National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 2, 2009 • Volume 6 / Number 11

The information and links on this page are no longer being updated and are provided for reference purposes only.

NEWS

Logo for the American Society of Clinical Oncology 2009 Annual Meeting Early Chemo to Prevent Ovarian Cancer Recurrence Fails to Increase Survival

A large study has found that women in remission for ovarian cancer who started chemotherapy to prevent a recurrence based on blood levels of the protein CA125 did not live longer than women who started chemotherapy only after symptoms of the disease arose.

The findings, several gynecologic cancer experts said, should influence clinical practice and make clinicians rethink how they monitor patients for recurrence and initiate additional treatments, or salvage therapies. Read more > >

IN DEPTH

UPDATES

  • Legislative Update

    • Senate Appropriations Subcommittee Reviews Proposed FY2010 Budget

    Cancer.gov Update

    • Tutorial on Targeted Cancer Therapies Available Online
    • U.S. and Canada Collaborate on Cancer Control Web Portal

    Notes

    • NCI's Pastan Awarded Feltrinelli Prize for Medicine
    • Freedman Named a DCCPS Branch Chief

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

Early Chemo to Prevent Ovarian Cancer Recurrence Fails to Increase Survival

Logo for the American Society of Clinical Oncology 2009 Annual Meeting

A large study has found that women in remission for ovarian cancer who started chemotherapy to prevent a recurrence based on blood levels of the protein CA125 did not live longer than women who started chemotherapy only after symptoms of the disease arose.

The findings, several gynecologic cancer experts said, should influence clinical practice and make clinicians rethink how they monitor patients for recurrence and initiate additional treatments, or salvage therapies.

“Chemotherapy can be safely delayed until there are signs or symptoms of recurrence.”

In an international, multicenter randomized clinical trial of more than 500 women, survival was identical between women whose treatment for recurrence was initiated based on CA125 levels and those who were treated at the onset of symptoms. CA125 can be an early indicator that their cancer has returned.

The results of the trial were presented Sunday at the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting in Orlando.

Most women diagnosed with advanced ovarian cancer will suffer a relapse after initial treatment, said the trial’s lead investigator, Dr. Gordon Rustin from Mount Vernon Cancer Center in the United Kingdom. As a result, many of these women undergo regular blood tests after treatment to monitor CA125. Many women, Dr. Rustin said, become “addicted” to CA125 screening, “and it causes great anxiety.”

The results of this trial, he stressed, show that “chemotherapy can be safely delayed until there are signs or symptoms of recurrence.”

Women in the trial had achieved complete remission after initial treatment for advanced ovarian cancer. Half were then randomly assigned to receive treatment once their CA125 levels reached more than twice the upper limit of normal levels; the others were not informed of their CA125 levels, and treatment for recurrence was only begun when there were clinical symptoms of relapse.

Women with advanced disease tend to have multiple relapses and undergo repeated rounds of chemotherapy. In this trial, in fact, women in the CA125 arm averaged 12 more rounds of chemotherapy than those in the symptoms arm, 30 rounds versus 18. Women in the CA125 arm also began second-line chemotherapy 4.8 months earlier than those in the symptoms arm, and third-line chemotherapy 4.6 months earlier.

Because CA125 monitoring has become so ingrained in the treatment of advanced ovarian cancer, this trial “is the kind of research that’s very difficult to do,” said Dr. Eric Winer, chief of the Division of Women’s Cancers at Dana-Farber Cancer Institute, during a press briefing. The results have the potential to improve patients’ quality of life, he said.

For women in remission, a doubling of CA125 levels, even if they remain in the normal range, has been shown to herald disease relapse up to 24 months before clinical symptoms appear, said Dr. Beth Karlan, director of the Division of Gynecologic Oncology at Samuel Oschin Comprehensive Cancer Institute, following the presentation of the trial results at the meeting’s plenary session.

Even so, she continued, “If early intervention with added chemotherapy does not improve overall survival and may in fact impair [patients’] quality of life, then why are we doing it?”

Because CA125 monitoring leads to more chemotherapy, Dr. Karlan noted, it may worsen cumulative toxicities, and could even impair response to future salvage treatments by hastening resistance to chemotherapy.

However, CA125 monitoring should not become obsolete, she said, noting that clinicians and patients need to be educated about the trial’s results. She also recommended less frequent monitoring of CA125 in asymptomatic patients and that clinicians consider delaying palliative chemotherapy until clinical recurrence.

Carmen Phillips

Cancer Research Highlights

Lung Cancer Screening Leads to High Rates of False Positives

Logo for the American Society of Clinical Oncology 2009 Annual Meeting

The use of computed tomography (CT) to screen people for lung cancer leads to high rates of false positives, often triggering follow-up tests and invasive procedures, researchers said at the ASCO annual meeting. Concerns about the risks and benefits of lung cancer screening with CT have been raised previously, but this is the first report to quantify the risk of obtaining false-positive results.

Dr. Jennifer M. Croswell of the NIH Office of Medical Applications of Research and her colleagues analyzed data from the Lung Screening Study (LSS), a randomized trial that compared two screening methods—CT and chest x-ray—in more than 3,000 current or former smokers between the ages of 55 and 74. The LSS, which was the feasibility study for the ongoing NCI-sponsored National Lung Screening Trial (NLST), found significantly more false positives in the CT group.

