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Wednesday, October 01, 2014

BY KURT SAMSON

 

In its first policy statement on obesity and cancer, the American Society of Clinical Oncology warns that obesity could soon become the leading cause of cancer in the United States.

 

The statement, now available online ahead of print in the Journal of Clinical Oncology, says that obesity will soon overtake tobacco use as a risk, and estimated that by 2030, as many as half a million cancers in the U.S. will be related to obesity. Research has increasingly shown that being obese or overweight increases the risk of cancer recurrence and reduces survival in cancer patients, with an estimated 84,000 cancer diagnoses each year that can be attributed to obesity. According to one study, it may contribute to 15 percent to 20 percent of all cancer deaths.

 

The ASCO statement calls for increases in education, research, and advocacy to raise public awareness--not only to prevent obesity-associated cancer, but also for obesity’s role in complications among patients.

 

‘4 Critical Priorities’

The document specifies four critical priorities for addressing the problem:

·     increasing education and awareness;

·     developing new physician tools and resources dedicated to the obesity-cancer link;

·    intensifying and highly coordinating research efforts; and

·    policy changes to increase access to obesity screening, diagnosis, and treatment.

 

"With nearly three in four Americans obese or overweight, obesity has become a tremendous public health challenge that also impacts cancer care and prevention today," ASCO Immediate Past President Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center and a coauthor of the report, noted in a statement accompanying the report.

 

"Cancer doctors need to play a lead role in reducing obesity's impact, both in the care of our patients and as advocates for broader action. We can't allow obesity to undo decades of progress in prevention, early diagnosis, and treatment of cancer."

 

To ensure that oncologists are better equipped to integrate obesity prevention and management into caring for their patients, and that patients have access to needed services, the policy statement calls for the Centers for Medicare and Medicaid Services to add obesity to the list of chronic diseases eligible for the proposed Complex Chronic Care Management Services payments, and encourages the Department of Health and Human Services to clearly define access to obesity treatment services in the new state health care exchange plans under the Affordable Care Act.

 

In an interview, Hudis noted that although the average person is aware that obesity is associated with higher risk of heart disease and diabetes, most are not aware of the cancer risk. Several factors are likely involved, he said: “I do not really know why this message has not penetrated but there has not been a concerted communication effort in the past. In addition, the impact is not as striking as with tobacco, and obesity has only recently been recognized for some tumor types.”

 

He said the main reason that obesity may surpass tobacco as the leading preventable cause of cancer is because there has been much success fighting tobacco use, although it remains a huge problem. “At the same time, rates of overweight and obesity continue to climb globally. In countries with good tobacco control, these are expected to replace tobacco use. We cannot modify our age, but we can modify our weight, in most cases,” he noted.

 

“Someday genetic screening may be possible to identify people at increased risk of obesity at an early age. Some studies have indicated a genetic predisposition, but to our knowledge the levels of overweight and obesity that we observe today are unprecedented, so there must be more than just genetics at play.”

 

Key Findings

The statement summarized some of the key findings on cancer and recurrence risk, as well as cancer-related mortality data among obese individuals diagnosed with early-stage disease. The report cited a recent meta-analysis of 82 studies, involving more than 200,000 breast cancer patients, which found a 75 percent increase in mortality among premenopausal women, and a 34 percent increase in postmenopausal women who were obese at the time of diagnosis, compared with those of normal weight.

 

Another study found that obese men appeared to have greater risk of aggressive prostate cancers and are also more likely to have advanced disease at diagnosis.

 

Two studies have shown that a body mass index (BMI) of greater than 352 kilograms per square meter may be linked to increased risk of colon cancer recurrence and mortality, but these data are less consistent.

 

Emerging data also suggest that obesity may be a prognostic factor in other malignancies as well, according to the statement.

 

In a new longitudinal study, reported this week at the American Association for Cancer Research Annual International Frontiers in Cancer Prevention Research Conference, obesity, greater body mass, and an elevated blood test for inflammation in adolescents and in early adulthood were found to increase the risk of colorectal cancer in later years, especially inflammation.

