LUNG CANCER SCREENING-TIME TO BEGIN

June 29, 2011 — Results from the landmark National Lung Screening Trial (NLST), which indicate that screening with low-dose helical computed tomography (CT) reduces mortality from lung cancer, have been published online in the New England Journal of Medicine.
The 53,000-person trial found a 20% reduction in deaths from lung cancer among current and former heavy smokers screened with low-dose helical CT, compared with those screened with chest radiograph (P = .004); the study has a median follow-up of 6.5 years. These principal findings were first reported publicly in October 2010, and were covered at the time by Medscape Medical News.
The newly published paper includes previously unavailable details on the diagnostic procedures performed after positive screenings and their related complications rates, as well as details on the lung cancers that were diagnosed.
The study has been accompanied by expressions of enthusiasm and gratitude from the American oncology community.
"It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, chief medical officer at the American Cancer Society (ACS), told Medscape Medical News.
"This study fills a huge gap in lung cancer control," said Bruce Johnson, MD, in a press statement from the American Society of Clinical Oncology, where he is a board member. "This is a very exciting and important result," added Dr. Johnson, who is from the Dana-Farber Cancer Institute in Boston, Massachusetts.
The positive study results beg the question of whether or not it is time for lung cancer screening programs in the United States.
The study authors, led by Christine Berg, MD, from the National Cancer Institute, think the evidence is not complete enough yet. "The current NLST data alone are . . . insufficient to fully inform such important decisions [on lung cancer screening recommendations]."
The authors have estimated the immensity of the potential impact of such policies.
Although there are only 7 million adults in the United States who meet the entry criteria for the NLST, there are an estimated 94 million adults who are current or former smokers, and thus potential screens, they suggest.
Whatever the target population, "a national screening program of annual low-dose CT would be very expensive," writes Harold Sox, MD, from Dartmouth Medical School in West Lebanon, New Hampshire, in an editorial that accompanies the NLST study. "I agree with the authors that policy makers should wait for more information before endorsing lung cancer screening programs," he writes, citing cost as his principal objection.
However, one clinician has seen enough data to endorse screening.
"There should be a national screening policy, with CT offered to and even recommended for all patients who meet the same criteria as the eligibility for the NLST," said Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, and author of the Blowing Smokelung cancer blog.
If such a policy is not forthcoming, the lung cancer community, including medical professionals, "should ask the government and insurance company leadership why they so clearly devalue the lives of people with lung cancer, compared with those afflicted with other cancers," Dr. West told Medscape Medical News.
Dr. West said that if results of this magnitude were seen in other cancers, especially breast cancer, there would be no questioning the cost of the screening. "Screening in other cancers that is widely accepted is based on far, far less impressive improvement in actual survival," he said.
"Our society routinely places a very different threshold for acceptance of lung cancer interventions than breast cancer interventions, which are often routinely and unquestioningly accepted as worthwhile interventions based on remarkably minimal absolute differences in outcomes," he pointed out.
"There is nothing less valuable about a life saved from lung cancer than a life saved from breast cancer or another cancer," said Dr. West.
Dr. Brawley suggested that professional opinion will influence forthcoming lung cancer screening policy. The ACS began drafting a lung cancer screening guideline when the NLST results were first announced. The ACS guideline will now be informed by the paper's new data, as well as by the medical communities' reaction to it, said Dr. Brawley. The ACS will be "monitoring the 'Letters to the Editor' reaction to the paper," he said.
Concerns About Harms
In NLST, participants were between 55 and 74 years of age and had a history of heavy smoking. They were screened once a year for 3 years, and were followed for 3.5 additional years with no screening.
There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, which is a relative reduction in mortality from lung cancer with low-dose CT screening of 20% (95% confidence interval [CI], 6.8 to 26.7).
The number needed to screen with low-dose CT to prevent 1 death from lung cancer was 320, Constantine Gatsonis, PhD, one of the study coauthors, told Medscape Medical News. He is from the Warren Alpert Medical School of Brown University in Providence, Rhode Island.
The rate of positive screening tests was more than 3 times higher with low-dose CT than with radiography (24.2% vs 6.9%) over all 3 rounds.
Most of the positive tests were false — 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false-positive results.
"The rate of false positives is very high, although the thoracic/pulmonology communities have certainly seen high rates of false positives with screening in the past," noted Dr. West.
The authors address the issue of false positives. "The vast majority of false-positive results were probably due to the presence of benign intrapulmonary lymph nodes or noncalcified granulomas," they write.
In a related concern, they note that the rates of complications after a diagnostic evaluation procedure for a positive screening test were "low." The rate of 1 complication or more was 1.4% in the low-dose CT group and 1.6% in the radiography group. The diagnostic methods and algorithms varied at the 33 sites and were not uniform per the protocol, the authors point out.
Dr. Sox observes that invasive diagnostic procedures were "few, suggesting that diagnostic CT and comparison with prior images usually sufficed to rule out lung cancer in participants with suspicious screening findings."
Dr. West said that lung screening is akin to prostate-specific antigen monitoring for prostate cancer. "Undergoing CT screening for lung cancer will require a careful discussion of the road that this may well lead people down, including the anxiety, additional imaging, and potentially invasive procedures that this pathway might well entail," he said.
The study authors point to another finding from the NLST as proof of the relative safety of lung cancer screening. The rate of death from any cause was reduced in the low-dose CT group, compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P = .02). "The decrease in the rate of death from any cause with the use of low-dose CT screening suggests that such screening is not, on the whole, deleterious," they conclude.
Another concern with CT screening is overdiagnosis, says Dr. Sox.
"Overdiagnosis probably occurred in the NLST," he writes. After 6 years of observation, there were 1060 lung cancers in the low-dose CT group and 941 in the radiography group. This may be evidence of overdiagnosis because, in a large clinical trial of screening tests, "the proportion of patients in whom cancer ultimately develops should be the same in the 2 study groups," he said. If the difference found to date between the 2 screening methods persists with more follow-up, this "suggests that one test is detecting cancers that would never grow large enough to be detected by the other test," Dr. Sox notes.
Finally, the study authors cite one last safety concern with CT screening — cancer caused by the CT scans themselves. "The association of low-dose CT with the development of radiation-induced cancers could not be measured directly," they write, adding that it is a "long-term phenomenon." Dr. Brawley said that previous research has indicated that for every 2000 spiral CT scans, there is at least 1 cancer caused (Radiology. 2004;232:735-738).
Cancers Detected
Low-dose CT screening fulfills an often-touted claim about cancer screening — that it detects more cancers earlier than would have been likely detected clinically. Indeed, 40% of the cancers in the low-dose CT group were stage 1A, whereas 21.7% were stage IV.
"Cancers discovered after a positive low-dose CT screening test were more likely to be early stage and less likely to be late stage than were those discovered after chest radiography," Dr. Sox explains.
Will the benefits of screening seen in the NLST be seen in community settings? Dr. Sox believes the applicability of the results is "mixed."
Diagnostic work-up and treatment did take place in the community, he acknowledged. "However, the images were interpreted by radiologists at the screening center who had extra training in the interpretation of low-dose CT scans and presumably a heavy low-dose CT workload," he writes.
Furthermore, both Dr. Sox and the study authors point out that the study population was not typical. Trial participants were younger and had a higher level of education than a random sample of men and women with a history of heavy smoking. This might have contributed to the high rate of adherence to the screening protocol in the study (more than 90%), says Dr. Sox.
The influential US Preventative Services Task Force (USPSTF) will make a determination about recommendations for lung cancer screening "by next year," said Dr. Brawley. In the meantime, while the USPSTF and organizations such as the ASC, which helped fund the study, and the American College of Radiology make their recommendations, physicians and patients should have a conversation about the harms and benefits of screening, he said.
Dr. Brawley, while emphasizing concerns about low-dose CT screening, said that "it's wonderful that we can say to high-risk people: 'We have something to offer you folks."
The study was conducted by the American College of Radiology Imaging Network and the National Cancer Institute's Lung Screening Study Group.
N Engl J Med. Published online June 29, 2011. Abstract, Editorial

