National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 1, 2011 • Volume 8 / Number 21

Cancer Research Highlights

Annual Screening with Chest X-Ray Does Not Reduce Lung Cancer Deaths

Annual screening for lung cancer using a standard chest x-ray does not reduce the risk of dying from lung cancer when compared with no annual screening, according to findings from the NCI-led Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. The results from a median of nearly 12 years of follow-up were published online October 26 in JAMA.

Participants in the trial who were randomly assigned to receive an annual chest x-ray for 4 consecutive years had nearly the same mortality rate from lung cancer as participants randomly assigned to receive usual care—that is, care they would typically receive in their own community.

PLCO is one of the largest cancer screening trials ever conducted. The trial involved nearly 155,000 participants between the ages of 55 and 74. Participants were screened for four different cancers at one of 10 designated centers between November 1993 and July 2001.

Unlike participants in the National Lung Screening Trial (NLST)—the results of which were initially presented late last year—PLCO participants were not at increased risk of cancer. Only 10 percent of participants were current smokers and 42 percent were former smokers. Among participants in the screening arm of the PLCO trial, 91.3 percent were screened at least once and 83.5 percent had all four chest x-rays. Only 11 percent of patients in the usual care, or control, arm of the trial had a chest x-ray to screen for lung cancer during the 4-year intervention period.

In NLST, screening with low-dose helical computed tomography (CT) was compared to chest x-ray in patients who were at increased risk of lung cancer, primarily because of their smoking history. The results showed a 20 percent reduction in lung cancer mortality associated with CT. When PLCO researchers looked at the subset of about 30,000 patients in their trial who would have been candidates for NLST based on their smoking history, there was a suggestion of a slight reduction in lung cancer mortality risk associated with screening at 6 and 13 years of follow-up. This finding, however, did not achieve statistical significance.

Only 18 percent of the lung cancers diagnosed in the screening arm of PLCO were diagnosed during the trial's intervention period. But, according to Dr. Christine Berg, of NCI's Division of Cancer Prevention, the principal investigator of the PLCO and NLST, a longer screening period most likely would not have made a difference given the lack of a mortality reduction in higher-risk participants.

Results from the trial "are as definitive as most studies get," Dr. Berg continued. "They really indicate that lung cancer screening with chest x-ray is of no benefit for reducing lung cancer mortality, regardless of an individual's risk profile."

Research groups are still analyzing the NLST results, Dr. Berg added, including the implications of the high false-positive rate associated with CT screening in that trial.

Radiation Therapy after Breast-Conserving Surgery Improves Survival

Radiation therapy after breast-conserving surgery substantially reduces the risk of cancer recurring in the breast and moderately reduces the risk of death from the disease, according to updated results from a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group.

The results, published online October 19 in The Lancet, are based on data from nearly 11,000 women who participated in 17 randomized trials that compared breast-conserving surgery with and without radiation therapy. Radiation therapy may help prevent breast cancer from recurring or spreading to other parts of the body by eliminating microscopic disease that remains in the breast after surgery.

Overall, the authors reported, radiation therapy was associated with a 16 percent drop in the absolute risk of breast cancer recurring in the first decade (from 35 percent to 19 percent); it was also associated with a 4 percent drop in the absolute risk of dying from breast cancer in the first 15 years after surgery (from 25 percent to 21 percent).

The success of radiation in reducing the recurrence of breast cancer depended on which biological subtype of the disease a woman had, the study found. Patients with estrogen receptor-positive tumors benefited more than women with estrogen receptor-negative and triple-negative disease.

The nearly 50 percent reduction in the relative risk of a 10-year recurrence of breast cancer exceeds that achieved with chemotherapy alone or hormonal therapy alone, wrote Dr. Thomas Buchholz of the University of Texas M. D. Anderson Cancer Center in an accompanying commentary. The improvement, he continued, was roughly equivalent to the benefits of trastuzumab (Herceptin) for patients with HER2-positive breast cancer. 

