FIRST JAK INHIBITOR FOR MYELOFIBROSIS

December 8, 2009 (New Orleans, Louisiana) — An experimental oral compound that could be the first-ever drug therapy for myelofibrosis has shown benefits in an ongoing open study, with unprecedented reductions of enlarged spleens, improvements in quality of life, and durable responses. "The results are amazing," said lead researcher Srdan Verstovsek, MD, PhD, associate professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

"The results are intriguing, but it is early days yet," countered another researcher involved in myelofibrosis, Karen Ballen, MD, director of the leukemia program at Massachusetts General Hospital in Boston.

Speaking here at the American Society of Hematology (ASH) 51st Annual Meeting, Dr. Verstovsek said there is no standard approved therapy for myelofibrosis. This is a rare syndrome, affecting about 1 in 100,000 people, so many hematologists and oncologists may not have come across these patients, he noted.

Myelofibrosis is among the worst of the myeloproliferative disorders, and is both debilitating and fatal, he explained. It causes fibrosis of the bone marrow, which limits blood production, causing anemia. "The spleen and other organs attempt to take over the production of blood cells, which causes massive swelling of the spleen. Patients have poor quality of life, with fatigue, weight loss, abdominal, bone, and muscle pain, night sweats, and sometimes severe itching." End-stage patients look as if they are severely malnourished, with thin limbs and a swollen abdomen, and usually die in a hospice. The average survival is about 5 to 7 years, but in about 20% of patients, the disease transforms to acute myeloid leukemia (AML) and they die within 4 to 6 months, he said.

The new drug resulted in a "massive reduction in spleen and liver organomegalopathy," as well as an improvement in quality of life, with patients able to eat more and walk further, Dr. Verstovsek told Medscape Oncology.

The drug is an experimental JAK inhibitor, known as INBC018424, under development by Incyte Corporation. It was tested in myelofibrosis after the discovery, in 2005, that these mutations in the JAK2 gene are seen in many patients with myeloproliferative disorders. Dr. Verstovsek noted that about 50% of patients with myelofibrosis have a JAK2 mutation, but he emphasized that the drug "benefits were seen in patients regardless of whether or not they had this mutation."

The drug is also an inhibitor of JAK1, which leads to myelosuppression as an adverse effect, but this can be controlled by "selectively targeting the dose," Dr. Verstovsek explained. The drug was originally used at a dose of 25 mg twice daily, but this led to thrombocytopenia in about 30% of patients, so the dose being used now is 15 mg twice daily, with individual dose optimization from 10 to 25 mg twice daily. "This has improved the safety while maintaining the efficacy of 25 mg twice daily, the maximum tolerated dose," he told the meeting.

The open study was conducted in 153 patients, and all of the patients benefited, he said. Patients who were receiving an optimized dose of the drug showed a median reduction of 33% in spleen volume, as measured by magnetic resonance imaging, a 50% reduction in symptom score, and an improvement in the 6-minute walk test by a median of 33 meters at 1 month and 70 meters at 6 months.

"There are also indications that there might be an impact on survival, but more follow-up is necessary," Dr. Verstovsek said. So far, 115 of the 153 patients (90%) who were enrolled in the trial remain alive, at an average follow-up of 16 months, he said. Patients with high-risk disease, the majority of patients in this trial, generally have an average survival of about 2 years, he added..

"There is also a suggestion — but again, only a suggestion — that the drug may be reducing the risk of transformation to AML," he added. So far, there have been 3 transformations to AML among the 153 study participants, a rate of 0.016 per patient-year, which compares with a historic-control rate of 0.056 per patient-year from 2 different studies in the literature.

Randomized Trials in Progress

Two randomized trials are now in progress, with a view to gathering data for registration. These data might be available for next year's ASH meeting, and the drug could be on the market by 2011, Dr. Verstovsek said.

One of the studies, known as COMFORT-1, will enroll 240 patients in the United States, Canada, and Australia, and will be a placebo-controlled trial of INCB018424, but patients in the placebo group who are not responding and/or who have an increase of 25% or more in their spleen size will be allowed to crossover, Dr. Verstovsek said. The other study, known as COMFORT-2, will be conducted in Europe; it will involve 150 patients and will be randomized in a 2:1 manner to INCB018424 or to standard of care, where physicians can use whatever therapies they choose. Details are available at www.comfortstudy.com.

Currently, treatment of myelofibrosis consists of treating the signs and symptoms of the disease, Dr. Verstovsek explained. The anemia is tackled with erythropoietin, the poor quality of life with steroids, and the cachexia with testosterone-like drugs such as danazol. The large spleen is sometimes treated with oral chemotherapy, such as hydroxyurea, and in selected cases it can be removed surgically, but he noted that this has a 9% mortality rate, even in specialist centers. There is also the option of bone marrow transplantation, but that carries a 15% mortality rate and "we don't know the benefit yet," he said.