For participants in the CT group, the risk of a false positive was 21 percent after one scan and 33 percent after a second. By comparison, those in the x-ray group had a false-positive risk of 9 percent after one test and 15 percent after two. Because the LSS only included two rounds of screening, Dr. Croswell said, its findings could provide only a conservative estimate of the impact of regular lung cancer screening with CT.

Of those with false-positive results, approximately 60 percent underwent at least one follow-up imaging exam, and slightly less than 2 percent had surgery. Complication rates from these surgeries were low, but a few patients had to be hospitalized for a collapsed lung or blood in the lung (less than 1 percent), and another 1 percent were treated for infections, the researchers said. Additional imaging exams and invasive procedures were also associated with false-positive chest X-rays.

All medical interventions, including screenings, have potential risks as well as potential benefits, the researchers stressed. False positives can create psychological stress and burden the health care system, Dr. Croswell noted.

Combo Treatment Boosts Survival in Biliary Tract Cancers

The combination of cisplatin (Platinal) and gemcitabine (Gemzar) helped patients with advanced, inoperable cancers of the biliary tract (gallbladder and bile duct) live several months longer than patients who received gemcitabine alone (11.7 versus 8.2 months), according to findings presented at the ASCO annual meeting. For patients with these rare but difficult-to-treat cancers, the combination therapy will likely become the new standard treatment, the researchers predicted.

“We consider cisplatin and gemcitabine to now be the worldwide standard of care and the backbone for further studies of patients with advanced biliary tract cancers,” lead investigator Dr. Juan Valle of the University of Manchester in the United Kingdom said in a press briefing before the meeting. At the briefing, ASCO President Dr. Richard Schilsky called the study “definitive” and added: “As one who treats these patients in my own clinic, it’s very comforting to have a clear standard of care to offer them.”

The final-stage ABC-02 trial included 410 patients with advanced biliary tract, gallbladder, or ampullary carcinoma. In addition to improving overall survival, the combination therapy delayed the progression of the disease by 2 months (8.5 versus 6.5 months). In both groups, side effects were similar, although there was a slight increase of neutropenia in patients receiving the combination therapy, the researchers said.

The next steps will involve trying to add some of the newer targeted cancer therapies to the combination and identifying which patients will benefit most from these treatments, noted Dr. Valle. He cautioned that adding another chemotherapy drug could increase toxicity without producing a benefit to patients.

Breast Cancer Drug Helps Patients with Gastric Cancer

The breast cancer drug trastuzumab (Herceptin) has been shown to improve the survival of patients with advanced gastric cancer. The addition of trastuzumab to standard chemotherapy helped patients live longer than similar patients who received chemotherapy alone, researchers said at the ASCO annual meeting.

The phase III ToGA trial compared the two treatments in 594 patients whose tumors showed elevated levels of the protein HER2, which is the target of trastuzumab. Patients who received trastuzumab plus chemotherapy lived 13.8 months, compared with 11.1 months for those who received chemotherapy alone, said lead investigator Dr. Eric Van Cutsem of the University Hospital Gasthuisberg in Leuven, Belgium. The results translate into a 26 percent reduction in the risk of death.

Trastuzumab is the first targeted drug to improve overall survival for patients with gastric cancer in a phase III trial, he said. And while the survival benefit was small, he added, the findings represent a rare advance in gastric cancer.

The combination treatment was well tolerated and there were no unexpected side effects in the trastuzumab group, Dr. Van Cutsem said. The rate of congestive heart failure, which is routinely monitored in trials involving trastuzumab, was similar between the groups. The incidence of decreased ventricular ejection fraction (a measure of the heart’s pumping ability) was 5.9 percent in the trastuzumab group compared with 1.1 percent in the chemotherapy-alone group. The reason for the low rate of cardiac effects, he said, may be because trastuzumab was not used in conjunction with anthracycline-based chemotherapy, which is how trastuzumab is often administered to breast cancer patients.

HPV Status Can Predict Outcome in Oropharyngeal Cancer

Patients with advanced forms of a cancer in the upper portion of their throat have better outcomes if their tumors are positive for the human papillomavirus (HPV), according to new data from a phase III clinical trial presented at the ASCO annual meeting. Although other studies have suggested a link between HPV status and outcome in patients who have oropharyngeal cancer, these new data provide the most definitive evidence, said the study’s leader, Dr. Maura Gillison of Ohio State University, at a recent press briefing.

Oropharyngeal cancer “can now be divided into those linked to prolonged use of tobacco and alcohol, and those linked to HPV,” she said. And determining HPV status, she added, “may now be part of routine clinical care…because of its prognostic implications in these patients.”

The findings come from a correlative study in the Radiation Therapy Oncology Group (RTOG) 0129 clinical trial, a phase III trial in which patients with stage III or IV oropharyngeal cancer were randomly assigned to receive different regimens of radiotherapy and the chemotherapy drug cisplatin. Nearly two-thirds of the tumor samples tested HPV-positive, Dr. Gillison said. Two years after treatment, 88 percent of the HPV-positive patients were still alive, compared with 66 percent of the HPV-negative patients. The absolute difference in survival increased over time.

