eliminating them would, more than any other single step, make a huge difference.
Three studies published Friday in the New England Journal of Medicine represent the most rigorous effort yet to see if there is a link between sugar-sweetened beverages and expanding U.S. waistlines.
"I know of no other category of food whose elimination can produce weight loss in such a short period of time," said Dr. David Ludwig, director of the New Balance Foundation Obesity Prevention Center at Boston Children's Hospital, who led one of the studies. "The most effective single target for an intervention aimed at reducing obesity is sugary beverages."
Previous research on the subject has been mixed, and beverage makers fiercely contest the idea that a single source of daily calories can bear so much responsibility.
"We know, and science supports, that obesity is not uniquely caused by any single food or beverage," said the American Beverage Association (ABA) in a statement. "Studies and opinion pieces that focus solely on sugar-sweetened beverages, or any other single source of calories, do nothing meaningful to help address this serious issue."
The NEJM studies, as well as an editorial and opinion pieces on the topic of sugary drinks and obesity, land as concern about obesity and its impact on public health is rising.
A report released this week projected that at least 44 percent of U.S. adults could be obese by 2030, compared to 35.7 percent today, bringing an extra $66 billion a year in obesity-related medical costs.
Last week, New York City adopted a regulation banning the sale of sugary drinks in containers larger than 16 ounces at restaurants and other outlets regulated by the city health department.
Sugary drinks are in the crosshairs because from 1977 to 2002 the number of calories Americans consumed from them doubled, government data show, making them the largest single source of calories in the diet. Adult obesity rates, 15 percent in the late 1970s, more than doubled in that period. The ABA points out, however, that consumption has since fallen, yet obesity rates keep rising.
Although most observational studies find that people who drink sugary beverages are more likely to be obese than people who do not, no cause-and-effect has been proved. People who drink sugary beverages, especially children, also watch more TV and eat more calorie-dense fast food, raising the possibility that liquid sugar is not the main culprit.
A 2008 analysis of 12 studies, led by a scientist who went on to work for the ABA, concluded that the association between sugary drinks and body-mass index (BMI) "was near zero."
Studies in which children cut their intake of sugary drinks found modest benefits, but "they were considered unconvincing," said Martijn Katan of VU University in Amsterdam: "Most had a small number of subjects and followed them for only a short time." He and his colleagues aimed to do better.
BUILDING A BETTER STUDY
For DRINK (Double-Blind Randomized Intervention in Kids), they gave 641 children aged about 5 to 12 and with a healthy BMI of just under 17 one 8-ounce (250 milliliter) noncarbonated drink per day, sweetened artificially or with sugar. The sugar-free drinks were specially formulated to look and taste like sugary ones so the kids would not know which they had.
About a quarter of the kids stopped drinking the beverages. Among those who stuck it out for 18 months, the sugar-free kids gained less body fat, 2.2 pounds (1 kilogram) less weight, and 0.36 units less BMI than the sugary-drink kids, the researchers report in the NEJM.
Why? There is good evidence that liquid sugar does not produce a feeling of fullness that other calories do. "When children substituted a sugar-free drink, their bodies did not sense the absence of calories, and they did not replace them with other food or drinks," said Katan.
DRINK doesn't answer whether switching to zero-calorie drinks would help obese kids. But another study in the same issue of NEJM suggests it might.
Researchers at Boston Children's had zero-calorie drinks delivered to 110 obese 15-year-olds who had BMIs of about 30 (where obesity starts), counseled them not to drink sugary beverages and offered other support.
After a year the teens had cut their intake of sugary drinks from almost two a day to zero and their daily calorie intake by 454. They had gained an average of 3.5 pounds (1.6 kilograms). By comparison, 114 teens who continued to consume sugar-sweetened beverages gained 7.7 pounds (3.5 kg) on average and ten times the BMI units: 0.63 compared to 0.06.
Once the deliveries stopped the two groups diverged less. After two years, teens who had received the no-cal drink deliveries had gained 9.5 pounds (4.3 kg) and 0.71 unit of BMI, compared to the control group's 11.2 pounds (5.5 kg) and 1.0 unit of BMI.
"It isn't surprising that after the intervention stopped, old behaviors crept back," said Ludwig of the New Balance Center. An "obesogenic" environment that promotes calorie-laden foods "overwhelms individuals' ability to maintain behavioral change" such as avoiding sugary drinks.
Hispanic teens benefited the most: Those receiving no-cal deliveries gained 14 fewer pounds after one year and almost 20 fewer pounds after two. That raised the possibility that genetic factors influence the effect of sugary drinks.
To investigate gene-environment-obesity links, scientists at Harvard School of Public Health looked at 33,097 people from long-term ongoing health studies, such as the Nurses' Health Study, identifying how many sugary drinks they consume and whether they have any of 32 genes linked to obesity.
The effect of genes on the likelihood of becoming obese was twice as large among people who drank one or more sugary drinks per day as among those who had less than one a month, the scientists report in the NEJM. In other words, belting back soda and sugary tea may turbocharge the genetic risk of obesity.
Conversely, eating a healthy diet devoid of sugary drinks keeps fat genes inactive. People with "fat genes" can be thinner if they avoid sugary drinks and other high-calorie foods.

