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

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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.”