Additional analyses ruled out other factors, such as age, performance status, and treatment, which might account for the superior outcomes seen in patients with HPV-positive tumors.

Due to the dramatic differences in treatment response, Dr. Gillison said, from this point forward RTOG and the Eastern Clinical Oncology Group will stratify all of their clinical trials by HPV status, and they will design clinical trials specifically for HPV-positive or -negative patients.

Bevacizumab Does Not Prevent Recurrence of Colorectal Cancer

Adding 1 year of treatment with the targeted drug bevacizumab (Avastin) to standard post-surgery treatment for early stage colorectal cancer failed to improve disease-free survival (the time that patients are free of tumor recurrence) after 3 years of follow up compared to the standard treatment alone, according to results presented at the ASCO annual meeting.

The NCI-supported C-08 trial, led by the National Surgical Adjuvant Breast and Bowel Project (NSABP), was the first phase III trial to report findings using an angiogenesis inhibitor as part of adjuvant therapy for an early stage cancer. Bevacizumab, which blocks blood flow to tumors, is already approved for use in advanced colorectal, breast, and lung cancers.

More than 2,700 stage II and III colorectal cancer patients whose tumors had been surgically removed were randomly assigned to receive either a 6-month course of the standard adjuvant chemotherapy regimen or chemotherapy plus bevacizumab, followed by an additional 6 months of bevacizumab alone. After 3 years, there was little difference in the disease-free survival rate, 75.5 percent versus 77.4 percent, respectively.

There was a statistically significant disease-free survival benefit during the year of active treatment with bevacizumab, stressed the trial’s leader, Dr. Norman Wolmark from Allegheny General Hospital in Pittsburgh. In fact, the benefit was nearly strong enough to stop the trial early. But “that efficacy disappeared after bevacizumab was no longer given,” he said.

Several recent animal model studies have suggested that, under certain circumstances, angiogenesis inhibitors, after initially shrinking tumors, could make them more aggressive and likely to metastasize. The investigators looked closely at this issue, Dr. Wolmark said, “and we saw absolutely no hint of a harmful rebound effect.”

Dr. Axel Grothey, from the Mayo Clinic, agreed that bevacizumab appears to have an effect only during treatment, but that it only seems to delay tumor recurrence, not prevent it. At this point, he stressed, bevacizumab should not be used as an adjuvant treatment outside of a clinical trial.

The NSABP hopes to launch a similar phase III trial in which bevacizumab is given in the adjuvant setting for 2 years, Dr. Wolmark said.

Drugs that Inhibit DNA Repair May Treat Advanced Breast Cancer

A new type of targeted agent that impairs a tumor cell’s ability to repair damaged DNA may be beneficial in women with hard-to-treat forms of breast cancer, according to findings from two small clinical trials presented at the ASCO annual meeting.

The phase II trials tested different agents that inhibit an important DNA-repair enzyme in tumor cells called PARP. The larger of the two trials, led by Dr. Joyce O’Shaughnessy from the Baylor Charles A. Sammons Cancer Center in Dallas, tested a PARP inhibitor called BSI-201. One hundred sixteen women with metastatic, “triple-negative” breast cancer (tumors negative for the HER2 protein and estrogen and progesterone receptors), whose disease had progressed despite prior treatment, were randomly assigned to receive chemotherapy with gemcitabine and carboplatin with or without BSI-201.

Women who received the BSI-201 and chemotherapy combination had significantly longer time to progression of their disease, 6.9 months compared with 3.3 months, and longer overall survival, 9.2 months compared with 5.7 months, than women who received chemotherapy alone. Overall survival was a secondary endpoint in the trial, Dr. O’Shaughnessy noted. The drug was “very well tolerated,” she said. “We couldn’t discern any added toxicity.”

In the second trial, Dr. Andrew Tutt from Kings College, London, and his colleagues tested an oral PARP inhibitor called olaparib as a single agent in women with advanced breast cancer whose tumors had mutations in the BRCA1 or BRCA2 genes and whose disease had persisted despite prior treatment.

Because of strong enrollment, the trial was expanded to test two different doses, Dr. Tutt said. The higher dose appeared to be more effective, with 40 percent of women who received the higher dose experiencing tumor shrinkage, compared to 22 percent in women who received the lower dose. The drug had minimal side effects, the most common of which were mild nausea and fatigue.

Bipar Sciences, which manufactures BSI-201, expects to launch a similar phase III trial of the agent this summer. Dr. Tutt said he is in discussions with Astra Zeneca, which manufactures olaparib, to move that agent forward into larger trials.

ALSO IN THE JOURNALS

Radiofrequency Ablation Effective Against Barrett Esophagus

About 10 percent of the 10 million adults in the United States who have chronic gastroesophageal reflux disease develop abnormal cell changes in the lining of their esophagus, a condition called Barrett esophagus (BE) that can lead to esophageal cancer. While 99 percent of adults with BE will not progress to cancer, their risk of developing esophageal cancer is still 100 times greater than that of the general population.

