RADIOTHERAPY AFTER LYMPHADENECTOMY FOR MELANOMA

November 3, 2009 — In melanoma patients with lymph node involvement, the use of radiation following lymphadectomy provided "dramatic improvement in local control" and "may be the new standard of care" for these patients.

This enthusiastic assessment came from the discussant of a new 217-patient melanoma study that was presented during the plenary session here at the American Society for Radiation Oncology (ASTRO) 51st Annual Meeting.

The discussant, Matthew Ballo, MD, from the University of Texas MD Anderson Cancer Center in Houston, was commenting on a phase 2 Australian study that shows, for the first time, that adjuvant radiation reduces the chance of melanoma returning.
In the randomized trial, melanoma patients treated with radiation after surgery had a statistically significantly lower risk of the disease returning to the lymph nodes than patients who did not receive radiation (19% vs 31%). Median follow-up was 27 months.

Dr. Ballo called the results "high-level evidence," purposely echoing the National Comprehensive Cancer Network's guidelines' terminology.

"I believe this is the only real advance in the treatment of melanoma in the past 15 years — since interferon came out," said lead study author Bryan Burmeister, MD, from Princess Alexandra Hospital in Brisbane, Australia, at an ASTRO press conference. He also believes that clinicians should now offer all nodal metastatic melanoma patients the option of radiation after surgery if they are at high risk for local recurrence.

"Eighty percent of patients who have lymph node dissection are at high risk of recurrence," he said.

Dr. Burmeister also noted that radiation is part of the routine protocol at some institutions, but that its effectiveness has never been proven.

"Until the trial was done, there has been a question about the value of radiation," he said.

Lymph node relapse or recurrence was the primary end point of the trial, and overall survival was one of the secondary end points.

"There is no evidence of a difference in overall survival between the radiation-therapy and observation groups," Dr. Burmeister told the audience at the plenary session.

This fact caused Dr. Ballo to temper his praise of the adjuvant therapy: "We cannot ignore the lack of overall survival benefit."

Dr. Ballo also noted that the trial needs "longer-term results", especially with regard to late toxicity, which is another secondary end point. Those toxicities include edema.

At High Risk for Recurrence

The multicenter study was undertaken in Queensland, Australia — "the melanoma capital of the world," said Dr. Burmeister.

The 217 patients all had completely resected nodal metastatic melanoma and were randomized to adjuvant radiotherapy (n = 109) and observation (n = 108). The patients had to have a minimum number of harvested nodes (partotid and neck, 2 to 25; axilla, 10; groin, 6).

They were at "significant risk" for lymph node field relapse based on any of the following:

• positive lymph nodes (at least 1 for partotid, 2 for neck and axilla, and 3 for groin)
• maximum lymph node size (30 mm or greater for partotid, neck, and axilla; 40 mm or greater for groin)
• extra-nodal spread

Dr. Ballo suggested that these requirements might have helped preclude any improvement in overall survival. "The disease burden may have been too high," he said.

The external-beam radiotherapy after lymphadectomy consisted of 48 Gy in 20 fractions over 4 weeks, said Dr. Burmeister.

There was a statistically significant improvement in lymph node field control with radiotherapy; 20 radiotherapy and 34 observation patients relapsed regionally (hazard ratio, 1.77; 95% confidence interval, 1.02 - 3.08; P = .041).

The early acute toxicity appeared "minimal," said Dr. Burmeister, with radiation dermatitis being the most common grade 3 adverse effect at 2 weeks. There were no grade 4 toxicities at either 2 or 6 weeks, he added.

The researchers have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 51st Annual Meeting: Abstract 3. Presented November 2, 2009.

GEMCITABINE AND CAPECITABINE FOR THYMIC EPITHELIAL TUMORS

Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs).

Palmieri G, Merola G, Federico P, Petillo L, Marino M, Lalle M, Milella M, Ceribelli A, Montella L, Merola C, Del Prete S, Bergaglio M, De Placido S, Di Lorenzo G.

Molecular and Clinical Endocrinology and Oncology Department, University Federico II, Napoli.

BACKGROUND: No previous prospective trials have been reported with capecitabine and gemcitabine (CAP-GEM) in patients with metastatic thymic epithelial tumors (TETs). We conducted a multicenter study to determine the activity and tolerability of this regimen in pretreated TETs. PATIENTS AND METHODS: A total of 15 patients were enrolled in the first stage of phase II study. All patients received CAP-GEM every 3 weeks. The primary end point was objective response rate (RR); secondary end points were toxicity, progression-free survival (PFS) and overall survival. RESULTS: Complete responses (CR) and partial responses were observed in three (20%) and three (20%) patients for a 40% RR, respectively. Grade 1-2 neutropenia, anemia and thrombocytopenia were the most common side-effects, noted in seven (46.7%), five (33.3%) and five (33.3%) patients, respectively. The most common grade 3 toxicity was neutropenia in three patients (20%). Median PFS was 11 months (95% confidence interval 4-17). The 1- and 2-year survival rates were 80% and 67%, respectively. CONCLUSION: We have decided to publish the preliminary results because this regimen was more active than that expected. Although our results are preliminary, CAP-GEM shows activity and safety in pretreated TETs. Furthermore, multicenter trials, also in first-line setting, are necessary to confirm our results.

KETOCONAZOLE AFTER TAXANE FAILURE

Activity of ketoconazole after taxane-based chemotherapy in castration-resistant prostate cancer.

Nakabayashi M, Oh WK, Jacobus S, Regan MM, Taplin ME, Kantoff PW, Rosenberg JE.

Lank Center for Genitourinary Oncology, Department of Medical Oncology, and Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

OBJECTIVE To assess the efficacy of the androgen-synthesis inhibitor ketoconazole as a secondary hormonal therapy in patients with castration-resistant prostate cancer (CRPC) previously treated with chemotherapy, as persistent androgens appear to play a role in the development and maintenance of CRPC. PATIENTS AND METHODS We retrospectively identified 34 patients with CRPC who were treated with ketoconazole as a secondary hormonal therapy after paclitaxel- or docetaxel-based chemotherapy for CRPC. They were treated with ketoconazole 200-400 mg three times daily with or without hydrocortisone. Patients with previous use of ketoconazole were excluded. Half the patients had received estramustine as part of their chemotherapy regimen. The primary endpoint was the proportion of patients with a decline of >/=50% in their prostate-specific antigen (PSA) level. PSA progression was defined by the PSA Working Group 1 Criteria. RESULTS Eight of the 32 evaluable patients (25%) had a PSA decline of >/=50%. The median time to progression (TTP) was 3 months (95% confidence interval, 1.2-5.4). A history of previous response to taxane-based chemotherapy was not associated with the response to ketoconazole. However, previous use of oestrogens for CRPC was significantly associated with a shorter TTP on ketoconazole (1.5 vs 10.2 months; P = 0.03). CONCLUSIONS Ketoconazole has moderate activity as secondary hormonal therapy in patients with CRPC previously treated with taxane-based chemotherapy, although the TTP was short. Previous treatment with oestrogenic therapy is associated with a shorter TTP.

MAXIPIME IS BACK

November 4, 2009 (Philadelphia, Pennsylvania) — Despite concerns raised after a meta-analysis suggested that increased mortality is associated with cefepime use in patients with febrile neutropenia and other infections, a new, more extensive meta-analysis should lay that fear to rest, researchers reported here at the Infectious Diseases Society of America (IDSA) 47th Annual Meeting.

