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July 28, 2009 • Volume 6 / Number 15

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NEWS

This color-enhanced slide shows a magnetic resonance image (MRI) of a breast. More Women Are Choosing Mastectomies at Mayo Clinic

More women have been having mastectomies to treat early stage breast cancer at the Mayo Clinic since 2004 than during the previous 6 years, according to an analysis of surgeries done at the clinic between 1997 and 2006. While the reasons for the apparent shift are not known, the rise in mastectomy rates marks a reversal—radical surgery to remove the breast had been in decline in the United States, and at the clinic.

The findings, published online July 27 in the Journal of Clinical Oncology, appear at a time when many in the field are wondering about the role of mastectomy in this disease. Read more > >

COMMENTARY

Director's Update: A Significant Milepost on the Cancer Informatics Super Highway

Five years ago, NCI launched the cancer Biomedical Informatics Grid (caBIG) as a pilot program to develop an electronic data infrastructure system for cancer research. It was an ambitious vision to create the world's largest biomedical research "highway." Last week, at the caBIG annual meeting, we had the opportunity to see just how successful this effort has become in a very short time.

Through caBIG, NCI has built an interoperable information network, a platform that supports the exchange of large volumes of research and clinical data, along with the requisite storage and information security that are all too important in an electronic era like today. In addition, caBIG has developed, and now makes freely available, more than 40 software tools that are being applied to basic and clinical research questions related to studying cancer and other diseases—from integrative cancer research tools, to the management of clinical trials, to the inventory, tracking, and clinical annotation of biospecimens. Read more > >

A MESSAGE TO READERS

Updated and Expanded Information about the Recovery Act and Challenge Grants

NCI has updated http://www.cancer.gov/recovery, its Web site with the latest information on the American Recovery and Reinvestment Act of 2009. The site now includes an overview of the legislation, NCI’s research objectives and signature initiatives, recently posted funding announcements, and an overview of awards. The site will be updated regularly. Your interest in the Recovery Act is important, and the institute welcomes your comments and suggestions.

IN DEPTH

UPDATES

  • FDA Update

    • FDA Issues Warning on Electronic Cigarettes
    • Labeling Change Narrows Use of Two Targeted Agents

    Notes

    • Wikipedia Academy Held at NIH

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

More Women Are Choosing Mastectomies at Mayo Clinic

This color-enhanced slide shows a magnetic resonance image (MRI) of a breast. This color-enhanced slide shows a magnetic resonance image (MRI) of a breast.

More women have been having mastectomies to treat early stage breast cancer at the Mayo Clinic since 2004 than during the previous 6 years, according to an analysis of surgeries done at the clinic between 1997 and 2006. While the reasons for the apparent shift are not known, the rise in mastectomy rates marks a reversal—radical surgery to remove the breast had been in decline in the United States, and at the clinic.

The findings, published online July 27 in the Journal of Clinical Oncology, appear at a time when many in the field are wondering about the role of mastectomy in this disease.

"We're seeing a change in how medicine is practiced, at least at the Mayo Clinic," said Dr. Matthew P. Goetz, a medical oncologist and leader of the study. "As a cancer community, we need to understand why that is happening. And then we need to step back and ask ourselves if this is really a good thing for patients."

One of the changes that occurred in the management of breast cancer during the study period was the introduction of magnetic resonance imaging (MRI). The investigators looked for evidence of a possible link and found that use of MRI was associated with mastectomy, though they could not show cause and effect.

Choosing Mastectomy, But Why?

The vast majority of Asian American women—in particular Vietnamese, Filipinas, and Chinese—who are diagnosed with breast cancer have mastectomies rather than breast-conserving therapy, and researchers in California are asking why. Through surveys of physicians and interviews with patients in the San Francisco Bay Area, the researchers have found that while clinical factors help determine a patient's treatment, cultural beliefs and norms also play a role.

For instance, a belief among some Asian American women that it is not important to preserve the breast after a diagnosis of cancer may have contributed to the pattern of treatment in this population, the researchers reported July 17 in BMC Public Health. In addition, some patients, particularly recent immigrants, may be hesitant to question the recommendation of a physician because to do so would be considered inappropriate.

The NCI-supported pilot study, led by Dr. Scarlett Gomez of the Northern California Cancer Center, aims to better understand the complex decision-making processes behind the high mastectomy rates. The findings could aid physicians in their interactions with patients who share these cultural beliefs, helping them deliver the most appropriate care.

"There is evidence from a number of institutions that MRI may change the management of breast cancer, and we're trying to ask whether using MRI will improve the survival of patients in the long term," said Dr. Goetz. "Right now we just don't have that data."

In the study, women who had a breast MRI were 10 to 15 percent more likely to have a mastectomy than other women. But the biggest increase in mastectomy rate occurred among women who did not have a breast MRI. This suggests that if MRI does play a role, it is certainly not the only factor, the researchers said.

"We cannot say from our study that getting an MRI led women to choose a mastectomy," Dr. Goetz said. "It's really unclear which factors are influencing women in their decisions."