 

Pathophysiological Factors

There are several reasons obesity may lead to increased cancer risk and greater mortality, according to the ASCO policy statement. For one, obesity can interfere with delivery of systemic cancer chemotherapy and can contribute to morbidity from treatment as well. Obesity is also a recognized risk factor in poor wound healing, postoperative infections, and lymphedema, as well as comorbid illnesses such as heart and cerebrovascular disease and diabetes among cancer survivors. Studies also indicate that obesity can increase the risk of developing second primary malignancies.

 

More than half of non–cancer-related deaths in cancer survivors result from cardiovascular disease and/or diabetes, research has shown.

 

“Given the excellent cancer-specific prognosis experienced by survivors of breast, prostate, and other early-stage cancers, the relationship between obesity and comorbid illness ultimately may have as great an impact on overall survival in the years after cancer diagnosis as the potential link between obesity and cancer recurrence,” the authors of the statement said.

 

“Despite the evidence linking obesity to poor outcomes in individuals with cancer and the benefits demonstrated in lifestyle intervention studies in cancer populations, cancer survivors are no more likely to be consuming a healthy diet, exercising, or maintaining a healthy weight, than are others without a history of cancer.”

 

Research Needs 

While such research has documented links between obesity and cancer, many critical areas of research are still needed to develop effective treatment and prevention strategies. Toward that end, the policy statement calls for the creation of a comprehensive, coordinated research agenda to address key questions, including whether weight loss can reduce the risk of developing or dying from cancer; how obesity should be treated differently among cancer survivors versus people at risk for cancer; and how and when weight management interventions should be initiated.

 

"Research has clearly established that there is a critical relationship between cancer and obesity, but more work is needed to determine whether weight loss, increased physical activity, and improved dietary quality can lower cancer rates and improve outcomes," said the first author of the ASCO policy statement, Jennifer A. Ligibel, MD, Chair of ASCO’s Energy Balance Working Group and a member of the Cancer Survivorship and Cancer Prevention Committees.

 

"No single organization or medical specialty can address obesity alone,” she emphasized.

 

ASCO will host a research summit on obesity and cancer later this year, bringing together researchers from multiple disciplines to identify specific research priorities and approaches related to obesity and cancer.

 

The Oncologist’s Role

The statement notes that a cancer diagnosis may serve as a “teachable moment” to patients to adopt risk-reducing or health-protective behaviors. Indeed, many cancer survivors report that they have attempted to make positive health behavior changes after a cancer diagnosis, one study found.

 

However, although research shows that the impact of a cancer diagnosis can last for years after the event, for many patients the emotional impetus needed to spur behavior change dissipates rapidly. This means that the oncologist and the oncology care team may be in a unique position to help patients lose weight and make other healthy lifestyle changes.

 

Oncologists have traditionally not taken an active role in weight management for patients and may feel they lack the training or skills necessary to help a patient initiate behavior change, according to the document. Also, historically, they may not have perceived this effort as directly related to the treatment of cancer itself.

 

Partnerships between oncologists, primary care providers, and other specialists, such as dietitians, physical therapists, and exercise specialists, are essential in effectively helping cancer survivors implement weight loss programs, the ASCO statement said.

 

The society is working to provide members and other oncology providers with weight-management guidelines for cancer survivors, tools for initiating conversations about weight loss with patients, and resources to help patients manage their weight. Earlier this year, ASCO issued a guide for oncology providers in an effort to encourage provider conversations with patients about the effects of obesity on cancer risk and cancer-related mortality, with a companion guide for patients. These as well as other obesity-related resources are available at ASCO.org/Obesity and Cancer.net/Obesity.

 

ASCO’s key point: “Knowing how and when to initiate a conversation about weight management is an important first step to helping patients lose weight and lead healthier lives after a cancer diagnosis.”

 

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Youth Obesity, Inflammation Raises Lifetime Colorectal Cancer Risk

Adolescents and young adult men who are obese or have elevated inflammatory blood markers appear to be at increased risk of developing colorectal cancer later in life, according to study findings presented at the AACR International Conference on Frontiers in Cancer Prevention Research.

 

During an average 35 years of follow-up, those who were obese -- as measured by body mass index as adolescents -- were 2.37 times more likely to develop colorectal cancer than their counterparts with a normal BMI. Those with high levels of inflammation had a 63 percent higher risk than did those with low levels.

