NEW PROGNOSTIC AND PREDICTIVE FACTORS FOR COLORECTAL CANCER

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Br J Cancer. 2009 Nov 24. [Epub ahead of print] Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients. Zlobec I, Molinari F, Kovac M, Bihl MP, Altermatt HJ, Diebold J, Frick H, Germer M, Horcic M, Montani M, Singer G, Yurtsever H, Zettl A, Terracciano L, Mazzucchelli L, Saletti P, Frattini M, Heinimann K, Lugli A. Institute for Pathology, University Hospital of Basel, Basel, Switzerland. Background:Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy.Methods:Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status.Results:In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) p="0.017)." p="0.01).Conclusions:TOPK" target="_blank" href="http://www.bjcancer.com/">www.bjcancer.com.

PMID: 19935791 [PubMed - as supplied by publisher]

ACTIVE SURVEILLANCE A VIABLE OPTION FOR PROSTATE CANCER

NEW YORK (Reuters Health) Nov 23 - Active surveillance of prostate cancer, with intervention offered for progressive disease, appears to be safe even for intermediate-risk disease in men over the age of 70, findings from a prospective cohort study suggest.

Although screening and early detection of prostate cancer reduces mortality, the risk of overtreatment is significant, comment Dr. Laurence Klotz and associates at the University of Toronto in the November 16th online issue of the Journal of Clinical Oncology.

However, older studies of watchful-waiting series of observation with no treatment option began prior to the availability of prostate specific antigen (PSA) testing and in nonscreened cohorts. As a result, cancer-specific mortality was relatively high.

Dr. Klotz and his team evaluated a watchful-waiting approach in which therapy was individualized according to the biologic behavior of the cancer.

The study cohort included favorable-risk patients (Gleason score 6 or less, PSA 10 ng/mL or less) as well as patients older than 70 years with PSA up to 15 ng/mL or Gleason score up to 7. Radical treatment was offered if PSA doubling time fell below 3 years or in the event of histological progression.

The favorable-risk subset represented 83% of the total group, according to the authors.

Out of 450 men (median age 70.3 years, median follow-up 6.8 years), only five died of prostate cancer within 10 years after diagnosis. Five- and 10-year cause-specific survival rates were 99.7% and 97.2%, respectively. All five who died of prostate cancer had progressive disease and were offered radical treatment (radiation or surgery), which was turned down by two.

The overall survival was 78.6%, with most patients dying of other causes. The hazard ratio for non-prostate cancer to prostate cancer mortality was 18.6.

Overall, 125 patients were treated radically, and another 10 received androgen-deprivation therapy alone. Of 117 patients for whom posttreatment PSA levels were known, 59 (50.4%) had PSA failure.

The authors also observed that no one in the stable cohort of untreated patients has experienced clinical progression. In the overall cohort, the PSA failure rate was 13%, comparable to rates following radical prostatectomy or radiation for favorable-risk patients.

Furthermore, they add, "PSA failure does not mean death as a result of prostate cancer."

The research team has initiated a prospective, randomized trial comparing surveillance to radical treatment among men reclassified as higher risk after a period of observation and repeat biopsy.

J Clin Oncol 2009.

TIMP-1 AS PROGNOSTIC FACTOR IN REANL CANCER

NEW YORK (Reuters Health) Nov 19 - Plasma levels of TIMP-1 (tissue inhibitor of matrix metalloproteinase-1) are independently prognostic of overall survival in patients with advanced renal cell carcinoma (RCC), according to data presented yesterday at the 2009 Molecular Targets and Cancer Therapeutics International Conference in Boston.

The finding comes from an exploratory biomarker analysis of a subset of patients in the phase III TARGET study (Treatment Approach in Renal Cancer Global Evaluation Trial).

In this trial, compared to placebo, the multikinase inhibitor sorafenib doubled progression-free survival and significantly improved overall survival in patients with advanced RCC who had failed one previous treatment.

Before treatment with either sorafenib or placebo, and at 3 and 12 weeks of treatment, the researchers measured plasma biomarkers that could potentially predict clinical outcome, including VEGF, CAIX, TIMP-1 and p21 Ras.

The lead investigator, Dr. Carol Pena of Bayer Healthcare Pharmaceuticals in Montville, New Jersey, reported that in univariate analysis, "elevated levels of any of these biomarkers correlated with shorter survival in the absence of treatment."

Specifically, using the median baseline level of each biomarker to define high versus low levels, the hazard ratios for elevated VEGF, CAIX, TIMP-1 and p21 Ras were 1.65, 2.26, 3.34 and 2.49, respectively.

In a multivariate analysis of 59 patients, "only TIMP-1 retained independent prognostic value, at a very good p value of <>

She also noted that TIMP-1 levels decreased in sorafenib-treated patients and increased in placebo-treated patients during the course of treatment. "This could suggest that plasma TIMP-1 may be indicative of disease progression," Dr. Pena told the conference.

"This is the first demonstration that I could find in the literature of plasma TIMP-1 being a prognostic factor for RCC," she said, adding: "It has been shown that TIMP-1 correlates with survival and other outcome measures in other tumor types...but this is the first correlation of plasma TIMP-1 and survival in RCC."

TIMP-1, Dr. Pena said, "could facilitate a more personalized approach to RCC treatment."

The 2009 Molecular Targets and Cancer Therapeutics International Conference is jointly sponsored by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer (EORTC).

DOCETAXEL AND TRASTUZUMAB IMPROVES SURVIVAL IN EARLY BREAST CANCER

NEW YORK (Reuters Health) Nov 19 - In women with node-positive or high-risk node-negative early breast cancer, disease-free survival was better when docetaxel was substituted for vinorelbine as an adjuvant therapy to fluorouracil, epirubicin and cyclophosphamide (FEC).

The large Finnish study also found that a short course of trastuzumab given alongside the docetaxel was effective and safe, particularly in terms of cardiac toxicity.

As reported in an online publication November 2 in the Journal of Clinical Oncology by Dr. Heikki Joensuu of Helsinki University and colleagues, the phase III trial involved 1,010 women no older than 65 (median age 50.9) who entered the study no more than 12 weeks after mastectomy or breast-conserving surgery.