New results published May 27 in the New England Journal of Medicine show that radiofrequency ablation (RFA) may be an effective treatment for BE. Dr. Nicholas J. Shaheen, of the University of North Carolina at Chapel Hill, and his colleagues conducted a trial of 127 BE patients who had either high- or low-grade dysplasia (abnormal cells with precancerous traits) in the lining of their esophagus.

Eighty-four of these patients received the RFA treatment, which involved inserting and then inflating a balloon into the esophagus in an outpatient procedure. Radiofrequency waves heated coils on the balloon’s surface to burn away only the layer of affected cells on the esophageal lining. The remaining 43 patients were part of a control group that received a “sham procedure.”

Low-grade dysplasia was completely eradicated in 90.5 percent of those receiving RFA, compared with 22.7 percent in the control group. High-grade dysplasia was eradicated in 81 percent of those receiving RFA, compared with 19 percent of controls. While RFA had side effects—transient chest discomfort and occasional narrowing of the esophagus—these were slight compared with those of esophagectomy, a treatment commonly used to treat high-grade dysplastic BE, which has a 3 to 5 percent mortality rate and complications in 40 to 50 percent of patients.

In an accompanying editorial, Dr. Jacques J.G.H.M. Bergman of the Academic Medical Center in Amsterdam said these results “suggest that surgery for high-grade dysplasia should no longer be offered routinely.”

Exposure to PCBs in the Home May Increase Risk of Childhood Leukemia

Between 1975 and 2004, the incidence of acute lymphoblastic leukemia (ALL), which occurs more frequently in children than in adults, rose significantly in the United States. Investigators from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and the University of California, Berkeley examined whether residential exposure to polychlorinated biphenyls (PCBs) or organochlorine insecticides such as DDT may increase the risk of ALL. These chemicals were banned in the 1970s but persist in the environment and are still found indoors, especially in older homes. Their findings are published in the June issue of Environmental Health Perspectives.

The researchers identified 203 children aged 7 years or younger living in 35 California counties and diagnosed with leukemia between 2001 and 2006. The children were living in their current home at the time of diagnosis. One hundred eighty four of the children with leukemia had ALL. The children were matched by age, gender, race, Hispanic ethnicity, and county of residence to 212 children who didn’t have leukemia.

Carpet dust samples were collected from the rooms where these children spent most of their time while awake in the home, to analyze for the chemicals being studied. Detection of any of the PCBs in the dust samples was associated with a twofold increased risk of ALL, and the risk increased with the concentration of total PCBs. ALL risk was not increased among children from homes with higher concentrations of DDT, chlordane, or the other measured organochlorine insecticides.

However, the researchers observed higher rates of ALL associated with detection of total PCBs and individual PCB types in carpet dust samples from homes of non-Hispanic whites compared with Hispanics and other races. The different results for these ethnic groups could not be explained by different concentrations in the homes or any of the other factors measured in the study.

“The fact that this is the first population-based study to evaluate residential levels of these chemicals and risk of ALL, and that findings were not consistent across ethnic groups, means that we need to use caution in the interpretation,” said DCEG lead author Dr. Mary Ward. “These results are interesting, but they need further study.”

Special Report

Treatment Vaccines for Cancer Perform Well in Clinical Trials

A researcher prepares a cancer vaccine dose to be administered to a patient A researcher prepares a cancer vaccine dose to be administered to a patient

Treatment vaccines that boost the immune system’s response to tumors may have important clinical benefits for patients with various types of cancer, according to results from several clinical trials presented at the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting in Orlando.

To many in the field, the findings represent an emergence of sorts for therapeutic cancer vaccines. Treatment vaccines have been the subject of intense study for more than 2 decades, but they have produced little in the way of FDA-approved cancer treatments. That could change based on the recent clinical trial results.

“The field has been getting more attention, and with these recent trials I think we’ll see a surge of interest in immunotherapy leading to much needed additional therapeutic options that improve survival without significant toxicity,” said Dr. James Gulley from NCI’s Center for Cancer Research, who is leading a number of clinical trials using treatment vaccines.

Therapeutic cancer vaccines, added Dr. Jeffrey Schlom, chief of NCI’s Laboratory of Tumor Immunology and Biology, have had a hard time gaining acceptance in part because they represent a different care paradigm. “A vaccine is the only therapeutic modality that doesn’t work on the tumor. It works on the patient’s immune system to keep the tumor in check,” he said.

Among the results that generated intense interest at the meeting were those from a large, phase III clinical trial of a vaccine called BiovaxID to treat patients with follicular lymphoma, the second most common type of non-Hodgkin lymphoma. Dubbed an idiotype vaccine, BiovaxID is customized for each individual patient from tumor cell proteins taken from tumor biopsies.

The trial, BV301, randomly assigned patients who had a sustained (6-month) complete response to standard chemotherapy to either BiovaxID plus two other immune-stimulating agents (GM-CSF and KLH) or the two immune-stimulating agents alone. Patients who received the vaccine had a 47 percent improvement in progression-free survival (survival without tumor growth) compared to those who only received the immune stimulants, 44.2 months versus 30.6 months, reported lead investigator Dr. Stephen J. Schuster from the University of Pennsylvania School of Medicine.