 

Researchers at Harvard School of Public Health analyzed data collected from 239,464 Swedish men conscripted into military service between the ages of 16 and 20 from 1969 to 1976. During their entrance physical, erythrocyte sedimentation rate was measured, as was their height and weight. By linking the conscription registry with Sweden’s national cancer register, the team next looked at colorectal cancer diagnoses through 2009, and 885 cases of were recorded.

 

“Our results suggest that early-life body mass index and inflammation may independently play a role in the development of cancer later in life,” said Elizabeth Kantor, PhD, a postdoctoral research fellow in the Department of Epidemiology.

 

However, further research is needed to better understand these relationships, she noted, pointing to limitations in the data. The registries used do not contain information on all variables, such as adolescent diet.

 

“Obesity was relatively uncommon among adolescents in Sweden at the time the cohort of men enlisted, and it is possible that ‘obesity’ in this study represents something different from what is represented by ‘obesity’ in populations in which this exposure is more ubiquitous,” she added.

 

The association needs to be investigated in large cohorts from different populations, and further research is needed to separately examine body mass index and inflammation from associated exposures and from exposures at other points as they age, Kantor said.

 

Asked his opinion, Clifford Hudis, MD, Immediate Past President of the American Society of Clinical Oncology and coauthor of the American Society of Clinical Oncology’s new position statement on obesity, said the study is consistent with the overall theme that has been observed elsewhere, that being overweight or obese represents a life-long health risk: “This is why we need to better understand this risk so that we can constructively address it,” he said.


Monday, September 29, 2014

 

BY MARY BROPHY MARCUS

 

Livestrong CEO Doug Ulman announced last week that he is leaving the Texas-based cancer charity and heading to Columbus, Ohio, to join Pelotonia, a successful young cancer fundraising organization. The grassroots non-profit sponsors an annual bike ride and has, in six years, pulled in more than $61 million with the single goal "to end cancer."

 

Ulman said he wasn't actively seeking a new role when a group of leaders from Pelotonia and The Ohio State University Comprehensive Cancer Center--James Cancer Hospital and Solove Research Institute approached him to join their team earlier this year.

 

"I'd known many of them on and off over the years through various partnerships," said Ulman, who attended Pelotonia's first fundraising bicycle ride in 2009 as a spectator. "I had admired Pelotonia and [founder] Dr. Michael Caligiuri from afar and what great success they'd had over such a short time. The job piqued my interest and as I've learned more, I think they have a lot of unlimited potential."

 

Ulman said he plans to begin visiting the organization's Ohio headquarters in November, and he and his wife Amy Grace and their three-year-old daughter and one-year-old son will move the family to the area in 2015.

 

During Ulman's 14-year tenure at Livestrong, the CEO helped build an internationally recognized organization and brand that raised half a billion dollars. He also saw the nonprofit organization through the difficult months following founder Lance Armstrong's 2013 confession that he used banned performance-enhancing drugs during his cycling career, including seven Tour de France victories.

 

As Ulman looks forward to his new job, so do his future colleagues.

 

When they were seeking a new CEO, Michael Caligiuri, MD, Director of The Ohio State University Comprehensive Cancer Center, Chief Executive Officer of Ohio State’s James Cancer Hospital (OSUCCC ) and Solove Research Institute, and the founder of Pelotonia, said, "Choices number one, number two, and number three were Doug.

 

"I have known Doug Ulman for over 10 years and have followed his trajectory as an amazing leader and advocate throughout that time," said Caligiuri, also a member of OT’s Editorial Board. "He is internationally networked throughout the medical, government, advocacy, and business communities, and he is one of the nicest people I know."

 

 

Pelotonia

How Pelotonia Started

Caligiuri said the idea to launch a grassroots fundraising bike event first came to him in 2008 when he became the CEO of "The James." With NIH and NCI funding drying up, he began brainstorming ways to create alternate streams of revenue to fuel cancer research there.

 

He wanted to come up with "a different kind of fundraiser, a grassroots fundraiser" that would inspire the Columbus community to become more aware of the problem of cancer and the need for research. He said Cindy Hilsheimer, President of The James Foundation Board, and Dan Rosenthal, now chairman of the Pelotonia board of directors, helped transform his idea into a reality. 

 

"The model we developed called for $2.5 million a year to underwrite the event in its entirety so that every dollar raised by the riders would go toward cancer research at The OSUCCC," Caligiuri explained.