The majority of participants had HER2-negative cancer and were randomized to treatment with either docetaxel/FEC or vinorelbine/FEC. The 232 women with HER2-positive disease were further randomized to receive or not receive trastuzumab.

The median follow-up was 62 months. Overall, women who received docetaxel had better distant disease-free survival than those treated with vinorelbine (P = 0.010) and also were less likely to have recurrence of breast cancer or develop cancer of the other breast.

Patients treated with trastuzumab also tended to have better overall survival than those who only received chemotherapy. Specifically, 19.1% of patients who received trastuzumab were diagnosed with distant recurrence or died without known cancer recurrence, versus 26.7% of those who did not receive trastuzumab (P = 0.12).

Furthermore, 10.4% of trastuzumab-treated patients died, compared with 18.1% of women with HER2-positive disease who did not receive the drug.

Distant disease-free survival was also better with trastuzumab than without, and better in those who received trastuzumab with docetaxel/FEC than in those treated with trastuzumab plus vinorelbine/FEC.

According to the report and an accompanying editorial, at least two additional studies of trastuzumab are under way. One compares docetaxel, nine weeks of trastuzumab and FEC to the same regimen but with trastuzumab continued for a total of 12 months. The other involves a large cohort of women with stage I breast cancer who receive 12 weeks of paclitaxel and trastuzumab, followed by maintenance trastuz

FIERCE DEBATE OVER MAMMOGRAPHY SCREENING

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

ASCO GUIDELINESS FOR STAGE IV LUNG CANCER

November 24, 2009 — Guidelines for using chemotherapy in the treatment of stage 4 nonsmall-cell lung cancer (NSCLC) have been updated by the American Society of Clinical Oncology (ASCO), and now include details of when to use targeted therapies.

The update, the first since 2003, was published online November 16 in the Journal of Clinical Oncology and on the ASCO Web site . It was prompted by a large number of new peer-reviewed studies, say the authors, led by Christopher Azzoli, MD, from the Memorial Sloan-Kettering Cancer Center in New York City.

The new recommendations are based primarily on statistically significant improvements in overall survival documented in prospective randomized controlled trials, say the authors. They add that treatment strategies that demonstrated an improvement only in progression-free survival prompted greater scrutiny about issues such as toxicity and quality of life.

First-Line Therapy

The recommendations for using cytotoxics in first-line treatment have not changed, but there are several additional recommendations about the use of targeted agents.

The guidelines stipulate that:

• For patients with a performance status of 0 or 1, a platinum-based 2-drug combination of cytotoxic drugs is recommended.
• For patients with a performance status of 2, single-agent chemotherapy is recommended.
• Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy.
• First-line chemotherapy should be stopped at disease progression, or after 4 cycles in patients not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than 6 cycles.

Platinum compounds are preferred over nonplatinum compounds because they are superior in response rate and marginally superior in overall survival, the authors explain. The choice of either cisplatin (Platinol) or carboplatin (Paraplatin) is acceptable because neither is consistently superior, they note; cisplatin might have better efficacy but carboplatin might have less toxicity.

There are not enough data to narrow down the selection of the platinum-based doublet on the basis of efficacy alone, and the clinician must often choose which drugs to use on the basis of other factors, including dosage schedules and adverse events, they add. The choice of a second drug in the platinum-based doublet can include the following: docetaxel (Taxotere), gemcitabine (Gemzar), irinotecan (Camptosar), paclitaxel (Taxol), pemetrexed (Alimta), or vinorelbine (Navelbine).

New in the update are recommendations on the use of targeted agents in first-line treatment, as follows:

• The addition of bevacizumab (Avastin) to carboplatin/paclitaxel is recommended, except in patients with certain characteristics (i.e., those with squamous cell carcinoma histology, brain metastases, clinically significant hemoptysis, inadequate organ function, a performance status greater than 1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension).
• The addition of cetuximab (Erbitux) to cisplatin/vinorelbine can be considered in patients with tumors testing positive for epidermal growth-factor receptor (EGFR), as measured by immunohistochemistry.
• First-line gefitinib (Iressa) use can be recommended for patients with activating EGFR mutations. However, if EGFR mutation status is negative or unknown, cytotoxic chemotherapy is preferred.
• Erlotinib (Tarceva) or gefitinib should not be used in first-line therapy in combination with cytotoxics in unselected stage 4 NSCLC patients.

Second- and Third-Line Treatment

There has been a change in the drugs recommended for use in second-line therapy. Previously, only docetaxel (Taxotere) was recommended for use after progression on platinum-based first-line therapy, and gefitinib was recommended after a failure of both platinum-based therapies and docetaxel. Now the guidelines state that docetaxel, gefitinib, erlotinib, and pemetrexed are acceptable as second-line therapies.

The guideline committee notes that pemetrexed was recently approved by the US Food and Drug Administration for maintenance therapy in NSCLC, but this is based on recently presented data that were "outside the scope" of the comprehensive data review undertaken.

Third-line therapy with erlotinib can be recommended for patients with a performance status of 0 to 3 who have progressed on or after second-line therapy and who have not previously received erlotinib or gefitinib. There is not enough evidence to make a recommendation for or against using a cytotoxic drug as a third-line therapy, the authors explain.

There is insufficient evidence to recommend the routine use of molecular markers to select systemic treatment in patients with metastatic NSCLC. "However, emerging data suggest that this paradigm is changing," write the authors. Some agents seem to be more effective or less toxic with certain histological subtypes, and recent studies have shown that therapy could be improved by selecting drugs based on molecular markers.

In addition, the updated guidelines considered the treatment of elderly patients, but conclude that age should not determine what treatment a patient receives. The committee also acknowledges that disparities exist, highlighting a recent study that found that only 36% of African American patients with stage 4 NSCLC receive first-line chemotherapy.

"Ethnic and racial minorities experience worse outcomes [than] whites in all stages of lung cancer, and these disparities are frequently due to communication barriers between doctors and their patients," Dr. Azzoli said in a statement. "When patients receive uniform clinical care, these disparities are minimized," he added.