PALIFERMIN REDUCES MUCOSITIS IN HEAD AND NECK CANCER

June 30, 2011 — Palifermin (Kepivance), which is currently approved for preventing mucositis associated with total-body irradiation and stem-cell transplantation in hematologic malignancies, also prevents oral mucositis in patients with head and neck cancer undergoing radiation and chemotherapy, according to 2 randomized trials published online June 13 in the Journal of Clinical Oncology.
Michael Henke, MD, who led both studies, told Medscape Medical News that "this shows for the first time that radiation-induced mucositis can be ameliorated — and this in a phase 2/3 design!" Dr. Henke is from the Department of Radiation Oncology at University Clinic in Freiburg, Germany. The multicenter studies included researchers from Austria, France, Germany, Hungary, Italy, Poland, Spain, the United Kingdom, and the United States.
The first study was a double-blind randomized placebo-controlled trial of 186 patients with stage II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Treatment included radiation, 60 or 66 Gy, after complete or incomplete resection, delivered at 2 Gy per fraction and 5 fractions per week. Treatment also included cisplatin 100 mg/m² on days 1 and 22 (and on day 43 with incomplete resection).
Patients were randomized to weekly palifermin 120 μg/kg or placebo from 3 days before and throughout radiochemotherapy. The primary end point was the incidence of severe oral mucositis (World Health Organization [WHO] grades 3 to 4).
Palifermin reduced oral mucositis incidence to 51% (41 of 92), compared with 67% (63 of 94) with placebo (P = .027), shortened median mucositis from 22.0 to 4.5 days, and prolonged time to severe mucositis development from 32 to 45 days. Mortality was similar in both groups.
The authors conclude that "palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful."
The second study randomized patients scheduled for definitive chemoradiotherapy for locally advanced head and neck cancer to either palifermin (180 μg/kg, n = 94) or placebo (n = 94) before starting chemoradiotherapy, and then once weekly for 7 weeks. Patients received conventionally fractionated radiotherapy (2.0 Gy per day for 5 days per week, to 70 Gy) with cisplatin (100 mg/m² on days 1, 22, and 43). The primary end point was the incidence of severe oral mucositis (WHO grade 3 to 4).
Palifermin cut the incidence of severe oral mucositis from 69% to 54% (P = .041), delayed median time to severe oral mucositis from 35 to 47 days, and shortened the median duration of severe oral mucositis from 26 to 5 days.
Adverse events, overall survival, and progression-free survival were similar in the 2 treatment groups.
The researchers conclude that "although palifermin reduced severe functional [oral mucositis], its role in the management of locally advanced [head and neck cancer] during chemoradiotherapy remains to be elucidated."
Dr. Henke said that although several of the end points were not statistically significant after multiplicity adjustment, he thinks that they would have been significant with larger sample sizes.
"Given the proof-of-principle that mucositis is reduced by [palifermin], I am quite positive that its clinical relevance will be proven after adjustment of drug scheduling/dosing," Dr. Henke said.
He added: "Any means to reduce mucositis will be helpful. It's really debilitating and makes our patients suffer. One way to go will be smaller phase 2 work on when and at what dose to administer the drug to patients receiving radiation for head and neck cancer." He also suggested that palifermin might have value in novel radiation techniques sparing normal tissue.
The studies were supported by Amgen. Dr. Henke reports being in employment or leadership positions at Amgen and owning Amgen stock.
J Clin Oncol. Published online June 13, 2011. Abstract, Abstract