Less-invasive procedures for treating early stage breast cancer came into favor in the early 1990s, when NIH recommended breast-conserving therapy—surgery to remove a tumor followed by radiation—for most women with the disease. The guidelines cited evidence that mastectomy and breast-conserving therapy were similar in terms of survival.

As doctors communicated this message to their patients, mastectomy rates declined throughout the United States during the 1990s. At the Mayo Clinic, rates fell steadily from 45 percent in 1997 to 31 percent in 2003. But between 2004 and 2006, mastectomies increased from 37 percent to 43 percent.

"We have all had the feeling that there are more women with early stage breast cancer having mastectomies, and the Mayo Clinic investigators have documented this in a nice way," said Dr. Monica Morrow, chief of the Breast Service at Memorial Sloan-Kettering Cancer Center.

In an accompanying editorial, she and Dr. Jay R. Harris of the Dana-Farber Cancer Institute stressed the need for more research on how to effectively communicate complex treatment choices to women facing the stress of a new cancer diagnosis.

"We know very clearly from the literature that breast-conserving therapy and mastectomy do not vary in terms of survival," said Dr. Morrow. "So it's a little concerning that more and more women seem to be opting for the more aggressive surgery."

She noted that further evidence of a possible shift in patient views of mastectomy includes a recent study showing increases in double mastectomies as a preventive measure among women diagnosed with cancer in only one breast.

"That report is another piece of evidence that points to a possible pendulum swing in public opinion about how aggressive patients with breast cancer want to be in preventing a recurrence or a contralateral breast cancer," said Dr. Amy Degnim, a breast surgical oncologist at the Mayo Clinic and coauthor of the current Mayo Clinic study.

She believes there may be multiple reasons for this recent change besides the increasing use of MRI. Women, for example, may be better informed about their treatment choices and side effects; attitudes about the risks of radiation treatment may be changing; and there is a greater awareness of breast reconstruction. Shifting attitudes among some physicians is another possibility.

At this point, Dr. Degnim added, it is difficult to know whether the apparent increase in mastectomies is a positive or negative development simply because too little is known about what the patients themselves think.

"Ultimately, if patients who choose mastectomy have equivalent survival and are happy with their treatment choice, then this change is not necessarily bad," she said.

Edward R. Winstead

Cancer Research Highlights

Breast Cancer Risk in Survivors of Childhood Cancer Quantified

In the largest study of its kind, researchers led by Dr. Peter Inskip of NCI's Division of Cancer Epidemiology and Genetics estimated the relationship between exposure to radiation during childhood cancer treatment and adult breast cancer risk in 6,647 women from the Childhood Cancer Survivor Study (CCSS). The results were published July 20 in the Journal of Clinical Oncology.

Overall, women who received any radiation therapy for their initial cancer were 2.7 times as likely to develop breast cancer. The risk increased linearly with increasing radiation dose to the area where the tumor developed in the breast, reaching 11-fold for doses in the highest category of exposure (40 Gray), relative to no radiation.

The women had been diagnosed with their primary cancer as children, between 1970 and 1986. One hundred twenty developed breast cancer by the end of 2001 and gave consent to have their medical records reviewed. The researchers matched each of the 120 women with 4 women in a control group from the CCSS who had not developed breast cancer. Medical physicists estimated radiation doses to the breast and ovaries.

Interestingly, women who had received radiation to the breast as well as a sterilizing radiation dose to the ovaries (which stops ovarian hormone production) had a sharply reduced risk of radiation-related breast cancer. "A radiation dose to the breast can cause damage that may potentially develop into cancer, but whether that damage does develop into cancer can be influenced by hormonal stimulation from the ovaries," explained Dr. Inskip.

The authors noted that modern radiation therapy for most types of childhood cancer uses substantially lower radiation doses than protocols used between 1970 and 1986. In addition, said Dr. Inskip, "we're highlighting the complications of treatment here, but we should remember that there has been remarkable progress in treating childhood cancer. Many children who might have died from their cancer are living due to advances in treatments."

Thalidomide Does Not Help in Small Cell Lung Cancer

Adding the drug thalidomide to chemotherapy did not help patients with small cell lung cancer (SCLC) live longer, but it did increase the risk of developing blood clots in veins deep within the body, British researchers reported in the Journal of the National Cancer Institute on July 16. Thalidomide was evaluated in this disease because of its ability to inhibit angiogenesis, or the growth of blood vessels, in tumors. Angiogenesis is thought to play an important role in SCLC, which accounts for about 20 percent of lung cancers.

The drug has improved survival for people with other cancers, but it provided no benefit in the first phase III, randomized trial of an antiangiogenic agent in SCLC. In the 724-person study, Dr. Siow Ming Lee of University College Hospital in London and his colleagues found that survival was essentially the same (about 10 months) in both the thalidomide group and the chemotherapy-alone group. Patients in the thalidomide group, however, faced a higher risk of clotting events such as deep vein thrombosis and pulmonary embolus.

In addition, patients with extensive disease in the thalidomide group fared worse than those in the chemotherapy-alone group. Targeting angiogenesis may not work as well in SCLC as in multiple myeloma and colorectal cancer, perhaps because of differences in the angiogenic pathways involved, the researchers concluded.