"The survival of patients with stage 4 NSCLC remains poor, and all eligible patients should be encouraged to participate in clinical research trials at any time during the course of their disease," the authors conclude.

Large Differences in Costs

A cost-effectiveness analysis is "beyond the scope of this guideline and did not impact on the recommendations," the authors explain, but note that the costs of the drugs vary, and provide some cost estimates in a table, reproduced in part below. The cost estimates are based on data from the Centers for Medicare and Medicaid Services.

Estimated Cost for 2 Cycles of Therapy

Drug	Estimated Cost ($)
Bevacizumab	14,040
Carboplatin	146
Cetuximab	18,981
Cisplatin	68
Docetaxel	5,060
Erlotinib	9,114
Gefitinib	4,255
Gemcitabine	6,914
Irinotecan	527
Paclitaxel	201
Pemetrexed	9,682
Vinorelbine	257

Dr. Azzoli reports having received research funding from Allos Therapeutics, Sanofi-Aventis, and Genentech BioOncology. The financial relationships of several of his coauthors are detailed in the paper.

J Clin Oncol. Published online November 16, 2009. Abstract

AN INTERESTING WAY TO LOWER COST

November 24, 2009 — In the United Kingdom, the National Health Service (NHS) has decided not to make 2 more cancer drugs available because of cost. This time, the axe has fallen on sorafenib (Nexavar) for liver cancer and (so far) on bevacizumab (Avastin) for metastatic colorectal cancer.

The use of these drugs for these indications is not cost-effective, according to the National Institute for Health and Clinical Excellence (NICE).

Among other cancer drugs that have been deemed not cost-effective are 4 products for renal cell cancer, which caused an outcry from British oncologists when it was announced last year. The 4 drugs are bevacizumab, sorafenib, sunitinib (Sutent), and temsirolimus (Torisel).

The decision for sorafenib, issued last week, noted that the lowest cost estimate was £52,600 per quality-adjusted life-year (QALY) gained, which is substantially higher than the £30,000 maximum set by NICE for being a "cost-effective use of NHS resources." This decision, a final appraisal, is published in detail on the NICE Web site.

A similar decision was made this week for bevacizumab use in metastatic colorectal cancer. This time the cost of the drug was calculated as £36,000 per QALY. However, this decision is preliminary, and the manufacturer, Roche, has said that it will continue to work with NICE on making the drug available. The company has already offered a scheme to lower the cost of treatment from an initial cost estimate of £62,000 per QALY, according to press reports.

Both of the decisions have sparked headlines about cancer patients being denied life-prolonging drugs. A particularly vocal criticism came from prominent oncologist Karol Sikora, MD, medical director of Cancer Partners UK and a former chief of the World Health Organization Cancer Program. Writing in the Daily Mail online after the sorafenib verdict, he said that, "as an oncologist, I despair of this decision."

"Doctors like me will now be put into a horrible position," he writes.

"It is our ethical duty to tell patients that this drug is one of the most advanced and effective ways of dealing with liver cancer. But then we will have to let their hopes down by explaining that it is not available on the NHS," he continues.

"That is no way to treat people when they are struggling to cope with a killer disease. Without hope, their final days will be all the more agonizing," Dr. Sikora says.

However, this is also the point that one reader hones in on in an online comment that questions spending "vast amounts of money on extending the lives of people who are going to die." Dr. Sikora says that the effects of sorafenib in liver cancer are "striking." Since it has been marketed, it has prolonged the lives of liver cancer patients by an average of 3 months — but he emphasizes that this is only an average, and some patients have not had any gain at all, whereas others have gained 2 to 3 years.

He also points out that the British decision about sorafenib puts it "hopelessly out of step with the rest of Europe," because every other country within the European Union makes the drug available on the state's healthcare or insurance system.

Are Some Cancers Less Fashionable?

"The denial of sorafenib highlights the way some forms of cancer seem to be politically more fashionable than others, with funding skewed in the direction," Dr. Sikora writes.

Breast cancer is the classic example, he says. Its high profile is reflected in the large sums given to screening programs, clinics, drug treatments, and publicity campaigns. He recalls that when trastuzumab (Herceptin) came onto the market, the UK Health Secretary at the time, Patricia Hewitt, announced that it would be available on the NHS even before NICE had concluded its investigation into cost-effectiveness.

But other major killers are badly neglected and attract little political enthusiasm, Dr. Sikora notes, citing liver and lung cancer as examples.

"I passionately believe that all patients should be treated equally," he says, and "should not be subject to vagaries of political fashion."

FOLATE SUPPLEMENTATION INCREASES CANCER RISK

November 23, 2009 — Folic acid and vitamin B supplementation was associated with an increase in cancer incidence, cancer mortality, and all-cause mortality in a new analysis with long-term follow-up of data from 2 trials conducted in Norway, where there is no folic acid fortification of foods.

The results are reported in the November 18 issue of the Journal of the American Medical Association.

The authors, led by Marta Ebbing, MD, from Haukeland University Hospital in Bergen, Norway, say that these results, although in need of confirmation, suggest that there is a need for "safety monitoring" because there is now widespread folic acid fortification of foods and increasing use of folic acid in dietary supplements.

However, the authors of an accompanying editorial points out that data from the United States, where there has been mandatory folic acid fortification of flour and other foods since 1998, have been showing a significant decrease in cancer incidence. "These national incidence rates do not support a substantial population-wide adverse effect of the magnitude suggested in the study," write the editorialists, Bettina F. Drake, PhD, MPH, and Graham Colditz, MD, DrPH, both from the Washington University School of Medicine in St Louis, Missouri.

"The population data from the United States do not suggest that there is a problem," Dr. Drake said in an interview with Medscape Oncology. She pointed out that folate supplementation used in the study resulted in much higher blood levels than would be seen after eating foods fortified with folic acid. In addition, the study was conducted in individuals with heart disease and was of limited duration.

