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Internal Medicine News
www.eclinicalpsychia tr ynews.com www.inter nalmedicinenews.com T he Leading Inde p endent Ne wspaper for the Inter nist—Since 1968

OCTOBER 15, 2007


Combined Insulin Regimens Often Become Necessary
Clinical trial shows need for dual therapy.

Cure Worse Than The Disease?
Cancer treatments can cause unbearable skin toxicity.

Senior Writer

In a 63-year-old woman and former smoker, helical CT reveals a lesion identified as an adenocarcinoma on left lower lobectomy.

Brain Protection
Diet and other lifestyle factors may help ward off Alzheimer’s disease.

CT Not Advised for Lung Ca Screening

San Francisco Bureau

n a controversial move, the American College of Chest Physicians has formally recommended against the use of lowdose helical CT scanning for general lung cancer screening, even in high-risk populations, except in the context of clinical trials. The ACCP also recommended against the use of serial chest radiographs and sputum cytologic evaluation to screen for the presence of lung cancer. “The evidence isn’t available to show that low-dose CT screening provides a mortality benefit,” Dr. W. Michael Alberts said in an interview. Dr. Alberts, the chief medical officer of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., chaired the ACCP committee that developed the guidelines. “Because there’s a very real potential for harm, it’s going to be important to prove or show a mortality benefit prior to recommending screening with a low-dose CT scan.” The second edition of the college’s “Diagnosis and Management of Lung Cancer” includes 260 guidelines, three of which involve lung cancer screening. It was published as a supplement to the September 2007 issue of the journal Chest (2007;132[sup-


pl.]:1S-422S). This edition updates the original version of the guidelines, published in January 2003. The screening guidelines were developed by a subcommittee headed by Dr. Peter B. Bach of the Memorial Sloan-Kettering Cancer Center, New York. Although acknowledging that lowdose CT scanning remains the most promising of the lung cancer screening techniques, the guideline authors maintain that—even though the existing data do suggest that low-dose CT increases the rate of detection of early-stage lung cancers—such See Lung Screening page 21

A M S T E R D A M — Most patients with type 2 diabetes who fail to achieve adequate glucose control with oral agents are likely to need combination insulin therapy in the long run, Dr. Rury R. Holman said at the annual meeting of the European Association for the Study of Diabetes. That conclusion was based on the first-year findings from the 3year multicenter, open-label Treating to Target in Type 2 Diabetes (4-T) study. The study is a comparison of three insulin treatment strategies—basal, prandial, or biphasic—added to oral antidiabetic agents in 708

patients with type 2 diabetes who had not achieved desired glucose targets with maximally tolerated doses of sulfonylureas and metformin. At year 1, only 8%-24% of the patients achieved a glycated hemoglobin level of 6.5% or less. “We’ve seen that you can use any of these insulins to improve glucose control, but the likelihood of achieving a 6.5% target is not that great ... and if you’re not successful, you’re likely to need two insulins,” said Dr. Holman, chief of the Diabetes Trials Unit at the University of Oxford (England), during a press briefing held at the meeting. The second and third years of See Insulin Regimens page 4

PET Project
Positron emission tomography finds additional lesions in esophageal cancer.

Gardasil: Cross-Protection Extends Potential Benefit

Chicago Bureau

The Majority of Drugs Dispensed in 2006 Were Generic
9.0% Brands with generic alternatives by 2009 11.1% More expensive brands with generic alternatives 17.4% Brands with no generic alternatives

4.5% Less expensive brands with generic alternatives

C H I C A G O — The quadrivalent human papillomavirus vaccine, Gardasil, offers cross-protection against cancer-causing HPV types that are not included in the vaccine, according to data reported in a late-breaking poster at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. A three-dose regimen of the human papillomavirus (HPV) type 6/11/16/18 vaccine demonstrated 62% efficacy in preventing cervical intraepithelial neoplasia

(CIN) grades 2 and 3 or adenocarcinoma in situ (AIS) caused by HPV 31 or 45, the two most common HPV types found in cervical cancer after HPV 16 and 18. Efficacy was 43% against CIN 2/3 or AIS due to HPV 31, 33, 45, 52, or 58, the five most common types found in cervical cancer after HPV 16 and 18. Efficacy was 38% for 10 nonvaccine oncogenic types (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, or 59), which cause more than 20% of cervical cancers worldwide, Dr. Darron Brown reported on behalf of the FUTURE Study Group. See Gardasil page 2

58.0% Generic

Note: Based on the average dispensing rates for Medco clients. Source: Medco Health Solutions Inc.