 

They established a 501c3 and named the event “Pelotonia,” a made-up word derived from the French word “peloton" meaning a group of bike riders.

 

The first ride took place in 2009, included 2,250 cyclers, and raised $4.5 million. By 2012, the fourth year, Pelotonia was the number one bike fundraising event in America, by riders, according to Caligiuri. By the fifth year, he said Pelotonia raised more than $61 million and was rated as the fasted-growing fundraiser in America.

 

A total of 7,270 riders participated in this year's July 2014 ride, and Caligiuri said they expect the tally to hit more than $20 million (race donations don't close until the end of October).

 

Christy Patton

Childhood cancer survivor Christy Patton, 31, has participated in the Pelotonia rides every year from the start--the first year as a volunteer and the last four as a rider. The Ohio State graduate, now Manager of Clinical Transformation at The Ohio State University Wexner Medical Center, said riders can pedal as far as 180 miles (over two days) or as few as 25 miles. The longer the ride, the more money you raise.

 

Some companies match their employees' fundraising dollars, too. People who are not physically able to participate or who prefer not to, can "virtually" ride. This year, 3,687 virtual riders raised funds.

 

The main event is a weekend affair held every summer that boasts gourmet food, rock bands, rest stops with bike mechanics, and free overnight accommodations at Kenyon College in Gambier, Ohio, for the 180 milers.

 

Patton logged 155 miles on her longest ride. "When I'm training, if I think I can't dedicate the time or I'm getting tired, all those doubts disappear when the event starts. You know you're part of something bigger. I know what it's like to go through cancer treatment, and as hard as the rides might be, it's nothing compared to that. I can give back to others," she said.

 

Riders can create a profile online at pelotonia.org either individually or as a group, or "peloton,” to keep track of donations. Patton and four other riders formed a team a few years ago that has tallied close to $50,000 in donations to date.

 

100% of Profits Go Directly to Cancer Research at The James

Caligiuri said one hundred percent of the profits go directly to cancer research at The James, including:

  • recruitment of "the best and brightest" scientists and physicians;
  • scholarships for undergraduate, graduate, and postdoctoral fellows;
  • idea grants that fund early research; and
  • state-of-the-art equipment that enables scientists to remain on the cutting-edge in their fields.

The first clinical work with ibrutinib in chronic lymphocytic leukemia was “fueled” with Pelotonia dollars, said Caligiuri. It's now an FDA-approved drug for both chronic lymphocytic leukemia and mantle cell lymphoma. Pelotonia has also funded the $3 million Ohio Colon Cancer Project Initiative (OCCPI).

 

Ulman’s Initial Goals

What will Ulman's initial goals be when he steps into his new role? They will involve building and extending the Pelotonia and the cancer center's brands, he said. "I think both Pelotonia and The James, both brands, have an opportunity to grow in unison. The James is one of the best cancer centers in the world, and yet I'm not sure the brand is well known."

 

He said the eight-man Pelotonia team he's joining is a passionate group. "There's a very engaged board that has shown tremendous leadership from the standpoint of supporting the team and the hospital and driving the community to get behind us. It's a dynamic I haven't seen very often, where everyone--academic, business, philanthropic, and the community--work together."

 

The Chairman of the Pelotonia Board of Directors, Daniel Rosenthal, said under Doug's leadership they hope to create an international brand and movement that will chase down cancer and defeat it.

 

"It's one of largest walk-ride fundraisers, and we want to leverage that weekend into a successful year-round brand that generates more money for cancer research. We wanted a global leader in cancer fundraising and advocacy and you can't find a better leader in those twin goals than Doug Ulman," Rosenthal said.

 

Ulman, who was diagnosed with a rare chondrosarcoma in 1996, and had two episodes of melanoma in 1997, said, "I feel so fortunate to be able to work in this field. I often have friends say, 'You're such a workaholic,’ but it's not work. It doesn't feel like work because I love what I'm doing."

 

Cyclist Patton said it's exciting for Pelotonia to have someone come from a big-name cancer charity with international recognition, and she hopes it helps lure more well-known sponsors, riders, and donors.

 

But for her, she said, the best part of the event in the years to come will always be the spectators: "You're riding along and there are people standing on the side of the road who are getting treatment now and they're cheering and thanking you. There's a man who stood on the course the last couple of years and he holds a sign that says, 'Thank you for saving my wife.'"