The notion that thalidomide has antiangiogenic effects in patients should be revisited, noted an accompanying editorial. But the biology of SCLC is still poorly understood, and the authors suggested that it may make sense to focus now on laboratory research that could lead to new insights and identify promising therapeutic targets.

New Role Found for Tumor-suppressor Protein

Japanese researchers have identified a previously unknown function for the protein p53, which helps the body suppress tumors. A team from the University of Tokyo found that p53 also plays a role in the processing of microRNAs, snippets of genetic material that regulate genes. The loss of p53 may affect the processing of several microRNAs with anticancer properties, the team reported in the July 23 Nature.

The gene for p53 is mutated in half of all cancers, and in a majority of tumors the p53 pathway is inactivated. The protein is thought to protect against cancer in cells with DNA damage by activating genes that cause the cells to either commit suicide or stop growing rather than progress to a tumor. Together with previous research, the new results suggest that p53 mutations can disrupt several tumor-suppressive functions at once, including the induction of cell suicide and the processing of microRNAs that help suppress abnormal cell growth.

These results may have implications beyond the cell's response to DNA damage and cancer, according to an accompanying editorial, because mutations in p53 could alter other aspects of RNA metabolism besides microRNA processing. Future studies will need to determine precisely which microRNAs are regulated by p53 and describe the underlying mechanisms involved.

Some researchers have been exploring ways to re-activate p53 in cells where the protein has been disabled, but this has so far proved to be a challenge. The current study suggests that doing so would restore anticancer functions that were previously unappreciated.

Clinical Trial Caution: Meeting Abstract May Differ from Final Publication

Randomized clinical trials of cancer therapies are often reported as preliminary results in the form of abstracts at major scientific meetings. But, as a new study documents, the conclusions of these abstracts may not agree with the subsequent final analyses published by the trial investigators in peer-reviewed journals. In about 10 percent of the trials analyzed, there was a reversal in the researchers' conclusions about the efficacy of treatment when the abstracts were compared with the final report.

Given the potential for non-final results to mislead and even affect how the trial continues, clinicians, investigators, and the organizers of conferences should be cautious when interpreting results from randomized clinical trials, Canadian researchers from the NCIC Clinical Trials Group reported online last week in the Journal of Clinical Oncology.

The researchers assessed 138 randomized clinical trials, published between 2000 and 2004, in four major cancers (lymphoma, breast, colorectal, and non-small cell lung cancer). For each trial, the researchers identified and analyzed corresponding abstracts that had been presented at seven major cancer meetings between 1990 and 2004. All of the abstracts presented efficacy results.

"A substantial percentage of trials will see an important change in their conclusions from the time of abstract presentation to the final publication," said lead investigator Dr. Christopher Booth of Queen's University Cancer Research Institute. "This means that clinicians need to be cautious before changing their practice based on preliminary results of randomized trials."

Just as important, the authors of abstracts have a responsibility to clearly identify non-final results, commented Dr. Benjamin Djulbegovic of the University of South Florida and H. Lee Moffitt Cancer Center & Research Institute, who studies clinical trials. "The bottom line is that people who use the information in these abstracts need to know when results are preliminary."

Director's Update

A Significant Milepost on the Cancer Informatics Super Highway

Dr. John E. Niederhuber Dr. John E. Niederhuber

Five years ago, NCI launched the cancer Biomedical Informatics Grid (caBIG) as a pilot program to develop an electronic data infrastructure system for cancer research. It was an ambitious vision to create the world's largest biomedical research "highway." Last week, at the caBIG annual meeting, we had the opportunity to see just how successful this effort has become in a very short time.

Through caBIG, NCI has built an interoperable information network, a platform that supports the exchange of large volumes of research and clinical data, along with the requisite storage and information security that are all too important in an electronic era like today. In addition, caBIG has developed, and now makes freely available, more than 40 software tools that are being applied to basic and clinical research questions related to studying cancer and other diseases—from integrative cancer research tools, to the management of clinical trials, to the inventory, tracking, and clinical annotation of biospecimens.

Today, some 1,500 individuals from more than 450 organizations representing 13 countries are participating in caBIG projects. caBIG technology has been used to link 50 of the 65 NCI-designated Cancer Centers, along with members of the NCI Community Cancer Centers Program, The Cancer Genome Atlas, numerous other NCI-supported scientific programs, and hundreds of scientists. And caBIG is now being used by other NIH institutes, including the National Heart, Lung and Blood Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of Child Health and Human Development. The FDA and scientists in the United Kingdom are using caBIG, and a new collaboration with researchers in India is underway.

During last week's meeting, NCI unveiled an exciting new collaboration with the Dr. Susan Love Research Foundation and its Love/Avon Army of Women, which will use caBIG to enable the first online breast cancer research cohort of a million women. This program will be able to securely manage massive amounts of clinical and demographic data, harnessing the enthusiasm of women around the globe to participate in research.