CANCER ON THE RISE IN PREGNANT WOMEN

NEW YORK (Reuters Health) Sep 19 - The number of pregnant women diagnosed with cancer has increased over the past couple of decades, a new study from Australia suggests.

In 2007, the most recent year studied, researchers found 192 out of every 100,000 pregnant and postpartum women received a cancer diagnosis - up from 112 per 100,000 women in 1994.

Researchers couldn't determine what was behind that increase in risk, but said it could be due in part to the older average age of expectant moms combined with better cancer detection.

Another explanation could be "the increased interaction with health services during pregnancy," said Dr. Christine Roberts, an obstetrics researcher at the University of Sydney who worked on the study.

Dr. Roberts said some doctors in her department had seen a few cases of expectant moms with cancer and wanted to know whether this was indicative of any increase in risk.

To try to answer that question, her group collected information from three large databases on births, cancer cases and hospital admissions in New South Wales, Australia. They had data on roughly 780,000 women who gave birth more than 1.3 million times between 1994 and 2008.

During the same period, there were about 1,800 new cancers diagnosed in pregnant women and those who'd given birth within the last year.

As diagnoses became more common over the years, pregnant women also got older, on average, the researchers noted in the obstetrics and gynecology journal BJOG.

For example, in 1994, 13% of pregnant women were over age 35, compared to almost 24% in 2007.

The risk of cancer is known to increase with age - and 35-plus women in the study were over three times more likely to get cancer compared to those under 30 in 2007. But age only accounted for a fraction of the increased cancer risk over time, the researchers found.

Dr. Lloyd Smith, who treats gynecologic cancers at the University of California, Davis, agreed that improved detection likely accounts for some portion of the increase in cases.

He pointed out that melanoma was the most common cancer diagnosed, affecting 45 out of every 100,000 pregnant or postpartum women.

Australia claims the highest rate of melanoma diagnoses in the world.

Given increasing awareness of the problem of melanoma in Australia, "they probably also have ramped up their surveillance of melanoma, so they're going to detect more," Dr. Smith, who wasn't involved in the new study, told Reuters Health.

Dr. Roberts said that despite the increase in cancer risk, it is still considered a rare event among pregnant or postpartum women.

Women in the study with cancer were more likely to plan an early birth, but "importantly there was no evidence of harm to the babies of women with cancer - they were not at increased risk of reduced growth or death," Dr. Roberts wrote in an email to Reuters Health.

She said more research on cancer treatments for pregnant women is needed.

Dr. Smith said that in his experience, treating pregnant patients has been extremely difficult. "When you have a pregnant woman who has cancer, the infant's at risk, the woman's at risk, the family is in extreme distress and they're seeking the best advice, which is often confused because no one knows quite what to do," he said.

One recent study found that chemotherapy does not appear to harm the fetus, while planning an early delivery to avoid chemo exposure to the baby is actually more risky (see Reuters report of September 27, 2011).