NEW PROGNOSTIC MUTATIONS IN MDS

June 29, 2011 — New mutations have been found in the bone marrow cells of patients with myelodysplastic syndrome (MDS), and some of these predict a poor overall survival, independent of established risk factors. The findings are reported in the June 30 issue of the New England Journal of Medicine.
"These findings indicate that mutations in specific genes help explain the clinical heterogeneity of myelodysplastic syndromes," say the researchers, led by Rafael Bejar, MD, PhD, from the Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
The research team was a collaboration of the top cancer centers in the United States — including the Dana-Farber Cancer Institute in Boston, the Memorial Sloan-Kettering Cancer Institute in New York City, and the M.D. Anderson Cancer Center in Houston, Texas — and was headed by Benjamin Ebert, MD, PhD, from Brigham and Women's Hospital.
Identifying these mutations will "improve the prediction of prognosis," the researchers note, and they explain that improving the prediction of prognosis is particularly important in this disease, because treatment is tailored to the predicted prognosis for each patient.
Currently, prognosis is determined by considering clinical features and karyotypic abnormalities, according to the International Prognostic Scoring System (IPSS). Patients are stratified into risk categories — low, intermediate 1, intermediate 2, and high — and each group is treated in a slightly different way.
This study shows that mutations independently predict poor survival, and that when this information is taken into account, it can change the risk stratification of a patient. For example, a patient who would have been considered to be at low risk using IPSS criteria, might now — taking into account mutational status — be considered to be at intermediate risk.
This could have an impact on how the patient is treated, said John Bennett, MD, from the James Wilmot Cancer Center at the University of Rochester, New York. Dr. Bennett, an international authority on MDS who is currently involved in updating the IPSS, was approached by Medscape Medical News for independent comment.
This finding that mutations predict prognosis "helps us to pick the winners and the losers," Dr. Bennett explained. The median overall survival in MDS is about 2 to 3 years, but some of these mutations are associated with a 3-fold lowering of median survival, he noted.
This signaling of a worse prognosis could trigger a change in treatment, he suggested. Currently, MDS patients who are considered to be at low risk are followed with a "watch and wait" strategy, and treatment is initiated by and directed at symptoms such as anemia, thrombocytopenia, and infections.
However, patients who are considered to be at intermediate risk or high risk are treated with hypomethylating agents, such as azacitidine (Vidaza, Pharmion) and decitabine (Dacogen, MGI Pharma).
This research suggests that about 20% of patients in the low-risk group have genetic mutations that predict a poor prognosis, which would shift these patients into an intermediate-risk category, Dr. Bennett explained. Similarly, the mutation findings shift some patients from the intermediate 1 to the intermediate 2 risk group.
"If you are a doctor who finds such a patient, what would you do?" he asked. "You could consider a hypomethylating agent, although there is no evidence at the moment that this would improve survival." Randomized clinical trials are now needed to explore this question, he explained.
"If I was a physician treating patients with MDS, which these days I no longer am," he noted, "I would lean toward treating the patients with mutations in the intermediate 1 risk group, but not those in the low-risk group."
Large Set of Samples
Although previous research groups have identified mutations associated with MDS, this is one of the largest studies to date. It identified several new mutations, in addition to demonstrating that they are independent predictors of poor survival.
Dr. Bejar and colleagues analyzed bone marrow aspirate from 439 MDS patients, and used a combination of next-generation sequencing and mass-spectrometry-based genotyping to identify somatic mutations in 18 genes, including 2 (ETV6 and GNAS) that have not been previously reported.
Half of the patients (51%) had at least 1 point mutation, and this included patients who had normal cytogentics, they reported.
Mutations in 5 genes (TP53, EZH2, ETV6, RUNX1, and ASXLI) predicted poor survival, independent of established risk factors.
In addition, mutations in 3 genes (RUNX1, TP53, and NRAS) were strongly associated with severe thrombocytopenia and an increased proportion of bone marrow blasts.
"As our study shows, somatic mutations in several genes are associated with distinct effects," the researchers conclude.
"It will soon be possible for clinicians to detect a broad range of point mutations in peripheral blood with the use of sensitive genotyping methods, which will not only improve the prognostication in MDS, but also facilitate the diagnosis of these disorders, the evaluation of disease progression, and the monitoring of response to treatment," they continue.
"The integration of mutation assessment in diagnostic classification and prognostic scoring systems has the potential to parse diverse MDS into a set of discrete diseases with predictable clinical phenotypes, prognosis, and responses to therapy," the researchers conclude.
Dr. Bennett added another hope to this forecast — that the identification of mutations might spur the development of targeted therapy for this disease, as it has in other areas of the cancer field. Homing in on mutations that drive the disease has shown some dramatic responses in leukemia, and recently in melanoma.
In his only criticism of the paper, Dr. Bennett pointed out that survival was reported as overall survival, whereas in MDS it is important to differentiate between overall survival and leukemia-free survival. This is particularly relevant in the low-risk group, where the main cause of death in patients younger than 60 years of age is leukemia; in those older than 60 years, the deaths are due to other complications. He speculated that the mutations are associated with poorer survival because they are pushing the transformation to leukemia, so that progression to leukemia is faster and occurs in more patients, but this is "inference from the data," he emphasized. It would be interesting to dissect the survival data further, and to separate out death from leukemia and death from other causes, he said.
N Engl J Med. 2011;364:2496-2506.

UNREPRODUCIBLE CANCER GENOMIC STUDIES

June 30, 2011 — Cancer research is increasingly being defined by genomics, and advances in technology have allowed researchers to identify candidate genes as prognostic, diagnostic, and therapeutic biomarkers for different subtypes of tumors. Genomic platforms also allow for the prediction of therapeutic response, and with it the promise of personalized therapy.
Proteomics and genomics have generated quite a bit of excitement in the scientific community because they bring a new level of complexity to the cancer field. However, this emerging field of research has also brought concerns about validation and reproducibility.
Perhaps the most publicized and glaring case of "data gone wrong" involved Anil Potti, MD, an oncologist and genomics researcher who was forced to retract 4 papers from peer-reviewed journals because of results that could not be reproduced. As previously reported by Medscape Medical News, Dr. Potti's saga involved not only concerns about the validity of his research, but allegations of misconduct. He eventually resigned from his positions at the Duke University School of Medicine and the Duke Institute for Genome Science and Policy in Durham, North Carolina.
Dr. Potti's research was directed at developing gene-expression signatures that predict responses to various cytotoxic chemotherapeutic drugs. The goal was to identify characteristics of individual patients that could be matched with specific. His published papers reported that his signatures had the capacity to predict therapeutic response, but the experiments could not be reproduced and the signatures could not be validated.
"One issue that is coming out is that these papers did get past peer review. Does that mean peer review is broken?" asked Keith Baggerly, PhD, professor in the Department of Bioinformatics and Computational Biology at the University of Texas M.D. Anderson Cancer Center in Houston. "No not really, and peer review is still one of the best methods we have," he answered.
"The types of errors that we are talking are not those that peer review would have caught," he told Medscape Medical News. "The type of data analysis required to find those errors is not really feasible in peer review."
Feasible to Check?
Peer review is not a "stamp" that the data are correct. "They may look plausible," Dr. Baggerly explained, "but before anyone uses this information in a clinical setting, its going to require some level of independent replication and verification."
Dr. Baggerly and colleagues attempted to reproduce Dr. Potti's findings at the request of investigators from the M.D. Anderson Cancer Center, who were interested in using the research pioneered by Dr. Potti and his group. However, they were unable to replicate the results. Incomplete data and documentation made the task difficult, and required the use of "forensic bioinformatics," the art of using raw data and reported results to recreate what was done to obtain the results, rather than just retest the model.
"Ideally, this is a craft that should not be required," said Dr. Baggerly. "The methods section should cover this. Empirically, that is not the case."
The situation becomes worse when it starts being applied to high-dimensional situations such as omics signatures. "The reason it becomes worse, in my view, is that I believe that our intuition about what makes sense in high dimensions is empirically very poor."
This means that to work with and trust high-dimensional signatures, "we need to have a fairly precise idea of how it is that they were assembled," he added.
To use "genomic signatures" as biomarkers, we need to know they've been assembled correctly. What is being discussed now, he pointed out, is when these explicit checks, which attempt to go back and reproduce the data, should be implemented.
When do we say that this has to be right and when do we try to confirm it, Dr. Baggerly asked. Currently, these questions are linked to a number of issues: "Are we going to spend a lot of hours and resources on this, or are we going to proceed to clinical trials? In other words, are we extending monetary resources or the human variety?"
If we decide that "this really has to be right before we move ahead, then the level that was sufficient for initial publication in a journal may not be enough," he said.
IOM Meeting
On March 30 and 31, the Institute of Medicine's (IOM) Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials held a meeting, which was spurred by the circumstances and events related to work the conducted by Dr. Potti and his colleague, Joseph Nevins, PhD, from the Duke Institute for Genome Sciences and Policy.
According to background information supplied by Duke University, the IOM committee's work came about after a request to IOM president Harvey Fineberg, MD, on July 21, 2010, from Victor J. Dzau, MD, chancellor for health affairs at Duke University, in consultation with Harold Varmus, MD, director of the National Cancer Institute. The request was for a "full and independent review of the issues surrounding genomic predictors of chemotherapy sensitivity, as well as to provide guidance on the appropriate scientific approaches to this rapidly evolving area of science and medicine."
Duke University notes in their perspective letter that "the foundational conclusions for the chemotherapy sensitivity predictors were compromised by corruption in validation datasets that invalidated those conclusions." The clinical trials were subsequently halted, and Dr. Baggerly and his colleague Kevin Coombes, PhD, were instrumental in uncovering the problems with these chemotherapy sensitivity predictors.
However, Drs. Baggerly and Coombes point out that the "goal of developing universal standards for omics research remains."
Dr. Nevins was one of the panelists at the IOM meeting. In his talk, he described the methodology used in the research conducted by he and Dr. Potti, and respond to the scientific criticisms and the nature of the data corruption that led to the retraction of the papers and the termination of the trials.
Dr. Nevins noted that despite the criticism of their results, they persisted in their work for several reasons. He pointed out that he did not recognize that a critical flaw in the research effort was one of data corruption, an apparent manipulation of validation data.
"The reason it was not recognized earlier was my focus on what I believed to be the fundamental criticism — a question of accommodating distinctions in cell line and tumor data," he said.
He added that they believed they had addressed this "fundamental issue with multiple validation results beyond the initial papers."
Despite the negatives, there are lessons to be learned. "Data corruption of the form we experienced can happen, but is not something one anticipates," he explained. "It is best to look at this and think how we can ensure the integrity of data in the validity of results."
One way of doing this is to make use of systems for tracking analyses in projects, Dr. Nevins pointed out. Another is to ensure that all data, methods, and software are made available in publications, along with the full integration of appropriate expertise in the work.
That we didn't ensure that all data methods and software were available in the publications was "a mistake."
There is some control during the publication process, explained Dr. Nevins. "I understand the difficulties of journals policing this, but it's doable. And it has to happen. People just can't submit papers if the data are not available, and papers can't be accepted if the data are not available."
Dr. Baggerly was also a panelist at the IOM meeting, and he offered recommendations from he and Dr. Coombes. What are needed, he said, are data, metadata (clinical information, run order, design information), evidence of provenance, the code, auditability before trials begin, and reproducibility.
"Investigators need to think of reproducibility as a goal from the outset," he said, and journals need to ask and check for code and data deposition. Journals also need to be prepared to host code and clinical data.
In addition, agencies need to provide data repositories, and they need to check for data and code availability at renewal time. They need to budget for reproducibility audits, Dr. Baggerly explained, and institutions need to help with training and infrastructure.
Dr. Potti Resurfaces
As reported by Medscape Medical News, Dr. Potti was suspended by Duke in July 2010, amid concerns about his research and whether or not he had lied on a grant application. When questions about Dr. Potti's credentials became public, the American Cancer Society suspended payment of a $729,000 grant that had been awarded to him to study lung cancer genetics.
According to Retraction Watch, Dr. Potti is now employed by the Coastal Cancer Center, an oncology practice with 4 offices in South Carolina and 1 in North Carolina.
In addition, it appears that Dr. Potti is trying to polish his tarnished image. In April, the Duke Chronicle reported that he had hired a reputation manager to "push down" unfavorable content on Internet search engine results.
The Duke Chronicle notes that this "raises ethical concerns." At least 5 Web sites have been registered that combine Potti's name in different arrangements: AnilPotti.com, AnilPotti.net, DrAnilPotti.com, PottiAnil.com, and PottiAnil.net. Although the content on these Web sites appears to be factually correct, none of them mention anything about the long and tumultuous saga of Dr. Potti's research, paper retractions, or misrepresentation.
Attempting to influence search engine results is not unethical, said Sheldon Krimsky, an expert on medical conflicts of interest and a professor at Tufts University in Boston, Massachusetts, in the Duke Chronicle article. However, ethics do come into play if a physician attempts to change the public record.
According to its official Web site, Coastal Cancer Center conducts clinical trials. There is no news on whether Dr. Potti will be involved in any of these trials.