Importantly, caBIG encompasses much more than storage and retrieval of data. It is a systematic approach to achieve information technology connectivity, making huge volumes of carefully annotated, well-catalogued data and open-source software freely available to the scientific community. Fully aware of the immense challenges that accompany this goal, caBIG is also the platform for a pioneer effort that we call the "Cancer Knowledge Cloud," a new method of instant access to information, tools, and computing power through the Internet. The "Cloud" is the next step toward a truly connected 21st-century research and cancer clinical care enterprise.

caBIG is also an integral component of NCI's overall vision to change the course of cancer research and treatment. NCI is developing the concept for a pilot center that will utilize the latest technologies to characterize both patients and their tumors. This center will be the test bed, if you will, for a new paradigm in translational research, which will match the specific needs of an individual, highly characterized patient with drugs specific to his or her cancer. We will take the "proof of efficacy" question for a novel molecular agent to the information cloud, asking that all genetically appropriate test subjects be identified for possible inclusion in a trial of that agent.

As you can imagine, the amount of information gathered will be huge, and it will be useful only if it is well organized, appropriately controlled, and accessible. We project quantities of data to go beyond petabytes (quadrillions of bytes) and into exabytes (quintillions of bytes). Fundamental to this connection is the electronic health record (EHR). caBIG's leadership is collaborating with the American Society of Clinical Oncology to create an open-source, cancer-specific EHR that will link all the constituents of the cancer community—researchers, clinicians, and patients—in a continuum of research, development, and care. This, in short, is where caBIG and the health care system must go in the years ahead.

Cancer is in many ways a model for the study of all disease. It is, then, no surprise that caBIG is helping to lead biomedicine into the digital age. Aneesh Chopra, the nation's first chief technology officer, remarked at the caBIG meeting that collecting information on all patient encounters and outcomes is essential to truly understand the drivers of disease and drug response and to develop innovative and new approaches to treatment and prevention. We owe it to the patients we serve to ensure that the larger biomedical community learns from their diagnoses, treatments, and clinical outcomes so that the whole of cancer research may move forward.

This is not a time to be timid. The worlds of information technology and biomedical research are converging. I am confident that caBIG will continue to provide the platform for innovation across the biomedical enterprise, and I look forward to seeing what it will accomplish in the next 5 years.

Dr. John E. Niederhuber
Director, National Cancer Institute

Special Report

New Lung Cancer Treatment Approach Raises Hopes and Debate

A number of clinical trials have tried and failed to improve survival in patients who have advanced non-small cell lung cancer (NSCLC) by extending the duration of their initial treatment. The premise behind the approach, often called maintenance therapy, is simple: In patients whose tumors regress following their initial treatment, give the cancer another kick while it's down, rather than waiting for it to regain steam before delivering further therapy.

Where past trials have failed, though, several recent phase III trials using more current agents have reported some success using maintenance therapy. To date, one trial has reported improved overall survival and a second, the SATURN trial, is slated to report improved overall survival next week at an international lung cancer conference. Several other trials have shown improvements in progression-free survival. Among patients with advanced disease, for whom survival can range from a few months to 1 or 2 years, any improvement is good news.

Positive Trials of Maintenance Therapy in NSCLC

Phase III Clinical TrialsFindings
Maintenance pemetrexed versus best supportive care (663 patients)Improved overall survival (OS) (15.5 versus 10.3 months, nonsquamous only) and progression-free survival (PFS)
Immediate versus delayed docetaxel (309 patients)Improved PFS (5.7 versus 2.7 months) with a trend toward improved OS, but not statistically significant
SATURN - Maintenance erlotinib versus best supportive care (889 patients)Slight improvement in PFS (12.3 weeks versus 11.1 weeks), with OS data to be reported on August 1
ATLAS - Erlotinib and bevacizumab maintenance therapy versus bevacizumab maintenance therapy (768 patients)Slight improvement in PFS of approximately 1 month

Even with the positive data, though, leading lung cancer experts disagree on some important details about precisely how maintenance therapy fits into the current treatment mix for advanced NSCLC, which now includes numerous options for first-, second-, and third-line treatments, some of which are targeted therapies.

The debate over maintenance chemotherapy has taken on renewed importance in recent weeks, with the FDA's approval of the first agent for use in this indication, pemetrexed (Alimta). Just how deeply this new treatment approach will reach into the clinic is unclear. According to Dr. Sherman Baker, Jr., of Virginia Commonwealth University's Massey Cancer Center, it's already being done on a limited basis and its use is now likely to expand.

"The question in my mind is, will we do it right?" he said. That is, will clinicians follow the approaches that clinical trials have shown offer a benefit? Dr. Baker also wonders if these trials will alter cancer specialists' mindset. "Will these trials change how we view advanced NSCLC—not just as a disease that is always fatal but as something that we may be able to make more of a chronic disease, where 2-year survivals are more common?"

This diagram of stage IIIA non-small cell lung cancer shows cancer in the lymph nodes, left main bronchus, pleura, diaphragm, and chest wall. This diagram of stage IIIA non-small cell lung cancer shows cancer in the lymph nodes, left main bronchus, pleura, diaphragm, and chest wall.