Two previous phase III trials using a similar vaccine in patients with follicular lymphoma had negative results. That may be because those trials included patients who had partial responses and stable disease, as well as complete responses, explained Dr. Ronald Levy of the Stanford University School of Medicine, during the meeting’s plenary session. In contrast, the analysis from BV301 was limited to patients who were “the best of the best”—that is, only those with sustained complete responses.

Drs. Levy and Schuster agreed that it’s still unclear how this vaccine would work in the context of the current standard of care for follicular lymphoma, which changed during the course of the BV301 trial and now includes the monoclonal antibody rituximab (Rituxan). Calling the trial a “qualified success,” Dr. Levy said other clinical trials will be needed to establish the best use of the vaccine in follicular lymphoma.

Another phase III trial that generated interest at the meeting used a long-studied peptide-based vaccine (a peptide is a small segment of amino acids) to treat patients with metastatic melanoma, a deadly skin cancer for which treatment advances have been rare.

When combined with IL-2, the standard of care for metastatic melanoma, treatment with the gp100:209-217(210M) peptide vaccine doubled the response rate of patients compared to those who received IL-2 alone, 22.1 percent versus 9.7 percent, reported one of the trial’s leaders, Dr. Patrick Hwu from the University of Texas M.D. Anderson Cancer Center. Response rate was the trial’s primary endpoint. There was a slight improvement in progression-free survival, 2.9 versus 1.6 months, and the preliminary analysis suggests a trend toward improved overall survival.

Calling the improvement an “important finding,” Dr. Lynn Schuchter from the University of Pennsylvania’s Abramson Cancer Center said the results are grounds for optimism. Therapeutic vaccines have been tested in melanoma for more than a decade with little success. Now there is a positive phase III clinical trial.

“It makes us think maybe this is a combination that will work,” she said.

There are a number of other immune stimulating agents under study that can be used in combination with the peptide vaccine, Dr. Hwu said. The next steps, he noted, will be to conduct another large trial to replicate these findings and continue testing different combinations.

In a smaller, phase II clinical trial with 122 patients, treatment with a vaccine developed at NCI, called Prostvac, showed a more than 8-month improvement in overall survival in patients with indolent metastatic prostate cancer. This is the second phase II trial to show a nearly identical benefit of Prostvac, which is comprised of two virus-based “vectors,” in the same patient population, explained Dr. Schlom. A larger, phase III trial is expected to begin in 2010.

The field is already moving toward combining different therapeutic vaccines, Dr. Schlom continued, with the idea of using them in earlier-stage disease, where he believes they will be most effective.

Carmen Phillips

Spotlight

Making Personalized Cancer Care Routine

Chest radiograph showing a tumor in the left lung Chest radiograph showing a tumor in the left lung [Enlarge]

A small group of oncologists and pathologists from five medical centers gathered last fall to talk about the nuts and bolts of personalizing cancer care. On the table were a host of practical issues related to one big question: Can hospitals routinely use genetic and molecular information from tumors to match patients with the most appropriate drugs in an affordable and timely manner?

The answer to this question may not come for years. But some lessons about what works and what doesn’t could emerge much sooner. Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center (MSKCC) have begun to screen all lung tumors for genetic changes that could reveal whether a particular treatment is likely to work or should be avoided.

“We believe the profiling of tumors will become more and more integrated with clinical practice in the future, and we want to see that happen sooner rather than later,” said Dr. Leif Ellisen, an oncologist at Mass General and co-director of a new molecular pathology lab that profiles the tumors. “Most centers realize that this is where the field of oncology is going in terms of directed therapies.”

He noted that interest in tumor profiling extends well beyond the centers that met last fall (which also included Dana-Farber Cancer Institute, University of Texas M.D. Anderson Cancer Center, and Vanderbilt Medical Center). In fact, personalizing cancer care is the theme of the American Society of Clinical Oncology (ASCO) Annual Meeting this week in Orlando.

At this stage, however, the approach has some important limitations. For starters, only a fraction of the molecular changes involved in cancer have been identified, and more drugs that target these changes are needed. At MSKCC, nearly half the lung tumors tested do not harbor one of the known gene mutations associated with the disease.

Lung Cancer: A Test Case 

Despite the limitations, the current understanding of lung cancer is vastly different from a decade ago, when most tumors were thought to be essentially the same and patients received the same drugs. Today, it’s clear that subsets of tumors are driven by gene mutations that activate cancer-promoting signals in cells and, in some cases, drugs are available to block these signals.

“We’re nearing a point where patients need not only a diagnosis of lung cancer but also to know the molecular subtype of the tumor,” said Dr. Lecia Sequist, who treats patients with lung cancer at Massachusetts General Hospital Cancer Center.

Mutations in the gene EGFR, for instance, tend to make tumors respond to gefitinib (Iressa) or erlotinib (Tarceva). These drugs are pills, taken once a day, that block critical signals in tumors and usually have fewer side effects than chemotherapy. While less than 30 percent of lung cancers in the United States carry the mutations, those that do have a 70 percent chance of responding to the drugs.