ANOTHER DIABETES DRUG LINKED TO CANCER

SAN DIEGO (Reuters) Jun 27 - A new type of diabetes pill being developed by Bristol-Myers Squibb and AstraZeneca was effective in a two-year study but more bladder and breast cancers have been found in patients treated with the drug.
In all studies so far completed, 1.4% of patients treated with dapagliflozin developed some type of cancer, compared with 1.3% of patients in the control group, said Elisabeth Bjork, vice president of development for dapagliflozin at AstraZeneca.
Nine bladder cancers have been observed in 5,478 patients treated with the experimental drug, compared with one bladder cancer seen in the 3,156 patients in control groups.
Six of the 10 had hematuria at baseline. Five were diagnosed with bladder cancer within a year after enrollment.
The companies also said nine cases of breast cancer have occurred in 2,223 women on dapagliflozin and one has been observed out of 1,053 women in control groups. All were diagnosed within a year after studies started.
ISI Group analyst Mark Schoenebaum said the timing of diagnosis within a year of therapy initiation and hematuria at baseline could be mitigating factors but the cancer findings are sure to be discussed by regulators.
Bjork said studies of dapagliflozin in animals found no carcinogenic signals.
"Importantly, overall cancers are not imbalanced," she said.
Bristol and AstraZeneca filed earlier this year for U.S. and European regulatory approval of dapagliflozin. An advisory committee to the U.S. Food and Drug Administration is set to review the application on July 19.
It is potentially the first in a new class of diabetes drugs designed to block glucose from being absorbed into the bloodstream through the kidneys, allowing more sugar to be excreted with urine.
Dapagliflozin leads to more sugar in the urine, which may serve as a nutrient for bacteria and pathogens that can cause infections, said Elisabeth Svanberg, vice president of development for dapagliflozin at Bristol-Myers.
In a two-year trial, urinary tract infections developed in 8% of type 2 diabetics treated with a placebo and metformin, 8% of patients on a 2.5 mg dose of dapagliflozin plus metformin, 8.8%t of patients on a 5 mg dose and 13.3% of patients receiving dapagliflozin 10 mg.
Genital infections were seen in 5.1% of patients receiving placebo plus metformin, compared to 11.7% for patients on the lowest dose of dapagliflozin plus metformin, 14.6% of patients on the 5 mg dose and 12.6% of patients on the 10 mg dose.
Other side effects included back pain, influenza, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, renal impairment or failure and events of hypoglycemia, according to data presented at the annual meeting of the American Diabetes Association.
Events of renal impairment or failure were reported in 1.5% of patients treated with placebo plus metformin, compared to 4.4% of patients on the lowest dose of dapagliflozin.
The 546-patient trial showed that the experimental drug resulted in greater and sustained improvements in glycemic control and sustained reductions in body weight compared to placebo, according to Cliff Bailey, head of diabetes research at Aston University, in Birmingham, England, and the study's lead investigator.