"We found no significant increase in death among cefepime-treated patients with febrile neutropenia, [compared with those treated with] comparator drugs, either in trial data or in patient-level data," stated Peter Kim, MD, from the US Food and Drug Administration (FDA). "Our study found no plausible reason for mortality related to the drug's safety or lack of efficacy."

Cefepime is a fourth-generation cephalosporin approved by the FDA in 1996. It is widely used to treat pneumonia, urinary tract infection, skin and skin-structure infections, complicated gastrointestinal infections, and, empirically, febrile neutropenia, Dr. Kim explained.

In 2007, a meta-analysis of 38 trials found that 30-day mortality was higher in patients treated with cefepime than in those treated with other beta-lactam antibiotics (Lancet Infect Dis. 2007;7:338-348), so the FDA decided to undertake a more thorough meta-analysis to determine if febrile neutropenia patients treated with cefepime had higher mortality.

The FDA meta-analysis was based on 88 trials from inside and outside the United States, and included the 38 trials from the 2007 analysis. This FDA meta-analysis involved more than 9000 patients treated with cefepime, and more than 8000 patients treated with comparator drugs. In addition, the FDA meta-analysis included patient-level data from 35 trials, 7 of them on febrile neutropenia; the 2007 meta-analysis had no patient-level data.

Of the 88 trials examined in the FDA meta-analysis, 24 were in febrile neutropenia and 22 were in pneumonia. Ceftazidime was the comparator agent in 47 trials.

Thirty-day all-cause mortality was 6.2% for cefepime and 6% for the comparator agents. In the 24 febrile neutropenia trials, 30-day all-cause mortality was 6.5% and 5.6%, respectively.

Skin and skin-structure infections were the only clinical conditions associated with a significant increase in mortality related to cefepime use, but Dr. Kim cautioned that this was based on only 2 clinical trials with a small number of subjects.

Looking at patient-level data from 35 trials (5000+ treated with cefepime and 4000 with comparator drugs), 30-day all-cause mortality with cefepime was 5.63% and with comparator drugs was 5.68%. In the 7 febrile neutropenia trials with patient-level data, mortality rates were 7.9% and 6.5%, respectively.

Dr. Kim said that the data suggested that mortality is lower with cefepime in the United States than in other countries, and that the patients who died in febrile neutropenia trials appeared to die of underlying causes or cancer.

"This FDA meta-analysis [of cefepime] is very important. This drug is safe and there was no difference in 30-day all-cause mortality using a drug that also treats Gram-negative organisms," said Paul G. Auwaerter, MD, IDSA program chair and clinical director of the Division of Infectious Diseases at Johns Hopkins University School of Medicine in Baltimore, Maryland.

A cautionary note came from Richard Whitley, MD, from the University of Alabama at Birmingham, who said: "Cefepime is a good antibiotic, but we should restrict its use to those who really need it. This drug was used in high-risk patients already at risk for death, and that may be why a signal was raised in the earlier meta-analysis. A meta-analysis is not a randomized controlled trial. Nothing should be put in the drinking water."

Dr. Kim and Dr. Auwaerter have disclosed no relevant financial relationships. Dr. Whitley reports financial ties with Gilead, 3-V, Biosciences, and Chimerics.

Infectious Diseases Society of America (IDSA) 47th Annual Meeting: Abstracts 550 and 694. Presented October 30, 2009.

BAMIA THEE

Thymidine phosphorylase to dihydropyrimidine dehydrogenase ratio as a predictive factor of response to preoperative chemoradiation with capecitabine in patients with advanced rectal cancer. Boskos CS, Liacos C, Korkolis D, Aygerinos K, Lamproglou I, Terpos E, Stoupa E, Baltatzis G, Beroukas K, Papasavvas P, Dimopoulos MA, Bamias A. 1st Radiation Oncology Department, "Agios Savvas" Anticancer Institute, Athens, Greece. PURPOSE: To identify if thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and ratio TP/DPD levels in tumor tissues are potential predictive factors for response to combined preoperative chemoradiation with capecitabine, in patients with locally advanced rectal cancer (LARC). METHODS AND PATIENTS: Between 2004 and 2006, 28 patients with LARC (cT2-T4, N0-N2) were treated with neoadjuvant chemoradiation. Total radiation dose was 50.4 Gy and daily dose was 1.8 Gy in 5.5 weeks. Capecitabine was administrated 1,650 mg/m(2)/day, 7 days/week. Preoperative staging was based on combined computer tomography and endorectal ultrasound. Tissue samples, both neoplastic and normal ones, were endoscopically taken before treatment for TP and DPD measurement with ELISA. Levels of total proteins were calculated by the Bradford method. RESULTS: Median TP, DPD, ratio TP/DPD levels in the primary tumors were 32.85 U/mg, 18.73 U/mg, and 1.64 respectively. Median ratio TP/DPD of patients with proven pathological "response" (downstaging of the disease) was higher than the "no response" group, 4.40 and 1.42, respectively (P = 0.0001). Levels of TP and DPD in tumor tissue did not reveal any statistically important difference between the two groups. CONCLUSIONS: TP/DPD ratio is a possible predictive factor for tumor response after concomitant preoperative chemoradiation with capecitabine in LARC. J. Surg. Oncol. (c) 2009 Wiley-Liss, Inc.

PMID: 19877119 [PubMed - as supplied by publisher]

DIABETES SLOWS ALZHEIMER PROGRESSION!

October 29, 2009 — Rather than accelerating cognitive decline, diabetes mellitus (DM) appears to slow this decline in patients with Alzheimer's disease (AD), according to results of a new study.

This finding was unexpected in light of previous research that documented faster cognitive decline in diabetic patients without dementia.

The results may have important clinical implications, said the study's lead author, Caroline Sanz, MD, from the Department of Diabetology, Metabolic Diseases and Nutrition at the Institut National de la Santé et de la Recherche Médicale, Toulouse, France.

"DM could be a relevant factor in predicting the rapidity of cognitive decline in AD patients," she said in an email interview. "As well, it is hoped that earlier and prompt treatment of DM before dementia is diagnosed may prevent the cerebrovascular lesions and may delay the onset of cognitive decline."

The study results were published in the October 27 issue of Neurology.

Similar Cognitive Function

This study was part of the Réseau sur la maladie d'Alzheimer Français (REAL FR) study, a 4-year prospective cohort study of patients with AD and their caregivers from 16 memory centers in France.

Included were 608 patients who were enrolled between April 2000 and October 2002 and followed-up for 11 to 47 months (median, 26 months). At baseline, the subjects had a Mini-Mental State Examination (MMSE) score of between 10 and 26.

At the start of the study, 63 patients (10.4%) had DM. Patients were considered to have diabetes if they were taking antidiabetic medications and/or reported a history of DM.

Cognitive function was similar between those with and without diabetes (MMSE, 20 vs 21; P = .79).

Compared with nondiabetic patients, those with the disorder were more likely to be men, be somewhat younger, have hypertension and cardiovascular disease, and have a higher body mass index. Diabetic patients also had more limitations in activities of daily living.

Those with diabetes were using more medications than nondiabetic patients (5 vs 3). Among the diabetic patients, 16 were using diet alone to control their DM, 31 took oral blood glucose-lowering drugs, and 16 used insulin.

During the course of the study, researchers used the MMSE twice a year to assess cognitive function. They defined mild dementia as a MMSE score between 26 and 20 and moderate dementia as a MMSE score between 19 and 10.

During the study, 94 patients died, 76 withdrew consent, 67 were institutionalized, 65 were lost to follow-up, 59 left the study because of their own or their caregiver's medical problems, and 49 dropped out for other reasons. This left 198 patients at the end of the study.