The Mass General test profiles 13 genes, including EGFR, that are altered in a variety of cancers. A team led by pathologist Dr. John Iafrate developed a process for automatically extracting DNA from standard tumor specimens and screening the DNA for 120 cancer-related changes. The pathology lab tests about 20 lung tumors per week, a number that will rise as the program is gradually expanded to include all cancer patients.

By making the test broad rather than focused on a single cancer, the researchers hope to pick up mutations that may be rare in one tumor type, but for which a treatment already exists. Some lung tumors have alterations in the gene HER2, for example, and these tumors may respond to the breast cancer drug trastuzumab (Herceptin).

“In our view,” said Dr. Ellisen, “medicine isn’t personalized if you’re only testing patients for the common mutations.”

Why Now?

A shift toward personalized care may be happening now because of technologies that can test for multiple genetic changes simultaneously, and also because of growing evidence that patients benefit. For instance, many colorectal cancer patients undergo gene testing before starting on cetuximab (Erbitux) to determine whether they are candidates for the treatment or should be spared the costs and side effects.  

“This approach is exactly what the patients want,” said Dr. Mark Kris, chief of the Thoracic Oncology Service at MSKCC. “They want to know that we’ve used all of our resources to analyze their cancers. It’s what clinicians want as well—to give patients treatments that are targeted to their particular disease.”

Interim results from the IPASS lung cancer trial, presented at the ASCO meeting, underscored the need for tumor testing. The randomized trial compared gefitinib and chemotherapy as a first-line therapy and found that patients with EGFR gene mutations tended to respond better to gefitinib. Other patients fared better with chemotherapy.

The study is relevant to personalized medicine because nearly all the participants fit the profile of someone who may benefit from gefitinib or erlotinib. That is, they were Asian nonsmokers or light smokers. Yet only some of these individuals—those with EGFR mutations—actually benefited from gefitinib.

This finding, Dr. Sequist noted, suggests that patients may need to have their genes tested rather than simply relying on doctors to make an educated guess about who will benefit most from these drugs.

“Incredibly Complicated”

The need to collect tissue samples from patients for testing and the fact that many tumors eventually develop resistance to targeted drugs are among the many challenges facing the new field. Another complication, the researchers said, is that patents on gene mutations in the future could narrow the scope of testing at some institutions.

Nonetheless, valuable lessons may come from the current programs, including how to make personalized cancer care work within the current health care system. The investigators have been sharing their experiences with colleagues, and later this year they plan to publish a summary of the meeting last fall.

“Doing this within the current health care system is unbelievably complicated,” said Dr. Kris. “This is not how hospitals work right now, and it is not how oncology is practiced.” The investigators need to both “work out the bugs” in the current systems and demonstrate the benefits of this approach to the medical establishment, he added.

“It’s not easy,” Dr. Kris continued, “but we and the other institutions doing this are all committed to taking this forward and making it the standard of care.”   

—Edward R. Winstead

Featured Clinical Trial

Imaging the Extent of Prostate Cancer

Name of the Trial
Phase I/II Pilot Study of Carbon-11 Acetate Positron Emission Tomography and 3-Tesla Magnetic Resonance Imaging in Patients with Localized Prostate Cancer Undergoing Prostatectomy (NCI-08-C-0092).  See the protocol summary.

Dr. Peter Choyke Dr. Peter Choyke

Principal Investigator
Dr. Peter Choyke, NCI Center for Cancer Research

Why This Trial Is Important
When doctors suspect a man has prostate cancer, they often use ultrasound to create images of the prostate gland and perform a series of core biopsies to collect samples of prostate tissue. Unfortunately, ultrasound does not provide very detailed images of prostate tumors, and “hit-or-miss” biopsy samples may not reveal the aggressiveness of the cancer. It is important, therefore, to develop more sensitive methods to detect and characterize prostate tumors.

Some other imaging methods, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), offer some benefits in detecting and characterizing prostate cancer, but both of these methods still lack the required level of sensitivity. MRI can help determine the physical boundaries of tumor tissue, but it is not very useful in assessing which parts of the tumor are most actively growing. PET scans using radiolabeled-glucose molecules are capable of revealing areas of rapid cell growth in many tumor types; however, prostate tissue does not readily metabolize glucose, making glucose-based PET scans unreliable for prostate cancer.

In this clinical trial, researchers are testing PET scans using a different radiolabeled molecule, carbon-11 (C-11) acetate, in conjunction with subsequent MRI to see if the resulting images allow better characterization of both the physical extent and the relative level of cellular growth of prostate tumors in patients known to have prostate cancer. Following the imaging tests, the patients will undergo surgery to remove their prostates. The removed prostates will then be examined to assess the accuracy of the imaging scans.   

“Detecting cancer when it is still confined to the prostate gland is the key to long survival,” said Dr. Choyke. “Unfortunately, current imaging techniques have very poor sensitivity for prostate cancer. Our purpose with this study is to validate the use of both C-11 acetate PET and the latest MRI technology to detect cancer at an early stage.

“This research complements other treatment and diagnostic work at NIH, including research in robotic prostatectomy, image-guided radiotherapy, and minimally invasive radio-diagnostic procedures, making NCI a unique institution for the treatment of prostate cancer,” Dr. Choyke added.