FDA APPROVING CANCER DRUGS FASTER THAN EUROPE

June 27, 2011 — Complaints that the US Food and Drug Administration (FDA) approves too few new drugs and takes too long to approve them have been contested by researchers from the Friends of Cancer Research advocacy group, on the grounds that (at least for oncology drugs), the FDA's track record is better than that of the European Medicines Agency (EMA). The report, by Samantha A. Roberts, PhD, and colleagues, was published online June 16 in Health Affairs.
The study tabulated the number of new oncology drugs approved by the FDA and the EMA from 2003 to 2010. It did not consider the rate of drug approvals as a function of the number of new drug approval applications.
During the time period studied, 35 new cancer drugs were approved by one or both of the regulatory agencies. The FDA approved 32 anticancer drugs and the EMA approved 26. All of the drugs that were approved by both agencies were available to patients in the United States first, which partly reflects the fact that pharmaceutical companies usually seek FDA approval before applying to the EMA.
The median time from marketing submission to marketing approval was 182 days for the FDA and 350 days for the EMA. Only 3 of the 32 anticancer drugs approved by the FDA took more than a year to receive approval.
The longer time to approval by the EMA is partly because the European Union requires 2 steps before a drug can be marketed. It must receive approval from the EMA Committee for Medicinal Products for Human Use, and then the European Commission must adopt that opinion.
User fees from the Prescription Drug User Fee Act of 1992 have helped provide the FDA with resources to shorten drug review times. That act is up for reauthorization in 2012. In discussing the upcoming reauthorization, Roberts et al write: "Increasing the speed of drug review times might not be as high a priority as achieving other objectives in advance regulatory science." In particular, they note, "the vast trove of data at the FDA must be transformed into a harmonized format and organized in a common database so that it can be queried by topic and analyzed to address key questions."
Dr. Roberts, who is a science policy analyst at the Friends of Cancer Research in Washington, DC, told Medscape Medical News that the researchers are emphatically not arguing that funds should be shifted from drug approval.
"We think the overall funding of the agency needs to increase (particularly federal funding) and that these additional funds need to be used for the regulatory science initiatives. It is important to note that this study only examines the review period at the very end of the long process of new drug development. Advancement of the regulatory science initiatives may help alleviate some of the challenges encountered at other stages of development and review, which have a large impact on the success of new medicines. These initiatives are aimed at things like developing new clinical trial designs that can incorporate biomarkers, so that the trials are more efficient, facilitating codevelopment of a drug with a corresponding diagnostic, and using informatics for real-time monitoring of accumulating safety and efficacy data of products that have already been approved," Dr. Roberts said.
She added: "We published these data to say that this is one aspect of oncology drug development that is going relatively well, at least for this snapshot in time, but funding for actual reviews would need to be at least maintained for this to continue. To really improve oncology drug development, what we now need is focus on and investment in making the clinical trial process itself smarter and more efficient."
Daniel Carpenter, PhD, who reviewed the study for Medscape Medical News, said that this study "brings data to a question that has been dominated by anecdote and hyperbole." Dr. Carpenter is the Freed Professor of Government and director of the Center for American Political Studies in the Faculty of Arts and Sciences at Harvard University in Cambridge, Massachusetts, and the author of a book on pharmaceutical regulation in the United States, entitled Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA (Princeton University Press, 2010).
Dr. Carpenter said that he agrees "with the authors that increasing the speed of drug review times is not as high a priority for future policy changes. There should be greater focus on the postmarketing study of drugs, and greater focus on reducing, where possible, the cost and time of drug development before FDA review. These are not simple questions with facile answers — the drug trials conducted during the [Investigative New Drug] stage are critical to public health, and they provide a public good of vast proportions, as their lessons are used downstream in prescribing decisions, the composition of formularies for hospitals and insurers, and very often in other firms' and scientists' drug development decisions. Yet I think that Roberts and colleagues are correct to suggest that less focus should be on approval times and more focus should be on what happens before the FDA review and on what happens after the FDA review."
Dr. Roberts and Dr. Carpenter have disclosed no relevant financial relationships.
Health Aff (Millwood). Published online June 16 2011. Abstract

NEW RECOMMENDATIONS FOR DYSLIPIDEMIA

June 29, 2011 (Gothenburg, Sweden) — The European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) have released new guidelines for the management of patients with dyslipidemia, providing up-to-date treatment recommendations for patients with the various lipid abnormalities. The new guidelines focus on the Systemic Coronary Risk Estimation (SCORE) for assessing individual patient risk, estimating the 10-year risk of a fatal atherosclerotic event, including MI, stroke, occlusive arterial disease, and sudden cardiac death.
"Previous guidelines in Europe were based only on global risk factors," Dr Alberico Catapano (University of Milan, Italy), the EAS task force chair, told heartwire . "We do acknowledge that a patient's risk is made up of several different factors, but we never had any specific guidance for the management of patients with dyslipidemia. This is important because dyslipidemia is one of the most significant risk factors contributing to cardiovascular disease."
Presenting the details of the ESC/EAS guidelines for the management of dyslipidemias during a plenary session here at European Atherosclerosis Society 2011 Congress, Catapano stressed that LDL cholesterol is still the primary target in the management of patients with dyslipidemia, but unlike the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, the European task force provides less wiggle room for physicians.
For patients at very high risk of cardiovascular disease, the ESC/EAS writing committee states that LDL-cholesterol levels should be lowered to less than 70 mg/dL, a target that is not optional, as it is in the NCEP guidelines. If less than 70 mg/dL can't be achieved, physicians should aim for a >50% reduction in LDL cholesterol. The nonoptional target is given a class IA recommendation, meaning that there is evidence and/or general agreement that the therapy is beneficial or useful and is derived from multiple randomized clinical trials.
For patients at high risk, the target LDL goal is less than 100 mg/dL, again differing from the optional recommendation in the NCEP guidelines. Among those patients at moderate risk of cardiovascular disease, those with a SCORE level ranging from >1% to <5%, the new treatment target is less than 115 mg/dL, a level that is lower than the 130-mg/dL target recommended in the NCEP ATP III. For moderate-risk patients, the evidence is not as strong and is based on consensus opinion or a small number of studies, retrospective analyses, and registries.
"Several clinical trials published and presented over the past few years have shown clearly that lower LDL-cholesterol levels are better," said Catapano.
Treatment options
Regarding treatment options, Catapano told heartwire that they recommend physicians prescribe statin therapy up to the highest dose possible or the highest tolerable dose to reach the target LDL-cholesterol level. For patients with statin intolerance, they recommend bile-acid sequestrants or nicotinic acid. Based on weaker evidence, they also state that a cholesterol-absorption inhibitor, alone or in combination with bile-acid sequestrants or nicotinic acid, may be considered in these statin-intolerant patients.
In addition to recommending LDL cholesterol as the primary target, the ESC/EAS task force states that total cholesterol can be considered a treatment target if other lipid analyses are unavailable and that triglycerides should be analyzed during the treatment of dyslipidemias in patients with high triglyceride levels. Non-HDL cholesterol should be considered a secondary target in patients with combined hyperlipidemias, diabetes, metabolic syndrome, or chronic kidney disease, as should apolipoprotein B (apoB).
On the other hand, the guidelines do not suggest a specific target level for HDL cholesterol or for ratios of apoB/apoA1 and non-HDL cholesterol/HDL cholesterol. Catapano said that while the guidelines do not recommend a specific goal for HDL-cholesterol levels, this does not mean that they should be ignored. He pointed out that HDL cholesterol is a strong risk factor for cardiovascular disease, and it is recommended clinicians use it when estimating risk. Nicotinic acid is the most effective drug for raising HDL cholesterol and "should be considered," according to the ESC/EAS, while statins and fibrates can also raise HDL cholesterol.
As reported by heartwire , large morbidity and mortality trials designed to show a clinical benefit with drugs that increase HDL cholesterol have come up short. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study of high-dose extended-release niacin (Niaspan, Abbott) given in addition to statin therapy in patients with a history of cardiovascular disease, high triglycerides (TG), and low levels of HDL cholesterol was halted prematurely because niacin offered no additional benefits in this patient population. The Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study, however, another large trial with niacin, is still ongoing. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was stopped in its tracks when it was shown the drug increased the risk of death and cardiovascular events.
Fibrate trials have been just as disappointing, with the ACCORD-Lipid and FIELD studies both failing to show a benefit of using fenofibrate.
Women, the elderly, and those with inherited dyslipidemias
The new guidelines also provide direction on managing a range of patients, including women, the elderly, diabetics, and those with chronic kidney disease. The elderly derive similar benefit from LDL lowering as younger patients, according to the task force, and there is no reason to treat female patients any differently, either. Postmenopausal women, those with an elevated risk of cardiovascular disease, would derive particular benefit from LDL lowering.
In the new document, the task force also lays out the magnitude of effect various lifestyle interventions have on lipid levels, such as reductions in saturated and trans fat, as well as reductions in body weight. They provide differing definitions of obesity depending on ethnicity, with South Asians having a more rigid definition of central obesity compared with whites.
Catapano emphasized that clinicians should also be aware of patients with inherited dyslipidemias. "The familial forms, not only familial hypercholesterolemia but also familial combined, occur in 1.5% to 2.0% of the population," he said. "It's a large number of patients who are at very high risk of cardiovascular disease."