The findings from this study "do not nullify the potential long-term benefits that folic acid fortification may have on population health," Dr. Drake explained. The measure was introduced to reduce neural tube defects in newborns (which arise from folate deficiency during pregnancy). A reduction was seen within a "few years," the editorialists note.

Concerns about a link between cancer and folic acid supplementation have been raised previously, most recently with regard to colorectal cancer, as reported by Medscape Oncology. At that time, leading expert on nutrition and cancer Walter Willet MD, DrPH, from the Harvard School of Public Health in Boston, Massachusetts, said: "I am certain that we are not causing an epidemic of colorectal cancer with folic acid fortification of flour." He added that there was a small increase in the incidence of this cancer soon after fortification was introduced, but this coincided with an increase in colonoscopy, and he pointed out that mortality rates from this cancer have been declining steadily.

Latest Results from Norway

The latest results come from 2 trials conducted in 6837 patients with ischemic heart disease, in which half the participants took supplements of vitamin B (including folic acid) to lower homocysteine levels to see if this would reduce cardiovascular outcomes. It did not, and these results are in line with other large trials. At the same time, both trials showed — independently — an increase in cancer in the supplementation group, compared with the placebo group, but this was not statistically significant.

In these 2 trials, participants took supplements containing folic acid (0.8 mg/d), vitamin B₁₂ (0.4 mg/d), and B₆ (40 mg/d), or various combinations of these. This dose of folic acid is 4 to 6 times higher than the average dose delivered by the mandatory fortification in the United States, and is twice the recommended daily allowance, the authors note, although they add that it is below the tolerable upper intake level of 1 mg/d set by the US Institute of Medicine.

The current analysis pooled results from the 2 trials, which had a median participation of 39 months, and added data from an observational posttrial follow-up of 38 months, giving a total duration of around 5.5 years. The authors note that pooling the data from the 2 trials is "justified" because they were nearly identical.

This pooled analysis found a statistically significant increase in cancer incidence, cancer mortality, and all-cause mortality.

Cancer Incidence, Cancer Mortality, and All-Cause Mortality Rates From the Pooled Analysis

End point	Supplement Group	Placebo Group	Hazard Ratio	95% Confidence Interval	P value
Cancer incidence	10%	8.4%	1.21	1.03–1.41	.02
Cancer mortality	4%	2.9%	1.38	1.07–1.79	.01
All-cause mortality	16.1%	13.8%	1.18	1.04–1.33	.01

These results for cancer outcomes are not supported by other studies of homocysteine-lowering vitamin B trials, the authors note.

Increased Incidence Driven by Lung Cancer

The increase in cancer incidence and mortality was "mainly driven by an increase in lung cancer incidence," the authors write. They also pointed out that 94% of the subjects who developed lung cancer were either current or former smokers.

So the "real headline of this study should be that smoking increases the risk of lung cancer," according to the Council for Responsible Nutrition, which issued a statement about the study.

Cancer Decreasing Significantly

In their editorial, Drs. Drake and Colditz write that these results indicate an excess of approximately 3.5 new cases of cancer per 1000 people per year, and 1 excess case of lung cancer per 1000 people per year. The excess deaths correspond to 1.7 cancer deaths per 1000 people per year.

"These numbers, if generalizable to the United States, would be substantial at the overall levels of total cancer incidence and mortality," they write. In addition, an increase in lung cancer incidence would be expected.

"However, the rates of total cancer incidence decreased significantly from 2001 to 2005, and the lung cancer incidence has also declined significantly," they point out.

Although the study suggests there is an association between folic acidsupplementation and an increase in cancer, the US population data suggest that there isn't a problem with folic acid fortification of foods and cancer, Dr. Drake told Medscape Oncology. Folic acid fortification has been mandatory in the United States for more than 10 years and, given the results of this study, we would have expected a significant increase in the incidence of cancer by now, she suggested.

One of the issues with clinical trials is that observations are reported with a short time frame after the implementation of an intervention, the editorialists note. This can often lead to "looking for effects that fit the time frame," they add. "By analogy, when keys are missing it is common to look for them under the lamppost where the light is, rather than in the murky location where the keys were more likely to have been dropped."

One of the coauthors on the paper, Klaus Meyer, PhD, is employed at the laboratory of Bevital AS. The other authors and both editorialists have disclosed no relevant financial relationships.

JAMA. 2009;302:2119-2126, 2152-2153.

NOVEL BIOMARKERS FOR CANCER CHEMOTHERAPY

November 23, 2009 — Advances in genomics, biotechnology, and molecular pathology have generated many candidate biomarkers that might help predict response to cancer therapy. The hope is that biomarkers will enhance the effectiveness and safety of cancer care by allowing physicians to tailor treatment to individual patients.

"This is an exciting time, in that we see that the past 30 years of basic research into understanding what actually causes cancer is beginning to pay off," said Lewis Cantley, PhD, director of the Cancer Center at Beth Israel Deaconess Medical Center in Boston, Massachusetts. "That knowledge is leading to therapies that are actually working."

Dr. Cantley, who moderated a press briefing during the AACR-NCI-EORTC 2009 International Conference on Molecular Targets and Cancer Therapeutics, noted that there is a lot of excitement in this area, and that "personalized cancer treatment and precision medicine are 'buzzwords'."

During the briefing at the meeting, researchers presented new data on markers of prognosis associated with metastatic and HER2-positive breast cancers, renal cell carcinoma, and other advanced solid tumors.

PK13K: A Novel Therapeutic Approach?

Phosphatidylinositol 3-kinase (PI3K) is thought to play an important role in tumorigenesis, and the PI3K signaling pathway is frequently dysregulated in a large spectrum of human tumors. Early data suggest that targeting PIK3CA, a mutation of the p110 subunit of PI3K, holds promise as a novel therapeutic approach.

In a small phase 1 trial, study author Filip Janku, MD, PhD, a clinical research fellow at the University of Texas M.D. Anderson Cancer Center in Houston, explained that 4 of 10 patients (40%) treated with a protocol that included a drug targeting the PI3K-AKT-mTOR pathway experienced a partial response.