Getting to this Moment

Although there is some disagreement on the role of maintenance therapy, there is no question about the duration of first-line chemotherapy in patients with advanced NSCLC—four to six cycles (most often four)—or that first-line chemotherapy should consist of a combination of agents that include a platinum chemotherapy drug such as cisplatin or carboplatin. Numerous trials have shown that these platinum-based "doublets" are highly effective, but that going beyond six cycles simply piles on toxicity without any added clinical benefit.

Maintenance therapy—as practiced in the phase III clinical trials that have reported positive results (see sidebar)—comes into play in patients whose tumors have responded to first-line therapy. These patients then immediately begin treatment with maintenance agents until their disease shows signs of progressing.

In the international phase III trial that garnered pemetrexed's FDA approval for this new indication, patients with advanced NSCLC of the nonsquamous type had a median overall survival of 15.5 months with pemetrexed maintenance therapy, compared with 10.3 months for those who received best supportive care. Progression-free survival also improved significantly. Patients with squamous cell carcinoma did not benefit from the maintenance therapy regimen.

Dr. Chandra P. Belani, the trial's principal investigator, believes the trial results establish maintenance therapy as a new standard of care for nonsquamous NSCLC. "Such a survival benefit with maintenance therapy has not been seen before," he said. Given the low rate of less-severe side effects seen with pemetrexed, he added, the potential survival benefits warrant its use.

"Whenever there is something new, there are going to be those who are reluctant to use it," Dr. Belani said. "But now that it is approved [by the FDA] based on the trial results, how can you deny it to patients?"

Dr. Nasser Hanna, from Indiana University's Simon Cancer Center, remains skeptical of maintenance chemotherapy for most patients with advanced NSCLC. The survival benefit in the pemetrexed trial, he argued, is not quite what it seems because many patients in the trial's non-maintenance arm did not receive the study drug or any approved second-line therapy once their disease progressed. And even low-grade toxicities, he added, "are not trivial," particularly in this patient population.

Similar results, Dr. Hanna continued, can be achieved in many patients even if they get a "holiday" from treatment—referring to the practice of giving patients time to recover from the duress of first-line treatment—or even if, as current guidelines recommend, the next round of treatment is not initiated until there are signs of progression.

In another positive maintenance therapy trial that used the chemotherapy drug docetaxel (Taxotere), published earlier this year, a significant percentage of patients in the non-maintenance arm did not receive docetaxel upon disease progression. However, patients who did had the same survival as those who received it immediately.

"I don't see these trials as demonstrating that maintenance therapy is necessary for the majority of patients," Dr. Hanna said. "But they do underscore the value of these agents in metastatic disease and the importance of not losing the opportunity to treat patients with these drugs."

That limited window of opportunity, argued Dr. Belani, is exactly why immediate administration of therapy is so important. "There is no way to predict which patient will benefit from a treatment holiday," he said. "After a treatment holiday, a third of patients can't go on to [receive the next] treatment. They either have a declining performance status, their cancer progresses, or they die."

No Longer "One and Done"

A key point to take away from the recent positive maintenance therapy trials is that they all involved FDA-approved second- and third-line treatments, said Dr. Mark Socinski from the University of North Carolina's Lineberger Comprehensive Cancer Center. This is a big change from earlier in this decade, he noted, when there were fewer effective first-line therapies for NSCLC, let alone anything beyond that.

"These trials are telling us that it's important for patients to get drugs known to improve survival," he said. "A maintenance strategy is one way to do that." Regardless of the strategy that's chosen, Dr. Socinski continued, the available data indicate that oncologists need to more closely consider the next line of therapy and educate their patients about it.

"We need to tell them, if your cough gets worse, if the pain gets worse, don't wait for your next appointment. Don't ignore your symptoms," he said. "Patients need to hear that something like that means their disease might be getting worse, and they need to know that getting active agents can help."

Carmen Phillips

Spotlight

Supportive Care Trials Face Challenge of Scientific and Ethical Inadequacies

In a systematic review published June 29 in the Journal of Clinical Oncology, researchers led by Dr. Nathan I. Cherny from the Shaare Zedek Medical Center in Jerusalem, Israel, argued that the vast majority of clinical trials comparing an experimental treatment against best supportive care (also called palliative care) have been neither scientifically valid nor ethical, due to a lack of standardization in the supportive care provided to patients.

Studies have previously indicated that supportive care in the clinic routinely fails to provide adequate pain and other symptom management or psychological and family support, stated the authors. "In addition," they explained, "evidence indicates that oncologists frequently feel inadequately prepared for this aspect of their work." In this review of oncology clinical trials published between 1966 and 2008, these issues that bedevil supportive care delivered in the clinic have now been shown to carry over into research.

Studies Lacking Standards

"If you're going to design a clinical trial where your control arm is supportive care, you need to embed in the protocol a standardized approach for how patients randomized into that arm will be treated, and it needs to be just as well defined as the experimental arm," said Dr. Ann O'Mara, head of palliative care research in NCI's Community Oncology and Preventive Trials Research Group. Dr. Cherny and his colleagues did not find this sort of standardized approach in the trials they reviewed.