MAMMMOGRAPHY SAVES LIVES

CHICAGO (Reuters Health) Jun 28 - The longest-running breast cancer screening study ever conducted has shown that regular mammograms prevent deaths from breast cancer, and the number of lives saved increases over time, an international research team said on Tuesday.
The study of 130,000 women in two communities in Sweden showed 30% fewer women in the screening group died of breast cancer and that this effect persisted year after year.
Now, 29 years after the study began, the researchers found that the number of women saved from breast cancer goes up with each year of screening.
"We've found that the longer we look, the more lives are saved," Professor Stephen Duffy of Queen Mary, University of London, whose study is to appear online June 28 in Radiology, said in a statement.
Dr. Stamatia Destounis, a radiologist at Elizabeth Wende Breast Care in Rochester, New York, who wasn't involved in the study, said radiologists have been quoting results of the Swedish study for years and the new findings show breast cancer screening is "even more of a benefit than we understood."
She said sweeping changes in the U.S. screening guidelines two years ago that scaled back recommendations on breast cancer screening caused a lot of confusion among doctors and patients about the benefits of mammograms.
"We've had to do a lot of education of the patients and their doctors. This will help for that," Dr. Destounis said.
In the study, women were divided into two groups, one that received an invitation to have breast cancer screening and another that received usual care.
The screening phase of the trial lasted about seven years. Women between 40 and 49 were screened every two years, and women 50 to 74 were screened roughly every three years.
"Our results indicate that in 1,000 women screened for 10 years, three breast cancer deaths would be prevented," Dr. Duffy said, adding that most of the deaths prevented would have occurred more than a decade after the screening had started.
"This indicates that the long-term benefits of screening in terms of deaths prevented are more than double those often quoted for short-term follow-up."
The new data adds to evidence on the long-term benefits of regular mammography screening.
SCREENING CONTROVERSY
New breast screening recommendations issued in 2009 by the influential U.S. Preventive Services Task Force, recommended against routine mammograms for women in their 40s and said women in their 50s should get mammograms every other year instead of every year.
The guidelines contradicted years of messages about the need for routine breast cancer screening starting at age 40, eliciting protests from breast cancer experts and advocacy groups who argued the recommendation for fewer screenings would confuse women and result in more deaths from breast cancer.
The changes were meant to spare women some of the worry and expense of extra tests needed to distinguish between cancer and harmless lumps. But the latest results from the Swedish study show the rate of false positive results was low.
"We saw the actual number of overdiagnosed cases was really very small - less than 5 percent of the total," Dr. Robert Smith, director of cancer screening at the American Cancer Society and one of the study's authors, said in a telephone interview.
Many groups, including the American Cancer Society, have stuck by their long-standing recommendations of a yearly breast exam for women starting at age 40, stressing that the breast X-rays have been proven to save lives by spotting tumors early, when they are most easily treated.
"I think for anybody who was beginning to have their faith shaken in the value of mammography, these data show mammography is quite valuable as a public health approach to reducing deaths from breast cancer," Dr. Smith said.
Dr. Duffy said he thinks screening women 40 to 54 every 18 months and screening women 55 and older every two years would be a reasonable schedule.
He said the new findings do not speak to the frequency of screening issue, but they do make clear that screening works.
"Everyone must make up their own mind, but certainly from combined results from all the screening trials, mammography in women aged 40-49 does reduce deaths from breast cancer," he said.
Breast cancer is the second-leading cause of cancer death among U.S. women, after lung cancer. It kills 500,000 people globally every year and is diagnosed in close to 1.3 million people around the world.

