LESS FREQUENT SCREENING FOR CERVICAL CANCER?

November 20, 2009 — First cervical cancer screening should be at age 21 years, and rescreening can be less frequent than previously recommended, according to newly revised evidence-based guidelines issued by the American College of Obstetricians and Gynecologists (ACOG). The ACOG's Committee on Practice Bulletins—Gynecology was posted online November 20 and will appear in the December print issue of Obstetrics & Gynecology.

Less Frequent Screening

The revised recommendations now call for cervical screening once every 2 years vs annually for most women younger than 30 years and once every 3 years for most women 30 years and older.

"The tradition of doing a Pap [Papanicolau] test every year has not been supported by recent scientific evidence," lead author Alan G. Waxman, MD, from the University of New Mexico in Albuquerque, said in a news release. "A review of the evidence to date shows that screening at less frequent intervals prevents cervical cancer just as well, has decreased costs, and avoids unnecessary interventions that could be harmful."

Either the standard Pap test or liquid-based cytology is suitable for all cervical cancer screening. Instead of annual screening, the ACOG now recommends that women aged 21 to 30 years who not at high risk be screened every 2 years and that women 30 years and older may be screened once every 3 years if they have had 3 consecutive negative cervical cytology test results.

Risk factors that may indicate the need for more frequent screening include HIV infection; immunosuppression; diethylstilbestrol (DES) exposure in utero; and treatment of cervical intraepithelial neoplasia (CIN) 2, CIN 3, or cervical cancer.

ACOG's earlier recommendation was to begin cervical cancer screening 3 years after first sexual intercourse or by age 21 years, whichever occurred first. To avoid economic, emotional, and future childbearing implications of unnecessary treatment of adolescents, ACOG has now moved the baseline cervical cancer screening to age 21 years.

The rationale is that invasive cervical cancer is very rare in women younger than 21 years, although the rate of human papillomavirus (HPV) infection is high among sexually active adolescents, because the immune system in most adolescent women clears the HPV infection within 1 to 2 years. In addition, adolescents have a higher incidence of HPV-related precancerous dysplasia because the cervix is immature, but most of these lesions resolve spontaneously without treatment.

Women treated with excisional procedures for dysplasia have recently been shown to have a significant increase in premature births.

"Adolescents have most of their childbearing years ahead of them, so it's important to avoid unnecessary procedures that negatively affect the cervix," Dr. Waxman said. "Screening for cervical cancer in adolescents only serves to increase their anxiety and has led to overuse of follow-up procedures for something that usually resolves on its own."

Regardless of age, women who have had a total hysterectomy for benign conditions and who have no history of high-grade CIN should discontinue cervical cancer screening.

The upper age limit for discontinuing cervical screening remains the same in the revised ACOG's guidelines, which recommend stopping cervical cancer screening at age 65 or 70 years for women who have at least 3 consecutive negative cytology results and no abnormal test results in the previous 10 years.

Women vaccinated against HPV should follow the same screening guidelines as unvaccinated women, according to the revised guidelines.

Revised Guidelines

Specific ACOG recommendations in the updated guidelines, based on good and consistent scientific evidence (level A), are as follows:

• Cervical cancer screening should begin at age 21 years and should be avoided at younger ages, when it may result in unnecessary and harmful workup and treatment in women who are at very low risk for cancer.
• For women aged 21 to 29 years, cervical cytology screening is recommended every 2 years.
• The interval between cervical cytology examinations may be extended to every 3 years for women at least aged 30 years who have had 3 consecutive negative cervical cytology screening test results and who have no history of CIN 2 or CIN 3, HIV infection, immunocompromised state, or DES exposure in utero.
• Acceptable screening techniques are liquid-based and conventional cervical cytology methods.
• Routine cytology testing should be discontinued in women who have had a total hysterectomy for benign conditions and who have no history of high-grade CIN.
• For women older than 30 years, an appropriate screening test is cytology combined with HPV DNA testing. When both these test results are negative in a low-risk woman 30 years or older, rescreening should be performed no sooner than 3 years later.

Specific ACOG recommendations in the updated guidelines, based on limited and inconsistent scientific evidence (level B), are as follows:

• Sexually active women younger than 21 years should be counselled and tested for sexually transmitted infections and should be counselled regarding safe sex and contraception. Cervical cytology testing is not necessary, and speculum examination need not be performed in asymptomatic women.
• Cervical cancer screening can be discontinued between the ages of 65 and 70 years in women who have 3 or more consecutive negative cytology test results and no abnormal test results in the past 10 years because cervical cancer develops slowly, and risk factors decrease with age.
• Women previously treated for CIN 2, CIN 3, or cancer remain at risk for persistent or recurrent disease for at least 20 years after treatment and after initial posttreatment surveillance. This group should therefore continue to be screened annually for at least 20 years.
• Even after the period of posttreatment surveillance, screening should continue for women status post hysterectomy with removal of the cervix who have a history of CIN 2 or CIN 3, or in whom a negative history cannot be documented. In this patient group, there are no good data to support or refute discontinuing screening.

Revised ACOG recommendations, based primarily on consensus and expert opinion (level C), are as follows:

• Physicians should inform their patients that annual gynecologic examinations may still be appropriate regardless of the frequency of cervical cytology screening, even if cervical screening is not performed at each visit.
• Women who were vaccinated against HPV-16 and HPV-18 should follow the same screening guidelines as nonvaccinated women.

A proposed performance measure recommended by ACOG is the percentage of women aged 21 to 29 years who have received a Pap test within the past 2 years.

Obstet Gynecol. Published online November 20, 2009.

IT HAPPENS EVERYWHERE-NEW BREAST CANCER SCREENING GUIDELINESS OPPOSED BY SOCIETIES

November 19, 2009 — Several professional organizations and expert groups have voiced their objections to new recommendations for breast cancer screening issued by the US Preventive Services Task Force (USPSTF) and published in the November 17 issue of the Annals of Internal Medicine.

"[The American Cancer Society] continues to recommend [mammography] screening annually for women 40 to 49 years of age," Victor G. Vogel, MD, MHS, FACP, national vice president for research at the American Cancer Society (ACS) in Atlanta, Georgia, told Medscape Medical News. "Clinicians should recognize that very few agencies, including the ACS, are altering their screening guidelines based on the USPSTF modeling results, which simply reanalyze previously published data."

Based on an evidence review, the updated USPSTF guidelines recommend against routine mammography screening for women before age 50 years, suggest that screening end at age 74 years, and recommend changing the screening interval from 1 year to 2 years.

In addition to the ACS, the American College of Radiology (ACR), the American College of Obstetricians and Gynecologists (ACOG), and several other expert groups recommend that clinicians and patients continue to follow earlier guidelines (see Table below for a detailed comparison with ACS guidelines). The ACS recommendations call for annual mammograms starting at age 40 years and continuing for as long as a woman is in good health; ACS has no specific upper age at which mammography screening should be discontinued. The society suggests that the decision to stop regular mammography screening should be individualized based on patient-specific, potential benefits and risks of screening within the context of overall health and estimated lifespan.

ACOG's recommendations are similar, except that mammography is recommended every 1 to 2 years from ages 40 to 49 years.

"We would urge primary care clinicians to continue to observe the ACR and ACS mammography guidelines and to talk with their patients regarding the benefits of mammography and any concerns their patients may have," M. Shawn Farley, ACR's director of public affairs, told Medscape Medical News.

Supporting Evidence

Dr. Vogel cited several lines of evidence supporting the ACS position, including evidence that early detection of breast cancer saves lives or improves survival (JAMA. 1995;273[2]:149–154).