. Ballen, who has been involved in trials of bone marrow transplantation in myelofibrosis, disagreed, and said that allogeneic bone marrow transplantation offers a curative treatment. Dr. Ballen told Medscape Oncology that, "in patients who are eligible, transplant can cure the disease." She acknowledged that many of these patients are too sick and too frail to undergo such a procedure, and so many more would be eligible for treatment with an oral drug, but she emphasized that the results so far are "preliminary."

Currently, allogeneic stem cell transplantation is the only known curative treatment, she said.

"Myelofibrosis is too complex to be eliminated by a single drug," Dr. Verstovsek said in a statement. JAK mutation is one of the underlying abnormalities, but it's not the sole cause of the disease. The new JAK inhibitor appears to "control the disease very well in most patients," he said, but "it will probably take combination therapies to cure myelofibrosis."

A NOVEL AGENT FOR CML

December 7, 2009 (New Orleans, Louisiana) — Tyrosine kinase inhibitors that target BCR-ABL mutations, such as imatinib (Gleevec), have become standard therapy in the treatment of chronic myeloid leukemia (CML). Although these agents have had a dramatic impact on survival, currently available tyrosine kinase inhibitors have not demonstrated activity in CML patients who harbor the Bcr-Abl T315I mutation.

There are currently no approved treatments for this small subset of patients, but a new therapeutic option might be on the horizon. According to data presented here at the American Society of Hematology 51st Annual Meeting, an experimental agent — omacetaxine (Omapro, ChemGenex) — is a potential treatment for CML that has a unique mechanism of action that is independent of tyrosine kinase inhibition.

Omacetaxine is a first-in-class cetaxine, and has demonstrated clinical activity as a single agent for a range of hematologic malignancies. It has a novel mechanism of action, in that it specifically binds to the ribosomal A-site cleft. This action inhibits the protein translation of short-lived oncoproteins that are upregulated in leukemic cells — in particular, Cyclin-D1, Mcl-1, and c-Myc. In January 2009, the US Food and Drug Administration granted orphan drug status to omacetaxine for the treatment of myelodysplastic syndromes.

This drug has shown durable hematologic and cytogenetic responses in CML, along with a tolerable safety profile, in a phase 2/3 study, reported lead author Jorge Cortes, MD, professor and deputy chair of the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston.

New Drugs Needed

"There was interest in this agent at the time when interferon was the treatment of choice in CML," said Dr. Cortes. "However, imatinib came along and displaced everything else because its impact was so spectacular. Now there is a renewed interest in this agent."

Richard A. Larson, MD, professor of Medicine at the University of Chicago in Illinois, and moderator of the press briefing at which the results were presented, said that there will always be a need for new agents. "Resistance occurs in chemotherapy, the same as it does in antimicrobial therapy," he explained.

"We now have a better understanding of mutations," he said. "So there may be other drugs sitting on shelves that may turn out to be useful."

High Response Rate Observed

Dr. Cortes and colleagues evaluated the safety and efficacy of subcutaneously administered omacetaxine in 90 patients with imatinib-resistant T315I+ Philadelphia chromosome positive CML. All of the patients enrolled so far have failed treatment with imatinib and 79% have failed therapy with at least 1 other tyrosine kinase inhibitor — either dasatinib, nilotinib, or both.

Patients received 1.25 mg/m² omacetaxine by subcutaneous injection twice daily for 14 days, every 28 days, until hematologic response. They then received omacetaxine 1.25 mg/m² twice daily for 7 days, every 28 days, as maintenance therapy.

Data were available from 81 patients in the trial. Of this group, 49 were in the chronic phase, 17 were in the accelerated phase, and 15 were in the blast phase.

A complete hematologic response was seen in 86% (n = 42) of the chronic-phase patients, Dr. Cortes reported, and the median duration of that response was 9 months. A total cytogenetic response rate of 41% was observed in chronic-phase patients, with a major cytogenetic response rate of 27.5%. Nine of these patients achieved a complete response, and a reduction in the baseline T3151 clone was achieved in 57% of patients in this group. Median survival time has not yet been reached.

For accelerated-phase patients, 35% (n = 6) experienced hematologic responses, with 5 patients achieving a complete response and 1 returning to chronic phase. The median duration of the response was 7 months, and median survival was 18.8 months.

Among those in blast phase, 47% had an overall hematologic response, with 3 complete responses. There was median response duration of 2 months, and median survival was 2.1 months.

Treatment was well tolerated overall, explained Dr. Cortes. Grade 3/4 adverse events were experienced by 68% of the cohort, and these were primarily hematologic. The most commonly reported events were thrombocytopenia, anemia and neutropenia. Nonhematologic toxicities were uncommon, with primarily grade 1/2 with diarrhea, fatigue, pyrexia, nausea, and asthenia being the most frequently reported.

Omacetaxine might provide a treatment option for a patient population that currently has no approved drug therapies, Dr. Cortes concluded.

Dr. Cortes and several of his coauthors report a relationship with ChemGenex, the manufacturer of the drug.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 644. Presented December 6, 2009.