AVSTIN FOR BREAST CANCER-FDA ANSWER IS STILL NO

June 30, 2011 — The answer is still no. After an unusual 2-day public hearing, the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee voted unanimously against bevacizumab (Avastin, Genentech/Roche) in breast cancer.
The FDA is in the process of revoking the metastatic breast cancer indication for the drug, after the recommendation of its advisory committee, which voted against the indication last summer.
But the manufacturer, Genentech, is fighting against this decision and requested an appeal — which was heard over the past 2 days. The company changed its tactic somewhat — whereas the previous advisory meeting considered a broadening of the original breast cancer indication, the focus this time was to ensure that the original indication remain approved.
The outcome for the breast cancer indication was again no.
The process now continues, and public comments will be accepted until July 28. The matter will not be closed until there is a final decision from the FDA commissioner, Margaret Hamburg, MD. Currently, no date has been set for this.
Until that time, the drug remains FDA approved for the breast cancer indication (i.e., in combination with paclitaxel), which was granted in 2008 on the basis of 1 clinical trial under the accelerated approval process.
This use of bevacizumab with paclitaxel was recently included as a "preferred regimen for recurrent or metastatic breast cancer," in the updated National Comprehensive Cancer Network breast cancer guidelines.
This combination of bevacizumab and paclitaxel also remains approved in Europe; an extension to this — approved just yesterday — covers the use of bevacizumab in combination with capecitabine (Xeloda, Roche) for the first-line treatment of metastatic breast cancer.
Emotionally Charged Meeting
This latest meeting had a different feel than the usual advisory committee meeting, and attracted a huge amount of media interest in the United States. It was interesting to note that the drug was referred to by its trade name throughout the meeting, even when it was being discussed by FDA officials.
The beginning of the meeting was emotionally charged. Outside the building, there was a demonstration of breast cancer patients and families in pink t-shirts holding placards proclaiming: Avastin saves lives. Inside, the meeting began with heartfelt testimonies from women with breast cancer who credited the drug with keeping them alive. There were also testimonials from husbands whose wives had breast cancer, from physicians reporting on patients who responded to the drug, and from several patient advocacy groups, the majority of which were petitioning the FDA to allow bevacizumab to remain available for the treatment of breast cancer.
The rest of the meeting focused on clinical data, and drilled down into the details of benefit and risks over and over. No matter how the data were presented by Genentech, however, FDA officials and members of the advisory committee were not swayed.
Richard Pazdur, MD, director of the Office of Oncology Drugs at the FDA, said that the data now available on bevacizumab in breast cancer come from 5 randomized clinical trials with more than 3500 patients. No trial has demonstrated a significant improvement in overall survival or in quality of life, he noted. In addition, none of the subsequent studies has confirmed the magnitude of benefit seen in the original trial in this indication — the E2100 trial of bevacizumab plus paclitaxel, which resulted in accelerated approval in 2008.
The totality of the data show that the benefits seen with bevacizumab do not outweigh the serious risks of this drug, Dr. Pazdur explained. He noted that bevacizumab has been associated with intestinal perforation and hemorrhage and that 10% of patients in clinical trials have apparently experienced bevacizumab-related mortality.
At the conclusion of the 2-day hearing, the advisory committee voted unanimously against the indication. All 6 members of the committee, including the patient representative, agreed that:

• the available evidence on bevacizumab "demonstrates that the drug has not been shown to be effective for the breast cancer indication for which it has been approved"
• "the drug has not been shown to be safe for the breast cancer indication for which it was approved"
• the drug "has not been shown to present a clinical benefit that justifies the risks associated with the use of the product for this indication"
• the drug should not remain approved while Genentech designs and conducts additional studies to verify the drug's benefit.

Committee member Mikkael Sekeres, MD, MS, from the Department of Translational Hematology and Oncology Research at Cleveland Clinic in Ohio, commenting on this last issue, said that there was nothing in the clinical data that "would make me feel comfortable about continuing to expose a lot of patients to risk without a clear benefit."
"We have tried to slice the pie in various ways, looking for benefit, looking at data from subgroups, but there is nothing to hang our hat on in these studies," he said.
Wyndham Wilson, MD, PhD, head of the lymphoma therapeutics division at the National Cancer Institute, and also on the advisory committee, emphasized the adverse events reported in the clinical trials and cited the Hippocratic oath: "First, do not harm."
"Withdrawal is indicated," he argued. "To not do that you would have to have compelling evidence." The confirmatory clinical trials (RIBBON and AVADO) were "extremely well done . . . but they did not show any reasonable benefit, there was no clinically meaningful improvement in progression-free survival, and there was no evidence that the drug was of benefit."
Contrast Between Emotions and Data
Striking in its contrast were the highly emotional testimonials about the drug and the cold analytical dissection of the data.
Women who have benefited from the drug argued that bevacizumab should remain available, because although it might not work in all women, it does work in some; in fact, some respond very well. One of the patients testifying was first treated with bevacizumab in 2007; she said her "quality of life is nothing short of miraculous."
However, 2 of the patient advocates pointed out that testimonials come from women who benefited from the drug, whereas all the women who had not benefited or who had died were not at the meeting.
For every woman who has shown a great response to bevacizumab, and who has benefited with a life extension, there is at least 1 woman, if not 2, who has died sooner as a result of taking this drug, said Diane Zuckerman, PhD, president of the National Research Center for Women and Families, who supported the FDA's decision to rescind the approval.
The same point was made in a blog post on the hearing, written by Frederick Tucker, MD, from Fredricksburg Oncology, in Virginia, on the Citizen Oncologist Web site. "The testimonials we hear are only from those who do well, a self-selected population. History, it is said, is written by the winners."
Dr. Tucker highlighted a key issue behind the testimonials — the suggestion that there is a group of breast cancer patients who respond particularly well to bevacizumab, and that the drug should remain available to them.
The suggestion is that these "super responders" have tumors that are somehow biologically different, and respond more profoundly to bevacizumab, perhaps because of raised levels of vascular endothelial growth factor, the growth factor targeted by the drug, Dr. Tucker wrote. There have also been suggestions that the drug has a greater response in triple-negative tumors and in patients with a BRCA mutation.
"But as yet there are no facts to support this," Dr. Tucker pointed out. "The Center for Drug Evaluation and Research was asked specifically if they thought there were subgroups that did respond well to [bevacizumab]. Their answer was a succinct no. There was nothing in the data accumulated in the 5 trials to suggest that one group of patients might do better with the drug than another."
The contrast between emotions and data was highlighted by Len Lichtenfield, MD, deputy chief medical officer for the American Cancer Society, who was blogging and tweeting live from the meeting. "Clearly we are in a place where emotion meets science, and the FDA's decision will prove to be a difficult one," he noted.
After the vote — unanimously in favor of withdrawing the breast cancer indication — there were protests from survivors, with women loudly voicing their disagreement; one said that this shouldn't be happening in the United States of America. "I could not sit there and hear the cries without feeling their pain and anguish," Dr. Lichtenfield wrote.
"The anxiety of breast cancer patients currently using [bevacizumab] is palpable and understandable," Dr. Tucker acknowledged. "The data say that they will do just as well without it, but to ask them to give up the drug is to ask them to make a leap of faith that I doubt I would be willing to make."
Oncologists in the United States have been struggling with this issue for nearly a year now, and have been reviewing other treatment options for metastatic breast cancer. This struggle will intensify when the final FDA decision is announced because withdrawal of the breast cancer indication will make it difficult for these patients to continue to use the drug.
Because bevacizumab is approved for use in other cancers, it could be used off-label for breast cancer, but would likely no longer be covered by medical insurance, so patients would have to pay out of pocket. At a cost of $8000 a month, few would be able to afford it.
An estimated 17,000 women in the United States are thought to be taking bevacizumab for breast cancer.
At the hearing, Dr. Zuckerman proposed a solution: "I would ask that Genentech continue its research into identifying the women who do benefit from bevacizumab . . . but as the company has already made so much money from the drug, I would ask that the company make the drug available for free to the women who are on it and are benefiting from it."
Bevacizumab is the best-selling anticancer drug in history, with annual sales of around $6 billion, around $1 billion of which is from the breast cancer indication.