"If the USTSF recommendations are adopted as policy — particularly if Medicare and private insurers try to use them as an excuse to cut cost — many women will die unnecessarily from breast cancer," Mr. Farley said. "The treatment costs associated with the disease may rise because cancers would be found at a more advanced stage. For those women diagnosed at a later stage, they may experience more invasive techniques to remove the cancers because the disease is more advanced."

Mr. Farley also cited 2 studies showing that the ACR/ACS approach to screening has significantly reduced breast cancer mortality since 1990: (1) Duffy SW. Interpretation of the Breast Screening Trials: A Commentary on the Recent Paper by Gotzsche and Olsen. The Breast. 2001;10:209–212, and (2) The Swedish Organized Service Screening Evaluation Group. Reduction in Breast Cancer Mortality from Organized Service Screening with Mammography: 1. Further Confirmation with Extended Data. Cancer Epidemiol Biomarkers Prev . 2006;15:45–51.

These studies have shown that breast cancer mortality decreased by nearly 2% per year during the 1990s, which was largely attributed to the benefits of screening. For women younger than 50 years, the decline was more than 3% per year. Since mortality rates peaked in 1989, a woman's risk of dying of breast cancer has decreased by 29%.

Mammography screening is also associated with detection of smaller tumors. In the early 1980s, when only 13% of US women had regular mammography, average tumor size at detection was about 3 cm. This decreased to 2 cm by the late 1990s, when 60% of women had regular mammography.

In addition, 17% of breast cancer deaths in 2006 were among women who were diagnosed between the ages 40 and 49 years, according to data from the ACS. A meta-analysis of randomized controlled trials published in a monogram of the National Cancer Institute (NCI) also showed benefits of screening mammography specifically in women aged 40 to 49 years (Hendrick RE. Monogr Natl Cancer Inst. 1997;22:87–92).

Widespread implementation of the updated USPSTF guidelines vs the professional society recommendations could therefore have significant public health implications over time.

"Data from the NCI SEER program show that since 1990, when widespread population-based screening of women 40 to 49 years of age began, death rates from breast cancer have declined [by] 3% per year," Dr. Vogel said. "This is attributable to both mammographic screening and the use of effective adjuvant therapies for early breast cancer detected by mammography. If we stop screening women 40 to 49 years of age, the death rates from breast cancer will rise progressively, and we will eliminate nearly 2 decades of progress in this disease."

USPSTF Responds

"The recommendations of the USPSTF for screening mammography were based on several lines of evidence: new studies and analyses of old studies since 2002, new evidence about the harms of screening, and the pulling together of evidence to attempt to define what the lifetime balance of benefit and harms might be for various starting and stopping ages for screening and also for different screening intervals," USPSTF Vice Chairman Diana B. Petitti, MD, MPH, professor of biomedical informatics at Arizona State University in Phoenix, told Medscape Medical News.

"The balance of benefits and harms of screening women starting at age 40 was small, [suggesting] that screening should not be routine, Dr. Petitti said. "This recommendation is not a recommendation against ever screening women age 40 to 49; it is a recommendation against routine screening of women starting at this age," she stressed.

"Rather, the decision about an age to begin screening (40 or 45 or 50) should be made based on a discussion that makes clear that the benefit of screening starting in the 40s is small, that the harms are small, and that the benefits are larger with an age to start screening of 50 compared with earlier, and the harms are smaller."

Dr. Petitti explained that the USPSTF last considered the topic of breast cancer prevention in 2002 and that topics considered by the USPSTF are rereviewed every 5 years. In 2007, the USPSTF commissioned the Oregon Health Sciences University Evidence Practice Center to conduct a review of evidence from 2002 forward. To obtain evidence regarding the questions of starting age, interval for screening, and ending age for screening (if any), the USPSTF also commissioned the Cancer Intervention and Surveillance Modeling Network to provide information about what the benefits and harms might be from mammography screening for various starting ages and intervals of screening and stopping ages.

"The evidence from 8 randomized trials of film mammography to screen for breast cancer starting at ages in the 40s shows that screening starting at age 40 to 50 reduces breast cancer mortality," Dr. Petitti said. "The evidence from the 8 trials combined shows that screening starting in the 40s reduces the chance of dying from breast cancer by 15%. The addition of information from this trial makes more precise the estimate of benefit of screening."

Potential harms of screening noted by Dr. Petitti include those related to false-positive results, such as undergoing additional tests (eg, repeat mammogram, ultrasound, biopsy) and waiting time involved in scheduling the tests and processing the results.

"It is not easy to weigh the benefits and the harms of screening," Dr. Petitti said. "A woman who is screened in her 40s and is found to have a cancer that is treatable/curable and would not have been treatable/curable if found later has a benefit.... The harms of mammography become lower with increasing age because of biological changes in breast density that make it 'easier' for a mammogram to distinguish cancer from other normal breast structures."

Dr. Petitti noted several lines of evidence supporting the USPSTF recommendation to screen every other year instead of screening every "1 to 2" years.

"First, randomized trials of mammography screening have included annual and biannual intervals, and these studies, as a whole, show that there is about a 15% benefit of screening for every-other-year screening," Dr. Petitti said. "Second, evidence from an NCI-sponsored study showed that most (at least 70% and as much as 99%) of the benefit of mammography is attained with every-other-year screening. Equally important, every-other-year screening substantially decreases the number of women who have a false-positive mammography test."

Cost Issues?

One of the concerns some experts have voiced is whether the updated USPSTF guidelines were in any way motivated by cost-cutting or healthcare-rationing objectives.

"It is not possible to know those issues because the task force did not discuss them," Dr. Vogel said. "They did acknowledge, however, that screening women 40 to 49 saves lives, but it requires screening more women to save 1 life than screening women 50 years and older."

"We believe that the USPSTF recommendations ring of cost cutting," Mr. Farley said. "We are not aware of any new information that would warrant such drastic changes in policy. The fact that it is a federally supported body, and that these recommendations come at a time when the government is trying to cut costs any way it can, certainly seem more than coincidental."

However, Dr. Petitti stated that cost considerations in no way affected the updated USPSTF recommendations.

"The USPSTF does not address issues of insurance and coverage and the USPSTF recommendations about breast cancer screening did not consider cost and were not based on cost-effectiveness studies or models of cost-effectiveness," Dr. Petitti said.

"Cost was not a word that was uttered during the deliberations of the USPSTF in formulating its recommendations," she added.

Clinical Implications

Other expert groups continuing to support annual screening mammograms for women beginning at age 40 years include the Seattle Cancer Care Alliance in Washington.

"Women need a clear message: Early detection offers a woman the best chance for a cure, and mammography is essential for early detection of breast cancer," Constance Lehman, MD, PhD, medical director of radiology and director of breast imaging at Seattle Cancer Care Alliance and professor and vice chair of radiology at the University of Washington School of Medicine, Seattle, said in a statement this week. "Failing to identify those women in their 40s with cancer and having them wait until they are screened at age 50 is a disservice. By then, breast cancer can be advanced and more difficult to treat."

Dr. Lehman noted that digital mammography significantly improves the detection of cancer in young women and in women with dense breast tissue, which was not considered in the analyses underlying the changed USPSTF recommendations. She recommended that women undergo mammography at centers capable of providing high-quality imaging.

The controversial USPSTF updated recommendations have also attracted considerable media attention and questions from the lay public.

"There is no question that the [USPSTF] recommendations have caused a great deal of confusion and worry among women and their families across this country," said US Department of Health and Human Services Secretary Kathleen Sebelius in a statement issued yesterday. "I want to address that confusion head on. The [USPTF] is an outside independent panel of doctors and scientists who make recommendations. They do not set federal policy and they don't determine what services are covered by the federal government."