WHAT'S HOT AT SAN ANTONIO

December 3, 2009 — New studies evaluating the possible influence of oral bisphosphonates on breast cancer incidence and investigating the effectiveness of trastuzumab (Herceptin, Genentech) in the adjuvant setting headline the offerings at the 32nd Annual San Antonio Breast Cancer Symposium.
Speaking with Medscape Oncology, director of the meeting, C. Kent Osborne, MD, called special attention to a late breaker that features new data from the North Central Cancer Treatment Group (NCCTG) N9831 trial. The study evaluates chemotherapy and the sequential or concurrent addition of 52 weeks of trastuzumab in operable HER2-positive patients (stages I to III).

"It's an exciting report," said Dr. Osborne, who is director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, Texas. "It will provide guidance on how to use trastuzumab in the adjuvant setting," he added.

The NCCTG investigators, including meeting presenter Edith Perez, MD, from the University of Miami in Florida, previously published 3-year outcomes data from the study (N Engl J Med. 2006;354:640-644). But this latest report, to be presented on December 12, details new "long-term" data, said Dr. Osborne.

Another large phase 3 study of trastuzumab in the adjuvant setting will be presented during the same meeting session.

The Breast Cancer International Research Group (BCIRG) will present updated data from its 006 trial. This trial, however, does not evaluate the timing of the administration of trastuzumab. Instead, it compares outcomes in patients treated with chemotherapy alone and chemotherapy plus trastuzumab. These data will be presented by Dennis Slamon, MD, from the University of California, Los Angeles.

But the Big Story Is . . .

The headline grabber of the meeting is likely to be a study from the landmark Women's Health Initiative that evaluates the relation between the use of oral bisphosphonates and breast cancer incidence.

The study will be presented on the afternoon of December 10 by Rowan T. Chlebowski, MD, PhD, from the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in California.

"The bisphosphonates are taken for bone preservation," noted Dr. Osborne, but he added that previous data with intravenous formulations suggest that they also have an effect on cancer. Indeed, at last year's symposium and at the 2008 American Society of Clinical Oncology meeting, studies were presented indicating that zoledronic acid (Zometa, Novartis) either shrunk tumors or reduced relapse rate in early breast cancer.

The use of bisphosphonates and the risk for postmenopausal breast cancer is the subject of a presentation from Israeli investigators; it will follow Dr. Chlebowski's presentation.

The effect of bisphosphonates on aromatase-inhibitor-associated bone loss is the subject of a number of presentations at the meeting.

Five-year final follow-up data will be presented on the Z-FAST study, which looks at the effect of zoledronic acid on aromatase-inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole (Femara, Novartis Pharmaceuticals). The study will be presented on December 11 (poster session 4) by Adam Brufsky, MD, from the University of Pittsburgh Cancer Institute in Pennsylvania.

Another presentation on zoledronic acid compares it with the novel experimental product denosumab (Amgen), which is close to launch. This study will compare effects that the 2 agents have on the incidence of skeletal-related events in breast cancer patients with bone metastases. On the afternoon of December 10, Alison Stopeck, MD, from the University of Arizona in Tucson, will present the results.

Denosumab can inhibit osteoclast activity that is associated with bone destruction and skeletal-related events, which are the hallmarks of bone metastases from breast cancer. Denosumab, a monoclonal antibody directed against RANKL, a key mediator in bone turnover, is a "first in its class" product.

More Data on Aromatase Inhibition

The symposium will also feature 2 presentations on major clinical trials of the aromatase inhibitor exemestane (Aromasin, Pharmacia).

The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial compares exemestane as initial adjuvant therapy with a sequential approach of tamoxifen followed by exemestane. The 5-year data will be presented on the morning of December 10 by Daniel Rea, MD, PhD. from the University of Birmingham in the United Kingdom.

An updated analysis of the international Intergroup Exemestane Study (IES) will be presented during the same session. The presentation will focus on disease-related outcomes; shorter-term data from this trial, which evaluates the use of exemestane or tamoxifen after 2 to 3 years of initial tamoxifen treatment, have already been published (Lancet. 2007;369:559-570).

Exemestane is molecularly different from the other 2 aromatase inhibitors, anastrozole (Arimidex, AstraZeneca) and letrozole, noted Dr. Osborne. "Exemestane is a type 1 inhibitor — the others are type 2 — and once it binds to the enzyme, it does not come off," he said.

New Data on Alcohol

Clinicians will also likely be interested in 2 studies of modifiable risk factors for breast cancer, namely alcohol consumption and obesity. "We know these 2 are risk factors for developing breast cancer," said Dr. Osborne.

What is notable this year is that there are new studies on the effects of alcohol and obesity in women who already have breast cancer. There is some previous research in this area, said Dr. Osborne, but "these are more definitive studies."

The Life After Cancer Epidemiology (LACE) Study examines the association between alcohol consumption (overall and type) and breast cancer recurrence and overall mortality in a prospective cohort of early-stage breast cancer survivors. The study will be presented on the morning of December 10 by Michelle Kwan, PhD, from Kaiser Permanente in Oakland, California.