Monday, September 29, 2014

 

BY ED SUSMAN

 

MADRID – The high-pitched buzz over the role of immunotherapy in treating lung and other cancers was reduced to a background hum with the disappointing results of treatment with a purported lung cancer vaccine, reported here at the European Society for Medical Oncology Congress.

 

In the study, non-small-cell lung cancer (NSCLC) patients whose tumor cells expressed the molecular target – the MAGE-A3 protein -- median disease-free survival after a 38.8-month follow-up of patients receiving the vaccine was 60.5 months, while the patients not receiving the vaccine had a disease-free interval of 57.9 months -- essentially no difference in outcome, reported Johan Vansteenkiste, MD, Professor of Medicine at Catholic University Leuven in Belgium.

 

Despite the failure of the trial, called MAGRIT, Vansteenkiste said it was too soon to write off immunotherapy as an anti-cancer strategy: “This type of technology in lung cancer did not work, but it is not necessarily the case for other cancers,” he said in an interview. “For prostate cancer, for example, there is already an immunotherapy product on the market that is in clinical use; for melanoma using the same MAGE-A3 vaccination, the results are still maturing and we have to wait for that data.

 

“Clearly there are differences from tumor-to-tumor type and it has always been the case historically and it is still the case. In lung cancer we have to work on reversing the immune suppressive environment, and that is what the checkpoint inhibitors do.”

 

At an ESMO news briefing that included the study, the moderator, Eric Van Cutsem, MD, Professor of Internal Medicine at the University of Leuven, said, “I don’t think the results diffuse the enthusiasm for immunotherapy in oncology. One of the big themes at this meeting is immunology. Dr. Vansteenkiste gave us some insights where it can move forward.

 

“It is correct that in oncology not every study will be successful, and even though this was a very large study in the adjuvant setting we should not be depressed. We should go on with testing of other agents such as checkpoint inhibitors.”

 

On the other hand, Martin Reck, MD, Chief Oncology Physician at Hospital Grosshansdorf in Germany, was more skeptical: “The results of the MAGRIT trial are disappointing for investigations of vaccines, particularly in non-small-cell lung cancer. There are now several big Phase III trials which did not meet the primary endpoint. The concept of vaccination in lung cancer has to be questioned, and checkpoint inhibition might be pursued instead.

 

“When the trial was designed, we were enthusiastic because we had a target, a good drug with the immune stimulatory addition, and we felt we were acting very early in the disease. If any immunotherapeutic approach was going to work, it should have been in this setting, and the results are therefore a big disappointment.”

 

Earlier Data Had Been Promising

Vansteenkiste said that researchers have been stymied for more than a decade in improving long-term survival in NSCLC following surgery and adjuvant chemotherapy. He noted that five-year overall survival after surgery and chemotherapy for such patients approaches 50 percent. Since discovering that MAGE-A3 was expressed on cancer cells but not on most normal cells, the researchers thought they had a way to treat patients after surgery and prevent cancer recurrence, and hence improved survival.

 

 “We were very excited in the Phase II study because the gene signature suggested it would be a predictive biomarker,” he said, “but in the larger Phase III trial we could not confirm that this was predictive. This study gives a final answer and that is also important. Does this trial mean the end of immunotherapy? No, but this vaccination-type technology we have now is probably ending with this study.”

 

In the news briefing, Vansteenkiste explained: “MAGRIT is the first clinical trial in non-small cell lung cancer to investigate immunotherapy in the adjuvant setting of early-stage disease.”

 

Study Details

Patients were eligible for the study if they were diagnosed with pathologically proven stages IB, II, or IIIA NSCLC, and had to have undergone surgery to completely resect the tumor to an R0 status. The primary tumor had to exhibit MAGE-A3-positivity through reverse transcription polymerase chain reaction testing in formalin-fixed paraffin-embedded tissue.

 

Patients had to be in ECOG Performance status 0, 1 or 2. They were also required to have adequate bone-marrow reserve, renal function, and hepatic function; and were ineligible if they were diagnosed with an autoimmune disease.

 

He noted that in one third of non-small-cell lung cancers, the tumors express MAGE-A3, and the MAGRIT trial confirmed those findings. Of the 13,849 individuals screened for the trial, 12,820 underwent testing for MAGE-A3, and 33 percent of these patients – 4,210 persons -- were found to have the gene. From that pool, 2,312 patients were randomized, and 2,272 actually participated in the trial.