Adjusted Model

The study found that cognitive decline was slower in patients with DM compared with patients without DM. In a model that adjusted for sex, age, education, dementia severity, cholinesterase-inhibitor use, and vascular factors, the mean difference in the rate of half-yearly cognitive decline between patients with and without DM was 0.38 MMSE points (SE = 0.15; P = .01).

Within the diabetes group, the rate of cognitive decline was similar between those using and those not using insulin (0.11; P = .68 in adjusted model) and between patients with diet-controlled diabetes compared with those taking antidiabetic medications (0.12; P = .65 in adjusted model).

Neuropathologic Differences

Neuropathologic differences between patients with and without DM may explain the slower cognitive decline among subjects with AD, said Dr. Sanz. Patients with diabetes may be more likely to have a mixed brain pathology (AD with cerebrovascular disease), and such patients tend to have a slower cognitive decline than patients with AD, she noted.

Diabetic patients with AD may take more cardiovascular medications such as antihypertension drugs, low-dose aspirin, or statins, and this might also contribute to a slower progression of cognitive decline. As well, insulin-sensitizing drugs may have beneficial cognitive effects.

One limitation of the study was that it lacked information on diabetes severity. In addition, underreporting of DM may have led to an underestimation of the effect of DM on cognitive decline.

Dr. Sanz pointed out that both diabetes and AD are common conditions in older people and that few effective treatment options exist to slow the progression of AD. "Identifying modifiable risk factors for prevention of AD is therefore important," she noted.

Dr. Sanz has disclosed no relevant financial relationships. For disclosures on other authors, please see original article.

Neurology. 2009;73:1359–1366. Abstract

NO NEED FOR HORMONE THERAPY FOR LOW RISK PROSTATE CANCER PATIENTS UNDERGOING RADIOTHERAPY

November 3, 2009 (Chicago, Illinois) — The practice of administering short-term hormone therapy to men with low-risk prostate cancer who undergo radiation therapy is not necessary.

The treatment does not improve survival in these men, according to the "greatly anticipated results" of a new study presented here during the plenary session of the American Society for Radiation Oncology (ASTRO) 51st Annual Meeting.

"This is a landmark, practice-changing study," said Matthew Smith, MD, who acted as a study discussant. Dr. Smith, who is from Harvard Medical School in Boston, Massachusetts, suggested that the broad use and uncertain benefits of short-term androgen deprivation fueled the anticipation about results.
This definitively establishes no benefit in men with low-risk disease," he continued. "Unquestionably, this is a setting where less is more," he said, after detailing the therapy's adverse effects.

However, short-term hormone therapy benefited men undergoing radiation for intermediate-risk prostate cancer, said Christopher U. Jones, MD, who presented the results on behalf of the Radiation Therapy Oncology Group (RTOG) 94-08 and is from Radiological Associates of Sacramento in California.

"The study is the first compelling evidence of survival benefit in men with intermediate risk," agreed Dr. Smith.

Despite these enthusiasms, both Dr. Jones and Dr. Smith explained that the new study is not the final word on short-term hormone therapy in intermediate-risk patients.

The radiation doses and techniques used in the current study, which started enrolling patients in 1994, are now dated, Dr. Jones said at a meeting press conference.

"In current practice, these intermediate-risk patients get a higher dose of radiation," he said, suggesting that modern radiation might eliminate the need for androgen deprivation in these patients.

Another RTOG study (08-15) is underway to evaluate more modern high-dose radiation methods and hormone therapy in these intermediate-risk patients, both he and Dr. Smith pointed out.

Comparable Outcomes in Low-Risk Patients

The landmark study presented at the meeting, with 1979 participants, is the largest prostate cancer study to date, and is still ongoing, Dr. Jones noted.

Originally, the study was designed to evaluate the treatment of men with low-risk prostate cancer only, but the definition of low risk evolved as the study got underway, Dr. Jones explained

"When we started this study in 1994, all of these patients were considered low risk," he said. As prostate-specific antigen (PSA) testing matured as a tool, it became clear that the study group could be further defined. "With the advent of PSA screening, we were able to further refine low- and intermediate-risk patients," he said.

Study participants were randomized to short-term androgen-deprivation therapy (2 months before and 2 months during radiation) plus radiation, or radiation therapy alone.

About a third of the patients were low risk (n = 685), which was defined as a Gleason score of 6 or less with a PSA level of 10 ng/mL or less and a tumor stage of T2a or less.

About one half of the patients were intermediate risk (n = 1068), which was defined as a Gleason score of 7, a Gleason score of 6 or less and a PSA of 10 to 20 ng/mL, or a Gleason score of 6 or less and stage T2b disease.

The remaining patients were high risk (n = 226), with Gleason scores of 8 to 10.

At 8 years, the overall and disease-specific survival rates were comparable in low-risk patients treated with hormones and radiation therapy than in those treated with radiation therapy alone.

"The combination of these 2 survival indicators suggests no need for hormone therapy in low-risk patients," Dr. Jones remarked.

Specifically, the overall survival rate at 8 years for patients treated with hormones and radiation therapy was 76%, compared with 73% for those treated with radiation therapy alone (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.83 - 1.39).

The disease-specific survival rate at 8 years for patients treated with hormones and radiation therapy was 98%, compared with 99% for those treated with radiation therapy alone (HR, 1.07; 95% CI, 0.83 - 1.39).

"Low-risk patients do not need to undergo the toxicities of hormone therapy," said Dr. Jones at a press conference, referring to hot flashes, loss of sexual function, liver toxicities, and other adverse effects.

Effective Therapy for Intermediate-Risk Patients

In the study, total androgen suppression was achieved with flutamide 250 mg twice daily and either goserelin 3.6 mg once a month or leuprolide 7.5 mg once a month.

The hormone therapy apparently benefited men with intermediate-risk disease.

At 8 years, the overall and disease-specific survival rates were favorable in intermediate-risk patients treated with hormones and radiation therapy, compared with those treated with radiation therapy alone.

Specifically, the overall survival rate at 8 years for patients treated with hormones and radiation therapy was 72%, compared with 66% for those treated with radiation therapy alone (HR, 1.23; 95% CI, 1.02 - 1.49).

"Among the intermediate-risk patients, there was a 23% greater chance of dying each year for patients treated with radiation alone," said Dr. Jones.

The disease-specific survival rate at 8 years for patients treated with hormones and radiation therapy was 98%, compared with 92% for those treated with radiation therapy alone (HR, 2.44; 95% CI, 1.47 - 4.04). "Patients treated with radiation alone were nearly 2 and a half times more likely to die from prostate cancer," said Dr. Jones.

The outcomes for the patients with high-risk disease were not as impressive as those for intermediate-risk disease, which probably reflects the fact that high-risk disease requires longer-term hormone therapy, Dr. Smith told the plenary audience.

Meaningful Results

"We wanted to know who needed short-term hormone therapy," said incoming ASTRO president Anthony Zietman, MD, about the original impetus behind the new study.

Although Dr. Jones's presentation emphasized 8-year data, the median follow-up time in the trial is a little more than 9 years, which approaches the length of time needed for meaningful results in prostate cancer, Dr. Zietman, who is from Harvard Medical School in Boston, told Medscape Oncology in an earlier interview. "Results need to be at least 10 years out to be meaningful."

He explained that the use of short-term androgen deprivation is not as widespread now as it has been in the past.

The use of short-term hormone therapy, especially leuprolide (Lupron), in low-risk prostate cancer patients undergoing radiation therapy jumped from about 10% of all such patients to about 50% during the mid- to late-1990s. "This almost became the norm with urologists," said Dr. Zietman.