It will be followed immediately by a presentation on the effect of obesity on the prognosis of women with early breast cancer. This Danish study will be presented by Marianne Ewertz, MD, from Odense University Hospital in Denmark.

32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009.

RADICAL HYSTERECTOMY FOR EARLY CERVICAL CANCER

NEW YORK (Reuters Health) Nov 27 - For women with early-stage cervical cancer, outcomes and survival are better with surgery than with radiation treatment, according to researchers. However, the advantage is limited to women with tumors 6 cm in size or less.

Dr. Jason D. Wright, of Columbia University College of Physicians and Surgeons, New York, and colleagues used data from the Surveillance, Epidemiology, and End Results database to compare survival for women with early-stage (stage IB1-IIA) cervical cancer who were treated with primary radiation or radical hysterectomy.

Of 4885 patients identified, 4012 women (82.1%) underwent radical hysterectomy and 873 (17.9%) underwent primary radiotherapy.

Cox proportional hazards analysis demonstrated an association between radical hysterectomy and a 59% reduction in cancer-specific mortality, a report in the November issue of the American Journal of Obstetrics and Gynecology indicates.

Adding adjuvant radiation to primary hysterectomy reduced overall mortality by 52%, the report shows.

Multivariate analysis showed that after stratification by tumor size, radical hysterectomy was associated with a 62% reduction in mortality for women with tumors of less than 4 cm compared with radiotherapy. For those with tumors of 4 to 6 cm, hysterectomy was associated with a 49% reduction in mortality rate. By contrast, survival was similar for radical hysterectomy and radiation among women with tumors that were greater than 6 cm.

"Patients and physicians should strongly consider primary surgery for patients with early-stage cervical cancer," Dr. Wright told Reuters Health.

"The decision on the best treatment for early-stage cervical cancer is often complex and involves patient preferences, cancer characteristics, and consideration of a patient's underlying medical problems," he explained. "Our findings must be placed in the context of these factors, but the survival advantage we noted should also influence treatment planning."

Am J Obstet Gynecol 2009;201:485e1-9.

CELL PHONES ARE SAFE

December 4, 2009 — It has been suggested that the use of cell phones is a risk factor for brain tumors, and the current debate over this issue has recently intensified. However, a new Scandinavian study did not find substantial changes in brain tumor incidence among adults 5 to 10 years after the use of cell phones sharply increased.

The researchers, in a report published online December 3 in the Journal of the National Cancer Institute, note that the use of cell phones sharply increased in the mid-1990s in Denmark, Finland, Norway, and Sweden. From 1974 to 2003, the incidence of brain tumors in these nations were stable, decreased, or continued a gradual increase that began before cell phones came on the market. The researchers did not detect any clear change in incidence trends from 1998 to 2003, a time period during which a possible association between cell phone use and cancer risk with an induction period of 5 to 10 years would have become evident.

"It should be noted that the population using mobile phones is very large; it is unprecedented in history that an exposure has become so prevalent in about 20 years," said lead author Isabelle Deltour, PhD, from the Institute of Cancer Epidemiology, Danish Cancer Society, in Copenhagen.

Currently, there is no clear biologic mechanism that explains how mobile phones would cause brain tumors, she told Medscape Oncology. "Experimental research has also, overall, shown evidence against a risk," she said. "But the etiology of brain tumors, in general, is poorly understood; the large majority of the cases remain unexplained, despite decades of research."

A large number of studies have investigated the relation between cell phone use and the risk of developing malignant and benign brain tumors and other types of cancers, but results from long-term studies are still limited. Study results have also not been consistent, and views among experts regarding the potential dangers of cell phone use have been conflicting.

As previously reported by Medscape Oncology, the controversy intensified in August, when a major report released by the International Electromagnetic Field Collaborative found that the regular use of cell phones can result in a "significant" risk for brain tumors.

Increased Incidence of Brain Tumors Not Seen

In the current study, Dr. Deltour and colleagues analyzed data from 1998 onward.

Cell phones were first introduced into Northern Europe in the mid-1980s, but they were not widely used until the early 1990s. Use sharply increased in the mid-1990s. Therefore, researchers contend, time trends in brain tumor incidence after 1998 are likely to be relevant to the evaluation of possible associations between brain tumors and cell phone use after 5 to 10 years of exposure.

They note that previous Scandinavian investigations found that the incidence of glioma was relatively stable from 1983 to 1998, whereas the incidence of meningioma rose between 1968 and 1997.

Dr. Deltour and colleagues analyzed the annual incidence rates of glioma and meningioma among adults between the ages of 20 and 79 years. Of a total population of 16 million adults, they identified 59,984 individuals who were diagnosed with brain tumors between 1974 and 2003.

During this time period, the incidence rate of glioma increased gradually by 0.5% per year in men (95% confidence interval [CI], 0.2% to 0.8%) and by 0.2% per year in women (95% CI, 0.1% to 0.5%). For both sexes, the incidence rate of glioma increased steadily among those 60 to 79 years of age (0.7% annual percent change for men, 0.5% for women). In other age groups, rates remained stable (ages 40 to 59 years) or declined (ages 20 to 39 years).

