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LUNG CANCER SCREENING ENDORSED BY ACS

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The updated guidelines on lung cancer screening released by the American Cancer Society (ACS) conclude that there is sufficient evidence for screening with low-dose computed tomography (LDCT) in certain high-risk individuals.
The guidelines were published online January 11 in CA: A Cancer Journal for Clinicians. They are an update of interim guidelines issued in 2010, and are based on a systematic review published last year (JAMA. 2012; 307:2418-2429).
The ACS supports screening for lung cancer for people 55 to 74 years with a history of smoking (at least a 30-pack-year history), in those who currently smoke, and in those who quit smoking in the previous 15 years. The ACS also supports an individual's decision not to be screened, even if they fall in this high-risk category.
The LCDT screen is performed annually, and the ACS emphasizes that people should be encouraged to join an organized screening program with expertise in lung cancer and multidisciplinary teams "wherever possible."
"The adoption of lung cancer screening could save many lives," Richard Wender, MD, from Thomas Jefferson University Medical College in Philadelphia, Pennsylvania, and colleagues state in the guidelines, citing evidence from the National Lung Cancer Screening Trial (NLST).
"At this time, there is sufficient evidence to support screening provided that the patient has undergone a thorough discussion of the benefits, limitations, and risks, and can be screened in a setting with experience in lung cancer screening," they add.
The National Comprehensive Cancer Network was the first to recommend annual screening with LCDT for certain populations (in 2011); the American Lung Association followed in 2012.
The American College of Radiology has announced that it is preparing its own set of guidelines to ensure that CT lung cancer screening is performed using "proper personnel, equipment, protocols, and follow-up."
Issues of Concern
Despite the official guidelines and enthusiasm from some medical centers, there has been reticencefrom some lung cancer experts, who are concerned that many details need to be resolved before national screening programs are implemented.
The ACS acknowledges some of these concerns in its guidelines, and notes that high-quality lung cancer screening in the United States "poses many challenges." Whether or not the benefit from screening observed in the NLST will be seen in community-based screening for lung cancer "could be influenced by many factors, and the answer awaits the results of further observations and research," Dr. Wender and colleagues write.
On the positive side, screening could detect lung cancer at an earlier stage and therefore save lives; on the negative side are limitations and potential harms, including the "relatively high" level of false-positive findings and the resultant anxiety and need for additional invasive tests (such as lung biopsy). In the NSTL, 96.4% of the postive screening results in the LDCT group and 94.5% in the radiography (control) group were false-positive results.
In addition, there is "a legitimate concern" that some smokers will view the chance to undergo screening as an excuse to continue smoking, Dr. Wender and colleagues note. They emphasize that "vigorous smoking cessation efforts must accompany LDCT screening for adults who are current smokers."
Another issue concerns payment. Currently, very few government or private insurance programs provide coverage for the initial LDCT for lung cancer screening.
Advice to Clinicians
The ACS guidelines outline specific recommendations for clinicians.
They advise that clinicians review the smoking history of all patients 55 to 74 years of age to identify those who are in relatively good health but who have a history of smoking (at least 30-pack-year) and currently smoke or have quit smoking in the previous 15 years.
Having identified these individuals, clinicians who have access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about lung cancer screening. This should include a discussion about potential benefits and harms, limitations, and for current smokers should include counseling on smoking cessation.
The guidelines emphasize that clinicians should not discuss lung cancer screening with individuals who do not meet the above requirements.
"Wherever possible, individuals who choose to undergo lung screening should enter an organized screening program at an institution with expertise in LCDT screening, with access to a multidisciplinary team skilled in evaluation, diagnosis, and treatment of abnormal lung lesions, " the guidelines advise.
They recommend that "if an organized, experienced screening program is not accessible, but the patient strongly wishes to be screened, they should be referred to a center that performs a reasonably high volume of lung CT scans, diagnostic tests, and lung cancer surgeries."
"If such a setting is not available, and the patient is not willing or able to travel to such a setting, the risks of cancer screening may be substantially higher than the observed risks associated with screening in the NSTL, and screening is not recommended," according to the guidelines.