 

In the 2:1 randomization scheme, 1,515 individuals were included in the group that received the vaccine candidate and 757 patients were placed in the placebo arm.

 

The median age of the patients was 63; about 76 percent were men; 57 percent of the patients in the study were from Europe; and 16 percent were from North America. Almost all the patients – 98 percent -- were characterized as being in ECOG Performance Status 0-1, and only seven percent said they had never smoked.

 

MAGE-A3 Cancer Immunotherapeutic was delivered as a recombinant protein, combined with immunostimulants. While shown to be safe and generally well tolerated, the vaccine was ineffective, Vansteenkiste admitted, noting that treatment failed to meet any of the primary endpoints.

 

“We need to go back to the bench to better understand the mechanisms of action,” he said. “Lung cancer creates a particular immunosuppressive environment. Several lung cancer vaccination trials have shown that vaccines create effective soldiers -- that is, antibodies and immune cells that are able to kill tumor cells and that have a treatment effect. But the problem occurs when they come to the environment of the tumor, where they are paralyzed by factors in the tumor.”

 

The trial was sponsored by GlaxoSmithKline Biologics.

 


Monday, September 29, 2014

 

BY ED SUSMAN

 

MADRID – The addition of the monoclonal antibody pertuzumab (Perjeta) to trastuzumab-based regimens appears to present a practice-changing, “unprecedented,” improvement in overall survival for women diagnosed with metastatic breast cancer, researchers reported here at the European Society for Medical Oncology Congress.

 

In presenting the results, the final data from the CLEOPATRA trial, Sandra M. Swain, MD, Professor of Medicine at Georgetown University and Medical Director of Washington Cancer Institute at MedStar Washington Hospital Center, said the pertuzumab/trastuzumab combination with docetaxel increased overall survival in this large placebo-controlled study by 15.7 months and conferred this improvement without increasing toxicity when compared with the same regimen without pertuzumab.

 

“I can’t tell you how happy I am to be here to tell you about our results,” she said at an ESMO news briefing. “I think many of us work our entire careers to have these kinds of results, and I have been working in this field for 30 years.”

 

Women treated with chemotherapy plus trastuzumab and pertuzumab achieved a median overall survival of 56.5 months compared with 40.8 months for women treated with placebo plus trastuzumab and docetaxel, she said.

 

20 Months Longer than Previous Analysis

“I think these results are phenomenal,” she said. “These are the final overall survival analyses of the CLEOPATRA study. These results are 20 months longer than the previous analysis. The hazard ratio is 0.68 which is very significant.

 

“What is more important for us as clinicians rather than statistics is the median survival. The median survival for trastuzumab is already very good at 40.8 months. Trastuzumab therapy really changed things for HER2-positive breast cancer, and now adding pertuzumab increased median survival by 15.7 months to 56.5 months. That, to me, is incredible. I’ve never seen that in any other trial of metastatic breast cancer.

 

“The 56.5 month median overall survival is unprecedented in this indication and confirms the pertuzumab regimen as first-line standard of care for patients with HER2-positive metastatic breast cancer.”

 

Eric Van Cutsem, MD, the moderator of the news conference, who is Professor of Medicine at Leuven University, Belgium, said in an interview, “I think this information is going to be practice changing in metastatic breast cancer. Such a big difference in outcomes in survival with such little toxicity is compelling.”

 

204 Centers, 25 Countries, 808 Patients

For the trial, Swain, a past President of ASCO (2012-2013) and her colleagues from 204 centers in 25 countries enrolled 808 patients in the CLEOPATRA study. A total of 406 women were assigned to receive trastuzumab plus docetaxel for at least six cycles of therapy unless they could not tolerate the drug – the actual median number of cycles completed was eight; the other 402 women were treated with the same regimen plus pertuzumab. Patients were treated until disease progression. About half the women in the study presented with advanced disease.

 

Pertuzumab was administered with a loading dose of 840 mg followed by a maintenance dose of 420 mg. A trastuzumab loading dose of 8 mg/kg was followed by a 6 mg/kg maintenance dose, and docetaxel was infused at a starting dose of 75 mg/m2, which could be escalated to 100 mg/m2 if tolerated. The drugs were given every three weeks.