The authors note that they did not observe a change in the glioblastoma incidence rate trend in the overall or age-specific analyses.

When looking at meningioma, they observed that the overall incidence rate of meningioma increased by 0.8% per year (95% CI,= 0.4% to 1.3%) in men and, after the early 1990s, by 3.8% per year (95% CI, 3.2% to 4.4%) in women. The increase seen in women during this period was driven by people 60 to 79 years of age, who contributed the largest number of cases.

Overall, the authors were unable to identify any clear change in long-term time trends in the incidence of brain tumors from 1998 to 2003 in any subgroup.

Possible Reasons for Current Finding

Dr. Deltour and colleagues write that this finding could be due any number of factors: that the induction period for brain tumors associated with cell phone use exceeds 5 to 10 years; that the increased risk in this population is too small to be observed; that the increased risk is restricted to subgroups of brain tumors or cell phone users; or that there is no increased risk.

"Because of the high prevalence of cell phone exposure in this population, and worldwide, longer follow-up of time trends in brain tumor incidence rates are warranted," the authors write.

"We can only speculate what can happen in the future about a possible risk factor, [the actions of which we do not know]," she said. "Our study, which is based on very good data, allows us to exclude a risk among adults until 2003, unless it is [not] detectable in all 4 Nordic countries combined, pointing to small risks."

She also noted that, because of the uncertainties in both brain tumor etiology and the mechanisms, the length of the induction period is not known, assuming that cell phones do indeed cause brain tumors. "If mobile phones do not cause brain tumors, then 'induction period' is a meaningless concept, and we will never observe any sudden sharp increase in the incidence rates," she said.

Some case–control studies, however, have reported increased risks 5 to 10 years after the exposure that are an order of magnitude of 2. "We do not confirm these results, and if the risk was of that magnitude, we would have observed a sudden sharp increase in our study."

The study was funded by the Danish Strategic Research Council.

J Natl Cancer Inst. 2009;101:1721-1724.

PREDICTIVE FACTOR OF TAMOXIFEN RESPONSE

NEW YORK (Reuters Health) Nov 25 - In premenopausal women with ER-positive breast cancer, high expression of serine-118-phosphorylated alpha estrogen receptors (ER-alpha-S118-P) is associated with an improved response to tamoxifen, European investigators report.

"Our study highlights the importance of assessing the functionality of a drug target," Dr. Goran Landberg at the University of Manchester, UK, and his associates write in the Journal of the National Cancer Institute published online on November 25.

About half of ER-alpha-positive breast carcinomas are resistant to tamoxifen. Until now, there have been no validated biomarkers that predict tamoxifen response in these tumors, although animal studies have indicated that ER-alpha-S118-P is required for the drug to work.

Dr. Landberg's group evaluated data from 239 premenopausal patients diagnosed with stage II, ER-alpha positive breast cancer in whom ER-alpha-S118-P status could be determined. The women had been randomly assigned to 2 years of adjuvant tamoxifen treatment or to no systemic treatment.

Immunohistochemical analysis revealed that 115 patients had low ER-alpha-S118-P expression and 124 had high expression.

In patients with high ER-alpha-S118-P expression, tamoxifen therapy was associated with a significant improvement in recurrence-free survival compared with no systemic treatment (23.7 vs 72.2 recurrences per 1000 person-years, hazard ratio = 0.36, p = 0.037).

On the other hand, tamoxifen therapy did not improve survival among patients with low ER-alpha-S118-P expression.

However, Dr. Landberg and associates caution, "Further investigations of the relationship between ER-alpha-S118-P status and survival in larger study populations are required before withholding tamoxifen treatment for certain patients can be recommended." They also recommend that a similar study be done among postmenopausal women.

J Natl Cancer Inst 2009.

WEEKLY PACLITAXEL IS BETTER

Cancer Treat Rev. 2009 Nov 26. [Epub ahead of print]

Overall survival benefit for weekly vs. three-weekly taxanes regimens in advanced breast cancer: A meta-analysis.

Mauri D, Kamposioras K, Tsali L, Bristianou M, Valachis A, Karathanasi I, Georgiou C, Polyzos NP.

Department of Medical Oncology, General Hospital of Lamia, Lamia, Greece; Panhellenic Association for Continual Medical Research (PACMeR), Greece.