The use tailed off somewhat when financial incentives to use the therapy ended, he said.

Although leuprolide use in low-risk patients was partly fueled by financial considerations, it was also probably spurred on by clinicians not sticking to evidence-based medicine, Dr. Zietman explained. "Clinicians took the evidence too far," he noted, referring to studies such as RTOG 86-10, in which the short-term therapy provided a number of benefits to men with locally advanced prostate cancer.

The new results provide some direction for clinicians, suggested Dr. Jones. "The study provides strong scientific evidence that shows us when to deliver hormone therapy with radiation in patients with localized prostate cancer," he said in a press statement.

American Society for Radiation Oncology (ASTRO) 51st Annual Meeting: Latebreaker. Presented November 2, 2009.

ANOTHER FAILURE OF ERYTHROPOIETIN

November 3, 2009 (San Diego, California) — A rigorously designed and conducted trial has shown that anemia treatment with darbepoetin alfa (Aranesp) is no better than placebo at reducing mortality, heart failure, heart attacks, or the need for dialysis in patients with diabetes, anemia, and chronic kidney disease (CKD).

If anything, darbepoetin alfa was associated with a higher risk for stroke and cancer-related mortality, said Marc A. Pfeffer, MD, PhD, who presented the data in a plenary session here at Renal Week 2009: American Society of Nephrology (ASN) 2009 Annual Meeting. Dr. Pfeffer is a senior physician in cardiovascular medicine at Brigham and Women's Hospital in Boston, Massachusetts.

He predicted that these findings would prompt clinicians to reconsider their use of darbepoetin. "One would have to ask themselves: What am I trying to achieve now that I know there's a risk?"

Several studies have shown that the "triple whammy" of diabetes, CKD, and anemia greatly increases the risk for all-cause mortality, Dr. Pfeffer explained. Anemia was considered a marker of risk because low hemoglobin is an independent risk factor for renal and cardiovascular events, especially among people with diabetes.

The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) was launched in 2004 to determine whether raising hemoglobin with darbepoetin in patients with diabetes, anemia, and CKD not requiring dialysis would lower the risk for death, cardiovascular morbidity, or death from end-stage renal disease. The trial was conducted at 623 centers in 24 countries; Dr. Pfeffer was the principle investigator.

A total of 4038 patients were randomized to receive darbepoetin alfa (n = 2012) or placebo (n = 2026). At baseline, the groups were comparable in age, sex, race, ethnicity, duration of diabetes, and history of cardiovascular disease, except for a significantly higher history of heart failure in the placebo group. The target hemoglobin level was 13 g/dL, and rescue therapy was instituted any time a patient's hemoglobin dropped below 9 g/dL. Double-blinding was maintained by having a computer determine who needed rescue therapy and directing clinicians to use prefilled syringes.

TREAT had 2 composite primary end points: a cardiovascular composite, consisting of death, myocardial ischemia, congestive heart failure, and stroke; and a renal composite, consisting of death and end-stage renal disease. Participants had type 2 diabetes, CKD, defined as an estimated glomerular filtration rate of 20 to 60 mL/min per 1.73 m², anemia, defined as serum hemoglobin of 11 g/dL or less, and transferring saturation of 15% or more. Subjects were followed for 48 months.

Darbepoetin alfa had a marked effect on hemoglobin level. The overall median hemoglobin level at baseline was 10.4 g/dL. Three months into the study, median hemoglobin was 12.5 g/dL in the darbepoetin group and 10.6 g/dL in the placebo group (P < .001). These levels persisted to the end of the trial.

However, correcting anemia had no effect on outcome. From the beginning of the study, the curves from the 2 groups showing the percent of patients experiencing cardiovascular or renal events overlapped nearly perfectly. In all, 632 patients in the darbepoetin group (31.4%) experienced some type of cardiovascular event, compared with 602 patients in the placebo group (29.7%; P = .41). For the renal composite, 652 of the darbepoetin patients (32.4%) experienced an event, compared with 618 (30.5%) of the people in the placebo group (P = .29). Among diabetic patients at risk for a cardiovascular event or mortality, darbepoetin "did not alter their journey" toward that outcome, Dr. Pfeffer said.

A particularly troubling finding was a doubling in the risk for stroke associated with darbepoetin. Over the course of the trial, 101 patients in the darbepoetin group (5%) experienced a fatal or nonfatal stroke, compared with 53 patients in the placebo group (2.6%; P < .001).

Composite and Component Event Rates in TREAT

End Point	Darbepoetin Alfa (%)	Placebo (%)	P
End-stage renal disease or death	32.4	30.5	0.29
Cardiovascular events or death	31.4	29.7	0.41
All-cause death	20.5	19.5	0.48
MI	6.2	6.4	0.73
Heart failure	10.2	11.3	0.24
Stroke	5.0	2.6	<.001

The trial excluded patients with active malignancy, but 348 participants had a history of malignancy. Of those patients, some developed cancer during the study. Deaths attributable to malignancy in that group was higher among people taking darbepoetin than among those taking placebo (P = .002).

Darbepoetin did relieve fatigue. Patients in the darbepoetin group reported a mean increase of 4.2 points on the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) score, compared with a mean of 2.8 points reported by the placebo group (P = .002). Changes of 3 points or more are considered to be clinically significant, said Dr. Pfeffer. However, there were no differences in energy level or physical function in the 2 groups.

The TREAT findings could have an impact on clinical practice, said president of the ASN, Thomas M. Coffman, MD, from Durham, North Carolina, who was not involved in this research. "This was a very well-designed study, and people will have to make therapeutic decisions based on this new information. Darbepoetin failed to show evidence of cardiovascular benefit across the board. It will likely lead to a reduction in the use of erythropoietin-stimulating agents."

Dr. Pfeffer concluded that "these findings mean that, for many patients, the risks of darbepoetin outweigh the modest benefits."

American Society of Nephrology (ASN) Renal Week: Abstract 7010. Presented October 30, 2009.

FULVESTRANT FOR HER2+ PATIENTS

Ann Oncol. 2009 Oct 29. [Epub ahead of print] Activity of fulvestrant in HER2-overexpressing advanced breast cancer. Robertson JF, Steger GG, Neven P, Barni S, Gieseking F, Nolè F, Pritchard KI, O'Malley FP, Simon SD, Kaufman B, Petruzelka L. Professorial Unit of Surgery, Division of Breast Surgery, University of Nottingham, Nottingham City Hospital, Nottingham, UK. BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression increases the aggressiveness of breast cancer cells resulting in poorer prognosis. Patients with HER2-positive disease are less responsive to endocrine therapies. Trastuzumab monotherapy results in objective responses in only approximately 15% of patients. Fulvestrant retains activity in cells overexpressing HER2 that are resistant to other endocrine treatments. This retrospective study evaluated response to fulvestrant treatment among HER2-positive patients with advanced breast cancer (ABC). PATIENTS AND METHODS: Clinical experience data from 10 treatment centres were pooled. Postmenopausal patients with predominantly hormone receptor-positive and HER2-positive disease were included. Clinical benefit (CB) was defined as the proportion of patients achieving a response to treatment (partial or complete) or stable disease lasting >/=6 months. RESULTS: Data for 102 patients were analysed. Fulvestrant resulted in an overall CB rate of 42% (43/101) in HER2-positive patients and 40% (25/63) in patients with visceral disease. Median duration of treatment was 14.5 months (range 6-44 months). Fulvestrant showed activity up to the fourth line of endocrine therapy and up to the seventh line of overall therapy. CONCLUSIONS: Results indicate that fulvestrant may be a suitable treatment option in extensively pre-treated patients with HER2-positive, hormone receptor-positive ABC. Further exploration of its use in this patient population is warranted.