For More Information
See the list of entry criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

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

Community Update

Through Play, Kids and Families Cope with Cancer

ShopTalk board game ShopTalk board game [Enlarge]

If you could look back and change something that you said or did in your life, what would that be?

It’s a difficult question for anyone to answer honestly, not to mention someone who is facing a life-threatening illness. Such a question can be especially difficult for children. But when posed in the atmosphere of play, answering becomes easier.

 “Play is really the way to uncover children’s feelings and help them explore their inner world, working through some of their fears and helping them find coping strategies,” explained Dr. Lori Wiener, head of the psychosocial section in NCI’s Pediatric Oncology Branch. She noted that the strategy can work well in some situations for adults, too.

Dr. Wiener developed a workbook to assist children being treated for cancer or HIV infection at NIH with talk therapy sessions, and found the tool to be very successful. She then partnered with Dr. Cindy Mamalian, an artist and psychologist, to develop a prototype board game version of the workbook and began testing it with her patients, gathering their feedback during the revision process.

Nearly 10 years later, the culmination of this project is ShopTalk, a board game that helps therapists lead conversations with pediatric cancer patients and their parents about difficult emotional issues related to the illness that has affected their lives. ShopTalk is the only such therapeutic game designed for children aged 7 to 16 years.

Dr. Wiener has been working with the nonprofit organization SuperSibs to distribute the sibling version of the game, and she has contacted psychosocial oncology programs at hospitals around the country that treat children with cancer. The response from those who are using ShopTalk has been very enthusiastic. 

“I have been using the game several times a week since I put it out in my office,” said Dr. Rachel Levi, a pediatric clinical psychologist in Oakland, CA. “Uniformly, the feedback has been positive from both me and the kids with whom I've used it.”

Other clinical psychologists and professors of pediatric medicine have written to Dr. Wiener with simple notes of “Thank you!” for providing them with such a valuable clinical tool.

Because critical information can be revealed through the course of play—suicidal feelings, for example, or non-adherence to medication regimens—Dr. Wiener stressed that the game should only be used with the supervision of a trained therapist so that opportunities for intervention aren’t missed.

ShopTalk is available in two versions, one for pediatric cancer patients and one for their siblings. All questions in both versions of the game are written in Spanish as well as in English. Therapists who are interested in obtaining a copy of the game should contact Dr. Wiener directly at wienerl@mail.nih.gov.  

ShopTalk players visit 10 different “shops” around the board, choosing one of 6 “gifts” from each store to place in their individual shopping bag when they choose to answer the question. The shops are named according to different themes: The Ball’s in Your Court sports store, for example, allows players to explore how they would respond to various social scenarios during treatment.

The added beauty of the game lies in its flexibility. Questions can be very simple, such as, “What is your favorite movie?” or they can be deeper, such as, “Do you think that children with a disease should be disciplined the same as kids who are healthy?” In this way, a therapist can tailor the game to the needs of the players, delving deeper with each round or tailoring the questions to an individual’s concerns or needs.

After hearing the question, the player is asked if they would like to buy the gift. If they’re not comfortable answering, they can say, “No thanks, just looking.” Questions can also be addressed to the entire group of players, allowing the chance for someone who isn’t comfortable talking about his or her own problem to learn through the experience of others.

Though it’s based on the premise of fun, ShopTalk clearly enters into emotionally charged territory. Dr. Wiener says that it’s important for people to talk about the thoughts that keep them awake at night, rather than struggling in silence.

“Many kids who have cancer are concerned about sharing information that will upset their parents,” she explained. “But their parents may be having these same thoughts. So they each end up coping in emotional isolation, putting a lot of energy into not thinking about what is troubling them. This game provides them a safe opportunity to find coping strategies together, so that they can focus their energy on healing, rather than avoidance.”

Last week, Dr. Wiener played ShopTalk with the family of a child who has cancer during a therapy session. One of the questions asked them to recall events from the day that each of them learned about the diagnosis, more than 4 years ago.

“They all remembered an amazing amount of detail,” she explained. “It gave them a chance to correct misperceptions about what had happened and what was said, and each obtained a new awareness about how traumatizing that particular time was for each of them. The conversation wouldn’t have happened if we weren’t playing the game.”

Brittany Moya del Pino

Legislative Update

Senate Appropriations Subcommittee Reviews Proposed FY2010 Budget

On May 21, the Senate Committee on Appropriations’ Subcommittee on Labor, Health and Human Services, Education, and Related Agencies held a hearing to examine the President’s proposed fiscal year 2010 budget for NIH and to discuss the $10.4 billion provided to NIH in the American Recovery and Reinvestment Act. NIH Acting Director Dr. Raynard Kington, NIAID Director Dr. Anthony Fauci, NHLBI Director Dr. Elizabeth Nabel, and NCI Director Dr. John Niederhuber testified.  

Senator Tom Harkin (D-IA), chairman of the Subcommittee, expressed concerns about how Recovery Act funds were being spent and what happens after funding runs out in 2011. Dr. Niederhuber testified that Recovery Act funds were allowing NCI to advance projects in early phase translational research and to expand The Cancer Genome Atlas project to include additional cancer sites, beyond glioblastoma, ovarian cancer, and lung cancer. 