 

Swain explained that preclinical and early clinical data suggested that the two drugs could be used together because the monoclonal antibodies were aimed at targeting the metastatic cancers at different sites in the cells.

 

In addition to the overall survival data, the researchers also performed an updated analysis of progression-free survival – finding that women who received pertuzumab appeared to gain an improvement of 6.3 months of progression-free survival.

 

“It does suggest that in this blinded study, progression-free survival was a good surrogate for overall survival,” she said. In the placebo arm, progression-free survival was 12.4 months; in the pertuzumab arm it was 18.7 months.

 

Pertuzumab did not seem to influence the emergence of adverse side effects, she said. “When you have additional treatments you often have additional toxicities, and rash, mucositis, and diarrhea were greater with pertuzumab.”

 

About 68 percent of patients receiving pertuzumab reported diarrhea compared with about 49 percent of patients on single antibody therapy. Rash was observed in 37.5 percent of patients on the dual-antibody therapy compared with 24 percent of those getting trastuzumab plus placebo. Mucosal inflammation was observed in 27 percent of patients on pertuzumab and 20 percent of patients on trastuzumab.

 

“There was a concern when we started this trial that we would see more cardiac events when we were using two monoclonal antibodies. But actually, we don’t,” Swain said. “Adverse events were very similar, and perhaps less with pertuzumab. Symptomatic left ventricular dysfunction – heart failure – was observed in 1.8 percent of patients on trastuzumab and in 1.5 percent of patients with pertuzumab plus trastuzumab. We did not have additional heart failure symptoms.

 

“Dropping of left ventricular pumping fraction to below 50 percent-- and asymptomatic dysfunction – was also less in the placebo arm--7.4 percent with trastuzumab and 6.1 percent with the combination,” she reported. “One new heart failure event in the pertuzumab group did resolve after the antibodies were stopped. And in 88 percent of the cases in which asymptomatic decline left ventricular function was observed, the condition was reversed.”

 

Subgroups

In response to questions regarding subgroups of patients and whether there were any groups who might benefit from the use of trastuzumab without pertuzumab, Swain said, “Based on the study results, and the consistency in the subgroups, I would recommend personally that all patients who have the opportunity to be treated for metastatic breast cancer receive dual-antibody therapy with pertuzumab and trastuzumab.

 

“There are studies ongoing -- particularly with women who have HER2-positive, estrogen receptor-positive tumors -- to see if they need to include pertuzumab. Right now, pending results of these trials, I would still give them the combination.”

 

Pivotal Study

CLEOPATRA was a pivotal Phase III study, funded by F. Hoffmann-La Roche Ltd. and Genentech, Inc., evaluating the addition of pertuzumab to trastuzumab and chemotherapy.  The study authors had previously reported that the pertuzumab regimen significantly extended progression-free survival and overall survival. The new data reports the results of survival in CLEOPATRA after a median of 50 months of follow-up.

 

The women who were enrolled in the trial were a median 54 years old. More than 35 percent were from Europe, about 31 percent were from Asia, 17 percent were from North America, and 14 percent were from South America. More than 75 percent of the metastases were visceral.

 

In the current analysis, overall survival was analyzed using all randomized patients, with no adjustments for cross-over once the study treatments were unblinded. Patients who crossed over from the placebo arm to the pertuzumab arm were analyzed as part of the placebo arm, explained. “As such, this is a very conservative final analysis of survival.”


Sunday, September 28, 2014

 

BY ED SUSMAN

 

MADRID – In those rare cases in which cancer is diagnosed in a pregnant woman, treatment with standard anti-cancer regimens has been shown in new data to benefit the mother and not harm the child she is carrying, researchers reported here at the European Society for Medical Oncology Congress.

 

In a case-control study that included 38 women and their infants and a like number of controls, Belgian researchers determined that giving chemotherapy in the second and third trimesters of pregnancy did not have any late-term sequelae in the children’s growth patterns.

 

“When chemotherapy is administered after the first trimester of pregnancy, we cannot discern any problems in the children,” said Frederic Amant, MD, Professor of Obstetrics and Gynecology at University Hospitals Leuven in  Belgium. “Fear about the risks of chemotherapy administration should not be a reason to terminate a pregnancy, delay cancer treatment for the mother, or to deliver a baby prematurely.