Despite new evidence presented by the USPSTF, Dr. Sebelius noted that "our policies remain unchanged. Indeed, I would be very surprised if any private insurance company changed its mammography coverage decisions as a result of this action."

Although she recommended additional research to help women prevent, detect, and fight breast cancer, Dr. Sebelius pointed out that mammograms continue to be an important lifesaving tool in that fight. She recommended that physicians and patients keep the lines of communication open — "talk to your doctor about your individual history, ask questions, and make the decision that is right for you."

"Organizations working to help women make choices about what to do to address breast cancer are more consistent than disparate," Dr. Petitti said. "There is no disagreement on the question of whether mammography has a benefit when done at ages 40 to 74. The question is about the absolute benefit as against the harms (negatives) of starting to screen at a younger versus older age."

A statement issued by the ACR very strongly opposed the new USPSTF recommendations and denounced the potential implications of adopting these guidelines on the health of US women.

"These unfounded USPSTF recommendations ignore the valid scientific data and place a great many women at risk of dying unnecessarily from a disease that we have made significant headway against over the past 20 years," said Carol H. Lee, MD, chair of the ACR Breast Imaging Commission.

"Mammography is not a perfect test, but it has unquestionably been shown to save lives — including in women aged 40 to 49. These new recommendations seem to reflect a conscious decision to ration care. If Medicare and private insurers adopt these incredibly flawed USPSTF recommendations as a rationale for refusing women coverage of these lifesaving exams, it could have deadly effects for American women."

Other ACS Breast Cancer Screening Guidelines

In addition to its mammography guidelines discussed above, ACS continues to advocate the following breast cancer screening guidelines:

• Clinical breast examination should be done about every 3 years for women in their 20s and 30s and annually for women aged 40 years and older.
• Women should promptly report to their healthcare providers any change they notice in their breasts. Breast self-examination is also an option beginning at age 20 years.
• For women at more than 20% lifetime risk for breast cancer, magnetic resonance imaging (MRI) and mammography should be performed every year. Women at 15% to 20% lifetime risk should consult with their physicians about the benefits and limitations of adding MRI screening to their annual mammogram.
• For women whose lifetime risk for breast cancer is less than 15%, annual MRI screening is not recommended.

The ACS also provides a comparison of its recommendations with the new USPSTF recommendations:

Comparison of Breast Cancer Screening Recommendations

Cancer Screening Age	ACS Recommendations	New USPSTF Recommendations
40 – 49 years	Annual mammograms are recommended starting at age 40 years and continuing for as long as a woman is in good health. There is no specific upper age at which mammography screening should be discontinued. Rather, the decision to stop regular mammography screening should be made on an individual basis based on the potential benefits and risks of screening within the context of a patient's overall health status and estimated longevity.	"C Grade": Recommends against routine screening mammography in women aged 40 to 49 years.
50 – 74 years		"B Grade": Recommends biennial screening mammography for women between ages 50 to 74 years.
≥75 years		"I Grade": Insufficient to assess the additional benefits and harms of screening mammography in women aged 75 years and older.

All experts interviewed for this article have disclosed no relevant financial relationships. The USPSTF is an independent, voluntary body supported by the Agency for Healthcare Research and Quality. Recommendations made by the USPSTF are independent of the US government and should not be construed as an official position of the Agency for Healthcare Research and Quality or the US Department of Health and Human Services.

Ann Intern Med. 2009;151:716–726, 727–737, 750–752. Abstract Abstract Abstract

WHEN TO BEGIN SCREENING WITH MAMMOGRAPHY?

November 16, 2009 ( UPDATED November 17, 2009 ) — The US Preventive Services Task Force (USPSTF) has issued new breast cancer screening guidelines, which are published in the November 17 issue of the Annals of Internal Medicine. The task force now recommends against routine mammography screening for women before age 50 years and suggests that screening end at age 74 years.

The new USPSTF recommendations are in opposition to other existing breast cancer screening guidelines from organizations such as the American Cancer Society and the American College of Radiology, which have both criticized the new document. Several agencies and organizations, such as the Seattle Cancer Care Alliance, have said they will continue to follow the American Cancer Society guidelines. However, according to an article in the New York Times, advocacy groups like the National Breast Cancer Coalition, Breast Cancer Action, and the National Women’s Health Network "welcomed the new guidelines."

Updated USPSTF Breast Cancer Screening Guidelines

The new USPSTF guidelines, which update those they issued in 2002, also recommend changing the screening interval from 1 year to 2 years and suggest that women aged 40 to 49 years who are at high risk for breast cancer consult with their clinician concerning the optimal time to begin regular, biennial screening mammography.

"Mammography, as well as physical examination of the breasts, can detect presymptomatic breast cancer," write Ned Calonge, MD, MPH, from the Colorado Department of Public Health and Environment in Denver, and colleagues from the USPSTF. "Because of its demonstrated effectiveness in randomized, controlled trials of screening, film mammography is the standard for detecting breast cancer; in 2002, the USPSTF found convincing evidence of its adequate sensitivity and specificity."

Because of insufficient evidence to determine the benefits and harms of screening mammography in women older than 75 years, the updated guidelines recommend stopping screening at age 74 years.

Because the USPSTF found adequate evidence that teaching self-examination is not associated with a decrease in breast cancer mortality rates, the task force recommends against teaching breast self-examination (BSE).

Current evidence is now insufficient to evaluate additional benefits and harms of clinical breast examination (CBE) for women aged at least 40 years. This recommendation is a change from the 2002 statement, which endorsed mammography screening, with or without CBE, annually or biennially for women 40 years or older.

Film mammography is associated with decreased breast cancer mortality rates, particularly in women aged 50 to 74 years, based on evidence to date. Women aged 60 to 69 years appear to have the greatest benefit, whereas evidence of benefit associated with film mammography is lacking for women aged at least 75 years.

Current evidence is insufficient to determine additional benefits and harms of either digital mammography or magnetic resonance imaging (MRI) as screening modalities for breast cancer vs film mammography. Therefore, the USPSTF did not recommend one form of mammography vs another.

The evidence base for the updated guidelines was a systematic review of published evidence of the efficacy of the 5 screening modalities in lowering breast cancer mortality rates. These include film mammography, CBE, BSE, digital mammography, and MRI.

Other evidence reviewed by the USPSTF included 2 studies commissioned by the task force. These were a systematic evidence review targeting 6 questions concerning the benefits and harms of screening and a decision analysis using population modeling techniques to determine anticipated health costs and outcome benefits of screening every year vs every 2 years, and of starting and ending mammography screening at various ages.

Specific Recommendations

Specific recommendations of the USPSTF, and the accompanying strength of recommendations, were as follows:

• The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. Based on patient context, including patient values concerning specific benefits and harms, individual decisions should be made regarding starting regular, biennial screening mammography before age 50 years (grade C recommendation).
• Women aged 50 to 74 years should undergo biennial screening mammography (grade B recommendation).
• Current evidence is insufficient to determine additional benefits and harms of screening mammography in women 75 years or older (I statement).
• In women 40 years or older, current evidence is insufficient to determine the additional benefits and harms of CBE beyond screening mammography (I statement).
• The USPSTF recommends against clinicians teaching women the technique of BSE (grade D recommendation).
• Current evidence is insufficient to determine additional benefits and harms of either digital mammography or MRI vs film mammography as screening modalities for breast cancer (I statement).

Evidence-Based Findings

The accompanying updated evidence review on breast cancer screening looked at published studies identified from a search of Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews through the fourth quarter of 2008, MEDLINE January 2001 to December 2008, and bibliographies of identified articles. Also reviewed were Web of Science searches and Breast Cancer Surveillance Consortium for screening mammography data.