The researchers identified clinical trials published in English between 1966 and 2008 for patients with advanced or metastatic cancers for which there were no standard treatments. These trials either compared an experimental treatment regimen and supportive care against supportive care alone (20 trials) or compared an experimental treatment regimen alone against supportive care (12 trials).

All but three of the identified trials provided minimal or no descriptions of the supportive care provided. In 21 of the studies, the supportive care provided was not standardized but instead was at the discretion of the treating investigator. Only one study described the training and experience of those providing the supportive care. "In most of the studies, the standard of [supportive care] was manifestly ad hoc, and there was no apparent use of invoked standards," stated the authors.

Implications for Study Results, Ethics

Deficiencies in the supportive care provided in these trials raise questions about the reported scientific outcomes. If patients in these trials did not receive appropriate, standardized supportive care, there's the risk "of a straw-man effect," explained Dr. Amy Abernethy, program director of the Duke University Cancer Care Research Program and one of the authors of the JCO study. "If the supportive care arm to which these new treatments are being compared is not standardized or as good as it could be, the difference between what we're calling best supportive care and the proposed new treatment can be exaggerated," she said. "I think that is the most important point we make in this article."

The lack of supportive care standards observed in these trials also raises ethical issues. "The contract you make with patients when they enroll in a trial is that you're going to make sure they have access to the best care they can have access to, the current gold standard," said Dr. Abernethy.

The authors of the JCO study recommend "that researchers and IRBs critically review [best supportive care] studies currently open," and that trials not providing this standard be amended or closed.

If the supportive care arm to which these new treatments are being compared is not standardized or as good as it could be, the difference between what we're calling best supportive care and the proposed new treatment can be exaggerated.

Reflections of Clinical Barriers

It's important to remember, said Dr. O'Mara, "that supportive care has really only taken off in the last 10 years," and that even with the recent development of guidelines and standards associated with supportive care, "a lot of people don't realize that there's a lot they don't know."

To identify and reduce the barriers to delivering appropriate symptom management and palliative care in the clinic (including a lack of knowledge among clinicians of current recommended best practices), NCI released a request for grant applications in 2004 on this subject, and the first findings from the 16 funded projects are beginning to emerge.

One major barrier that cannot be addressed with research alone, said Dr. Diane Meier, director of the Center to Advance Palliative Care and an NCI grantee, is the current reimbursement system in the United States. "Oncologists are paid to give treatment. There is no incentive to have, for example, a 90-minute family meeting about goals of care. In fact, there's a huge financial penalty. Unless we get a regulatory and reimbursement system that actually pays for outcomes, it's going to be very difficult to change this."

Reforming Best Supportive Care Studies in Oncology

"As someone who performs clinical trials, what I need is a menu of necessary supportive care that can be followed and standardized as part of the protocol, and it has to be fundamentally practical—something I can feasibly do," said Dr. Abernethy.

No such menu currently exists, but her co-author, Dr. Yousuf Zafar, recently received an NIH grant to develop standards for supportive care in oncology clinical trials. He is assembling an expert panel of oncologists, clinical trial investigators, and palliative care specialists to identify both the major problems with best supportive care delivered in the clinical trials setting and potential solutions. An independent group of clinical trial investigators will then evaluate the feasibility of the panel's recommendations.

The project's final step will be a clinical trial to compare outcomes and quality of life between patients receiving the newly defined standard of supportive care and those receiving ad hoc supportive care, as is often provided in the clinic. "This will give us a solid foundation upon which to build evidence-based supportive care" in clinical trials, explained Dr. Zafar.

Sharon Reynolds

A Closer Look

TechnologyThis is the first article in a new series of stories related to cancer technology. Look for the symbol on the left in an upcoming issue for the next article in the series.

Study Supports Use of Existing Technology for Clinical Proteomics Research

Image of test tubes and a pipette from a patient brochure produced by NCI's Clinical Proteomic Technologies for Cancer initiatives

A new study has found that an existing technology used in other aspects of biomedical research may play an important role in the long-sought quest to identify reliable protein biomarkers in blood samples that can signal the early presence of cancer or its return. The results represent major findings from NCI's Clinical Proteomic Technology Assessment for Cancer (CPTAC) Network—an effort to improve the science and technology underlying the field of clinical proteomics research—and enable the translation of discoveries from the field into the clinic.

The highly collaborative, team-based study that involved eight laboratories from the CPTAC Network (see sidebar) did not attempt to discover new biomarkers or prove that previously discovered biomarkers could accurately identify the early presence of an aggressive cancer. Rather, the study's chief aim was to determine whether the technology, multiple reaction monitoring with stable isotope dilution mass spectrometry (SID-MRM-MS), could reliably detect and quantify levels of prespecified proteins (using defined fragments of these proteins known as peptides), and whether the results would be consistent or reproducible across testing sites.