LACK OF SLEEP LINKED TO MORE AGGRESSIVE BREAST CANCER

For the first time, lack of sleep has been associated with more aggressive breast cancers, according tofindings published in the August issue of Breast Cancer Research and Treatment.
The study was conducted in 101 women with early-stage estrogen-receptor-positive breast cancer who were assessed with the Oncotype DX test, which guides treatment in early-stage breast cancer by predicting the likelihood of recurrence.
The worst scores on the recurrence probability test were found in women who reported having the least sleep at night. Specifically, having fewer than 7 hours of sleep a night during the 2 years before the diagnosis was associated with a greater risk for recurrence.
However, this association between less sleep and breast cancers that are more aggressive and more likely to recur was strong only in postmenopausal women (P = .0011), not in premenopausal women (P = .80).
"This is the first study to suggest that women who routinely sleep fewer hours may develop more aggressive breast cancers than women who sleep longer hours," said lead author Cheryl Thompson, PhD, in a press statement. She and her coauthor, Li Li, MD, PhD, are from Case Western Reserve University in Cleveland, Ohio.
The study findings are limited by the "relatively modest sample size," the authors acknowledge.
Nevertheless, the study adds to the literature on sleep duration and breast cancer. Four previous studies, all of which assessed breast cancer risk and did not specifically look at breast cancer aggressiveness, have had "mixed results," according to the authors. Three of these have suggested that sleep can reduce the risk for breast cancer and 1 found no association at all.
Medscape Medical News asked Simone P. Pinheiro, ScD, from the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), for her opinion on this study.
Before joining the FDA, Dr. Pinheiro was the lead author of the large prospective study that "did not find convincing evidence to support an association between habitual duration of sleep and subsequent development of breast cancer" (Cancer Res. 2006;66:5521-5525). However, information on habitual sleep duration was obtained prior to the development of breast cancer in that study, she emphasized.
The study by Drs. Thompson and Li "suggests" a "significant inverse correlation" between sleep duration and breast cancer aggressiveness among women diagnosed with breast cancer, Dr. Pinheiro noted.

"These results could also reflect the effect of subclinical (not yet diagnosed) breast cancer on sleep duration," she said in an email. In other words, a woman's nascent breast cancer might have caused sleep disturbance, she explained.
So, is lack of sleep a new risk factor for aggressive breast cancers?
The authors believe it might be. "Our data suggest that lack of sufficient sleep may cause biologically more aggressive tumors," they write. But they note that "further work will need to be done to more thoroughly characterize the biology underlying this epidemiological association."
Less Sleep and Recurrence Scores Defined 
All of the study participants are enrolled in a larger 412-patient case–control breast cancer study. As such, they were recruited at diagnosis and asked about lifestyle matters, including average sleep duration in the previous 2 years. Many of the breast cancer patients in the study underwent Oncotype DX testing.
The authors designated 3 levels of nightly sleep: 6 hours or less, 6 to 7 hours, and 7 or more hours.
Using previously published data on the recurrence probability test, they determined that scores below 18 predict a low risk for recurrence, scores of 18 to 30 predict an intermediate risk, and scores of 31 or higher predict a high risk.
Overall, less sleep was found to be correlated with a higher score. Risk for recurrence was intermediate in patients who slept 6 hours or less (mean recurrence score, 27.8) or 6 to 7 hours (mean recurrence score, 18.0) and low for patients who slept 7 or more hours (mean recurrence score, 16.4).
Thus, getting an average of less than 7 hours of sleep a night was associated with an intermediate risk and getting 7 or more hours was associated a with low risk. However, this finding was only statistically significant in the subset of postmenopausal women.
The lack of a strong association in premenopausal women is explainable, say the authors.
"It is well known that there are different mechanisms underlying premenopausal and postmenopausal breast cancers," they explain. "Our data suggest that sleep may affect carcinogenic pathway(s) specifically involved in the development of postmenopausal breast cancer, but not premenopausal cancer."
The positive findings in postmenopausal women remained statistically significant after adjustment for possible confounders, including age, physical activity, smoking status, and body mass index.
"Effective intervention to increase duration of sleep and improve quality of sleep could be an underappreciated avenue for reducing the risk of developing more aggressive breast cancers and recurrence," said Dr. Li in a press statement.
This study adds to the literature on lifestyle factors that can affect breast cancer and its related risk. These studied factors are increasingly diverse and include night-shift work, light in the bedroom, and more obvious variables such as obesity.

RISK OF HEART FAILURE WITH TRASTUZUMAB

Clinical trials have already shown that breast cancer patients who receive treatment with anthracyclines and trastuzumab (Herceptin, Genentech/Roche) are at increased risk for heart failure and cardiomyopathy.

Now, an observational cohort study conducted in a "real-world" setting suggests that this risk might be much higher.

The study, led by Erin J. Aiello Bowles, MPH, from the Group Health Research Institute in Seattle, Washington, was published online August 31 in the Journal of the National Cancer Institute.