"Mammography screening reduces breast cancer mortality for women aged 39 to 69 years; data are insufficient for older women," write Heidi D. Nelson, MD, MPH, from Oregon Health & Science University in Portland, and colleagues. "False-positive mammography results and additional imaging are common. No benefit has been shown for CBE or BSE."

Inclusion criteria for studies were randomized controlled trials with breast cancer mortality outcomes for screening effectiveness and studies of varying designs and multiple data sources regarding harms. The reviewers found that for women aged 39 to 49 years, mammography screening was associated with a 15% decrease in breast cancer mortality rates (relative risk, 0.85; 95% credible interval, 0.75 - 0.96; 8 trials). However, data are lacking for women 70 years or older.

Radiation exposure from mammography is low, and adverse experiences are common but transient and do not alter screening practices. The estimated rate of overdiagnosis from screening ranges from 1% to 10%. Compared with older women, younger women have more false-positive mammography results and additional imaging but fewer biopsies. Trials of CBE are ongoing. In trials of BSE, benign biopsy results increased, and there were no decreases in mortality rates.

Study Limitations

Limitations of this review include lack of studies in older women, lack of digital mammography studies, and lack of MRI studies.

"We can improve primary and secondary breast cancer prevention effectiveness by implementing risk assessment in primary care and mammography facilities and providing tailored recommendations for prevention based on individual risk," Karla Kerlikowske, MD, from San Francisco Veterans Affairs Medical Center in San Francisco, California, writes in an accompanying editorial.

"Health professionals will need education about how to communicate breast cancer risk to women, potential benefits and harms of prevention interventions, and how to assist women in understanding which factors might influence their choice to have an intervention or not. Women should have the opportunity to make informed choices about primary and secondary breast cancer prevention on the basis of their risk for disease and the potential benefits and harms of prevention interventions."

The guidelines were supported in part by a National Cancer Institute–funded Breast Cancer Surveillance Consortium cooperative agreement and National Cancer Institute–funded University of California, San Francisco, Breast Cancer Specialized Programs of Research Excellence.

The updated evidence review was supported by grants from the Oregon Evidence–based Practice Center under contract to the Agency for Healthcare Research and Quality, the Veterans Administration Women's Health Fellowship, and the Oregon Health & Science University Department of Surgery in conjunction with the Human Investigators Program.

The USPSTF is an independent, voluntary body supported by the Agency for Healthcare Research and Quality. Recommendations made by the USPSTF are independent of the US government and should not be construed as an official position of the Agency for Healthcare Research and Quality or the US Department of Health and Human Services.

The review authors, task force, and editorialist have disclosed no relevant financial relationships.

Ann Intern Med. 2009;151:716-726, 727-737, 750-752.

DO NOT USE CYP2C19 INHIBITORS WITH PLAVIX

November 17, 2009 — The FDA has today issued a new public-health warning on the possible interaction between clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and the proton-pump inhibitor (PPI) omeprazole (Prilosec, Procter & Gamble) [1,2]. The alert states: "New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole."

But the timing of the this alert appears peculiar, given that just a few weeks ago, what was said to be the definitive answer to this issue--the only randomized clinical trial on the interaction--was reported, showing absolutely no hint of any reduction in effect of clopidogrel in patients taking omeprazole.

Cardiologists contacted by heartwire were surprised at the new FDA announcement.

Dr Peter Berger (Geisinger Medical Center, Danville, PA) said: "I was shocked by the strengthened warning. Proper subgroup analyses from randomized trials, including CREDO, TRITON, PRINCIPLE, and preliminarily from PLATO and CURRENT, all indicate that no interaction exists. And as shown by the registries, all these trials indicate just how different patients on and not on a PPI are from one another. And then a preliminary analysis of data from the COGENT trial, a trial dedicated to specifically examining clopidogrel with a PPI vs placebo, fails to suggest even the slightest signal of a negative interaction. For the FDA to then strengthen the warning of a interaction is baffling, to say the least."

Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) had similar concerns: "It is certainly reasonable for the FDA to inform clinicians of the platelet-function data, but their interpretation of the clinical action oversteps the evidence, I believe. As we know from COGENT, there is not a difference in clinical events when combining clopidogrel with omeprazole. Recommendations on clinical care should be based on randomized trials with clinical end points. For clinical effects of this pharmacologic interaction, what we see are no adverse cardiac effects. We need to see how the final published data look--but I don't think the 'info sheet's' recommendation to avoid these medications is the correct advice based on the clinical data."

Cannon added: "I wonder just what vetting of these clinical recommendations FDA has done. Have they consulted with the relevant specialty societies? The [American Gastroenterological Association] AGA, AHA, or ACC? Hopefully the ACC/AHA/AGA expert panel, cochaired by Drs Deepak Bhatt and Robert Harrington, can meet urgently to review the data and make an updated recommendation (or reaffirm their current standing recommendation--which I think is actually correct as written) that for patients at high risk of GI bleeding on aspirin and clopidogrel we should use PPIs."

The FDA says it is aware of the COGENT study and that "it might provide information about the effect of this interaction on clinical outcome." It adds: "Although the FDA has not fully reviewed the study results, the applicability of these data is limited because of the study design and follow-up."

New Studies From Sponsor

The FDA alert says the new information on which its warning is based comes from new studies conducted by the sponsor that compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets in people who took clopidogrel plus omeprazole vs those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in people who received clopidogrel with omeprazole compared with those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart, the statement adds.

Based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way. In addition, the manufacturer of clopidogrel is conducting follow-up studies to explore this and other drug interactions.

The agency advises patients using clopidogrel to consult with their healthcare provider if they are currently taking or considering taking omeprazole. It adds that patients who use clopidogrel and need a medication to reduce stomach acid can use antacids or H2 antagonists such as ranitidine, famotidine, or nizatidine, because the FDA does not believe that these medicines will interfere with the anti-clotting activity of clopidogrel. However, cimetidine should not be used, it says.

The FDA adds that the manufacturers of clopidogrel have agreed to look at other possible drug interactions with clopidogrel.

It also says that other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. "Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel," it adds.

The FDA says it is continuing to investigate other drug interactions with clopidogrel and plans to present on this issue at the next meeting of FDA's Drug Safety Oversight Board in November.

HELLO CRETE

Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer.

Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; on behalf of the Breast Cancer Investigators of the Hellenic Oncology Research Group.

Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete.

BACKGROUND: The purpose of this study was to compare docetaxel plus epirubicin versus docetaxel plus capecitabine combinations as front-line treatment in women with advanced breast cancer (ABC). PATIENTS AND METHODS: Previously untreated patients with ABC were randomly assigned to receive docetaxel 75 mg/m(2) plus epirubicin 75 mg/m(2) (DE) on day 1 or docetaxel 75 mg/m(2) on day 1 plus capecitabine 950 mg/m(2) orally twice daily on days 1-14 (DC) in 21-day cycles. Previous anthracycline-based (neo)-adjuvant chemotherapy was allowed if completed >1 year before enrollment. The primary objective of the study was to compare time to disease progression (TTP). RESULTS: One hundred and thirty-six women were treated on each arm and median TTP was 10.6 versus 11.0 months (P = 0.7), for DE and DC, respectively. According to RECIST criteria we observed 15 (11%) versus 11 (8%) complete responses and 55 (40%) versus 61 (45%) partial responses (P = 0.8), with DE and DC, respectively. Severe toxicity included grade 3-4 neutropenia (57% versus 46%; P = 0.07), febrile neutropenia (11% versus 8%; P = 0.4), hand-foot syndrome (0% versus 4%; P = 0.02), grade 2-3 anemia (20% versus 7%; P = 0.001) and asthenia (12% versus 6%; P = 0.09) with DE and DC, respectively. CONCLUSIONS: The DE and DC regimens have similar efficacy but different toxicity. Either regimen can be used as front-line treatment of ABC.