When broken down by individual disease, there were 2 responses in 3 endometrial cancers (67%), 1 in 4 ovarian cancers (25%), and 1 in 1 breast cancer (100%) .

Dr. Janku and colleagues analyzed 117 tumor samples from patients with advanced cancers of various types and observed that 12% had PIK3CA mutations. The mutations appeared to be most frequent in endometrial, ovarian, head and neck, breast, and colon cancers; no mutations were found in patients with melanoma or cervical cancer.

"The numbers are very small," said Dr. Janku, pointing out that although the results were intriguing, they needed to be interpreted with caution and confirmed in a larger population of patients.

Targeting Metastatic and HER2 Breast Cancers

The inherited variation of the gene cytochrome P450 2D6 (CYP2D6) and the use of CYP2D6-inhibiting medications can negatively affect overall survival in patients with metastatic breast cancer, said study author Laureen Lammers, PharmD, from Erasmus MC, in Rotterdam, the Netherlands.

"The CYP2D6 phenotype was an important predictor of treatment outcome in women with hormone-receptor-positive metastatic breast cancer who were treated with tamoxifen," said Dr. Lammers, PharmD. The use of drugs that inhibit CYP2D6 also worsened the outcome of tamoxifen therapy, and "should therefore be discouraged," she explained. One class of drugs that inhibit CYP2D6 are the selective serotonin reuptake inhibitors, and advice to avoid SSRIs in patients receiving tamoxifen was highlighted earlier this year. "We recommend that doctors avoid the combination of CYP2D6 inhibitors together with tamoxifen, not only in the adjuvant setting but also for patients who are treated for metastatic breast cancer," said Dr. Lammers.

The metabolism of tamoxifen is complex, but it is known that CYP2D6 is necessary to metabolize it into the active metabolite endoxifen. In their study, Dr. Lammers and colleagues reviewed patient charts for 99 women who received tamoxifen treatment for hormone-receptor-positive metastatic breast cancer, and analyzed the data to assess patient and tumor characteristics, time to progression, the use of CYP2D6 inhibitors, and overall survival.

They found that patients with a poor CYP2D6 metabolizer phenotype had worse overall survival than those who were extensive metabolizers (hazard ratio [HR], 2.11; P = .031). The time to progression was also shorter in poor metabolizers than in extensive/intermediate metabolizers (1.7 vs 2.9 years; P = .089). Overall survival was also shorter (5.4 vs 9.9 years).

These findings were also true for patients taking tamoxifen who were also taking drugs that inhibit CYP2D6, the researchers noted.

A second presentation, also focused on breast cancer, suggested that a protein known as Trim62 could be a potential biomarker to predict the biologic response of breast cancer cells to anti-HER2 therapeutics such as lapatinib (Tykerb).

Small amounts of the cell-cycle inhibitory protein p27 are predictive of a poor outcome in breast cancers. Trim62 appears to be responsible for the misregulation of the regulatory protein p27 in HER2-positive breast cancer tumors. Understanding the mechanism of p27 mislocalization in breast cancers might offer insight into pathways of oncogenic transformation, reported researchers from the Fred Hutchinson Cancer Research Center in Seattle, Washington. It might also provide new markers for predicting clinical responses to specific therapies.

In tumor cells, levels of p27 are typically lower within the cell's nucleus while, at the same time, they are retained or increased in the cytoplasm, explained lead author Claire M. Faltermeier, a research assistant in the lab of Jim Roberts, MD, PhD, at the Hutchinson Center's Basic Sciences Division. In the nucleus, p27 functions as a tumor suppressor by inhibiting cell proliferation, but new evidence suggests that cytoplasmic p27 has an oncogenic action and might interact with the GTPase RhoA to promote cellular migration and motility.

"Just like Dr. Jekyll and Mr. Hyde, p27 has a good side and a bad side," she said at the briefing.

Cytoplasmic p27 could be a marker of tumor cell invasiveness and metastatic potential and, to further investigate the mechanism of p27 mislocalization in breast cancers, Ms. Faltermeier and colleagues developed antibodies that reliably detected cytoplasmic p27. Using the antibodies, they also identified a subset of breast cancers positive for HER2 that exhibited increased amounts of cytoplasmic p27.

In parallel experiments, they discovered that Trim62, an E3 ubiquitin ligase, regulates the stability of p27, and that is it overexpressed in HER2-positive breast cancers.

The researchers investigated the role of Trim62 in modulating the response of breast cancer cells to anti-HER2 therapeutics. Lapatinib, which is an HER2/epidermal growth-factor receptor inhibitor, increased levels of p27; this increase in p27 was observed exclusively in the nucleus. Reduction of Trim62 increased cellular sensitivity to lapatinib, and when Trim62 levels were reduced in HER2-positive cancer cells, p27 that was in the cytoplasm moved to the nucleus and the cells stopped proliferating. Conversely, overexpression of Trim62 had the opposite effect.

"Collectively, our results suggest that Trim62 underlies the misregulation of p27 in HER2-positive breast cancer cell lines," the authors write.

Plasma Biomarkers Predict Outcomes in Renal Cancer

Although the findings are preliminary, researchers have identified several plasma biomarkers that appear to be predictive of overall survival in advanced renal cell carcinoma (RCC).

A component of the phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) was to identify plasma biomarkers for possible prognostic value. TARGET demonstrated sorafenib (Nexavar) to be effective and safe for patients with advanced RCC in whom first-line therapy had failed. The study consisted of 903 patients with advanced clear cell RCC who were randomized to receive either sorafenib or placebo.

Carol Peña, PhD, associate director for clinical cancer biomarkers at Bayer HealthCare Pharmaceuticals, and colleagues conducted an analysis on a subset of the patients enrolled in TARGET to evaluate the relation between biomarker levels and outcomes.

"We looked at biomarkers for prognosis of RCC in the absence of treatment and also looked at biomarkers that predict response to sorafenib," said Dr. Peña.