This study adds to the understanding of the association between trastuzumab and heart failure, writes Ann M. Geiger, MPH, PhD, from Wake Forest School of Medicine in Winston-Salem, North Carolina, in an accompanying editorial. In this study, the median follow-up time is a year longer than that of previous clinical trials, and the incidence of heart failure appears to increase with longer follow-up.

"These results provide additional evidence that heightened risk of heart failure is a long-term effect of previous trastuzumab use rather than a short-term increase associated with current or recent use," she writes.

"This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials," Dr. Geiger notes.

Real-World Community Setting

"Clinical trials have shown that anthracyclines and trastuzumab are not only effective at improving survival, but are also associated with an increased risk of heart failure. However, these studies typically exclude older women and women with chronic diseases, so we really don't know what the real-world estimate of heart failure risk associated with these drugs is," Bowles told Medscape Medical News.

"Our goal was to describe not only the population of women with breast cancer who do and who do not receive these drugs, but also to estimate the risk of heart failure associated with these drugs in a real-world community practice," she said.

In this population-based retrospective study, Bowles and her colleagues from the Cancer Research Network analyzed data from 12,500 women diagnosed with incident invasive breast cancer from January 1, 1999 to December 31, 2007.

The women were patients for at least 12 months before their diagnosis at 6 health maintenance organizations in different areas of the United States.

The risk for heart failure and cardiomyopathy with anthracycline alone, trastuzumab alone, anthracycline followed by trastuzumab, and other chemotherapy was compared with no chemotherapy.

Among the women in the analysis, 5807 (46.5%) received no chemotherapy, 3697 (29.6%) received anthracycline-based chemotherapy alone, 112 (0.9%) received trastuzumab-based therapy without anthracycline, 442 (3.5%) received anthracycline plus trastuzumab, and 2442 (19.5%) received other chemotherapy.

The mean age of the population was 60 years (range, 22 to 99 years), 85.8% were white, and the median follow-up time was 4.4 years (interquartile range, 2.6 to 6.9 years).

The researchers found that women who received anthracycline or anthracycline plus trastuzumab were younger. Of the women who received anthracycline alone, 86.4% were younger than 65 years, as were 89.6% of the women who received both anthracycline and trastuzumab.

Younger women were also diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy than women who received other chemotherapy or no chemotherapy.

The small proportion of women who received trastuzumab without anthracycline were older (more than 65 years) and had more comorbidities.

The researchers also found that the risk for heart failure was higher among women who received anthracycline alone than among those who received no chemotherapy, and that the magnitude of that risk was similar to what has been reported in clinical trials.

For that population, the risk for heart failure or cardiomyopathy was higher than among those who received no anthracycline (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11 to 1.76). The increased risk was similar to that seen with other chemotherapy (adjusted HR, 1.49; 95% CI, 1.25 to 1.77).

However, the risk for heart failure associated with trastuzumab following anthracycline was much higher than has been reported in clinical trials (adjusted HR, 4.12; 95% CI, 2.30 to 7.42)

Overall, for anthracycline, the cumulative incidence at 5 years was 4.3%. But for the women who received anthracycline and then trastuzumab, the 5-year cumulative incidence was 20.1%.

"It is a lot bigger than what has been reported from the clinical trials," said Bowles. "But keep in mind that this is a much broader population that we looked at. We have a lot more older women who are already at an increased risk for heart failure, so that is going to drive up our results."

Bowles said this study can be generalized to other women, whereas the results from clinical trials are only applicable to the populations in those trials.

"We know clinical trials are very well done, they're very controlled and have great internal validity because they control any kind of confounding for age and other characteristics, but their generalizability to people who many not be included in those trials is really limited," she explained.

"Our results are much more generalizable, but at the expense of the internal validity. But we did our best to control for age, comorbidities, and any other things that we thought would affect the results. I think our study provides a nice complement to clinical trials," she said.

Long-term Follow-up

In her editorial, Dr. Geiger notes that the results of this study add to the evidence that anthracycline and trastuzumab (in particular) increases the risk for heart failure or cardiomyopathy as a long-term effect.

Dr. Geiger concludes that there is a need to monitor women who have received trastuzumab on an ongoing basis, and calls for prudence in using trastuzumab outside of clinical trials.

She also highlights a role for observational studies. This study "illustrates how observational studies complement randomized controlled trials by capturing valuable information about treatment outcomes for the vast majority of women who are unable to access a trial."