National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 29, 2012 • Volume 9 / Number 11

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Cancer Research Highlights

Panel Reviews Benefits and Harms of CT Scans for Lung Cancer Screening

A panel of experts has reviewed the evidence regarding the benefits and harms of screening for lung cancer with low-dose computed tomography (CT) and concluded that the technology may benefit some individuals at high risk for lung cancer. But the panel cautioned that many questions remain about the potential harms of screening and how to translate screening into clinical practice.

The review, published in JAMA on May 20, was a collaborative effort by the American Cancer Society, the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network.

"We found that CT screening has the potential to reduce lung cancer deaths in some smokers and former smokers when utilized appropriately, but there are many unanswered questions about its risks and whether it will work as well in clinical practice as it has in carefully conducted trials," lead author Dr. Peter B. Bach of Memorial Sloan-Kettering Cancer Center said in a statement.

Based on the results, ASCO and ACCP issued a clinical practice guideline for physicians. The guideline suggests that screening be offered to smokers and former smokers aged 55 to 74 who have smoked for 30 pack years and either continue to smoke or have quit smoking within the past 15 years. Individuals who do not belong to these categories or who have serious health conditions that would limit their life expectancy, rule out curative treatment for lung cancer, or both, should not be offered screening.

In addition, screening should be done at facilities that can deliver the level of care provided to participants in the National Lung Screening Trial (NLST).  Results from that trial, which were published last year, showed that screening with low-dose CT led to a 20 percent reduction in lung cancer deaths compared with chest x-ray screening.

The NLST investigators noted that the harms of screening should be considered in future clinical recommendations. Potential harms include false-positive results and unnecessary follow-up procedures, such as needle biopsies and bronchoscopies.

Dr. Bach and his colleagues categorized the strength of the recommendations in the new guideline as "weak" based on "moderate" or "low" quality research data. However, additional results from the NLST and from European studies will appear in the coming years. When these data become available, the clinical practice guidelines will be reassessed, Dr. Bach explained.

"As we understand more about the risks and the benefits [of low-dose CT screening], the calculus is very likely to change," he wrote in an e-mail message. "In which direction, it is impossible to predict."

Further reading: "Crunching Numbers: What Cancer Screening Statistics Really Tell Us"

Lung Cancer Drug Shows Promise against Several Childhood Cancers

Preliminary results from a phase I clinical trial suggest that the targeted drug crizotinib (Xalkori) may be effective in children with cancer whose tumors harbor genetic alterations in the ALK gene. In some children, the drug caused all signs of the disease to disappear (complete response). Crizotinib is already approved by the Food and Drug Administration to treat patients with lung cancer whose tumors have ALK mutations.

The findings were presented at a press briefing on May 16 in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

Sponsored by the Children's Oncology Group (COG) Phase I Consortium, the study included 70 children whose cancers had progressed on standard treatments. Many had one of three diseases that have been associated with abnormalities in the ALK gene: anaplastic large cell lymphoma (ALCL), neuroblastoma, or a rare type of sarcoma, called inflammatory myofibroblastic tumor (IMT). All of the patients in the trial had seen their disease progress following standard therapy.

When possible, the researchers tested patients' tumors for ALK mutations, but this was not required for enrollment. The study assessed the safety of the drug, which is given as a pill, and established an optimal dose. "Overall, this drug is extremely well tolerated," said Dr. Yael Mossé of Children's Hospital of Philadelphia and the University of Pennsylvania at the press briefing.

Seven of the eight children with ALCL had complete responses. Some remained on the drug without the disease progressing for as long as 18 months. Most cases of ALCL in children are driven by ALK mutations, and COG researchers are developing a new clinical trial to learn how to effectively use crizotinib in children newly diagnosed with that disease. 

Of the eight patients with aggressive neuroblastomas, two had complete responses. These two patients, who had documented ALK abnormalities, remained on therapy for 9 months to more than 2 years without the disease progressing, Dr. Mossé noted.