Plasma levels of vascular endothelial-growth factor (VEGF), soluble VEGF receptor (VEGFR)-2, CAIX, TIMP-1, and p21 Ras were measured at baseline and after 3 and 12 weeks of treatment. Using the median baseline level of each biomarker to define high and low levels, univariate analysis of patients from the placebo group showed that elevated VEGF (HR, 1.65; P = .002), CAIX (HR, 2.26; P = .034), TIMP-1 (HR, 3.34; P = .001), and p21 Ras (HR, 2.49; P = .016) correlated with poor prognosis.

However, multivariate analysis of CAIX, TIMP-1, Ras, and VEGF together with clinical variables in patients in the placebo group showed that TIMP-1 was independently prognostic for survival. In this exploratory analysis, explained Dr. Peña, there was also no correlation between baseline levels of plasma VEGFR-2, CAIX, TIMP-1, or Ras and the efficacy of sorafenib.

The sample was small and the study was performed retrospectively, so further trials are needed, she said. "But it suggests that TIMP-1 may have value as a prognostic marker for renal cell carcinoma."

AACR-NCI-EORTC 2009 International Conference on Molecular Targets and Cancer Therapeutics: Abstracts B134, C118, A36, A64. Presented November 9, 2009.

GEMCITABINE AND CISPLATIN FOR SALIVARY TUMORS

Cancer. 2009 Nov 18. [Epub ahead of print]

A phase 2 study of platinum and gemcitabine in patients with advanced salivary gland cancer: a Trial of the NCIC Clinical Trials Group.

Laurie SA, Siu LL, Winquist E, Maksymiuk A, Harnett EL, Walsh W, Tu D, Parulekar WR.

Department of Medical Oncology, Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.

BACKGROUND:: Salivary gland cancers are rare, histologically diverse, and varied in their biologic behavior and responsiveness to systemic therapy. To the authors' knowledge, there currently is no standard chemotherapy for these tumors, but cisplatin-based regimens are often used. This phase 2 trial evaluated the combination of gemcitabine with cisplatin (carboplatin in those with protocol-defined contraindications to cisplatin). METHODS:: Fit, consenting adult patients had advanced, metastatic, or locoregionally recurrent salivary gland cancer (any histologic subtype) that was not suitable for radiation or surgery. Therapy was comprised of gemcitabine at a dose of 1000 mg/m(2) administered intravenously on Days 1 and 8, and cisplatin at a dose of 70 mg/m(2) on Day 2, of a 21-day cycle. If carboplatin was substituted, it was administered on Day 1, targeted to an area under the concentration-time curve of 5 mg/mL/s. Response was assessed every 2 cycles according to Response Evaluation Criteria In Solid Tumors. Patients received up to 6 cycles. The primary endpoint was objective response. A 2-stage design was used, with a response rate of 45% required to declare the regimen active. RESULTS:: Thirty-three eligible patients were enrolled, of whom 30 were response evaluable. Eight objective responses were observed (1 complete and 7 partial) for a response rate of 24% (95% confidence interval, 11-42%), with responses observed in all histologic subtypes. Toxicity was within that expected for this combination. CONCLUSIONS:: This regimen did not meet the predefined criteria to be declared active in advanced salivary gland cancers. Enrollment of patients with these rare cancers into well-designed clinical trials remains an urgent priority. Cancer 2010. (c) 2009 American Cancer Society.

DIAMANTIDOU SPEAKING

Oncology. 2009 Nov 17;77(5):293-299. [Epub ahead of print]

Cetuximab-Based Treatment of Metastatic Anal Cancer: Correlation of Response with KRAS Mutational Status.

Lukan N, Ströbel P, Willer A, Kripp M, Dinter D, Mai S, Hochhaus A, Hofheinz RD.

III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Deutschland.

Background: No standard chemotherapy regimen can be defined for patients with metastatic squamous cell carcinoma of the anus due to the low incidence of this disease and the high cure rate of localized tumors. Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far. Methods: We report on 7 patients with metastatic anal cancer treated with cetuximab - a chimeric antibody against EGFR - on a compassionate use basis along with the results of KRAS mutational analysis. Results: Marked tumor shrinkage was noted in several patients using cetuximab monotherapy or cetuximab/irinotecan combination as first or subsequent treatment line (usually after failure of cisplatin-based regimens). Two out of seven patients harbored KRAS mutations. Both patients had progressive disease receiving cetuximab, while the remaining 5 patients had either a partial remission (n = 3), a minor remission (n = 1) or no change lasting >/=6 months after previous rapid tumor progression. Conclusion: Cetuximab-based treatment appears to be a valuable treatment option for patients with metastatic KRAS wild-type anal cancer after failure of or as an alternative to cisplatin/5-fluorouracil-based therapy. Copyright © 2009 S. Karger AG, Basel.

ESTHESIONEUROBLASTOMA-A RARE TUMOR

J Neurooncol. 2009 Nov 19. [Epub ahead of print]

Advanced adult esthesioneuroblastoma successfully treated with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine.

Turano S, Mastroianni C, Manfredi C, Biamonte R, Ceniti S, Liguori V, De Simone R, Conforti S, Filice A, Rovito A, Viscomi C, Patitucci G, Palazzo S.

Mariano Santo Hospital, UOC Oncologia Medica Azienda Ospedaliera Cosenza, Cosenza, Italy, galactus76@yahoo.it.

The esthesioneuroblastoma is a rare neuroendocrine tumor that derives from the olfactory cells. In the last 20 years, around 1,000 cases have been described, with an overall survival rate of 60-70% at 5 years. The most common symptoms are nasal bleeding, nasal clogging and, in locally advanced cases, signs/symptoms of intracranic hypertension such as papilla edema, cefalea, and vomiting. The standard treatments are surgery and radiotherapy. Chemotherapy can be used in an adjuvant/neoadjuvant setting and in the metastatic phase, even if its role is still not established with certainty. Here, the case is reported of a young man (38 years old) with a locally advanced esthesioneuroblastoma. Two months before coming to our clinic, he had been treated elsewhere with debulking surgery through bilateral frontal craniotomy. After surgery, MRI showed residual disease in the nasal cavities and in the medial wall of the orbits responsible for blindness and bilateral exophthalmos within a month: a very short time. Octreoscan and whole body CT scan confirmed a locally advanced disease, in the absence of metastases. Chemotherapy was begun with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine with granulocyte colony-stimulating factor (G-CSF) support after every cycle. Soon after the first cycle, an important reduction of pain and decrease of the exophthalmos and vertigos was observed. No improvement in blindness was seen. The patient is still stable after 24 months of follow up.