Screening, surgery, pathology, radiation therapy, and systemic therapy have all changed substantially since most of the women entered the trials included in this analysis. Therefore, the absolute reduction in recurrence with radiation therapy in future patients might differ greatly from that recorded in these trials, the authors noted.

Nevertheless, the benefit was seen in a wide range of patients with very different absolute risks. This suggests that the approach might have similar benefits for future patients who receive breast-conserving surgery but who are not comparable with the women included in the trials analyzed here, the authors concluded.

Targeted Therapy Shows Benefit in Rare Type of Thyroid Cancer

Treatment with the multitargeted agent vandetanib (Caprelsa) improved progression-free survival in patients with medullary thyroid cancer (MTC), according to findings from a randomized clinical trial. Earlier this year, the Food and Drug Administration (FDA) approved vandetanib for the treatment of patients with MTC based on initial findings from the phase III trial. MTC is a rare cancer, accounting for only 5 percent of all thyroid cancer cases, and radiation and chemotherapy have limited effects once the cancer progresses to an advanced stage.

The trial's results were published online October 24 in the Journal of Clinical Oncology.

At 24 months of follow-up, median progression-free survival had not yet been reached for patients who received vandetanib, reported Dr. Samuel Wells of the Medical Oncology Branch in NCI's Center for Cancer Research and his colleagues. Estimated progression-free survival for the patients treated with vandetanib was 30.5 months, compared with 19.3 months for patients who received a placebo.

The double-blinded trial enrolled 331 patients with MTC who were randomly assigned to receive vandetanib or a placebo. All patients had locally advanced disease or distant metastases. If there was evidence that their disease was progressing, patients in the placebo arm could opt to receive open-label vandetanib.

In addition to the improvement in progression-free survival, the objective response rate was higher and several other disease-related measures were better in the vandetanib arm than in the placebo arm. One of the drug's targets is RET kinase, and the measurable response rate appeared to be higher in patients with RET mutations than in those without mutations. Because so few patients were defined as not having a RET mutation, the response rate in RET mutation-negative patients remains uncertain.

Because 52 patients in the placebo arm received open-label vandetanib, the authors explained, it may not be possible for the trial to show an improvement in overall survival.

A number of side effects were more common in patients who received vandetanib, including diarrhea, nausea, and hypertension; 12 percent of patients stopped taking the drug because of side effects.

Vandetanib's side-effect profile should influence which patients with MTC receive the drug, wrote Drs. Benjamin Solomon and Danny Rischin of the Peter McCallum Cancer Center in Australia in an accompanying editorial. The 8 percent of patients treated with vandetanib who had QTc prolongation, a type of heart rhythm disturbance, is "particularly concerning," they continued. Because of the risk of QTc prolongation, vandetanib is only available under a Risk Evaluation and Mitigation Strategy.

Patients with advanced MTC who are not exhibiting symptoms should simply be monitored for evidence of disease progression, Drs. Solomon and Rischin advised. "In contrast, patients who are symptomatic, have a high disease burden, or have rapidly progressing disease stand to benefit the most from treatment with vandetanib."

Study Confirms Letrozole Prevents More Breast Cancer Recurrences than Tamoxifen

After a median of 8 years of follow-up from a large randomized trial, women with estrogen-receptor positive breast cancer who received 5 years of treatment with the aromatase inhibitor letrozole were less likely to have their cancer recur or to die during follow-up than women who had 5 years of treatment with tamoxifen. In addition, 5 years of sequential treatment—either 2 years of letrozole followed by 3 years of tamoxifen or 2 years of tamoxifen followed by 3 years of letrozole—was not better than 5 years of letrozole alone at preventing recurrence or death. These results, from the BIG 1-98 trial, were published online October 20 in Lancet Oncology.