Published online June 28 in Nature Biotechnology, the study was successful on both counts, said lead investigator Dr. Steven Carr from the Broad Institute of the Massachusetts Institute of Technology and Harvard University. "The testing approach demonstrated that multiplexed protein assays based on SID-MRM-MS could be made to be highly reproducible within individual labs and from lab to lab," he said.

The reproducibility was a critical finding, he continued, because it had not been previously demonstrated and because some of the labs involved had no prior experience with SID-MRM-MS.

Participating CPTAC Labs

The eight laboratories which participated in this study were:
  • Broad Institute of the Massachusetts Institute of Technology and Harvard
  • Buck Institute for Age Research
  • Fred Hutchinson Cancer Research Center
  • Monarch Life Sciences
  • Skirball Institute at New York University
  • University of California, San Francisco
  • University of Victoria, British Columbia
  • Vanderbilt University School of Medicine

It's also important, added Dr. Henry Rodriguez, director of NCI's Clinical Proteomic Technologies for Cancer (CPTC) program, because although proteomics has generated optimism as a means of detecting fatal cancers in their earliest stages, the field has been plagued by failures to reproduce findings from individual studies on a given set of blood or tissue samples.

CPTAC is part of an effort, Dr. Rodriguez continued, to help address the areas of "variability" that have contributed to these reproducibility problems, such as differences in collecting and storing blood and tissue samples and applying different technologies and computer software in proteomic science. Improvements in these areas can also enhance the overall conduct of biomarker science, he stressed.

For example, the CPTAC study authors believe that their results indicate a testing approach based on SID-MRM-MS may be an ideal bridge between the discovery stage of protein biomarkers, where hundreds to thousands of potential leads are often turned up by a single study, most often using conventional mass spectrometry; and the clinical validation phase, in which highly sensitive, antibody-based tests are developed for use in large clinical trials to determine whether a biomarker or panel of biomarkers can reliably detect or rule out the presence of cancer. Although no firm figures are available, such antibody-based tests are thought to take more than a year to develop at a cost of up to several million dollars.

Culling through the thousands of potential markers generated in the discovery phase to identify the most promising ones to move forward into the validation phase has been the biggest rate-limiting step in proteomics biomarker research to date, Dr. Carr and his CPTAC colleagues wrote. Because of its targeted nature, high sensitivity (as much as 100 times higher than conventional mass spectrometry methods), and ability to assay tens of proteins simultaneously, the SID-MRM-MS technology "has the potential to become the critical filter used to assess candidate biomarker performance in a sufficient number of patient samples before committing the very substantial time and resources required to create clinical-grade immunoassays," the CPTAC research team wrote.

The study involved a rigorous, systematic approach to assess whether SID-MRM-MS could be an effective tool in this prevalidation—or verification—phase. "This highly important work, introduced by the CPTAC Network, can help move the field forward reliably and efficiently," Dr. Rodriguez said.

The study consisted of multiple sub-studies of increasing complexity to enable the investigators to define and understand sources of variability. The first involved the addition of "signature" peptides derived from the seven targeted proteins, as well as versions of these peptides that were tagged, or labeled, with radioactive tracer molecules, into a standardized plasma sample at multiple concentrations. ("Signature peptides" are unique to each protein in the genome and also provide high sensitivity for mass-spectrometry analysis.) The subsequent studies systematically introduced additional sources of variability, from added sample handling and processing steps up to the final study that simulated a real biomarker verification study.

The CPTAC team's study represents the "first critical step" in assessing SID-MRM-MS in this prevalidation phase, Dr. Carr said. The CPTAC group has already launched a follow-on study to evaluate reproducibility, using a 10-fold increase in the number of peptides and also enriched protein samples prior to SID-MRM-MS analysis to improve sensitivity (the ability to detect protein biomarkers present at very low concentrations) 10-fold over the current study.

The raw data from the study are available on the CPTC Web site. Interested investigators can obtain the reagents, study samples, and detailed study protocols there, as well. "The methods have been finely detailed, so as proteomics laboratories begin to explore the technology either for biomarker verification or for targeted detection of proteins or their modifications in basic biological studies they have a way to benchmark themselves," Dr. Carr said.

In addition, Dr. Rodriguez noted, CPTAC is working with the FDA to provide scientific support for potential future guidance that defines requirements for those developing multiplexed proteomics-based assays for use in clinical care.

Carmen Phillips

Featured Clinical Trial

Comparing Second-line Therapies for Advanced Lung Cancer

Name of the Trial
Phase III Randomized Study of Pemetrexed Disodium Versus Erlotinib Hydrochloride As Second-Line Therapy in Patients with Advanced Non-Small Cell Lung Cancer (NCCTG-N0723). See the protocol summary.

Dr. Alex Adjei Dr. Alex Adjei

Principal Investigators
Dr. Alex Adjei, NCCTG; Dr. Martin Edelman, CALGB; Dr. David Carbone, ECOG; Dr. Fred Hirsch, SWOG; and Dr. Geoffrey Liu, NCIC-CTG

Why This Trial Is Important
Advanced non-small cell lung cancer (NSCLC) remains a very difficult disease to treat, with most patients dying within a few years. Nevertheless, some advances in treatment are occurring. The chemotherapy drug pemetrexed can prolong survival in some patients and is a standard second-line treatment for patients with progressive or recurrent NSCLC following initial chemotherapy. The targeted drug erlotinib has also helped some patients with advanced NSCLC live longer and is FDA-approved for this use.