The researchers also reported that the drug had antitumor activity in some patients with IMT. No effective treatments are available for patients with this disease, but about half of IMTs have ALK abnormalities.

This study shows that by understanding "the molecular driver of the tumor, we have the prospect of seeing dramatic responses [in patients]," said ASCO President Dr. Michael P. Link.

The ALK gene appears to be expressed early in development and then shut down after birth, explained Dr. Mossé. This makes the gene an appealing therapeutic target, she added, because it is normally switched off in the body.

Approximately 200 to 250 children are diagnosed with one of these cancers in the United States each year and would be candidates for this treatment based on abnormalities in the ALK gene, Dr. Mossé estimated.

Further reading: "Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance"

Antipsychotic Drug Controls "Breakthrough" Nausea and Vomiting after Chemotherapy

In a phase III clinical trial, the antipsychotic drug olanzapine (Zyprexa) was significantly more effective than metoclopramide (Reglan) in controlling chemotherapy-induced nausea and vomiting (CINV) that occurs in some patients despite preventive treatment for these side effects. (Olanzapine is approved by the Food and Drug Administration to treat schizophrenia and bipolar disorder.) Dr. Rudolph Navari of Indiana University School of Medicine-South Bend presented the results at a May 16 press briefing held in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

The double-blinded randomized trial is the first study to demonstrate an effective treatment for "breakthrough" CINV, defined as nausea and vomiting that persist despite preventive treatments. About 30 to 40 percent of patients receiving certain chemotherapy drugs experience breakthrough CINV, which usually develops 2 to 4 days after treatment.

Dr. Navari and his colleagues studied 80 patients who developed breakthrough vomiting or nausea after treatment with chemotherapies that are known to induce vomiting, such as cisplatin, cyclophosphamide, and doxorubicin. Patients were randomly assigned to receive either daily oral olanzapine (10 mg) for 3 days or oral metoclopramide (10 mg) three times per day for 3 days.

During the 72-hour follow-up period, 71 percent of patients receiving olanzapine had no vomiting, compared with 32 percent of patients receiving metoclopramide. Olanzapine prevented nausea in 67 percent of patients, versus 24 percent for metoclopramide. The differences between the two treatment groups were statistically significant, and neither drug caused severe side effects.

"The recommendation from ASCO and other international guidelines is to use your best antiemetics up front," explained Dr. Navari. "Then, if patients develop breakthrough nausea and vomiting, there really haven't been any good options." Metoclopromide is often used in such cases, "but it hasn't been that effective," he said.

The results "are a great step forward for quality of life for our patients," Dr. Sandra Swain, ASCO president-elect, said at the press briefing. For some patients, breakthrough CINV is so debilitating that they will "opt out of curative treatment," she added.

Targeted Drug Shows Potential in Advanced Solid Tumors and Brain Metastases

Results from two early-phase studies of dabrafenib, given alone or combined with another targeted drug, show that the drug is safe and may be effective for patients with advanced melanoma, melanoma brain metastases, and other solid tumors with mutations in the BRAF gene.

The first study, a phase I trial published online May 17 in The Lancet, included 184 patients with melanoma or advanced solid tumors. Of these, 179 patients had BRAF mutations in their tumors. The patients received varying amounts of oral dabrafenib to establish a safe, tolerable dose for use in further studies.

Of the 36 patients with BRAF-mutated metastatic melanoma, but no brain metastases, who received 150 mg of dabrafenib twice a day (the recommended phase II dose), half had a partial or complete response, reported Dr. Gerald S. Falchook of the University of Texas MD Anderson Cancer Center and his colleagues. But most patients developed drug resistance, with a median time to disease progression of 5.5 months.

Dabrafenib at any dose led to partial responses in patients with papillary thyroid and non-small cell lung cancer, as well as in one patient with colorectal cancer. Seven other patients with colorectal cancer, a patient with ovarian cancer, and another with a gastrointestinal stromal tumor had stable disease.