PMID: 19875750 [PubMed - as supplied by publisher]

EML-4ALK AS A PREDICTIVE MARKER FOR RESPONSE TO EGFR THERAPY

Investigators at Massachusetts General Hospital in Boston conducted an analysis of the fusion oncogene EML4-ALK and the more well-studied epidermal growth factor receptor (EGFR) mutation among a group of patients with non-small-cell lung cancer who possessed at least 2 of the following features: (a) female sex; (b) no smoking or only a light smoking history; (c) Asian ethnicity; and (d) adenocarcinoma. Of the 141 tumors satisfying these criteria, 22% were found to have a mutation in EGFR, 13% had the EML4-ALK mutation, and 65% did not have a mutation in either EGFR or EML4-ALK ("wild-type").

The subgroup of individuals with EML4-ALK mutations was younger and more likely to be male compared with the wild-type and EGFR-mutation populations. Similar to the EGFR-mutation patients, those with EML4-ALK mutations were more likely to be light smokers or never-smokers. All but 1 of the 19 EML4-ALK mutant tumors were adenocarcinomas.

Of the 10 EML4-ALK patients who received treatment with an EGFR tyrosine kinase inhibitor, none achieved an objective response. By contrast, the response rate in this population to standard cytotoxic chemotherapy as well as the overall survival rate were similar to those seen in the wild-type patient population.

Viewpoint

Although this interesting study requires confirmation by other investigators, its data suggest that the documented presence of an EML4-ALK mutation, which is observed in as many as 10% to 15% of patients with non-small-cell lung cancer, indicates that the malignancy will be unresponsive to tyrosine kinase inhibition of EGFR.

Of particular interest in this report is that among the patients who were light smokers or never-smokers and did not possess an EGFR mutation, one third were found to have an EML4-ALK mutation. These data add to growing evidence for the relevance of specific molecular testing in non-small-cell lung cancer such that, in the relatively near future, it might be possible to develop therapeutic paradigms optimized for the individual patient based on unique characteristics of each cancer. Such decisions will include not only the particular drugs that should be used, but also (as appears to be the situation with EML4-ALK) the agents that should be avoided due to a predicted lack of efficacy.

Furthermore, these data demonstrate the serious limitations associated with making management decisions based solely on morphology and clinical history; some earlier reports suggested that the combination of no or limited smoking history and adenocarcinoma morphology would indicate a high probability of response to EGFR inhibition.

NSAIDs AND SURVIVAL AFTRE COLORECTAL CANCER DIAGNOSIS

NEW YORK (Reuters Health) Oct 29 - Women who regularly use nonsteroidal anti-inflammatory drugs (NSAIDs) have better survival after a colorectal cancer (CRC) diagnosis, research indicates.

"A wide body of evidence links use of NSAIDs to a reduced risk of CRC," Dr. Jason A. Zell, from the University of California, Irvine, and colleagues note in the October 13 online issue of Cancer. Until now, however, "potential survival benefits associated with NSAID use" had not been established.

To investigate, the researchers analyzed data from 621 women in the California Teachers Study, all with a first primary invasive CRC.

Prior to their CRC diagnosis, roughly 64% did not use NSAIDs regularly, 17% used them 1 to 6 days per week prior, and 20% reported daily use. Overall, roughly 17% percent of the cohort had regularly taken NSAIDs for less than 5 years and approximately 18% reported regular use extending back 5 years or more.

Outcomes were tracked from the date of CRC diagnosis until death or December 31, 2005, which yielded a mean follow-up of 3.4 years and a median of 2.8 years.

"Pre-diagnosis regular NSAID use (defined as 1 to 3 times per week, 4 to 6 times per week, or daily use) was associated with a 42% reduced risk of death from colorectal cancer (HR, 0.58), compared to no regular NSAID use," Dr. Zell noted in an email to Reuters Health.

In addition, compared with no regular NSAID use, regular pre-diagnosis use was associated with improved overall survival (HR 0.71), and regular use for 5 years or more was associated with improved overall survival (HR 0.55) and CRC-specific survival (HR 0.40) in adjusted analyses.

When patients were analyzed by the site of their cancer, women with colon cancer and at least 5 years of NSAID use prior to diagnosis had a significant reduction in CRC-specific mortality (HR, 0.46) but not overall mortality (HR, 0.65). No such effect was observed in the subset of patients with rectal cancer, however.

"If confirmed in other studies, these findings may have important implications for tertiary cancer prevention," the researchers note.

"Several NSAID-based colorectal cancer secondary and tertiary prevention clinical trials are already in the late stages of development," Dr. Zell told Reuters Health. "It is hoped that these new clinical trials will provide definitive recommendations for colorectal cancer risk reduction among colorectal cancer survivors."

Cancer 2009.

NEUTROPENIA AFTER CHEMOTHERAPY AND SURVIVAL OF NSCLC PATIENTS

Br J Cancer. 2009 Nov 3;101(9):1537-42. Epub 2009 Sep 29.

Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03.

Kishida Y, Kawahara M, Teramukai S, Kubota K, Komuta K, Minato K, Mio T, Fujita Y, Yonei T, Nakano K, Tsuboi M, Shibata K, Atagi S, Kawaguchi T, Furuse K, Fukushima M.

Department of Clinical Trial Design and Management, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. ykishida@kuhp.kyoto-u.ac.jp

BACKGROUND: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. RESULTS: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). CONCLUSION: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

ADVANTAGES OF SCREENING HAVE BEEN OVERSOLD?

October 23, 2009 — In a comment that has triggered widespread media coverage, the chief medical officer of the American Cancer Society (ACS) admitted that the benefits of cancer screening, especially for prostate and breast cancer, have been oversold.

"I'm admitting that American medicine has overpromised when it comes to screening. The advantages to screening have been exaggerated," the ACS's Otis Brawley, MD, told the New York Times in an October 21 article.

With this statement, a long-simmering controversy — about how the benefits of prostate and breast cancer screenings are emphasized at the expense of discussion of the harms — seems to have boiled over, at least momentarily. The story has been covered by many major media outlets, including ABC News, NBC Nightly News, CNN, the Jim Lehrer News Hour, and National Public Radio.

Hours after Dr. Brawley's comments were published, the ACS released an official press statement from Dr. Brawley that shifted focus back to the benefits of screening — and away from his earlier candid interview about the downsides of screening.

"While the advantages of screening for some cancers have been overstated, there are advantages, especially in the case of breast, colon, and cervical cancers. Mammography is effective — mammograms work and women should continue get them," reads Dr. Brawley's statement.

The statement also reiterated the ACS's stand that men should make an "informed decision" about whether prostate cancer screening is "right for them."

Dr. Brawley's original comments apparently arose in an interview with the Times about an essay published in the October 21 issue of the Journal of the American Medical Association about the need to rethink prostate and breast cancer screening.

The essay argues that new approaches to screening for breast and prostate cancer are needed, because the current methods have not led to a "significant reduction in deaths" from the 2 diseases.

Explaining the Case for a Rethink

The essay, written Laura Esserman, MD, MBA, and Yiwey Shieh, AB, both from the University of California, San Francisco, and Ian Thompson, MD, from the University of Texas Health Science Center, San Antonio, calls for a rethink on cancer screening and offers a 4-pronged program for improvement.

They decided to write the essay when they realized how similar prostate and breast cancers and their screening problems are.

A central problem with the screenings for both of these cancers seems to be that they have increased the burden of low-risk cancers without reducing the burden of more aggressive cancers, the essayists write.