Researchers from 27 countries enrolled 8,010 postmenopausal women with invasive breast cancer that could be removed surgically in the trial. After surgery, the women were randomly assigned to one of four groups: 5 years of letrozole (letrozole monotherapy), 5 years of tamoxifen (tamoxifen monotherapy), or one of the two sequential treatment groups. Novartis, the maker of letrozole, provided funding for the trial, along with NCI and the International Breast Cancer Study Group.

In 2005, preliminary results from the trial showed that letrozole alone was better than tamoxifen at preventing early recurrences, and when given the option to cross over, 619 of the 2,459 women in the tamoxifen-only arm chose to cross over to receive letrozole. Since crossover can complicate interpretation of trial results, the researchers performed a traditional intention-to-treat analysis (which includes only data from the original treatment assignments) and a type of analysis designed to account for crossover.

In the intention-to-treat analysis, women who received letrozole alone had a disease-free survival rate of 73.8 percent at 8 years, compared with a rate of 70.4 percent for women who received tamoxifen alone. Women who received letrozole alone also had better overall survival at 8 years than women receiving tamoxifen alone (83.4 versus 81.2 percent). The differences between the groups were slightly greater in the analysis accounting for the crossover. Neither of the two sequential treatments provided better results than letrozole alone.

Although these updated results show that letrozole reduces risk of relapse and improves survival compared with tamoxifen, "use of a sequence might be reasonable for patients at low-to-intermediate risk of relapse, those for whom starting or continuing letrozole is contraindicated, or in cases where 5 years of letrozole might not be available," concluded the authors.

"These two drugs have different side effects, and this study shows that a woman has options," said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI's Division of Cancer Treatment and Diagnosis, who was not involved in the research. "If the side effects from letrozole are intolerable, benefits are maintained by switching to tamoxifen rather that stopping hormonal therapy altogether."

Study Suggests Smaller Melanoma Excision Margins May Be Option for Some Patients

A randomized controlled trial of patients with stage IIA–C cutaneous melanoma thicker than 2 mm found that a 2-cm surgical resection margin is sufficient and is as safe for patients as a 4-cm margin in terms of overall survival, according to a report published online October 21 in The Lancet.

The study, which took place from 1992 to 2004 in nine European clinics, assigned 936 patients to receive treatment with either a 2-cm or a 4-cm resection margin. After a median follow-up of 6.7 years, 181 patients in the 2-cm margin group and 177 in the 4-cm group had died. Both groups had a 5-year overall survival rate of 65 percent.

Controversies and discussions about optimal surgical excision margins for patients with thick melanomas have lasted many years, according to the study's authors, led by Dr. Peter Gillgren of the Karolinska Institute in Sweden. Wide excisions can lead to poor cosmetic results, lymphedema, long hospital stays, frequent need for skin grafts, or complicated skin flap reconstructions. "A trade-off exists between a wide excision, with consequent surgical difficulties, and the relapse risk with a narrow excision, which could compromise disease-free survival or, worse, overall survival," the researchers noted.

Several recent studies and a meta-analysis by the Cochrane Collaboration have found no significant differences in the rate of local recurrence or in overall survival with smaller excision margins for melanoma. However, prior to the current study "no randomised controlled trial of equal size has been done comparing surgical excision margins of 2 cm and 4 cm for patients with cutaneous melanoma thicker than 2 mm," the researchers wrote.

In an accompanying editorial, Dr. John Thompson of the Melanoma Institute Australia and Dr. David Ollila of the University of North Carolina at Chapel Hill noted that the current study's conclusions about the comparability of 2-cm versus 4-cm excision widths "need to be tempered by the knowledge that the originally planned equivalence trial design had a target accrual of 2,000 patients, yet fewer than 1,000 were enrolled."

As a result, they explained, the trial lacked the statistical power to prove the two treatment options are equivalent. Instead, the study showed that a 2-cm margin was not inferior to a 4-cm margin. The editorialists also noted that a new clinical trial is being planned to test whether a 1-cm margin is equivalent or noninferior to a 2-cm margin.

