Two new double-blind, randomized clinical trials suggest that the prophylactic use of the antibacterial agent levofloxacin can reduce the risk of fever, bacterial infections, and hospitalizations in patients undergoing chemotherapy who are likely to develop neutropenia, a dangerously low white blood cell count. Both studies were published in the September 8 New England Journal of Medicine (NEJM).
The studies - one conducted in Italy, the other in the United Kingdom - had slightly different designs. The Italian study randomized 760 patients about to undergo chemotherapy and who were at risk for prolonged neutropenia (7 days or more) to receive levofloxacin or placebo until the neutropenia resolved. Patients in the treatment group were less likely to develop a fever, which was the study's primary endpoint because it is indicative of an infection, than those in the placebo group (65 percent vs. 85 percent). Treatment-group patients were also less likely to have documented cases of bacterial infections than the placebo group. Antibacterial prophylaxis did not improve survival compared with placebo.
The second study involved 1,565 patients scheduled to undergo cyclic chemotherapy who were randomized to a placebo or levofloxacin for 7 days when the risk of neutropenia was highest. In the first chemotherapy cycle, 3.5 percent of patients in the treatment group developed a fever, compared with 7.9 percent of those on placebo. Patients on levofloxacin also had lower hospitalization rates, 15.7 percent vs. 21.6 percent. Again, no difference in survival was documented.
The prophylactic use of antibacterial agents has been controversial, especially because of concerns about increasing the spread of drug-resistant bacteria. Neither study was designed to specifically address the issue of resistance, although one study did show an increase in drug-resistant bacteria in those treated with levofloxacin.
"One way to maintain the benefits described in the two current studies but minimize the risk [of bacterial drug resistance] is to restrict its use to those at highest risk," suggested Dr. Lindsey R. Baden, an NEJM deputy editor, in an accompanying editorial. "Efforts to improve risk stratification will be critical to minimize unnecessary use of antimicrobial agents and simultaneously preserve the benefits described in the two studies."
Men who survive testicular cancer face an increased risk of developing a second cancer for at least 35 years after treatment, and young patients may face increasing levels of risk as they get older, according to the largest study to date of testicular cancer survivors.
Ten-year survivors who had been diagnosed with testicular cancer at age 35 had twice the risk of developing a second cancer as someone in the general population - and this risk remained elevated for 35 years. Patients diagnosed at younger ages faced higher risks than those diagnosed at older ages.
Testicular cancer primarily affects young men and is largely curable, but second cancers arising from the late side effects of treatment - especially radiotherapy - are a leading cause of death among survivors. Cancers of the bladder, colon, lung, pancreas, and stomach accounted for 60 percent of those reported, according to findings in the September 21 Journal of the National Cancer Institute (JNCI).
Dr. Lois B. Travis, of NCI, and her colleagues examined data from more than 40,000 survivors from tumor registries in Europe and North America, and identified a total of 2,285 second solid cancers. They found for the first time significant excesses of malignant mesothelioma and esophageal cancer, likely reflecting the past use of chest radiotherapy.
The researchers note that despite the risks of second cancers, it is clear that "the remarkable gains in survival provided by treatments for testicular cancer far outweigh the risk of this serious late effect." In the July 20 JNCI, Dr. Travis and her colleagues reported that the long-term risk of testicular cancer patients developing a second cancer in the opposite (contralateral) testicle is very low.
After preliminary data showed improved disease-free survival among women with estrogen receptor-positive breast cancer who received letrozole following tamoxifen, results from the MA.17 clinical trial were announced in 2003, a year ahead of schedule, and participants in the placebo group were unblinded and offered the study drug instead. The study team recently released a more detailed analysis of the drug's efficacy and toxicity up to the time of unblinding. Their findings are published in the September 7 JNCI.
The updated data from 5,170 patients show that after 4 years of follow-up, 94.4 percent of women who received letrozole survived without disease recurrence, compared with 89.8 percent of those who received the placebo. In general, women who received letrozole and women who took the placebo saw no difference in overall survival, though the drug did seem to improve overall survival among a subset of women who had positive axillary lymph nodes, as well as those who had taken tamoxifen for more than 5 years. Toxic side effects of concern included those related to bone metabolism and cardiovascular disease, but bone fractures and cardiovascular events occurred equally between the two study groups.
"[Our preliminary findings] have changed clinical practice, but because the median follow-up was short the question of duration of therapy remains unanswered for the time being," the authors conclude, indicating that analysis of data from patients who switched to letrozole after the 2003 unblinding may provide the answer.
Hot flashes are one of the most common symptoms in women receiving treatment for breast cancer, especially hormone treatments such as tamoxifen. In a prospective, randomized, double-blind, placebo-controlled study of 420 breast cancer patients experiencing hot flashes, the anticonvulsant drug gabapentin reduced these symptoms by about half in some women. The multicenter study was based at the University of Rochester Medical Center in New York and published in the September 3 Lancet.
Nonhormonal treatments for hot flashes became a priority in 2002 when early results from the National Institutes of Health Women's Health Initiative showed adverse effects related to hormone replacement therapy, including increased breast cancer risk. Drugs such as the antidepressant venlafaxine and the antihypertensive clonidine are currently used to mitigate hot flashes. Lead author Dr. Kishan J. Pandya said in an interview that gabapentin now provides another good alternative, especially for patients already taking antihypertensives. Gabapentin is FDA-approved to treat epilepsy, and is also used for neuropathic pain.
The women in the study took a placebo, 300 mg of gabapentin, or 900 mg of gabapentin each day for 8 weeks and kept a diary to describe their hot flashes. The 900 mg dose produced significantly better results than the 300 mg dose after 8 weeks, reducing the frequency of hot flashes by 44 vs. 30 percent, and the severity by 46 vs. 31 percent. Other menopause symptoms among the three groups were not significantly changed, except for suppressed appetite and decreased pain in the 900 mg group of women.
A Food and Drug Administration (FDA) advisory panel last week recommended that the agency approve the targeted agent erlotinib (Tarceva) for use in combination with gemcitabine (Gemzar) to treat patients with advanced pancreatic cancer. The approval was based on the results of a clinical trial announced earlier this year in which the combination offered a small, but statistically significant, improvement in survival compared with gemcitabine plus placebo.
Members of the panel, the Oncologic Drugs Advisory Committee, struggled with whether a single trial demonstrating a nearly 13-day improvement in median survival - which could be accompanied by severe bouts of diarrhea and rash, as well as lower rates of life-threatening events such as stroke - was enough to justify an approval recommendation.
Despite the lack of options for these patients, several committee members, including the chair, Dr. Silvano Martino from the USC Keck School of Medicine, and Dr. Bruce Cheson from the Lombardi Comprehensive Cancer Center at Georgetown University, were not convinced that the data were compelling enough. But most committee members, while acknowledging the minimal benefit provided by adding erlotinib to gemcitabine, felt it represented a first step in the right direction.
"This was a positive study in a tough disease," said committee member Dr. Maha Hussain from the University of Michigan. "I don't think we ought to be the judge on what patients would choose."
The median survival and adverse events data could be misleading, added Dr. Mace Rothenberg, from Vanderbilt-Ingram Cancer Center. Diarrhea and rash could be controlled by decreasing the dose of the drug, he noted, while data on average survival showed that many patients in the erlotinib arm lived 5 weeks or so longer than those in the placebo arm.