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Pulmonary Medicine

Clinical Rounds


Clinical Trial Data Inadequate
Lung Screening from page 1

CT screening fails to reduce the number of late-stage lung cancers or the risk of dying from lung cancer. They suggest that this may be because many of the additional cancers detected are small, indolent cancers, which lead to unnecessary invasive procedures that carry a cost in morbidity and mortality. The subcommittee’s analysis includes a theoretical model of the time it takes for a given nodule to double in size. They estimated that the doubling time of lung tumors resulting in deaths is approximately 40-70 days, whereas research shows that the doubling time of early cancers identified by CT screening ranges from 149 to 813 days. “As best I know, this is the first time that anyone has tried to make a public health policy statement against screening based upon theoretical considerations of nodule doubling time,” said Dr. James L. Mulshine of Rush University Medical Center, Chicago, in an interview. “This is a totally unvalidated tool, and really not the grist for evidence-based analysis.” “The recommendations weren’t based on that at all,” Dr. Bach responded in an interview. Instead, he said, the model was intended to provide one possible explanation for the fact that studies have so far failed to demonstrate that screening results in demonstrable improvements in mortality. Dr. Mulshine said that some studies were omitted from the analysis unfairly, and that the guideline authors interpreted other studies selectively. He is on the board of directors of the Lung Cancer Alliance (www.lungcancer alliance.org), which is spearheading opposition to the new screening guidelines. Since 2006, the nonprofit alliance has received $160,000 in grants from General Electric Co., which makes CT scanners, and grants from other sources. Dr. Mulshine, who has published extensively on his lung cancer screening research, was coauthor of an influential 2005 review ar-

ticle (N. Engl. J. Med. 2005;352:2714-20). He participates in the International Early Lung Cancer Action Program. Dr. Mulshine acknowledged a lack of persuasive evidence from double-blind studies showing reduced mortality related to lung cancer screening. One such study may be completed as early as 2009, but possibly not until 2011. Data from another study won’t be available for another 2 years or so after that. “We all hope that the randomized,

Helical CT offers a closer view of the adenocarcinoma shown on p. 1.

controlled trials will show a mortality benefit,” Dr. Alberts said. “We’d like to have that outcome, at which time maybe low-dose CT scanning should be recommended. But at this time, the evidence is not available, and there is potential evidence that it may be harmful. As a result, we can’t in all good conscience recommend CT scanning at this point.” But Dr. Mulshine noted that while waiting for results from those randomized trials, 160,000 Americans die every year from lung cancer, in part because most lung cancer is not diagnosed until stage III or IV. And he cited data showing that morbidity and mortality from diagnostic procedures conducted as a result of screening are low in “centers of excellence.” Also, the last 5 years

have seen a significant improvement in noninvasive procedures, improvements that are likely to continue if more research is done in this area. But for Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, “the issue isn’t diagnostic procedures. It’s the morbidity and mortality from subsequent surgery that concerns me. ...It’s true that centers for excellence report low morbidity and mortality rates from their surgery. But experience suggests that, due to many factors, morbidity and mortality rates are higher when these procedures are performed in community settings.” Dr. Mulshine maintained that “from a methodological perspective, independent of the merits of screening, [the guideline’s authors] have just not done society, or the public in general, or their association of chest physicians, any particular service. ... It’s a somewhat extreme, unsupported view that they promoted. Screening is a very complex issue, associated with enormous promise but also with many, many undeveloped aspects. And they really did not educate their people about the critical issues.” He prefers the position of the U.S. Preventive Services Task Force, which states that there is insufficient evidence to recommend for or against lung cancer screening. “The American Cancer Society does not recommend routine CT screening for lung cancer at this time,” Dr. Lichtenfeld noted in an interview. “Understanding that some people will nonetheless want to proceed with screening, they should have a careful discussion with their doctor regarding the potential risks that could result.” According to Dr. Mulshine, several factors should enter into a decision on screening, such as the patient’s medical and family history, his or her smoking history, and even whether the screening would be done at a center of excellence or at a local freestanding screening clinic. For current smokers, the dialogue should include advice and assistance in smoking cessation. ■