SHORT TERM ANTHRACYCLINE CARDIOTOXICITY IS LOW

November 16, 2009 — Anthracyclines are a common component of adjuvant breast cancer treatment regimens, but the long-term use of these agents has been associated with the development of cardiomyopathy and congestive heart failure.

However, in a new study that addresses the short-term cardiac safety of dose-dense doxorubicin and cyclophosphamide (ddAC) with or without concurrent bevacizumab (Avastin), researchers report that the regimen is not associated with frequent acute or short-term declines in left ventricular ejection fraction (LVEF).

In the study, published online November 9 in the Journal of Clinical Oncology, the authors report that post-ddAC LVEF at 2 months was normal in all of the patients except 1. Median baseline LVEF was 68% (range, 52% to 82%), and was the same 2 months after therapy whether they received bevacizumab (median, 68%; range, 53% to 80%) or not (median, 68%; range, 47% to 81%).

"Although there was no direct comparison with standard regimens, we now have the additional information that early cardiotoxicity with dose-dense regimens is not prohibitive," write Michael S. Ewer, MD, JD, from the University of Texas M.D. Anderson Cancer Center in Houston, and Steven M. Ewer, MD, from the University of Wisconsin School of Medicine and Public Health in Madison, in an accompanying editorial.

These early data are also important for patients who hope to benefit from subsequent trastuzumab, they note, because it doesn't appear that dose-dense regimens will significantly interfere with candidacy for further adjuvant treatment.

"However, any assumption that these regimens will not cause future problems is perhaps premature," they write.

Cardiologists and oncologists should continue to work together to find ways of identifying patients most at risk and those with impaired cardiac reserves, the editorialists note. "Despite the fact that we continually learn more about the cardiotoxicity of anthracyclines, the problem is not likely to go away any time soon," they say.

How to Interpret the Data

Lead study author Patrick G. Morris, MD, from Memorial Sloan Kettering Cancer Center in New York City, pointed out that, as discussed in the editorial, asymptomatic short-term declines in ejection fraction measured by multiple gated acquisition scan and/or echocardiogram do not reliably predict long-term risk for congestive heart failure.

There is also a need for biomarkers for cardiac injury, which his team is currently working on, he said.

"The cardiac safety of adjuvant trastuzumab beyond 5 years is unknown since there are no data from the adjuvant trastuzumab studies," Dr. Morris told Medscape Oncology. "But it is already known from AC followed by paclitaxel CALGB 9741 that dose-dense chemotherapy is associated with one half the rate of grade 3 to 4 cardiac events, compared with conventionally scheduled AC."

Based on their results, Dr. Morris concluded that "we did not identify a significant incidence of short-term cardiac toxicity and we believe that, for appropriately selected patients, trastuzumab can safely be incorporated into dose-dense anthracycline-based regimens."

"What is critical is that we did not identify an increase in the expected rate of cardiac safety events for doxorubicin when the biologics were added," he said.

Study Details: 3 Cohorts

In this study, a multicenter team prospectively evaluated the short-term cardiac safety of ddAC, with or without bevacizumab, in women with breast cancer who were eligible for adjuvant/neoadjuvant therapy.

From January 2005 to May 2008, 245 patients were enrolled in 1 of 3 sequential clinical trials. Patients with human epidermal growth-factor receptor 2 (HER2)-positive breast cancer were treated in trials 1 and 2, and patients with HER2-normal breast cancer (node positive or high-risk node negative) were treated in trial 3.

Women in all 3 trials received intravenous (IV) AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²) once every 14 days, supported by pegfilgrastim. The protocols were as follows:

• In trial 1, AC therapy was followed by IV paclitaxel (175 mg/m²) every 2 weeks for 4 cycles, and pegfilgrastim 6 mg subcutaneously (SQ) on day 2. IV trastuzumab (Herceptin) was given weekly (4 mg/kg loading dose followed by 2 mg/kg), starting with paclitaxel, and was continued every 3 weeks (6 mg/kg) after the completion of chemotherapy for 1 year.
• In trial 2, AC was followed by weekly paclitaxel (80 mg/m²) for 12 doses. Trastuzumab therapy was the same as in trial 1, but oral lapatinib (Tykerb) 1000 mg daily was added concurrently with paclitaxel/trastuzumab for 1 year.
• In trial 3, AC was given concurrently with bevacizumab (10 mg/kg) once every 2 weeks. This was followed by IV nab-paclitaxel (Abraxane) 260 mg/m² every 2 weeks for 4 cycles, with pegfilgrastim (6 mg SQ) on day 2. After chemotherapy was completed, bevacizumab was changed to 15 mg/kg once every third week for 12 cycles to complete the year of treatment.

Patients also received tamoxifen or aromatase inhibitors as appropriate, and radiation therapy was recommended, as per institutional guidelines.

Data on LVEFs were available for 241 patients in the cohort at 2 months, and post-ddAC LVEF was normal in 240 of 241 women (99%). Overall, 96 patients (40%) had LVEF declines of less than 10%, and the majority had stable or improved LVEFs, compared with their baseline values.

Change in LVEF After Dose-Dense AC With or Without Bevacizumab at 2 Months

Change in LVEF	Number of Patients (n = 241)	Percent
≥16%	2	0.8
10%–15%	7	3.0
<10%	96	40.0
<5%–10%	35	15.0
<5%	61	25.0
Stable or improved	136	56.0

At 6 months, LVEF was normal in 217 of the 222 patients who were available for follow-up (98%). Median LVEF was 65% (range, 24% to 80%), and there was little difference between patients who received bevacizumab (median, 64%; range, 51% to 77%) and those who did not (median, 65%; range, 24% to 80%). An asymptomatic decline in LVEF to below the normal limit was observed in 3 patients, and an asymptomatic decline of more than 15% was observed in 6 patients (3%). In the latter group, all 6 patients experienced subsequent improvement in LVEF.

Change in LVEF After Dose-Dense AC With or Without Bevacizumab at 6 Months

Change in LVEF	Number of Patients (n = 222)	Percent
≥16%	7	3
10%–15%	24	11
<10%	102	46
<5%–10%	46	21
<5%	56	25
Stable or improved	89	40

The authors note that LVEF declines of less than 10% were common and occurred in 102 of 222 patients (46%), and the LVEF was stable or improved in 89 patients (40%).

Congestive Heart Failure Uncommon

Congestive heart failure developed in 3 of 245 patients (1.2%) within 6 months of initiating chemotherapy, all of whom had received anti-HER2 therapy (1 patient in trial 1 and 2 patients in trial 2). At month 12, an additional patient treated in trial 2 developed congestive heart failure, and 1 patient in trial 3 developed congestive heart failure at month 15 (3 months after completing therapy).

The authors point out that longer-term follow-up of cardiac toxicity of ddAC, with and without bevacizumab, and lapatinib is ongoing. "Assessment of biomarkers for cardiac injury in ongoing and future trials may allow us to see if there is any correlation with asymptomatic declines in LVEF," they note.

Several of the study authors report serving as a consultant or in an advisory role, or receiving honoraria or research funding from 1 or more pharmaceutical companies; see paper for details. Dr. Michael S. Ewer reports serving as a consultant/advisor for Hoffman La Roche, Genentech, GlaxoSmithKline, and Methylgene; and receiving honoraria from Roche Canada and Sanofi-Aventis. Dr. Steven M. Ewer reports receiving honoraria from Sanofi-Aventis.

J Clin Oncol. Published online November 9, 2009. Abstract, Abstract

ZARNESTRA AND NEXAVAR COMBINATION ACTIVE IN THYROID MEDULLARY CARCINOMA

Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies.