BACKGROUND: Taxanes have been extensively tested in patients with advanced breast cancer, but it is unclear whether their weekly use might offer any benefits against standard every three weeks administration. We therefore performed a meta-analysis of randomized controlled trials that compared weekly and every three weeks taxanes regimens in advanced breast cancer. METHODS: The endpoints that we assessed were objective response rate, progression free survival (PFS) and overall survival. Efficacy data for paclitaxel and docetaxel were separately analyzed. Trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. RESULTS: Omicronbjective response rate was notably better when paclitaxel was used as every three weeks regimen (7 studies, 1772 patients, fixed effect model pooled RR 1.20 95%CI 1.08-1.32 p<0.001). class="yshortcuts" id="lw_1260304458_14">random effect model HR 1.02, 95%CI 0.81-1.30 p=0.860); while OS was statistically higher among patients receiving weekly paclitaxel (5 studies, 1471 patients, fixed effect model pooled HR 0.78, 95%CI 0.67-0.89 p=0.001). No differences were observed for the weekly compared to the every three weeks use of docetaxel either for objective response, PFS and OS. Overall, the incidence of serious adverse events, neutropenia, neutropenic fever, and peripheral neuropathy were significantly lower in weekly taxanes schedules. The incidence of nail changes and epiphora were significantly lower in the every three weeks docetaxel regimens. CONCLUSIONS: Use of paclitaxel in weekly regimen give overall survival advantages compared with the standard every three weeks regimen. The observed survival benefit does not seem to stem from an increased potency of the drug with weekly regimens. The use of weekly paclitaxel regimens is therefore recommended for the treatment of locally advanced/metastatic breast cancer.

BETTER TO GIVE TRASTUZUMAB WITH CHEMOTHERAPY?

NEW YORK (Reuters Health) Dec 02 - In women with axillary node-positive breast cancer, giving trastuzumab after the end of adjuvant chemotherapy and radiation did not significantly reduce their risk of relapse, European researchers report online in the Journal of Clinical Oncology.

The report, by Dr. Marc Spielmann of the Institut Gustave Roussy, Villejuif, France, and colleagues, noted that almost all previous trials of trastuzumab in similar populations reported a statistically significant benefit, with risk reductions ranging from 36% to 58%.

Regarding possible reason(s) for their findings, the authors point out that "the most robust data for trastuzumab efficacy came from trials that evaluated a concomitant schedule" rather than a sequential one.

Subjects in the multicenter study were drawn from among 3,010 women with axillary node-positive nonmetastatic breast cancer who had been randomized to receive one of two chemotherapy regimens (either fluorouracil, epirubicin and cyclophosphamide or epirubicin and docetaxel) plus radiation (if breast surgery had been conservative).

The 528 women with tumors that over-expressed human epidermal growth factor receptor 2 (HER2) were randomized a second time, to receive either a one-year course of trastuzumab, or observation.

Trastuzumab was given as an 8 mg/kg loading dose and a maintenance dose of 6 mg/kg every three weeks for up to 18 cycles. The HER2-positive women had a median age of 48 years.

Three-quarters of those slated to get trastuzumab received it for at least six months. The main reason for discontinuing trastuzumab was cardiac events (41 patients), although no deaths from cardiac causes were reported.

After a median follow-up of 47 months, trastuzumab treatment was associated with a nonsignificant 14% decrease in the risk of relapse and with no difference in the risk of death. Three-year disease-free survival rates were 81% with trastuzumab and 78% with observation. Three-year overall survival rates were 95% with trastuzumab and 96% in controls.

Going back to their point that earlier reports showed a benefit of trastuzumab when it was given with, rather than after, chemotherapy, the researchers add: "Preclinical data suggest that, in addition to exerting direct antiproliferative effect on cancer cells, the concomitant use of trastuzumab could increase the taxane sensitivity of cancer cells."

J Clin Oncol 2009.

NOT AS GOOD AS IT COSTS

December 3, 2009 — Survival for the advanced stage of the most common form of lung cancer is slightly better than it was 20 years ago, a new study says.

Reporting in the November issue of the Journal of Thoracic Oncology, researchers say one-year survival of people with stage IV non-small-cell lung cancer has improved from 13% in 1990-1993 to 19% in 2002-2005 -- but still is less than 20%.

Lead author Daniel Morgensztern, MD, of the Washington University School of Medicine, tells WebMD that he feels the improvement is “only modest” and rather disappointing. The article calls the findings “sobering.”

“There has been a small but statistically significant improvement in survival for patients with stage IV non-small-cell lung cancer over the last 16 years,” he tells WebMD. “In absolute numbers, however, the survival improvement ... is hardly a reason to celebrate.”

Morgensztern and colleagues analyzed patients over four equally divided time periods between 1990 and 2005, identifying 129,337 people with stage IV non-small-cell lung cancer from the Surveillance, Epidemiology and End Results (SEER) registry. Non-small-cell lung cancer is the most common type of lung cancer. Stage IV means that the cancer has spread to distant areas of the body.

Better Lung Cancer Survival

In the first period, 1990-1993, the study says 13.2% of patients with this stage of the disease survived a year and 4.5% survived two years. By the fourth period, covering 2002-2005, one-year survival had improved to 19.4% and two years to 7.8%.

That’s significant, he tells WebMD, but much more improvement is needed.

“With so much effort and research on lung cancer, we hope for more robust improvements soon,” he says.

The study attributes some of the improvement to the development of new chemotherapy agents and treatment regimens, such as the introduction of targeted therapies. “The main tasks are to identify which treatment fits best for individual patients and develop new treatments with increased efficacy and decreased toxic effects,” he tells WebMD.