More Points Covered By the Guidelines
n addition to the three recommendations on lung cancer screening, the ACCP has issued 257 recommendations on the prevention, diagnosis, and treatment of lung cancer. The ACCP classifies its evidence-based guidelines as strong (grade 1) or weak (grade 2) based on a balance of risks, benefits, burdens, and costs. The college also classifies the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on study design, consistency of results, and directness of the evidence. The recommendations include these points: The guidelines recommend mind-body modalities to reduce anxiety, mood disturbances, or chronic pain (grade 1B); massage therapy for anxiety or pain (grade 1C), as long as it does not involve deep or intense pressure near cancer lesions or anatomical distortions (grade 2C); and acupuncture for poorly controlled pain or for side effects such as neuropathy or xerostomia (grade 1A) and for nausea and vomiting (grade 1B). In terms of lung cancer chemoprevention, the guidelines recommend against supplementation with β-carotene, vitamin D, retinoids, N-acetylcysteine, and aspirin (grade 1A). Even for individuals at risk of lung cancer or with a history of lung cancer, there are insufficient data to recommend any agent—either alone or in combination—for chemoprevention, except in the context of a clinical trial (grade 1B). Regarding palliative care, patients should be reassured that pain can be treated safely and effectively, and all patients should be questioned regularly about their pain (grade 1A). Patients with mild to moderate pain should be managed first with acetaminophen or an NSAID, and then with an opioid when pain becomes more severe (grade 1B). Those with pain unresponsive to standard methods should be referred to a specialized pain clinic or a palliative care consultant (grade 1C).


BRCA1 Predicted Poor Outcomes in Lung Cancer Patients


Contributing Writer

B A R C E L O N A — Overexpression of BRCA1, one of the genes associated with aggressive breast cancer, also predicts cisplatin resistance, faster recurrence, and reduced survival in people with non–small cell lung cancers, Dr. Rafael Rosell said at the 14th European Cancer Conference. Dr. Rosell and colleagues at the Catalan Institute of Oncology have identified nine genes, all involved in the process of DNA repair, that may have value in predicting the behavior and treatment responsiveness of lung tumors. By far the biggest red flag is BRCA1. The investigators assessed expression of these nine genes in tumor tissue obtained from 126 people with stage IA-IIIA squamous cell carcinoma or adenocarcinoma. Overall, 42% of patients had stage IB tumors and 26% had stage II. Only

BRCA1 had independent prognostic value. Patients in the uppermost quartile of BRCA1 expression showed much greater resistance to cisplatin-based treatment regimens, and were twice as likely to die within 3 years, compared with those in the lowest quartile. Median time to recurrence was 22 months among the high BRCA1 expressors, and median survival was 29 months. Among those in the lowest quartile, the majority was still alive and disease free after 3 years. The data suggest that only 30% of the high expressors would still be alive at 40 months after surgery, while 70% of the low expressors would survive. By 60 months, the probability of survival drops to about 20% for those with high-BRCA1 primary tumors, but remains around 60% for the low expressors. Overall, having a highBRCA1–expressing tumor doubled the hazard ratio for recurrence and mortality, compared with having a low-BRCA1–ex-

pressing tumor, Dr. Rosell reported at the conference, which was sponsored by the Federation of European Cancer Societies. He and his colleagues obtained very consistent findings in a validation cohort of 58 patients. They will publish a retrospective analysis late this year, and they are developing a prospective trial to validate and quantify the predictive value of BRCA1 expression for clinical decision making. BRCA1 plays a central role in repair of DNA damage. Several earlier studies have shown that low levels of BRCA1 expression correlate well with cisplatin sensitivity, while increased BRCA expression is associated with treatment resistance. “These findings could have significant therapeutic impact,” Dr. Rosell said. “Perhaps those patients with high-BRCA1–expressing tumors should just bypass cisplatin altogether, and go directly to taxane-based therapies.” Commenting on the findings, Dr.

Alexander Eggermont, president of the newly formed ECCO organization, said, “If this will be validated in future studies, it will really change the landscape of diagnostic testing and treatment decision making. “Genetic profiling is showing us how differently tumors can behave, though they may look the same histologically,” Dr. Eggermont added. “We’re moving away from one-size-fits-all treatment. In this case, perhaps some patients can be spared treatment with cisplatin, which would be unlikely to work for them.” Dr. Rosell expects a long debate before practices change. Because cisplatin has been the standard of care for non–small cell lung cancer for so long, he explained, and because nearly all of the clinical trials for these cancers are cisplatin-based, there will likely be a fair amount of resistance to anything that challenges the preeminence of the drug or suggests that some patients would be better off without it. ■