Hong DS, Sebti SM, Newman RA, Blaskovich MA, Ye L, Gagel RF, Moulder S, Wheler JJ, Naing A, Tannir NM, Ng CS, Sherman SI, El Naggar AK, Khan R, Trent J, Wright JJ, Kurzrock R.

Division of Cancer Medicine, Department of Investigational Therapeutics (Phase 1 Program), Unit 455, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. dshong@mdanderson.org

PURPOSE: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib. EXPERIMENTAL DESIGN: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth). RESULTS: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had > or =50% reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (> or =6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months). CONCLUSIONS: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.

CETUXIMAB AND RADIOTHERAPY FOR HEAD AND NECK CANCER

November 16, 2009 — Cetuximab (Erbitux) plus radiotherapy should be considered a standard option in the treatment of locoregionally advanced squamous cell carcinoma of the head and neck, say researchers reporting long-term benefits from this combination.

The latest results, published online November 6 in the Lancet Oncology, show that the statistically significant improvement in overall survival for this combination is maintained after 5 years of follow-up.

The 5-year overall survival was 45.5% in patients who received the combination, compared with 36.4% in patients treated with radiotherapy alone, the researchers report. The updated median overall survival was 49 months for the combination and 29.3 months for radiotherapy alone (P = .018).

"The absolute benefit was 9% at 5 years, which is a pretty substantial finding," lead researcher James Bonner, MD, from the University of Alabama at Birmingham, said in an interview with Medscape Oncology.

Cetuximab plus radiation offers "an important treatment option for this group of patients," the authors conclude.

This view is in keeping with the guidelines issued by the National Comprehensive Cancer Network (NCCN) in 2007, which incorporated the option of cetuximab plus radiation after the 3-year significant survival advantage from this trial was reported (N Engl J Med. 2006:354;567-578).

Other options for such patients include the use of radiotherapy alone and the use of cytotoxic chemotherapy with radiation (chemoradiation), which often involves cisplatin. Compared with chemotherapy, the adverse effects with cetuximab are "much less," Dr. Bonner reported, but he emphasized that each patient should be evaluated individually for toxicity tolerance.

Another notable finding from this trial is the significantly better response to cetuximab in patients who developed a skin rash while taking the drug than in those who did not. This correlation between good response and skin rash with cetuximab has been reported previously (in patients with colon cancer), but this is the first time it has been seen in patients also undergoing radiotherapy, Dr. Bonner noted.

Chemoradiation a Popular Treatment Option

Chemoradiation has become a popular treatment option for locoregionally advanced head and neck cancer in recent years, the authors note; a large meta-analysis has shown a significant advantage over radiotherapy alone.

The meta-analysis was first published in 2000 with 63 trials, but was updated to include more recent trials; the update with 87 trials was published this year (Radiother Oncol. 2009:92:4-14). Both showed a statistically significant improvement in survival after chemoradiation, compared with radiotherapy alone, Dr. Bonner said, with a 5-year survival advantage of 4.5%.

The 9% benefit at 5 years that has been reported for cetuximab and radiation looks better, Dr. Bonner conceded, but he said the 2 results cannot be compared directly. This result for cetuximab and radiation comes from just 1 trial, whereas the benefit reported in the meta-analysis came from many different trials, some of which individually reported a greater benefit (e.g., 11%) and others of which showed no significant improvement. In addition, the cetuximab trial generally used radiotherapy delivered twice daily, which has been shown to produce better results than delivery once daily; once-daily delivery of radiation was used in many of the older trials in the meta-analysis. "That's another caveat to the whole field," he said.

Dr. Bonner also noted that at the time that this trial was being designed, in 1998, radiotherapy alone was the standard of care for these patients; the addition of cetuximab was the experimental group.

The trial was conducted in 424 patients with locoregionally advanced squamous cell carcinoma of the head and neck who were randomized to receive radiotherapy with or without cetuximab.

The overall survival benefit for the combination seen at 5 years (45.5% vs 36.6%) is "remarkably similar" to that seen in the 3-year analysis (55% vs 45%), the authors explain. This supports the validity of 3-year overall survival as a surrogate for long-term overall survival, they add.

These updated 5-year survival results provide further support for the combination of cetuximab plus radiotherapy as a standard treatment option, they conclude.

Further Trials Underway

Currently, the NCCN guidelines suggest that the intensity of treatment should be dictated by the severity of the disease or tumor burden. They describe the 3 cornerstones of treatment as radiotherapy alone, radiotherapy plus systemic therapy (such as cetuximab or cytotoxic chemotherapy), and sequential treatment of induction chemotherapy followed by concomitant chemoradiotherapy.

However, the authors note that more study is needed to determine if these severity-based recommendations are appropriate. An ongoing phase 3 trial is exploring the use of cetuximab with cisplatin chemoradiation and will "provide the rationale for further exploration in earlier stages of disease," they say.

Quite separately, cetuximab has shown good results in patients with advanced head and neck cancer when it was added to chemotherapy in the EXTREME trial, as previously reported by Medscape Oncology. These patients have metastatic disease that is considered incurable, and they are not treated with radiotherapy, Dr. Bonner explained. In contrast, the patients in the trial conducted by his team had locoregional disease that had not spread beyond the clavicles; these patients are considered curable, he added.

The study was funded by ImClone Systems, Bristol-Myers Squibb, and Merck KgaA, which manufacture and market cetuximab. Dr. Bonner reports serving as an occasional consultant, with honoraria for presentations, for Bristol-Myers Squibb, ImClone Systems, Merck KgaA, Oncolytics, and Sanofi Aventis. Several of his coauthors have disclosed relevant financial relationship; full details can be found in the paper.

Lancet Oncol. Published online November 6, 2009. Abstract

THE EFFECT OF IMATINIB ON PIGMENTATION

Arch Dermatol. 2009 Nov;145(11):1313-6.

Disappearance of lentigines in a patient receiving imatinib treatment for familial gastrointestinal stromal tumor syndrome.

Campbell T, Felsten L, Moore J.

Department of Dermatology, UC Davis Medical Center, 3301 C St, Ste 1300, Sacramento, CA 95816, USA. tmac.2010@yahoo.com

BACKGROUND: Gastrointestinal stromal tumors (GISTs) harbor gain-of-function mutations of the c-kit tyrosine kinase receptor. Imatinib mesylate is an inhibitor of c-kit and is indicated in the treatment of chronic myeloid leukemia and GISTs. Reported adverse effects of imatinib include hypopigmentation, depigmentation, and hyperpigmentation. Although the exact mechanism by which these occur is unclear, it is likely that inhibition of c-kit leads to downstream inhibition of the tyrosinase gene promoter and thus to inhibition of pigment production. OBSERVATIONS: A 45-year-old woman with a history of multiple dysplastic nevi and lentigines was diagnosed as having familial GIST syndrome. Treatment with imatinib mesylate was started in an attempt to decrease the tumor load. Three months after treatment initiation, the patient noted a decrease in the number of pigmented lesions, lightening of the skin in her genital area, and graying of her terminal hair. CONCLUSIONS: The potential association between a specific genetic mutation and pigmentation changes secondary to imatinib therapy may account for the variety in presentation of this potential side effect. Further genetic studies paired with melanocyte-specific or c-kit-specific stains of affected tissue are warranted to better understand the relationship between the genetic mutation and the effect of imatinib on pigmentation.

TB INCREASES LUNG ADENOCARCINOMA RISK

Senior author Dr. Bao-Sen Zhou of China Medical University, Shenyang and colleagues observe that a number of retrospective studies have suggested a relationship between pre-existing TB and lung cancer, but findings have been inconsistent.