 

“Before, we would say that you should not give chemotherapy before delivery, but that was not good for either the baby or the mother,” he said in an interview. “We now say, ‘It is better to give chemotherapy during the pregnancy because it is better for the child, and it is better for the mother’.”

 

In fact, he said during a news breifing here sponsored by ESMO, that the only factor that appears to slow development of the child is prematurity – not chemoterapy or other treatments to treat the cancer.

 

“The clinical implications of this study should be that there are fewer terminations of pregnancy, less delay in maternal treatment, and less iatrogenic premature delivery.”

 

He said that in 61 percent of the cases the cancer discovered is breast cancer, usually found through breast palpitation: “These cases are never found through screening, but by clinical examination. The cancer stage is always more advanced in women who are pregnant than when breast cancer is found in the general public, due to physiological changes in the breast during pregnancy that make it more difficult to feel a mass.”

 

Amant also said that previous work appears to show similar long-term outcomes between women diagnosed with breast cancer while pregnant and those diagnosed when they are not pregnant. “We do think that in pregnancy, the diagnosis is not worse,” he said.

 

Another 22 percent of the women in the study were diagnosed with hematological cancers. There were an average of four cycles of chemotherapy during the patients’ pregnancies, and about 91 percent of the women received polychemotherapy regimens.

 

Amant acknowledged that concerns about the potential impact of cancer treatment on unborn children has until recently left some oncologists hesitant to administer treatments to pregnant cancer patients, but his study appears to be reassuring that prompt treatment – at least after the first trimester of pregnancy – is safe.

 

Bayley Scales of Mental Development

In scrutinizing outcomes on the Bayley Scales of mental development  comparing the control children and those exposed to chemotherapy, Amant said, “You can see there is a nice overlap of these outcomes. We did not see any difference in Bayley scale whether the children were or were not exposed to chemotherapy.”

 

He said the data reveal that children who are born prematurely appear to do worse in development that children who were carried to full term -- “but this is the same for children if they were exposed to chemotherapy in utero or not. So prematurity is a problem, but not chemotherapy.”

 

All the women in the study were treated in the second or third trimester. “We did not compare whether there was a difference in the duration of treatment because the numbers were not large enough to see a difference,” he said. “In the future we will do this. The cognitive system is still forming in the second trimester, more so than in the third trimester, so there might be a difference, but we haven’t done that comparison for this study.”

 

Study Specifics

The researchers followed children who were exposed to chemotherapy in utero from the International Network for Cancer, Infertility and Pregnancy registry and who were assessed for mental development and cardiac health. At a median age of almost two years, mental development as measured by the Mental Development Index was in the normal range for both groups of children, and were not significantly different. Similarly cardiac dimensions and functions were within normal ranges for both groups. The children underwent electrocardiography and echocardiography to obtain their comparisons.

 

The children were a median age of 20.5 months, range of 18 to 42 months. Echocardiography was administered to 24 children who were exposed to anthracyclines in utero and 24 controls who were a median age of 22 months.

 

In a second study, the team also determined that in a study of 16 children and 10 adults who had been exposed to radiotherapy in utero, neuropsychological, behavioral, and general health outcomes for those exposed to radiotherapy were within normal ranges. One child had a severe cognitive delay, but other pregnancy-related complications are confounding factors, the researchers reported.

 

Becoming Pregnant after Cancer Diagnosis/Treatment

Another study from the group shows the importance of thinking about contraception during cancer diagnosis and cancer treatment: The pregnancy database identified 29 out of 897 women who became pregnant after an initial diagnosis of cancer.

 

“We need much more work in this field, especially among women who get pregnant during chemotherapy,” the moderator of the news briefing, Giuseppe Curigliano, MD, Director of Experiment Therapeutics at the European Institute for Oncology in Milan, said in an interview.

 

“The primary message of his study is that you have nine weeks in which you don’t have to deliver chemotherapy to women who got pregnant, but after this interval, if you expose a woman to a chemotherapy to treat a breast cancer or any other type of cancer, this is safe for the children.

 

“The findings are important even if it is just 38 children in the study. This really is a huge number when you consider that pregnancy and cancer is a rare entity in clinical practice. Knowing that delivering chemotherapy does not effect the brain development or the heart development is really gratifying information.”