Mammography and prostate-specific antigen (PSA) testing, although having "some effect," have led to the well-documented overdiagnosis and overtreatment of breast and prostate cancers, they note.

"We are not saying that screening is bad. It's what you do with the information that makes it good or bad," Dr. Esserman told Medscape Oncology. "We need to refocus and figure out how to tailor screening," she summarized.

She supports Dr. Brawley for speaking out on this issue. "Otis had a lot of courage. The American Cancer Society should not be afraid of Otis's message."

The messages about cancer screening need to evolve, suggested Dr. Esserman.

"I think people like the simple message that screening is good and are uncomfortable with complexity. I understand that. However, cancer is a complicated disease. We need to expand our messages to say, among other things, that many screen-detected cancers are slow growing and may not need treatment," she said.

Other messages should include the mention of harm and the fact that screening will not find all cancers early, Dr. Esserman added.

With regard to the latter, Dr. Esserman said that a recent study indicates that most stage II and III breast cancers actually turn up clinically, between normal planned screens.

"It's just not true to say that 'if you get a mammogram, all will be well'," she explained.

Problems With Prostate and Breast Cancer Screening

It is estimated that more than 1 million men have been overtreated for prostate cancer since the advent of widespread PSA testing in the mid-1980s.

Furthermore, as the essayists point out, the intensive PSA screening has not resulted in a significant difference in prostate cancer mortality between the United States and the United Kingdom, where PSA screening was not widely adopted.

The essayists also note that although evidence indicates that breast cancer screening saves lives, 838 women, aged 50 to 70 years, must undergo screening for 6 years to avert 1 death. However, this 1 life saved generates "thousands of screens, hundreds of biopsies, and many cancers treated as if they were life-threatening when they were not," they write.

A critic of mammography recently told Medscape Oncology that such mammography facts are in stark contrast with what is most publicized about the screening, namely that "mammography saves lives."

While Dr. Brawley's comments have garnered great attention, another ACS official recently suggested to Medscape Oncology that public education about breast cancer screening is in need of improvement. "We all have to do a better job to best inform the public about the benefits and harms of screening mammography," said Bob Smith, PhD, director of cancer screening at the ACS.

Dr. Esserman believes the time is right to improve both patients' and clinicians' understanding of screening. "If you don't take a hard critical look, then you miss the opportunity to improve things," she said.

A Plan for Improved Screening

In their essay, the authors chart a new 4-point course for breast and prostate cancer screening that will "significantly reduce death and morbidity" from the cancers.

First, more powerful markers that identify and differentiate cancers with significant risk from those with minimal risk are needed.

Second, the treatment burden for minimal-risk disease must be reduced. Methods currently exist to identify low- and high-risk cancers in both the breast and prostate, they emphasize. For instance, in prostate cancer, low-volume lesions with low Gleason scores have a low-risk for death. Minimal-risk disease should not be called cancer; it should be called indolent lesions of epithelial origin (IDLE), they say.

Third, improved tools to support informed decisions are needed. "Information about risks of screening and biopsy should be shared with patients before screening," they write. Currently, an estimated one third of PSA tests take place without even the most basic doctor–patient discussion, as reported by Medscape Oncology.

Finally, a greater emphasis on prevention, including the use of proven cancer preventive agents, such as finasteride for preventing prostate cancer and tamoxifen and raloxifene for preventing breast cancer, is needed.

An estimated $20 billion is spent to screen for prostate and breast cancer in the United States. The essayists call for 10% to 20% of that amount to be invested in an effort to improve screening.

This article grew out of collaboration initiated within the National Cancer Institute's Early Detection Research Network and was supported by grants U01CA111234 and U01CA086402. The authors have disclosed no relevant financial relationships.

JAMA. 2009;302:1685-1692. Abstract

NULLIPARITY NAD BREAST CANCER AGGRESSIVENESS

NEW YORK (Reuters Health) Oct 28 - Nulliparity and late-life first childbirth are associated with more aggressive breast cancer, according to Swedish researchers.

"We found that nulliparous women had a statistically significant high risk of grade III and HER2 over-expressing tumors," Dr. Salma Butt, of Malmo University Hospital, Sweden, and colleagues write in the October 15th issue of the International Journal of Cancer.

"Further, our study showed that women with late first childbirth had a higher risk of developing tumors with lobular type, grade III, high expression of cyclin D1, (and) low expression of p27," the researchers add.

For their analysis, the authors used data on 17,035 women in the Malmo Diet and Cancer Study (1991 to 1996), a prospective population-based cohort with linkage to the Swedish Cancer Registry until December 31, 2004.

A total of 622 breast cancer cases were evaluated for invasiveness, tumor size, axillary lymph node status, grade, tumor proliferation (Ki67), HER 2, cyclin D1, and p27. The authors also examined the tumors for tumor type according to WHO classification and hormone receptor status.

Nulliparity was linked to an increased risk of breast cancer compared to uniparity (RR 1.39), but the association fell short of statistical significance.

Nulliparous women were more likely to have large tumors (>20 mm) (RR 1.89), high Ki67 levels (RR 1.95), high cyclin D1 levels (RR 2.15), grade III tumors (RR 2.93), and HER2 positive tumors (RR 3.24).

Compared to women who had a first child before age 20, women who were older than 30 at first childbirth had a slightly higher risk of breast cancer (RR 1.39). Women with a first childbirth after 30 also had an increased risk of grade III tumors (RR 2.67), high levels of cyclin D1 (RR 2.69), low levels of p27 (RR 2.23), and lobular breast cancer (RR 2.51).

There was no association between parity and any specific breast cancer subgroup defined by estrogen or progesterone receptor status and histological type. Similarly, breast cancer risk in relation to axillary node status was not linked with parity.

"It is possible to hypothesize that the mechanism behind the observation in nulliparous women and women with a late age at first childbirth are similar as both these categories have breast tissue that is not fully evolved," the researchers explain. "Their breast tissue could, hence, be more susceptible to initiating and promoting factors."

Int J Cancer 2009;125:1926-1934.

LYNCH SYNDROME AND PANCREATIC CANCER

NEW YORK (Reuters Health) Oct 27 - The risk of pancreatic cancer in families with Lynch syndrome is more than 8 times higher than in the general population, according to a paper in the October 28 issue of the Journal of the American Medical Association.

Lynch syndrome is an autosomal dominant disorder caused by defects in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. The mutations increase patients' risk for colon cancer, endometrial cancer, and other neoplasms, Dr. Sapna Syngal of the Dana-Farber Cancer Institute in Boston and her colleagues note.

To quantify the pancreatic cancer risk associated with these mutations, Dr. Syngal and her team looked at 6,342 people from 147 Lynch syndrome families. Thirty-one families, or 21.1%, had one or more cases of pancreatic cancer affecting 21 men and 26 women.

The estimated relative risk of pancreatic cancer was particularly high for individuals aged 20 to 49 years (hazard ratio, 30.5). The hazard ratio decreased with age, to 5.1 for people 50 to 70 years old.

The absolute cumulative risk of developing pancreatic cancer was 1.31% at age 50 and 3.68% at age 70. By comparison, according to the article, the Surveillance, Epidemiology and End Results (SEER) database shows population-based cumulative incidences of 0.04% and 0.52% for ages 50 and 70 years, respectively.

"Pancreatic cancer is a clinically relevant component of Lynch syndrome and quantifying this risk for gene carriers should be incorporated into clinical management," the researchers say.

In an interview with Reuters Health, Dr. Syngal advised that physicians treating patients with pancreatic cancer ask whether other cancers run in the family. Patients who report a family history of colon or endometrial cancer -- and their family members -- should be tested for mutations that cause Lynch syndrome.