Smoking Still a Factor

Lung cancer is the most common cause of cancer-related death in the U.S., killing an estimated 162,000 people in 2008, the researchers write. The use of positron emission tomography (PET scan) has been associated with increased detection, the researchers write, and Morgensztern tells WebMD such scans should be considered more often.

Still, he tells WebMD, the outlook for lung cancer patients is chilling.

“In terms of new hope, you should remember that the median survival remains very poor, less than seven months in the general population,” he tells WebMD.

Smokers, he adds, should quit.

“The probability of developing lung cancer decreases in former smokers, although it remains unclear if it ever reaches the probability of the general nonsmoking population,” Morgensztern says.

LONG DURATION OF PROTECTION WITH HPV VACCINE

December 3, 2009 — The Cervarix vaccine, manufactured by GlaxoSmithKline, provides a high level of long-term protection against human papillomavirus (HPV) types 16 and 18. According to new data published online December 3 in The Lancet, the HPV 16/18 AS04-adjuvanted vaccine offered sustained protection and long-term efficacy for up to 6.4 years.

The researchers found that the vaccine was 95.3% effective against incident infection with HPV 16/18, and was 100% effective against 12-month persistent infection. Effectiveness against cervical intraepithelial neoplasia grade 2 and above (CIN2+) was 100% for lesions associated with HPV 16/18 and 71.9% for lesions independent of HPV.

They also noted that during months 63 to 76, antibody concentrations against HPV 16 and HPV 18 were at least 13 and 12 times higher, respectively, than concentrations recorded after clearance of a natural infection, as demonstrated in a previous study (Lancet. 2007;369:2161-2217).

How long immunogenicity will last is a very important question that our paper partially answers, explained study author Barbara Romanowski, MD, a clinical professor in the Division of Infectious Diseases at the University of Alberta in Edmonton. "Our results demonstrate that antibody levels are excellent after 6.4 years of follow-up, and a subset of these women will continue to be followed for at least 9.5 years," she told Medscape Oncology.

"Mathematical modeling suggests that the antibody levels might last at least 20 years, but this will have to be borne out with long-term follow-up studies," she added. "The key message of this study is that the bivalent HPV vaccine has high efficacy against HPV 16 and 18, and provides cross protection against other high-risk HPV strains. The vaccine is highly immunogenic and safe.

The US Food and Drug Administration approved Cervarix in October 2009 for use in the prevention of cervical cancer and precancerous lesions caused by HPV 16 and 18 in women 10 to 25 years of age. It has been commercially available in the European Union and other nations since 2007.

As previously reported by Medscape Oncology, large clinical trials found the vaccine to be 93% effective in preventing CIN2+ associated with HPV 16 and 18.

Affordability and Long Duration Needed for Poor Nations

The evidence from large phase 3 trials suggests that vaccinating girls before they reach adolescence against HPV 16 and 18 would be cost-effective in preventing cervical cancer in even the poorest countries, provided the cost of vaccination falls to US$10, writes Gary M Clifford, PhD, from the International Agency for Research on Cancer in Lyon, France, in an accompanying editorial.

However, he notes, "the greatest source of uncertainty with respect to the potential effect of HPV vaccines remains the duration of the immune response. If vaccine boosters are needed later, the complexity of program delivery, particularly in low-resource countries, increases considerably."

The GAVI Alliance, a global health partnership between the private and public sectors that subsidizes vaccines for the poorest nations, is currently reviewing HPV vaccine as a candidate for sustainable financing, he writes, but eligible countries will need to obtain the maximum benefit for every dose of HPV vaccine administered.

The target age for the vaccine is a balancing act — early enough to catch girls before sexual debut but late enough to provide an as-yet-unknown duration of immunity that will offer protection for as long as possible, writes Dr. Clifford.

The results of the current trial suggest that this window of protection is at least 6 years, he notes, adding that it "leads us to strongly suspect that, as these and other vaccinated women are followed up, the period of protection might be much longer."

Follow-Up Shows High Efficacy, Long Duration of Immune Response

The study was conducted by the GlaxoSmithKline Vaccine HPV-007 Study Group, and is an extended follow-up of an efficacy trial that began in 2001. The initial study examined 1113 women between the ages of 15 and 25 years (560 in the vaccine group and 553 in the placebo group). All participants had normal cervical cytology and were HPV 16/18 seronegative and oncogenic HPV DNA-negative (14 types) at initial screening.

The follow-up study took place at 27 sites in 3 countries between November 10, 2003 and August 9, 2007. Of the 1113 women in the initial study, 776 continued in the follow-up study, and 700 (90%) completed the study. Cervical samples were tested every 6 months for HPV DNA, primarily to assess the long-term effectiveness of the vaccine in the prevention of incident cervical infection with HPV 16, HPV 18, or both.