INDUCTION CHEMOTHERAPY WITH CETUXIMAB

J Clin Oncol. 2009 Nov 16. [Epub ahead of print] Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial. Kies MS, Holsinger FC, Lee JJ, William WN Jr, Glisson BS, Lin HY, Lewin JS, Ginsberg LE, Gillaspy KA, Massarelli E, Byers L, Lippman SM, Hong WK, El-Naggar AK, Garden AS, Papadimitrakopoulou V. Departments of Thoracic/Head and Neck Medical Oncology, Head and Neck Surgery, Radiation Oncology, Biostatistics, Radiology, and Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX. PURPOSE: To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m(2) and carboplatin (area under the curve = 2) with cetuximab 400 mg/m(2) in week 1 and then 250 mg/m(2) (PCC). PATIENTS AND METHODS: Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis. RESULTS: After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046). CONCLUSION: ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.

PMID: 19917840 [PubMed - as supplied by publisher]

ALCOHOL CUTS RISK FOR HEART DISEASE

November 20, 2009 — Spanish men who drink alcohol have a reduced incidence of coronary heart disease (CHD), according to results in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) trial, published in the November 19 Online First issue of Heart.

"Spain is the world's third largest wine producer and ninth largest beer producer. In 2003, Spain was also in sixth position in the world ranking of alcohol consumption," write Larraitz Arriola, MD, from the Public Health Department of Gipuzkoa, Basque Government, San Sebastian, Spain, and colleagues.

Spain also has one of the lowest CHD mortality rates in the world, along with China, Switzerland, and France.

Although the association between alcohol consumption and CHD has been widely studied, with most studies showing a reduced risk for CHD with moderate alcohol intake, "there are numerous discussions regarding whether this association is causal or biased," the study authors write.

Inverse Association Between Alcohol Intake and CHD

The aim of this study was to describe the association between alcohol intake and CHD risk in the EPIC cohort.

The investigators assessed the alcohol intake of 15,630 men and 25,808 women for a median of 10 years from their responses to a validated dietary history questionnaire.

Participants reported how many glasses of beer, cider, wine, sweet liquor, distilled spirits, or fortified wines they consumed per day or week during the 12 months before they were recruited into EPIC. Total alcohol intake was calculated by multiplying the average ethanol content of a standard glass of whatever type of alcohol was consumed. In Spain, a "standard drink or glass" is estimated to contain approximately 10 g of alcohol.

Participants also provided information on lifestyle, including exercise and tobacco use, and other potential risk factors for heart disease, such as obesity and high cholesterol levels. All were free of CHD at baseline.

During the 10 years of follow-up, there were 609 coronary events (481 in men and 128 in women), for an incidence rate of 300.56/100,000 person-years for men and 47.93/100,000 person-years for women.

The investigators found an inverse association between alcohol consumption and CHD.

In a multivariate analysis that adjusted for smoking status, height, educational level, age, physical activity, waist-to-hip ratio, vitamin E, antithrombotic and antihemorrhagic drugs, and energy intake, the researchers found that in men, moderate, high, and very high alcohol consumption was associated with a reduced risk for CHD.

The adjusted hazard ratio (HR) was 0.90 (95% confidence interval [CI], 0.56 - 1.44) for former drinkers, 0.65 (95% CI, 0.41 - 1.04) for low consumers, 0.49 (95% CI, 0.32 - 0.75) for moderate consumers, 0.46 (95% CI, 0.30 - 0.71) for high consumers, and 0.50 (95% CI, 0.29 - 0.85) for very high consumers.

"The HR decreases in the first two categories and then remains stable for the moderate, high and very high categories," the study authors point out.

Women also benefited from alcohol intake, but the effects were not statistically significant, perhaps because of the small number of coronary events they experienced, the study authors write.

A limitation of the study could be residual or unmeasured confounding, they suggest. "Although we adjusted for several potential confounders in our different models, we could never be sure about the remaining confounders," they write. In addition, some of the participants may have changed their alcohol consumption when they became aware of their heart disease symptoms.

The study authors conclude: "Alcohol intake in men aged 29-69 years was associated with a more than 30% lower CHD incidence. This study is based on a large prospective cohort study and is free of the abstainer error."

Not an Interventional Study

William S. Harris, PhD, director of cardiovascular health research at the University of South Dakota, Sioux Falls, disagrees with this conclusion.

The assertion that alcohol lowers heart disease risk by almost a third, at least in men, misstates the findings, he told Medscape Cardiology.

"This is an epidemiological study, not an interventional study. Just because people who report drinking more have less heart disease does not mean that drinking lowers risk for heart disease. This is an extremely common logical fallacy," he said.

The study supports the idea that alcohol may have some cardioprotective effects. However, "until you take a group of people and randomly assign them to drinking alcohol or not, which is never going to happen, and then follow them for...[a certain amount of] years to see who has heart attacks, you can never say that 'alcohol lowers heart disease risk,' all you can say is that people who report drinking...[times] alcoholic beverages per day have less heart disease than people who drink...[a certain amount of] drinks per day. This is the kind of study that generates hypotheses, not conclusions."

In response to the comments by Dr. Harris, Dr. Arriola told Medscape Cardiology that, of course, she agrees her study is an epidemiologic study.

Dr. Arriola also told Medscape Cardiology: "As Dr. Harris says, there is no possible interventional study to investigate the association between alcohol consumption and CHD. So cohort studies are probably the best and the only ethical approach to study the relationship."

She added: "Of course, cohort studies have their limitations. But what we found in our study was that those men who drank alcohol had less CHD than those who did not drink. And that is what we tried to explain in the paper."

Dr. Arriola and Dr. Harris have disclosed no relevant financial relationships.