To investigate further, the researchers examined data from 37 case-control studies and 4 cohort studies that together involved more than 19,000 cases and 118,000 controls.

Their meta-analysis of risk estimates found a significantly increased lung cancer risk associated with pre-existing TB. This was not due to confounding effects of tobacco use, the authors said. In fact, the relative risk in never smokers was 1.8.

In studies that controlled for smoking, the relative risk of lung cancer with TB was 1.74. After adjusting for lifetime environmental tobacco smoke exposure, this rose to 2.93.

Pooled estimates for adenocarcinoma showed a significant association (relative risk, 1.60) with a history of TB. There were no significant associations between TB and squamous cell or small cell lung cancer, however.

The researchers conclude by pointing out that "increased lung cancer risk appeared greatest within the first 5 years after TB diagnosis, but the risk for lung cancer remained 1.99-fold elevated for more than 20 years after TB diagnosis."

Int J Cancer 2009;125:2936-2944.

NEW CANCER DRUGS IN PIPELINE

November 19, 2009 — Innovations in drug development, target selection, and new discoveries in molecular and cell biology have had a profound affect on cancer therapy. During a press briefing at the Molecular Targets and Cancer Therapeutics international conference, sponsored by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer, researchers gave an overview of several new compounds that are in preclinical or early-phase trials.

The presentations included information on the role of heat shock protein 70 (hsp70) as a novel therapy for breast cancer, compounds that target leukemia stem cells, tolerability results of the experimental agent cediranib (AstraZeneca) for use in pediatric recurrent or refractory solid tumors, and sensitivity results in colorectal cancer with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (AstraZeneca), which has already shown promise in breast cancer.

"This research spans studies on the genetic make-up of cancer cells, validation studies on the roles of key signaling proteins and pathways, the development of novel agents, and the testing of those agents in a variety of preclinical and clinical settings," said session moderator Sara A. Courtneidge, PhD, DSc, professor and director of the Tumor Microenvironment Program and director of academic affairs at the Burnham Institute for Medical Research, La Jolla, California, in a statement.

Novel Therapy for Breast Cancer

Preclinical in vitro and in vivo studies have shown that targeting heat shock response proteins with panobinostat (Novartis), combined with an autophagy inhibitor, has promise as a novel treatment strategy in breast cancer.

Panobinostat is an experimental agent that selectively inhibits the enzyme histone deacetylase, which leads to apoptosis of malignant cells through multiple pathways.

One of the hallmarks of cancer is the stress phenotype, explained study author Kapil Bhalla, MD, director of the Medical College of Georgia Cancer Center in Augusta. The stress phenotype is collectively induced by hypoxia, deprivation of nutrients, acidosis, and increased reactive oxygen species, and is exhibited as metabolic and protein misfolding/denaturing stress. This process leads to the constitutive activation of the heat shock response, with elevated levels of heat shock proteins and induction of autophagy.

Elevated levels of hsp70 and hsp90 promote proper protein folding and inhibit both the intrinsic and extrinsic pathways of apoptosis. "The focus of this work was how hsp70 regulates the process of autophagy," said Dr. Bhalla.

Dr. Bhalla and colleagues evaluated the stress phenotype of breast cancer cells in vitro and in vivo. They first determined that, in the in vitro setting, the stress induced by nutrient withdrawal or treatment with panobinostat resulted in hyperacetylation of hsp70, which in turn induced autophagy in cultured breast cancer MB-231 and MCF-7 cells.

To determine the in vivo role of hyperacetylated hsp70 in autophagy, the researchers obtained tumor cell lysates that had grown in the mammary fat pads of nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice implanted with MB-231 xenografts. Cells were analyzed from tumors of various sizes, and the reseasrchers found that there was a size-dependent increase in the intracellular levels of hyperacetylated hsp70, as well as in Beclin1 and LC3II, both markers of autophagy.

Collectively, they note, these findings suggest that the stress-phenotype-associated heat shock response and the increase in acetylated hsp70 promotes autophagy. The findings also demonstrate that in established breast cancers, autophagy can be selectively targeted by cotreatment with agents such as panobinostat and an autophagy inhibitor.

Identifying Compounds That Target Leukemia Stem Cells

Sean McDermott, PhD, research investigator in the Department of Internal Medicine, Hematology-Oncology at the University of Michigan Medical School in Ann Arbor, discussed how his team identified a new paradigm for screening against leukemia stem cells.

"We wanted to identify compounds that would specifically target leukemia stem cells and hopefully not target normal blood-forming stem cells at the same time," said Dr. McDermott. "In the end, we were able to screen a library of 4000 small molecules that have been used by numerous other labs and companies over the past 10 years and came up with 3 compounds."

Instead of using traditional cell lines, the researchers screened a collection of 4000 known bioactive, off-patent, and natural compounds against 2 leukemia cell lines. They initially identified 76 compounds that were positive against both lines and, because leukemia stem cells share some pathways with hematopoietic stem cells (HSCs), the researchers counter-screened potential hits on normal HSCs and progenitor cells, identifying only 10 compounds.

Of these 10, 3 targeted stem cells — ciclopirox olamine, etoposide, and kinetin riboside. When tested against cell lines of primary acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), kinetin showed efficacy at levels similar to the AML chemotherapeutics cytarabine and mitoxantrone. In 2 of 4 samples, kinetin riboside inhibited engraftment of primary AML cells in NOD/SCID mice.

Ciclopirox olamine, a clinically used antifungal, targets stem cells by chelating intracellular iron and inhibiting the ribonucleotide reductase enzyme, without harming normal HSCs.

The third agent, etoposide, was screened with cells obtained from 51 patients with AML and 12 patients with CML. "We were amazed by it," said Dr. McDermott. "We saw a huge range of responses in AML and CML."

Etoposide was effective in vitro on 29% (15 of 51) of primary AML cells and 67% (8 of 12) of CML cells, and inhibited the NOD/SCID mouse engraftment of 3 responsive AML samples. "We looked at responders and nonresponders, and saw a dramatic response only in responders," he said. "At this time, it seems possible to identify patients who might benefit from etoposide treatment clinically."

Early Cediranib Study Promising in Pediatric Patients

Preliminary evidence shows that cediranib might have activity in childhood sarcomas; in addition, it appears safe, with tolerable adverse effects. To date, 3 of the 13 patients enrolled in the phase 1 trial have experienced partial shrinkage of their tumor, and the 12 mg/m² once-daily dose was found to be tolerable.

Cediranib is an orally bioavailable small-molecule inhibitor of the tyrosine kinase activity of vascular endothelial growth-factor receptor (VEGFR)-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4), and c-KIT. The goal of this study was to determine the toxicity profile, dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of cediranib in a population of children and adolescents with relapsed or refractory solid tumors.

"Our end points were pretty standard for a phase 1 trial," said study author Elizabeth Fox, MD, MSCR, a staff clinician in the Pediatric Oncology Branch at the National Cancer Institute. "We were also monitoring for an objective response, using RECIST [Response Evaluation Criteria in Solid Tumors] and [World Health Organization] criteria."

Patient diagnoses were Ewing's sarcoma (n = 3), osteosarcoma (n = 2), alveolar soft part sarcoma (n = 2), synovial sarcoma (n = 2), and other solid tumors (n = 4).

It is always exciting to see an objective response in a phase 1 trial, Dr. Fox pointed out. A patient with Ewing's sarcoma, who was treated at the lowest dose level of 8 mg/m², experienced more than a 70% reduction in tumor volume. In addition, partial responses were seen in 2 patients with synovial sarcoma at the 12 mg/m² daily dose.

Adverse events in this population were similar to those seen in adults taking cediranib, Dr. Fox noted. Nondose-limiting toxicities included anorexia, fatigue, diarrhea, abdominal pain, nausea, headache, rash, increased thyroid-stimulating hormone, decreased left ventricular function, and proteinuria.