HPV Vaccine Reduces Anal HPV Infection and Precancerous Lesions

Results of a study of men who have sex with men revealed that vaccination with the human papillomavirus (HPV) vaccine Gardasil, which protects against HPV types 6, 11, 16, and 18, reduced their risk of persistent anal HPV infection and decreased the incidence of anal intraepithelial neoplasia, a lesion known to precede anal cancer. The findings were published October 27 in the New England Journal of Medicine.

The incidence of anal cancer has been growing by around 2 percent a year in the general population. Anal cancer is especially prevalent in men who have sex with men.

In the study, researchers led by Drs. Joel Palefsky and Anna Giuliano of the H. Lee Moffitt Cancer Center and Research Institute randomly assigned 602 men between the ages of 16 and 26 to receive the HPV vaccine or a placebo. After 36 months of follow-up, men who received all three doses of the vaccine had 77.5 percent fewer cases of anal intraepithelial neoplasia related to HPV types 6, 11, 16, and 18. The risk of persistent anal infection with the same HPV types was reduced by 94.9 percent. No serious vaccine-related side effects were reported.

Although the study was not long enough to measure the vaccine's effect on anal cancer directly, these results, in agreement with a previous study, suggest that the HPV vaccine may reduce the risk of anal cancer, which is caused by HPV-16 and -18.

"There is currently no routine screening and treatment of anal intra-epithelial neoplasia of grade 2 or 3 to reduce the risk of anal cancer," the authors explained. "Vaccination may be the best long-term approach to reducing the risks of both anal cancer and anal condyloma."

 

Also in the Journals: Low-Dose Nicotine Does Not Promote Lung Tumor Growth in Mice

A recent study in mice showed that low-dose nicotine did not promote lung tumor growth, contrary to findings from some previous preclinical studies. The study, published online October 25 in Cancer Prevention Research, suggests that extending the duration of nicotine replacement therapy (NRT) use, which is under consideration by the Food and Drug Administration, will not increase lung cancer risk in former smokers.

To determine the effects of nicotine on lung tumor formation, tumor growth, and metastasis, Dr. Phillip A. Dennis and his colleagues in NCI's Medical Oncology Branch administered nicotine in drinking water to mice at levels comparable to those seen in humans using NRT.

Low-dose nicotine "did not increase tumor number or size, and did not affect overall survival," wrote the researchers. Nor did nicotine enhance the growth or metastasis of tumors formed from lung adenocarcinoma cell lines that were derived from mice treated with a chemical that causes K-ras gene mutations. K-ras mutations are common in tobacco-related lung cancers in humans.

These data suggest that low doses of nicotine do not have an appreciable effect on tumor promotion, whereas the data from previous studies suggest that larger doses do, the authors concluded. Dr. Dennis cautioned, however, that results obtained with these mouse models may not be relevant to all smoking-related lung cancers.

Also in the Journals: Mobile Phones Do Not Raise Brain Cancer Risk

An update of a Danish linked-registry cohort study found no increased risk of brain cancer among mobile phone users, researchers reported October 19 in the British Medical Journal. The researchers also found no increased risk when they limited the cohort to people who had been subscribing for more than 10 years, when gliomas and meningiomas were analyzed separately, and when tumors in the anatomical region closest to the handset were analyzed, noted the authors of an accompanying editorial.

The study compared the incidence of cancer among 358,403 Danish mobile phone subscribers with the incidence of cancer among nonsubscribers from 1990 through 2007. In an effort to eliminate potential statistical biases that have plagued other mobile phone studies, the researchers used subscription and registry data.

Related NCI Cancer Bulletin articles: "Dr. Martha Linet on Cell Phone Use and Cancer Risk," "Study Finds No Overall Increased Brain Tumor Risk from Cell Phones"