The effectiveness of using endoscopic ultrasound and computed tomography to monitor high-risk families for pancreatic cancer is being studied, Dr. Syngal said, but for now there is no way to prevent the disease in at-risk individuals. But, she added, individuals with any pancreatic cancer-associated mutations should quit smoking, because this is the one known lifestyle-related risk factor for the disease.

JAMA 2009;302:1790-1795.

GENE TESTING FOR PHEOCHROMOCTOMA

October 29, 2009 (Honolulu, Hawaii) — A project aimed at reducing genetic testing costs has developed a model based on pheochromocytoma. A new study validates the efficacy of using clinical parameters to predict individuals who carry the mutations. The study also shows that prioritizing specific genetic sequences in testing for diseases is an effective way to reduce analytical costs in genetic diseases.

Zoran Erlic, MD, from the Department of Nephrology, Section of Preventive Medicine, University Medical Center, Albert-Ludwigs University, in Freiburg, Germany, presented the cost-reduction strategy here during the American Society of Human Genetics 59th Annual Meeting.

Pheochromocytoma is one of a larger group of paraganglioma (PGL) tumors (head and neck paragangliomas [HNPs]). Malignant or nonmalignant tumors of the adrenals, as well as of the neck and thorax, can be sporadic or part of a hereditary syndrome. Genetic screening has shown that pheochromocytomas typically involve changes in at least 5 susceptibility genes:

• SDHB and SDHD are succinate dehydrogenase subunit genes B and D; changes in these genes cause PGL syndrome type 1 and type 4.
• von Hippel-Lindau disease, occurring in about 20% of pheochromocytoma patients, is caused by germline mutations in the VHL tumor suppressor gene.
• Changes in RET cause multiple endocrine neoplasias (MEN2).
• Neurofibromatosis 1 is associated with mutations in the NF1 gene; approximately 1% of neurofibromatosis patients have pheochromocytomas.

The cost of diagnostic scanning for all 5 genes is close to $8000. Scanning for NF1 is the most expensive ($4800), and the remaining scans each cost more than $3000.

The current study scanned 1149 index cases, 30% of which had a mutation in 1 of the 5 susceptibility genes. About 70% of the cases were mutation-negative. It was clear that patients carrying the NF1 mutation had clinical features of the NF1 syndrome. NF1 screening would not be required in other patients.

Among VHL carriers, 54% had "clinical anamnestical evidence" of von Hippel-Lindau syndrome — that is, they demonstrated a secondary response to an immunogenic substance after the antibodies were no longer detectable in the blood. Similarly, 61% of RET mutation carriers showed clinical anamnestical evidence of MEN. Dr. Erlic asked in his presentation whether such clinical observations could predict testing results, including the presence of mutations.

To determine the order in which genes should be tested, investigators "looked for the frequencies of these patients based on different patient characteristics . . . and made the statistical approach in testing order," Dr. Erlic told Medscape Pathology & Lab Medicine. "Then we validated our flow of gene testing orders . . . and it was confirmed that it was really working."

The prioritized order of genetic tests for patients with head and neck paragangliomas [HNP] was SDHD, SDHB, RET, and VHL. Patients with no HNPs and with a single tumor outside the adrenals would be better served by a different testing order: SDHD, VHL, SDHB, and RET. The algorithm developed by this group had a sensitivity of 95.7%.

The average cost of testing for each patient would be approximately $1876, rather than $3116 — a savings of about 40%. Eight carriers were missed by applying this algorithm, but Dr. Erlic believes that such failures would decrease in frequency. Asked about the 8 missed cases, he noted that there were no clinical predictors prior to mutation screening. Two cases had medullary thyroid carcinoma at ages 47 and 52 years, respectively; a tumor had been found in the other 6, but with no further manifestation years later. One case was lost to follow-up.

"What we really wanted to create was a model [that is] really easily obtainable with simple data like gender, tumor number, tumor location, without looking for a . . . chemical profile, which can be treated somehow, depending on the lab that is performing it," explained Dr. Erlic. "The clinical cost . . . is going to be cheaper and cheaper because we believe that more and more genes will be involved, modifier genes will be identified. So we really want to introduce it to clinical practice, the genetics clinic," he said, "and we need to learn to consider these economic reasons."

Session comoderator David Malkin, MD, associate chief of research (clinical), senior staff oncologist, senior scientist, and codirector of the Cancer Genetics Program at The Hospital for Sick Children, Department of Pediatrics, Division of Oncology, in Toronto, Ontario, expressed concern about not incorporating biochemical assays into the model.

"I think that's very important and should be incorporated," he told Medscape Pathology & Lab Medicine. "I mean, [assays] have a cost, but they're not going to be as costly as a [genetic] test. So that might make it easier to select out the group that the test will be beneficial for, and also cost," Dr. Malkin observed.

Taking questions from the audience, Dr. Erlic agreed that chemical testing "would help us improve our model, and also involves the order to test in." However, "this is the first study published so far, and only 2 centers can do this chemistry. We want it to be easily available to each pathologist in the world. We want an algorithm based on simple data to get the price down," he concluded.

Dr. Erlic and Dr. Malkin have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 116. Presented October 23, 2009.

NO PREDICTIVE ROLE FOR HER2 ECD

Prognostic and Predictive Value of HER2 Extracellular Domain in Metastatic Breast Cancer Treated With Lapatinib and Paclitaxel in a Randomized Phase III Study.

Finn RS, Gagnon R, Di Leo A, Press MF, Arbushites M, Koehler M.

Geffen School of Medicine at UCLA; Norris Cancer Center, University of Southern California, Los Angeles, CA; Medicine Development Centre Oncology, GlaxoSmithKline, Collegeville, PA; and the Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.

PURPOSE: The HER2 extracellular domain (ECD) is enzymatically cleaved from the cell membrane. Shed ECD in serum has been studied as both prognostic and predictive markers. Lapatinib is a dual inhibitor of HER2 and epidermal growth factor receptor kinases. We examined the prognostic and predictive role of HER2 ECD in a randomized trial of paclitaxel with placebo or lapatinib in women with HER2-negative or -unknown breast cancer. PATIENTS AND METHODS: Patients (n = 579) with newly diagnosed metastatic breast cancer (MBC) were randomly assigned to paclitaxel with placebo or lapatinib. HER2 status was determined centrally. ECD was centrally measured by enzyme linked immunoassay in available samples at baseline (b; n = 472), week 9, and every 12 weeks thereafter. Results were correlated to overall response rate (ORR) and progression-free survival (PFS). RESULTS: Elevated baseline ECD (bECD) levels (>/= 16 ng/mL) did not predict HER2 tumor status (sensitivity, 62%; specificity, 75%). In HER2-negative tumors, elevated bECD was not correlated with improved efficacy for lapatinib plus paclitaxel versus placebo plus paclitaxel (ORR: odds ratio, 1.6; 95% CI, 0.1 to 3.8; P = .365; PFS: hazard ratio, 0.94; 95% CI, 0.60 to 1.47; P = .797). ECD levels tended to decrease over time when bECD was elevated. ECD conversion from low to high was associated with worse PFS. Converting from high to low was associated with a better PFS. A consistently low ECD level had better PFS than a consistently elevated ECD. All associations were found to be independent of lapatinib. CONCLUSION: HER2 bECD does not predict lapatinib benefit in patients with HER2-negative MBC. Changes in ECD status correlates with patient outcome regardless of treatment given. Measuring HER2 ECD is not currently recommended for predicting benefit to lapatinib.