Two patients have completed 1 cycle of cediranib 17 mg/m² daily, with 1 patient experiencing grade 3 nausea (dose-limiting toxicity).

The researchers are currently evaluating the effects with 17 mg/m² of cediranib and have proposed to the Children's Oncology Group that a phase 2 study be conducted in selected childhood solid tumors.

PARP Inhibitor Olaparib for MSI Colorectal Cancer

As previously reported by Medscape Oncology, early research shows that the PARP inhibitor olaparib demonstrated antitumor activity in breast, ovarian, and prostate cancers associated with BRCA1 and BRCA2 mutations. Researchers now report that olaparib showed activity against cell lines of homologous recombination-deficient MRE11 mutant microsatellite instable (MSI) colorectal cancer.

"It's been where we see the greatest levels of homologous recombination deficiency that we've been able to focus phase 2 trials," said study author Mark O'Connor, PhD, chief scientist at KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom. "There are currently phase 2 trials ongoing in triple-negative breast cancer and serous ovarian cancer."

Cells that are deficient in homologous recombination DNA repair or signaling pathways are potentially sensitive to PARP inhibition; examples include inactivating MRE11 mutations that have been linked to mismatch-repair-deficient MSI colorectal and endometrial cancers.

A proportion of colorectal cancers have microsatellite instability, explained Dr. O'Connor. "What we wanted to do was to test whether or not colorectal cancer cells that were MRE11 deficient and microsatellite unstable were more sensitive to olaparib than those that weren't," he said.

The analyses by Dr. O'Connor and colleagues revealed that MRE11 mutant and MSI colorectal cells were sensitive to olaparib treatment, whereas microsatellite stable MRE11 wild-type cells remained insensitive. All olaparib-sensitive colorectal cancer cell lines were homologous recombination deficient, and they confirmed that the loss of MRE11 expression can confer sensitivity to olaparib.

These results provide evidence and suggest that patients with MSI and MRE11-deficient colorectal cancer could be suitable candidates for treatment with olaparib, the authors note.

American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer (EORTC) Molecular Targets and Cancer Therapeutics International Conference: Abstracts B21, A51, A5, A114. Presented November 16, 2009.

ASCO CLINICAL PRACTICE GUIDELINESS FOR STAGE IV NSCLC

. J Clin Oncol. 2009 Nov 16. [Epub ahead of print]

American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer.

Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G.

Memorial Sloan-Kettering Cancer Center, New York, NY; Virginia Commonwealth University, Massey Cancer Center, Richmond; American Society of Clinical Oncology, Alexandria; Virginia Cancer Center, Richmond, VA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Northwest Oncology & Hematology Associates, Coral Springs, FL; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore; National Cancer Institute, Bethesda, MD; Helen F. Graham Cancer Center, Newark, DE; Hematology/Oncology of Indiana, PC, Indianapolis, IN; Nebraska Cancer Specialists, PC, Omaha, NE; Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; University of Texas, Southwestern Medical Center, Dallas, TX; British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.

AGGRESIVE TREATMENT OF OVARIAN CANCER NOT SUPPORTED BY DATA

November 19, 2009 (Philadelphia, Pennsylvania) — A survey designed to collect information on practice patterns of physicians treating women at high risk for ovarian cancer shows an increase in the aggressiveness of treatment in the past 7 years, according to research presented here at the American Public Health Association 137th Annual Meeting.

In 2001, the Cancer Genetics Network (CGN) began a screening study in women at high risk for ovarian cancer, based on rising CA125 blood levels, said Heather L. Symecko, MPH, a program manager at the Biostatistics Center at Massachusetts General Hospital in Boston.

Researchers collected longitudinal CA125 data to screen healthy women with a family history of ovarian cancer, aiming to detect elevated or changing levels of serum CA125 using a statistical algorithm — hence, the name of the study: Risk of Ovarian Cancer Algorithm (ROCA). The investigators calculated ovarian cancer risk and based their treatment recommendations accordingly: to redo the test in 3 months, to refer the patient for transvaginal ultrasound, or to refer the patient for surgery.

2001 vs 2008: Treatment Choices for Women at Risk for Ovarian Cancer

Practice patterns in 2001 were compared with those in 2008.

"In order to determine if practice patterns have changed over the past 7 years, a follow-up survey was distributed to the participating centers," Ms. Symecko told Medscape Public Health & Prevention. Physicians from 12 of the 15 clinical centers participating in CGN agreed to take part in this survey. She noted that pre- and posttrial surveys were not matched by individual physician; however, the respondents' demographics (median age, years in practice, board-certification specialty) suggested that they are the same cohort.

In addition to demographic information for the treating physicians, the questionnaire included identification of tools used to classify a patient as high risk, use of CA125 testing and transvaginal ultrasound in screening, and use of risk-reducing salpingo-oophorectomy and hormone-replacement therapy in patient management.

More Testing, More Salpingo-Oophorectomies at an Earlier Age

"We found an increase in the aggressiveness of how physicians were treating ovarian cancer; they are using CA125 [testing] more in 2008, as opposed to 2001," she said. Physicians who were board-certified in gynecology (including gynecologic oncology) reported a 30% increase in CA125 testing in premenopausal women between 2001 and 2008. Similarly, physicians who were board-certified in medicine or medical oncology reported about 10% more CA125 testing in 2008 than in 2001. There was also an increase in the frequency of testing, from every 6 months in 2001 to every 3 months in 2008.

"We also asked [physicians] about the recommended age for risk-reducing salpingo-oophorectomy, and we found that they were recommending it earlier in 2008 than they were in 2001," Ms. Symecko said.

"An increase in the percentage of women undergoing salpingo-oophorectomy — and at earlier ages — was also noted," she added. In 2001, 38% of BRCA-positive women between 35 and 40 years of age had salpingo-oophorectomies, compared with 48% in 2008.

Data presented earlier this year at the annual meeting of the American Society of Clinical Oncology showed that there is no survival benefit from early treatment based on elevated blood levels of CA125, so there was no value in the routine measurement of CA125 in the follow-up of ovarian cancer patients.

In 2008, for all women under the age of 50 without a history of breast cancer but who were BRCA mutation carriers, all physicians recommended salpingo-oophorectomy followed by hormone-replacement therapy. This was a practice that was unchanged from 2001. However, if women with the BRCA mutation had a previous diagnosis of breast cancer, an increasing number of physicians recommended short-term hormone-replacement therapy — 70% of physicians in 2008, compared with 50% in 2001.

Currently, Practice Lacks Supporting Scientific Evidence

"That's what the physicians are doing," said Ms. Symecko, who acknowledges that the results are not necessarily "generalizable across all physicians, [because] this was a group of physicians at academic universities who were recruiting for an ovarian study," in total 20 respondents in 2001 and 14 in 2008.

The next step is "to get studies like the ROCA done, to actually find out the significance, sensitivity, and specificity of CA125 testing, because the physicians are all using it, and they are using it frequently," she observed.

"Physicians are mostly interested in knowing what to do next," Paul Meissner, MSPH, director of Research Program Development at Montefiore Medical Center in the Bronx, New York, said in an interview with Medscape Public Health & Prevention. "A study like this is a reflection of what they are doing, it's an issue around communicating what is actually known [about the CA125 biomarker] and getting it into the hands of people who can do something with it," he added.

"To get the science to back-up the practice is something that really needs to be done," concluded Ms. Symecko.

Ms. Symecko and Mr. Meissner have disclosed no relevant financial relationships.

American Public Health Association (APHA) 137th Annual Meeting: Abstract 203073. Presented November 9, 2009.