Heart. Published online November 19, 2009. Abstract.

GENETIC BASIS OF HEARING LOSS FROM CISPLATIN

November 20, 2009 — Scientists at the University of British Columbia, Vancouver, Canada, have identified genetic variants associated with ototoxicity that occur in more than half of children treated with cisplatin. The report, published online November 8 in Nature Genetics, raises the possibilities that individuals at higher genetic risk for ototoxicity could receive lower cisplatin doses, alternative drug treatments, or be chosen for otoprotectant studies.

Cisplatin is a highly effective platinum-based chemotherapeutic agent whose anticancer action is the result of platinum complexes that bind and cause DNA cross-linking, eventually resulting in apoptosis. Adverse effects include nephrotoxicity, neurotoxicity, and ototoxicity. Hearing loss is reported in 10% to 25% of adults who receive cisplatin and in 41% to 61% of children. Hearing loss that predates language acquisition is particularly serious, and cisplatin therapy is often reduced or discontinued when ototoxicity occurs in young children.

Participants in this study were recruited by the Canadian Pharmacogenomics Network for Drug Safety, a consortium that studies adverse drug reactions in children. The discovery group consisted of 54 children from pediatric oncology units who had received cisplatin therapy. Among them, 33 had "serious cisplatin-induced toxicity," as noted in moderate to severe hearing deficit (loss of 25 dB or more). The others experienced no significant hearing loss.

Ototoxicity May Be More Common in Boys

A replication study of 112 additional children treated with cisplatin at pediatric oncology units throughout Canada found 73 with moderate to severe hearing loss. In the replication group, boys were significantly more likely to demonstrate ototoxicity (67% boys vs 50% girls; P = .042). Interestingly, ototoxicity was far less frequent in children with germ-cell tumors (6.6%) than with other pediatric cancers (26.8%; P = .0006).

"We are unsure of the cause of this [sex effect] and only observed this difference in the second cohort of patients," said first author Colin J. D. Ross, PhD, research associate, Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, and the Child and Family Research Institute, Children's and Women's Health Research Centre of British Columbia, Vancouver, via email to Medscape Pathology & Lab Medicine.

"As our work in this area continues, we will be further examining this gender difference," Dr. Ross said. The lower ototoxicity in children with germ-cell tumors is also of interest. "This may be related to different cisplatin administration protocols for patients with this tumor type," said Dr. Ross, "and we are following up on this finding now."

David R. Freyer, DO, MS, pediatric oncologist, director of the LIFE Survivorship and Transition Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, and Department of Pediatrics, Keck School of Medicine, University of Southern California–Los Angeles, observed by telephone to Medscape Pathology & Lab Medicine, "I'm not sure if that was a reflection of some other covariants...the dose of the cisplatin, gender. Those germ-cell patients actually tend to be older, interestingly enough," he said. Dr. Freyer was not involved in the study.

"To my knowledge, there are no data that adequately explain why young children are affected more than older children are," Dr. Freyer continued. "Studies have shown that the breakpoint seems to be around 4 or 5 years of age. If you're younger than that when you get treated...there's more of an ototoxic effect than there is at an older age," he said. Hearing loss occurs in older children and teenagers but is more frequent in young children.

TPMT and COMT Associated With Ototoxicity

Nearly 2000 single nucleotide polymorphisms (SNPs) in participants' DNA were analyzed to identify variants of 220 genes that influence the "absorption, distribution, metabolism, and elimination" of drugs and drug metabolites, and any association with cisplatin ototoxicity. Variants of genes TPMT and COMT were highly associated with cisplatin-induced hearing loss.

A TPMT variant was found in 27.3% of children with cisplatin ototoxicity in the discovery cohort and 21.9% of those in the replication group; the same SNP occurred in none of the discovery control patients and in only 2.4% of replication cohort control patients (P = .00022; after Bonferroni correction, P = .032). A COMT variant was present in 33.3% and 29.2% of children with cisplatin ototoxicity in the discovery and replication groups, respectively; the same SNP occurred in 50.0% and 58.3% of children in the respective control cohorts (P = .00055; but after Bonferroni correction, P = .076).

DNA sequencing of these genes demonstrated 2 additional variants in TPMT that impair TPMT enzyme activity, and 1 additional variant associated with cisplatin ototoxicity in COMT (P = .000182; after Bonferroni correction, P = .0261). Cisplatin-associated hearing loss was more severe (P = .0000027) and had earlier onset (P = .00009) in children with more than 1 risk allele.

"We are enrolling additional patients in our studies to address this question [of allele effects], because of the rarity of some of the risk alleles," said Dr. Ross. "Only 3 patients were homozygous for TPMT risk variants, all...developed serious hearing loss. Similarly, only 5 patients were homozygous for the COMT risk variant, all...developed serious hearing loss," he noted.

In addition, the first TPMT risk allele mentioned occurred in 5% of people of European heritage, 1.7% of Asians, and 51.7% of Africans — the latter is consistent with the more common cisplatin-associated nephrotoxicity in blacks; data for ototoxicity in African populations are not known.

"Incredibly Important" Study

"This study...is just incredibly important, and the data are very compelling — preliminary, but compelling," said Dr. Freyer. He mentioned a collaboration planned between the Vancouver-based group and the Children's Oncology Group study, which will validate the results in a larger patient population.

"Some of those patients who are being studied for the gene mutation are also going to be treated with this preventative medication, called sodium thiosulfate," Dr. Freyer noted. If a preventative effect is confirmed across the population, it will be interesting to see whether children with these gene variants are preferentially protected, raising the possibility of targeted interventions in the future.

"That can be the direction that this is going," predicted Dr. Freyer. "Identify who these patients are at risk, right up front, and then target interventions toward that group, those most at risk."

Dr. Ross reported that the study was funded as part of the peer-reviewed Genome Canada Applied Health Research Program; pharmaceutical industry partners (which include Pfizer, Eli Lilly, Merck Frosst, and Janssen-Ortho) had no formal or informal role in this program of research. Dr. Freyer has disclosed no relevant financial relationships.

Nat Genet. Published online November 8, 2009.