NEW DRUG REGIMENS FOR HCV INFECTION

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Twelve weeks of sofosbuvir and ribavirin treatment may be sufficient for sustained antiviral activity in untreated and pretreated patients with hepatitis C virus (HCV) genotype 1, 2, or 3, according to the findings of an open-label, phase 2 trial.
Edward J. Gane, MD, from the New Zealand Liver Transplant Unit, Auckland City Hospital and the Gastroenterology Department, Christchurch Hospital, both in New Zealand, and colleagues published their findings in the January 3 issue of the New England Journal of Medicine.
"The results from this study confirm that sofosbuvir, an oral nucleotide analogue polymerase inhibitor, combined with ribavirin, is a very effective treatment in patients infected with both genotype 1 and non–genotype 1 HCV, without cirrhosis," Dr. Gane told Medscape Medical News by email. "This regimen is very well tolerated: all oral, short-duration (only 12 weeks), and without any significant drug interactions or specific toxicity."
In the study, the authors treated patients as follows: 4 groups of 10 previously untreated patients with HCV genotype 2 or 3 infection each received sofosbuvir plus ribavirin for 12 weeks, with 3 groups also receiving peginterferon alpha-2a for 4, 8 or 12 weeks (groups 1 - 4); a group of 10 previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir alone for 12 weeks (group 5); a group of 10 previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir plus peginterferon alpha-2a and ribavirin for 8 weeks (group 6); a group of 10 patients with HCV genotype 1 infection who did not respond to previous treatment and a group of 25 previously untreated patients with HCV genotype 1 infection both received sofosbuvir plus ribavirin for 12 weeks (groups 7 and 8).
Among the patients in groups 1 to 4, all 40 patients had undetectable HCV serum levels up to 48 weeks after treatment. In addition, all patients in group 6 had a sustained virologic response (SVR) at 12 weeks after the end of treatment and all 9 patients for whom data were available had an SVR at 24 weeks.
The authors excluded patients with positive tests for hepatitis B surface antigen, hepatitis B core immunoglobulin M antibodies, or HIV antibodies. In total, 6 (60%) of 10 patients in group 5 and 21 (84%) of 25 patients in group 8 had an SVR at 24 weeks after treatment, whereas only 1 (10%) of 10 patients in group 7 had an SVR.
Among the patients without SVRs at 24 weeks, deep sequencing revealed the presence of the S282Tmutation in only 1 patient; no other mutations at conserved sites were identified.
No patient was forced to discontinue treatment because of adverse events. The most common adverse events included headache, fatigue, insomnia, and nausea.
Regarding hematologic events, sofosbuvir monotherapy was associated with modest (0.54 g/dL) decreases in hemoglobin levels. Patients who received peginterferon were more likely to experience hematologic abnormalities, and the degree of changes in hemoglobin levels was more severe among these patients.
Similarly, neutropenia and thrombocytopenia were only observed in patients who received interferon. No grade 3 or 4 elevations of bilirubin levels were observed, and only a single patient (in group 8) relapsed within 2 weeks after the end of treatment and displayed increased alanine aminotransferase levels.
Remaining Questions
In an email to Medscape Medical News, Dr. Gane identified several questions that remain to be addressed: "Will the excellent efficacy and tolerability in this phase 2 study be confirmed in the larger phase 3 studies, which contain patients with cirrhosis?" Dr Gane asked. "Which other antiviral agent should be combined with sofosbuvir to improve efficacy in treatment-experienced patients? Can such short-duration, all-oral therapy be administered in the community, thereby increasing treatment access?"
Donald M. Jensen, MD, director of the Center for Liver Diseases, the University of Chicago, Illinois, who was not involved in the study, noted that the treatment groups were small and fairly homogenous, thus requiring validation in larger, more representative cohorts. "We also need to know why prior interferon treatment failure predisposes to relapse but not on-treatment response and why this is more common in genotype 1a subjects (though few genotype 1b subjects were included in the present investigation)."
Dr. Jensen told Medscape Medical News by email: "Can this be overcome with longer treatment durations or combination with other antivirals? We also need to understand how ribavirin prevents relapse…a question that has plagued us for decades."
Ira M. Jacobsen, MD, chief of the Division of Gastroenterology and Hepatology from Cornell University in New York, also noted that the mechanism of ribavirin's role remains unclear. "Whether 12 weeks of sofosbuvir plus ribavirin will really provide 100% SVR rates in genotypes 2 and 3 remains to be answered by larger trials that are ongoing," Dr. Jacobson told Medscape Medical News by email. "Also unanswered is what will be required to achieve satisfactory SVR rates, preferably similar to naive patients, in nonresponders to previous peginterferon and ribavirin therapy. Optimization in genotype 1–naive patients is also a question."