DIABETES LOW LDL ALBUMINURIA AND CANCER RISK

NEW YORK (Reuters Health) Oct 27 - Patients with type 2 diabetes who have low LDL cholesterol and albuminuria face an increased risk of developing cancer, say researchers from Hong Kong in the October Diabetes Care. The good news is that statin use in such patients may eliminate the elevated risk.

"These findings should not form the basis for a screening test for cancer but rather stimulate further research in this emerging area of therapeutic challenge, i.e., diabetes and cancer," Dr. Juliana C. N. Chan from The Chinese University of Hong Kong told Reuters Health in an email.

Dr. Chan and colleagues explored the interaction between low LDL cholesterol, albuminuria, and cancer risk in 3793 statin-naive diabetics and 1483 patients in whom statin treatment was initiated during a median follow-up of 5.2 years.

Patients who used statins were more likely to use other drugs and develop cardiovascular complications but less likely to have cancer and die, compared with patients who did not receive statin treatment, the authors report.

The presence of both LDL cholesterol <>

This suggests that the previously reported increase in cancer risk among type 2 diabetic patients with low LDL cholesterol is conditional on the presence of albuminuria, the investigators say.

Patients with low LDL cholesterol and albuminuria who did not use statins faced a 4.8-fold increased cancer risk, the researchers note, but patients with both risk factors who were treated with statins during follow-up did not have an increased cancer risk.

"From a clinical perspective, our findings should help to resolve the concerns regarding use of statins and cancer risk in type 2 diabetes," Dr. Chan said. "Not only is statin use not associated with increased cancer risk, this drug appears to have protective effects against cancer in patients with high LDL-C level and those with dual presence of low LDL-C and renal dysfunction."

"These observations are not causal but suggest complex interplays between lipid and growth promoting pathways which may be dependent on renal function," Dr. Chan concluded.

Diabetes Care 2009;32:1826-1832.

ANTICONVULSANTS INCRESE GBM SURVIVAL!

NEW YORK (Reuters Health) Oct 28 - Glioblastoma patients treated for seizures with enzyme-inducing anticonvulsant (EIAC) drugs survive longer and have slower disease progression than patients treated with other anticonvulsants.

This paradoxical finding, reported in the October issue of Neurology, comes from a cross-sectional analysis of data from three nonsimultaneous trials involving glioblastoma patients, all administered by the Mayo Clinic.

As the researchers explain in their report, EIACs - such as phenobarbital, phenytoin, carbamazepine, and primidone -- induce P450 microsomal enzymes, leading to enhanced metabolism of many common chemotherapeutic drugs. Oncologists have long believed that these drugs restrict the achievement of effective chemotherapeutic levels.

"We were worried, originally," that the EIACs would make cancer drugs less effective, Dr. Kurt Jaeckle of the Mayo Clinic in Jacksonville, Florida, told Reuters Health.

With this hypothesis, he and his colleagues studied database records on 620 newly diagnosed glioblastoma patients who entered the treatment trials between 1994 and 2002. Treatments and anticonvulsant use were dictated by the three trial protocols and treating physicians.

At enrollment, 432 patients were being treated with EIACs, 14 were on a non-EIAC, and 159 were not taking any anticonvulsant. Fifteen subjects had missing data on anticonvulsant use. There was no significant difference in EIAC use between the three trials (p=0.28). The study did not consider changes in EIAC administration that occurred after enrollment. All but 48 patients had died by the time of the analysis.

Compared to non-EIAC patients, those on EIACs were on average slightly younger (median 55 vs 58 years, p=0.0057), had slightly higher Mini-Mental State Examination scores (median 29 vs 28, p=0.045), were less likely to have had only a biopsy (13.4% vs 27.8%, p<0.0001),>

Median overall survival was 12.3 months for patients on EIACs and 10.7 months in those not on EIACs (p=0.0002). The projected hazards ratio on multivariate analysis was 0.75.

Median progression-free survival was also significantly longer in the EIAC group: 5.6 months vs 4.8 months in the no-EIAC group (p=0.003).

Seizure history had no clear bearing on overall survival or progression-free survival.

"What we found, to our amazement, was that people who were on enzyme-inducing anticonvulsants were actually living longer than the ones that were not," Dr. Jaeckle said.

He and his co-authors point out that trials in 2005 and 2006 found EIACs to be an independent predictor of progression-free survival in glioblastoma and to be correlated with better outcome in anaplastic glioma. But, the researchers add, while they are not the first to challenge conventional wisdom about EIACs, they are the first to use the effect of these drugs as their primary end point.

They admit, however, that while they have correlated EIAC use with longer survival and slower progression, "a cause-and-effect relationship for this association cannot be derived from this analysis."

If a direct etiology is uncovered, Dr. Jaeckle suspects it will be a drug metabolite with anti-tumor activity. He added that other groups are already using in vitro methods to understand how anticonvulsants and their metabolites may affect tumor cells.

Neurology 2009;73:1207-1213.

QUALITY OF LIFE AND LUNG CANCER SURVIVAL

.

J Clin Oncol. 2009 Oct 26. [Epub ahead of print] Quality of Life Supersedes the Classic Prognosticators for Long-Term Survival in Locally Advanced Non-Small-Cell Lung Cancer: An Analysis of RTOG 9801. Movsas B, Moughan J, Sarna L, Langer C, Werner-Wasik M, Nicolaou N, Komaki R, Machtay M, Wasserman T, Bruner DW. Henry Ford Hospital, Detroit, MI; American College of Radiology; University of Pennsylvania; Thomas Jefferson University; Fox Chase Cancer Center, Philadelphia, PA; University of California, Los Angeles, Los Angeles, CA; The University of Texas M. D. Anderson Cancer Center, Houston, TX; and Washington University, St Louis, MO. PURPOSE: To determine the added value of quality of life (QOL) as a prognostic factor for overall survival (OS) in patients with locally advanced non-small-cell lung cancer (NSCLC) treated on Radiation Therapy Oncology Group RTOG-9801. PATIENTS AND METHODS: Two hundred forty-three patients with stage II/IIIAB NSCLC received induction paclitaxel and carboplatin (PC) and then concurrent weekly PC and hyperfractionated radiation (to 69.6 Gy). Patients were randomly assigned to amifostine (AM) or no AM during chemoradiotherapy. The following pretreatment factors were analyzed as prognostic factors for OS: Karnofsky performance status, stage, sex, age, race, marital status, histology, tumor location, hemoglobin, tobacco use, treatment arm (AM v no AM) and QOL scores (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [QLQ-C30] and Lung Cancer 13 [LC-13]). A multivariate (MVA) Cox proportional hazards model was performed using a backwards selection process. RESULTS: Of the 239 analyzable patients, 91% had a baseline global QOL score. Median follow-up time was 59 months for patients still alive and 17 months for all patients. Median baseline QLQ-C30 global QOL score was 66.7 on both treatment arms. Whether the global QOL score was treated as a dichotomized variable (based on the median score) or a continuous variable, all other variables fell out of the MVA for OS. Patients with a global QOL score less than 66.7 had an approximately 70% higher rate of death than patients with scores >/= 66.7 (P = .004). A 10-point higher baseline global QOL score corresponded to a decrease in the hazard of death by approximately 10% (P = .004). The other independent QOL predictors for OS were the QLQ-C30 physical functioning (P = .011) and LC-13 dyspnea scores (P = .012). CONCLUSION: In this analysis, baseline global QOL score replaced known prognostic factors as the sole predictor of long-term OS for patients with locally advanced NSCLC.

PMID: 19858383 [PubMed - as supplied by publisher]