Due to the strong interest in the challenge grants, Senator Harkin was concerned that fewer than 5 percent would be funded. Dr. Kington predicted that NIH would more than double its initial commitment of $200 million, allowing the agency to fund a greater number of challenge grants. Dr. Kington also noted that every institute and center at NIH funds research related to cancer, and NIH has initiated a strategic planning process co-chaired by Dr. Niederhuber and Dr. Stephen Katz, director of NIAMS and a senior investigator at NCI. 
 
For more information about this and other NCI congressional activity, visit the NCI Office of Government and Congressional Relations’ Web site.

Cancer.gov Update

Tutorial on Targeted Cancer Therapies Available Online

DVD cover for Understanding Targeted Therapies for Cancer tutorial DVD cover for Understanding Targeted Therapies for Cancer tutorial

NCI recently added a new tutorial to its Understanding Cancer Series, a collection of educational tutorials for life science teachers, health professionals, and the interested public. Understanding Targeted Therapies for Cancer, the first animated tutorial in the series, provides an overview of this emerging approach to cancer treatment. The tutorial explains the three main types of targeted therapies, their risks and benefits, how they differ from conventional chemotherapy, which targeted therapies are currently FDA-approved, and how one can find clinical trials that are evaluating these new treatment approaches.

View or download Understanding Targeted Therapies for Cancer at http://www.cancer.gov/cancertopics/
understandingcancer/targetedtherapies
or contact Donna Kerrigan at kerrigad@mail.nih.gov to request a DVD.

U.S. and Canada Collaborate on Cancer Control Web Portal

Screenshot of Cancer Control P.L.A.N.E.T. Canada Web site

In a collaborative effort, NCI and the Canadian Partnership Against Cancer (CPAC) have expanded the Cancer Control P.L.A.N.E.T. (Plan, Link, Act, Network with Evidence-based Tools) Web portal from the United States to Canada.

The U.S. Cancer Control P.L.A.N.E.T. Web portal was launched after extensive usability testing in April 2003 by NCI’s Division of Cancer Control and Population Sciences in collaboration with the Agency for Healthcare Research and Quality, the American Cancer Society, the Centers for Disease Control and Prevention, the Commission on Cancer, and the Substance Abuse and Mental Health Services Administration. The Canadian site follows the same design as the U.S. site, while engaging Canadian cancer control practitioners and researchers in usability testing to ensure that the Canadian site meets their needs. 

Both the Canadian and U.S. sites provide a single point of access to high-quality tools and resources from multiple national organizations, which can be used to design, implement, and evaluate evidence-based cancer control plans and programs.

Notes

NCI's Pastan Awarded Feltrinelli Prize for Medicine

Dr. Ira Pastan Dr. Ira Pastan

Dr. Ira Pastan, chief of the Laboratory of Molecular Biology in NCI’s Center for Cancer Research, will receive the 2009 International Antonio Feltrinelli Prize for Medicine, which will be awarded in Rome this June by the Accademia Nazionale dei Lincei. The organization, founded in 1603, is considered Italy’s most prestigious scientific society and includes Galileo as an early member. This is the first time an NIH scientist has received the award. Presented every 5 years, the International Antonio Feltrinelli Prize for Medicine includes a gold medal and a monetary prize of 250,000 Euros.

Dr. Pastan’s early research focused on understanding the mechanism of action of polypeptide hormones and defining their pathway of entry into the cell. He was among the first to clone and sequence the EGF receptor and demonstrated that it is amplified in many cancers. Realizing that powerful toxins could be targeted to kill specific cells, Dr. Pastan and Dr. David FitzGerald designed and produced novel recombinant immunotoxins that have a cancer-seeking antibody genetically fused to a portion of Pseudomonas exotoxin A. His clinical research group, led by Dr. Robert Kreitman, tested these new treatments in humans and found that BL22 produced a very high rate of complete remissions in patients with drug-resistant hairy cell leukemia.

Freedman Named a DCCPS Branch Chief

Dr. Andrew Freedman Dr. Andrew Freedman

Last week, Dr. Andrew N. Freedman was appointed chief of the Clinical and Translational Epidemiology Branch (CTEB) in the Epidemiology and Genetics Research Program in NCI’s Division of Cancer Control and Population Sciences (DCCPS). 

CTEB supports, directs, and stimulates research on clinical, environmental, and genomic factors that influence cancer progression, recurrence, new primary cancers, and mortality. It also supports and coordinates research on factors that contribute to the development of cancer among individuals with underlying diseases and conditions.

Dr. Freedman earned his Ph.D. in epidemiology from the University of Buffalo and Roswell Park Cancer Institute. He was a postdoctoral research fellow in the Genetic Epidemiology Branch of NCI’s Division of Cancer Epidemiology and Genetics before he joined DCCPS in 1997 as a molecular epidemiologist in the Applied Research Program’s Risk Factor Monitoring and Methods Branch. Dr. Freedman’s research focus includes pharmacoepidemiology and pharmacogenomics, and he is internationally known for his work in molecular cancer epidemiology and cancer risk prediction.