The 150 mg dose of dabrafenib taken twice per day also shrank asymptomatic brain lesions in nine of ten patients with advanced melanoma, completely eliminating them in four of these patients. The median time to disease progression for patients with brain metastases was 4.2 months. All 10 patients were alive at 5 months, and two survived beyond a year. (Patients with brain metastases typically survive for fewer than 5 months.) The researchers suggested that dabrafenib may enter the brain when metastases disrupt the blood-brain barrier, which normally keeps drugs out of the brain.

The most common adverse effects of dabrafenib treatment were skin lesions, fatigue, and fever.

Further trials of dabrafenib, including a phase II study in patients with asymptomatic brain metastases and a phase III randomized controlled study of dabrafenib versus dacarbazine in patients with BRAF-mutant advanced or metastatic melanoma, are under way. 

The second trial tested dabrafenib in combination with trametinib, which targets the MEK protein, in patients with BRAF-mutant metastatic melanoma. In preclinical studies, the combination was more effective than either drug alone. Dr. Jeffrey Weber of the H. Lee Moffitt Cancer Center discussed preliminary results of the phase I/II trial at a May 16 press briefing held prior to the American Society of Clinical Oncology annual meeting.

Of the 77 patients treated with any of four doses of the drug combination, 8 percent had a complete response, 49 percent had a partial response, and 38 percent had stable disease. Among the 24 patients taking 150 mg of dabrafenib twice a day and 2 mg of trametinib once a day (the dose that will be used in the phase II study), 8 percent of patients had a complete response, 54 percent a partial response, and 38 percent stable disease. In this subset of patients, the time to disease progression was 10.8 months.

Dr. Weber noted that only 3 percent of patients who received both drugs developed squamous cell cancers, compared with 15 to 25 percent of patients in previous studies who took dabrafenib or another BRAF inhibitor alone. Although 22 percent of patients who received both drugs developed a rash, there was an almost complete absence of the acneform rash usually seen with MEK inhibitors. However, high fever was more common among patients taking the combination than in patients in previous studies who took a single BRAF inhibitor, and in some cases high fever led to a dose reduction or treatment delay.

"Obviously, we have to be cautious—it's only a cohort of 24 patients—but [the finding] looks extremely encouraging," said Dr. Weber. A phase III trial testing the drug combination in patients with advanced melanoma has just begun.

Also in the Journals: Program Helps Older, Overweight Cancer Survivors Lose Weight, Eat Better

A tailored, home-based program has helped older cancer survivors who were overweight or obese eat better, get more exercise, lose weight, and maintain these improvements over time, according to findings from the Reach Out to Enhance Wellness (RENEW) study. Dr. Wendy Demark-Wahnefried of the University of Alabama at Birmingham and her colleagues reported their results May 21 in the Journal of Clinical Oncology.

The study included more than 600 survivors of breast, prostate, or colorectal cancer who were older than age 65, sedentary, and overweight or obese. Participants received tailored print materials and telephone counseling at regular intervals over the course of a year.

Further research to improve older cancer survivors' health and quality of life is important, the study authors noted, because this population numbers over 7 million and is increasing rapidly.

Also in the Journals: Coffee Drinking May Be Associated With Lower Risk of Death

Results from a large study of older adults suggest that coffee drinking may be associated with a lower risk of death. Those who reported at the start of the study that they drank coffee (whether caffeinated or decaffeinated) had a slightly lower risk of death from heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections—but not cancer—than those who did not report drinking coffee.

Compared with people who did not drink coffee, those who consumed three or more cups of coffee per day had approximately a 10 percent lower risk of death.

The study, led by Dr. Neal Freedman of NCI's Division of Cancer Epidemiology and Genetics, was observational and could not determine whether coffee drinking actually reduced the risk of death. The findings appeared May 17 in the New England Journal of Medicine.

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