 

IT HAPPENS EVERYWHERE-WRONG SITE SURGERY OCCURS 40 TIMES A WEEK IN USA

June 29, 2011 — Despite intense efforts to prevent wrong-site surgery in recent years, the adverse event "that should never happen" occurs about 40 times a week nationwide, the Joint Commission Center for Transforming Healthcare said today.
The center announced the preliminary results of a project with 8 hospitals and ambulatory surgery centers. The facilities found that problems with scheduling and preoperative/holding processes, as well as ineffective communication and distractions in the operating room, contributed to increasing the risk for wrong-site surgery. A "time out" without full participation by all key people in the operating room was identified as another contributing factor that increased risk.
"The 8 hospitals and [ambulatory surgery centers] identified where errors can creep into the process and took steps to correct them," Mark R. Chassin, MD, FACP, MPP, MPH, president of the commission, said during a news conference today. "We hope to use their experience as a roadmap to measure risks.
"All facilities and physicians who perform invasive procedures are at some degree of risk," he said. "The magnitude of this risk is often unknown or undefined. Providers who ignore this fact, or rely on the absence of such events in the past as a guarantee of future safety, do so at their peril. Unless an organization has taken a systematic approach to studying its own processes, it is flying blind."
Because wrong-site surgeries are relatively rare events, they are difficult to study. Research has shown that there is usually no single root cause of failure. Instead, such events are frequently the result of a cascade of small errors. "There's no silver bullet or easy answer," Dr. Chassin said.
Wrong-site surgery includes invasive procedures on the wrong patient in addition to wrong-procedure, wrong-site, and wrong-side surgeries. In 2010, it was the third most common sentinel event reported, Dr. Chassin added.
The 8 facilities found that addressing documentation and verification issues in the preoperative/holding areas decreased defective cases that increase the risk for wrong-site surgery from a baseline of 52% to 19%. In turn, the incidence of cases containing more than 1 defect decreased 72%.
"We found that in 39% of cases, errors were introduced that increased risk," he said. "The biggest was inadequate information about the patient. Often, the information is taken by a staffer in the surgeon's office, who may have to deal with several hospitals and different protocols. Confusion can result. The solution is a carefully standardized way of collecting information."
Marking the incision site varies greatly within facilities, increasing the risk for a preventable error. "In the past, the mark was made in the holding area," said Mary Reich Cooper, MD, JD, senior vice president and chief quality officer of Lifespan Corporation, which has 4 hospitals in Providence, Rhode Island.
"We found discrepancies between what was seen there before the surgeon arrived and what he thought he was doing in the operating room," Dr. Cooper said. "So now we have surgeons go out to the holding area to make the initial mark. Then in the [operating room,] before the procedure starts, we affirm that mark, asking if everyone sees the mark. We shut down our [operating room] for a day and put everyone through training. Every new staffer gets the same training."
Dr. Chassin noted that unapproved pens had been used to do the marking. "Sometimes, the mark was washed away during the prep," he said. "So make certain that only approved indelible pens are used. This was a simple but important intervention."
Time-outs were handled inconsistently in several locations. "Was the time-out occurring before prep and drape, or after? Who leads the time out? The circulating nurse or the attending surgeon?" said Tom Feldman, chief executive officer, Center for Health Ambulatory Surgery Center in Peoria, Illinois. "We closed some gaps and decreased variation. That helps everyone in awareness."
"At the time-out, we stop all activities so we can all focus on this last opportunity to correct a mistake," said Dr. Cooper. "Everyone needs to stop what they're doing. We script the staff to ask if everyone can see the mark. Everyone must respond before the operation proceeds."
Dr. Chassin urged physicians and hospitals to view the joint commission's Targeted Solutions Tool, which provides a step-by-step process to measure performance. The first set of solutions focuses on improving hand hygiene. Additional solutions for wrong-site surgery will be added in the fall. Solutions for problems with hand-off communication will be added later in the year.
The 8 facilities that volunteered for the project are AnMed Health, Anderson, South Carolina; Center for Health Ambulatory Surgery Center, Peoria; Holy Spirit Hospital, Camp Hill, Pennsylvania; La Veta Surgical Center, Orange, California; Lifespan-Rhode Island Hospital, Providence; Mount Sinai Medical Center, New York City; Seven Hills Surgery Center, Henderson, Nevada; and Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

ERLOTINIB MAINTENANCE FOR NSCLC REFUSED IN UK-NOT IN GREECE

June 29, 2011 — The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom has upheld its original decision to refuse erlotinib (Tarceva, Roche) maintenance treatment for locally advanced or metastatic nonsmall-cell lung cancer (NSCLC). In an unusual move, executives from the institute have explained why in a special report published online June 29 in the Lancet Oncology.
The NICE decision means that erlotinib maintenance therapy for NSCLC will not be funded by the National Health Service (NHS) for patients in England and Wales. The drug remains approved for this indication, so patients could receive this treatment, but only by paying for it privately.
Erlotinib is also indicated for second-line treatment in lung cancer patients who have failed at least 1 previous chemotherapy regimen. Clinical trial data support its use as a first-line therapy in patients with an EGFR mutation, but this indication has not been approved as yet.
Not Cost Effective
The refusal to cover maintenance therapy is controversial. The initial decision, made in July 2010, was followed by a flurry of media reports about life-extending therapy being denied to patients. It was also followed by an appeal from the manufacturer, with an offer of a patient-access scheme, which would provide the drug at a discount to the NHS.
These strategies were unsuccessful, however, and the final ruling was negative. Perhaps because of the controversy, NICE now explains how the committee arrived at its decision.
The indication was not allowed on the basis of a lack of cost effectiveness and the number of patients affected, NICE executives explain.
The key evidence for the appraisal comes from the SATURN trial, in which erlotinib was compared with placebo in patients with advanced or metastatic NSCLC whose disease had not progressed after 4 cycles of platinum-based first-line chemotherapy. The trial involved 889 patients, of whom 487 (55%) had stable disease after first-line chemotherapy.
That trial showed a statistically significant improvement in progression-free survival in the erlotinib group, compared with the placebo group (12.1 vs 11.3 weeks; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.56 to 0.83; P < .0001). There was also a statistically significant improvement in mean overall survival (11.9 vs 9.6 months; HR, 0.72; 95% CI, 0.59 to 0.89; P = .0019).
The NICE executives point out that very few British patients participated in the SATURN trial, and that a high proportion of the trial participants had better prognostic factors than those seen in clinical practice in the Untied Kingdom, which could overestimate the efficacy of erlotinib. The results from this trial therefore have "limited generalizability to UK patients," the committee concludes.
In addition, the NICE committee points out that the size of the cumulative population eligible for treatment with erlotinib is "not small."
Economic models based on the SATURN results were used to calculate cost effectiveness. The manufacturer calculated that, compared with best supportive care, the incremental cost-effectiveness ratio for erlotinib maintenance worked out to ₤47,743 per quality-adjusted life year (QALY) gained for patients with stable disease. The NICE committee arrived at a figure of ₤59,336, and concluded that this figure "was the most plausible."
Both calculations are much higher than the upper limit of ₤30,000 per QALY that NICE uses as a cut-off in its appraisals.
Lancet Oncol. Published online June 29, 2011. Abstract