Erlotinib targets a protein called EGFR, which is found in abundance in some cancers and is thought to promote cancer cell growth. In contrast, pemetrexed inhibits cancer cell growth by interfering with DNA synthesis.

Some researchers have proposed that patients who have extra copies of the gene that makes EGFR (a phenomenon known as EGFR gene amplification) may be more likely to benefit from erlotinib than patients without such gene amplification. The only way to determine this for certain, though, is to carry out a randomized clinical trial comparing the effects of erlotinib with those of a standard drug in patients with and without EGFR gene amplification.

In this trial, patients with advanced NSCLC that has recurred or progressed after initial chemotherapy will be tested for EGFR amplification and then randomly assigned to receive either pemetrexed or erlotinib. Doctors want to see if patients with amplified EGFR fare better on erlotinib and whether those without amplified EGFR genes benefit more from pemetrexed. They will also measure the levels of other potential biomarkers of response to treatment, such as mutations in EGFR and in another gene, KRAS, and try to correlate them with response to these drugs.

"We're comparing two medications already approved and proven effective as second-line therapy for lung cancer, but what we want to know is: Can we tell by looking at the biomarkers whether one drug is better than the other for certain patients?" said Dr. Adjei.

"Until now, the way we've treated lung cancer is blindly," he added. "This is the first time we've had an opportunity to see if a test can help us tailor specific therapies for specific patients. Studies like this are absolutely crucial if we are to achieve the promise of personalized medicine for cancer care."

For More Information
See the lists of entry criteria and trial contact information or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

See the Special Report from October 2008 for more about the gene testing in this trial.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/ft-all-featured-trials.

FDA Update

FDA Issues Warning on Electronic Cigarettes

A sparging apparatus is used to test the levels of nicotine and related compounds in an e-cigarette. A sparging apparatus is used to test the levels of nicotine and related compounds in an e-cigarette.

Carcinogens and a chemical commonly used in antifreeze were discovered during a laboratory analysis of "electronic cigarettes," also called e-cigarettes, conducted by the FDA, the agency announced last week. Resembling cigarettes in shape and size, but containing no tobacco, electronic cigarettes are battery-operated devices that have small cartridges filled with nicotine, propylene glycol (a chemical used in an array of products), and often candy-like flavorings that are transformed into vapor and inhaled by users. They are commonly sold online and in malls and are often promoted for use in settings where smoking is not permitted.

The FDA's Division of Pharmaceutical Analysis tested 18 cartridges from two leading brands of electronic cigarettes, NJOY and Smoking Everywhere. Diethylene glycol, a toxic chemical used in antifreeze, was detected in one sample and a number of carcinogens, including nitrosamines, were detected in other samples.

"Because these products have not been submitted to the FDA for evaluation or approval, at this time the agency has no way of knowing, except for the limited testing it has performed, the levels of nicotine or the amounts or kinds of other chemicals that the various brands of these products deliver to the user," the agency explained in a MedWatch report.

"The FDA is concerned about the safety of these products and how they are marketed to the public," said FDA Commissioner Dr. Margaret A. Hamburg. Of special concern to parents, stated the FDA, is the fact that e-cigarettes are sold without any legal age restrictions and their different flavors (e.g., chocolate, strawberry, and mint) may appeal to youths. E-cigarettes also lack any health warnings like those used with conventional cigarettes and FDA-approved nicotine replacement products.

The agency believes that electronic cigarettes should be classified as a "combination drug-device product" that can be regulated under the Federal Food, Drug, and Cosmetic Act, but its jurisdiction has been challenged in a case pending in federal district court.

Labeling Change Narrows Use of Two Targeted Cancer Treatments

The FDA has approved label changes to cetuximab (Erbitux) and panitumumab (Vectibix) that advise against their use in patients with metastatic colorectal cancer whose tumors have certain genetic mutations. The changes are based on retrospective studies of several clinical trials which found that patients with specific mutations in the KRAS gene derive no benefit from the drugs. Both agents target the epidermal growth factor receptor.

In January, the American Society of Clinical Oncology issued a "provisional clinical opinion" recommending that all patients with metastatic colorectal cancer be tested for these mutations and that those found to have the mutations should not receive either agent. In addition to sparing patients unnecessary toxicities, a study presented earlier this year estimated that using these agents based on the results of KRAS testing could save more than $600 million annually.



Notes

Wikipedia logo

Wikipedia Academy Held at NIH

Volunteer editors from Wikipedia came to the NIH campus on July 16 to give scientists and science writers an introduction to the online encyclopedia, as well as tutorials on how to contribute and edit articles. The event was the first Wikipedia Academy in the United States. Representatives from across the NIH, including NCI, attended the event, the stated goal of which was to make health information more accessible and reliable.