GASTRIC CANCER RISK WITH PERNICIOUS ANEMIA

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Patients with pernicious anemia have an increased relative risk of developing gastric cancer, a meta-analytic review of relevant studies confirms.
The authors estimate a pooled gastric cancer incidence in pernicious anemia of 0.27% per person-years.
Although a risk of gastric cancer in relation to pernicious anemia is reported in the literature, the studies differ from each other in terms of sample size and methods for the identification of gastric cancer used during the follow-up period, said Dr. Bruno Annibale and colleagues from University Sapienza, Rome, Italy in a report online December 10 in Alimentary Pharmacology & Therapeutics.
"Gastric cancer is the most severe long-standing complication of pernicious anemia and, to our knowledge, this is the first systematic review on the estimate of gastric cancer incidence-rate," they note.
Through a literature search, the researchers identified 27 articles published between 1950 and 2011 that reported the incidence of gastric cancer in pernicious anemia.
In meta-analysis, the overall gastric cancer relative risk with pernicious anemia was 6.8 (95% CI 2.6 - 18.1).
Among a total of 22,417 patients, 417 new cases of gastric cancer were identified in 157,319 person-years of follow-up, corresponding to an overall pooled gastric cancer incidence-rate per person-year of 0.26%, with a range between 0% and 1.2%.
When the researchers considered only the six studies with active follow-up protocols involving gastroscopy and histology, the pooled gastric cancer incidence-rate per person-years was 0.27% (95% CI 0.25 - 0.29), corresponding to seven new gastric cancer cases observed in 2,563 person-years.
In their paper, the authors note that the range of annual incidence rates for gastric cancer in pernicious anemia overlaps that reported in the literature for patients with atrophic gastritis, which is between 0% and 1.8% per year.
In email to Reuters Health, study co-author Dr. Edith Lahner said an "important take home message is that patients with pernicious anemia should be considered patients with atrophic gastritis, a condition at higher risk for gastric cancer, in which regular endoscopic-histological monitoring seems to be of benefit."
She noted that an expert panel advised an interval of every three years, in a paper by Dinis-Ribeiro et al in Endoscopy this year.
"In other words, the atrophic gastritis associated with pernicious anemia seems not to be all that different from the atrophic gastritis without pernicious anemia," Dr. Lahner said.
In their paper, the authors point out that almost half of the studies they included in their analysis were of low or very low quality, based on the Newcastle-Ottawa Quality Scale for cohort studies, which permits a critical appraisal of data.
"Although the 27 included studies showed similar incidence rates for gastric cancer, clinical and methodological heterogeneity was present," they say. Ten studies were retrospective (37%), and hospital records were often the sources of patients for these studies. Nonetheless, they say the incidence-rates of gastric cancer were similar among the studies irrespective of the study design and the source of patients.
The overlap of the pooled gastric cancer incidence per person-year of 0.27%, calculated from the six studies with active follow up by gastroscopy and histology, and the overall estimate obtained by considering all studies supports the "robustness of our analysis," the authors say.
"Thus, the main finding of this systematic-review," they say, "is the similarity of the incidence-rates of gastric cancer, which are remarkably stable among all studies despite major heterogeneity between individual studies in terms of their design (country of study location, sources of selection of participants, sample size, type and methods of follow-up, methods for identification of gastric cancer)."
"At this point," Dr. Lahner said, "we need further studies to determine the extent of the gastric cancer risk and the usefulness and time scheduling of follow-up in patients with pernicious anemia."
In their paper, the authors say the increased risk for gastric neuroendocrine tumors in patients with pernicious anemia "could represent an additional potential rationale for endoscopic surveillance in these patients."
The study was supported by grants from the Italian Ministry for University and Research, PRIN 2007 and from University Sapienza of Rome 2010-2011 Italy. The authors have declared no conflicts of interest.