The researchers observed that high vaccine efficacy was achieved against any cytologic abnormal change of atypical squamous cells of undetermined significance or greater, or against low-grade squamous intraepithelial lesions or greater that were associated with HPV 16, HPV 18, or both.

The vaccine was 100% effective for both CIN1+ and CIN2+ associated with HPV 16, HPV 18, or both. None of the vaccine recipients had a CIN event during the 6.4 years of follow-up, and all new cases of CIN2+ that were identified during the follow-up period occurred in the placebo group.

An analysis of cytohistologic end points independent of HPV DNA in the lesion showed that there was an efficacy rate of 35.4% against any cytologic abnormal changes of atypical squamous cells of undetermined significance or greater, and an efficacy rate of 39.4% for low-grade squamous intraepithelial lesions or greater. They also noted that the vaccine was highly effective against any CIN1+ and CIN2+, and nearly all recipients (99%) remained seropositive for anti-HPV 16 and anti-HPV 18 total immunoglobulin G antibodies.

Safety profiles were similar between the vaccine and placebo groups. In the vaccine group, 30 women (8%) reported a serious adverse event, as did 37 women (10%) in the placebo group. None of the serious adverse events that were reported were judged to be related or possibly related to vaccination, the authors note, and there were no deaths.

The study was funded by GlaxoSmithKline Biologicals (Belgium). A number of study authors have disclosed relevant financial relationships; these are detailed in the paper.

Lancet. Published online December 3, 2009.

NEOADJUVANT CHEMOTHERAPY FOR GASTRIC CANCER

Ann Surg Oncol. 2009 Nov 26. [Epub ahead of print]

Neoadjuvant Docetaxel, Capecitabine and Cisplatin (DXP) in Patients with Unresectable Locally Advanced or Metastatic Gastric Cancer.

Ann Surg Oncol. 2009 Nov 26. [Epub ahead of print]

Neoadjuvant Docetaxel, Capecitabine and Cisplatin (DXP) in Patients with Unresectable Locally Advanced or Metastatic Gastric Cancer.

Sym SJ, Chang HM, Ryu MH, Lee JL, Kim TW, Yook JH, Oh ST, Kim BS, Kang YK.

Division of Oncology, Department of Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

BACKGROUND: This phase II study was conducted to evaluate the efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin and capecitabine (DXP) in patients with unresectable locally advanced and/or intra-abdominal metastatic gastric cancers. METHODS: Patients with advanced gastric cancer (AGC), clinically unresectable because of local invasion or limited intra-abdominal metastasis in para-aortic lymph nodes and/or the peritoneum based on multidetector row computed tomography, were enrolled. DXP consisted of docetaxel 60 mg/m(2) i.v. and cisplatin 60 mg/m(2) i.v. on day 1, and capecitabine 937.5 mg/m(2) twice daily p.o. on days 1-14 every 21 days. Surgery was performed after 4-6 cycles of DXP. RESULTS: Thirty-six (74%) of the 49 patients enrolled underwent surgery, and 31 (63%) had an R0 resection. R0 resection was possible in 15 of 21 patients (71%) with unresectable locally advanced lesions, 12 of 17 patients (70%) with para-aortic lymph node metastasis but only 4 of 11 patients (36%) with peritoneal metastasis. Grade 3/4 toxicities included neutropenia (69%), febrile neutropenia (4%) and hand-foot syndrome (8%). CONCLUSIONS: Neoadjuvant DXP may offer a reasonable chance of curative surgery in AGC patients with unresectable locally advanced or para-aortic lymph node metastasis.

RADIATION FOR NEUROENDOCRINE TUMOR PALLIATION

November 26, 2009 — Radiation therapy is effective in achieving local control and palliation in patients with pancreatic neuroendocrine tumors (PNTs), and it produces high rates of symptomatic palliation.

In the November 15 issue of the International Journal of Radiation Oncology-Biology-Physics, researchers report that PNTs were sensitive to treatment with external-beam radiotherapy (EBRT), despite the fact that this type of tumor is often considered to be radioresistant.

The authors note that this perception is "somewhat surprising," considering the fact that the management of PNTs is limited to anecdotal experiences. They also point out that data from published case reports suggest just the opposite — that PNTs might be responsive to radiation therapy and chemoradiotherapy, and that PNTs often present as unresectable tumors, making EBRT an attractive option for managing the disease.

"There are misconceptions about the use of radiation, but we believe that it is a good palliative therapy," said study author Edgar Ben-Josef, MD, associate professor in the Department of Radiation Oncology at the University of Michigan in Ann Arbor. "We conducted this study to evaluate our experience with it."

High Rate of Response and Palliation

The team reviewed records for 35 patients, which is thought to be the largest case series of PNTs to be treated with EBRT. They found that 39% of patients experienced a response to radiation therapy, the actuarial 3-year local freedom from progression rate was 49%, and symptom palliation was achieved in 90% of the cohort.

"We recommend that physicians consider radiation therapy for these patients," Dr. Ben-Josef told Medscape Oncology. "It is an effective tool but is underutilized."

Largest Series to Date

These patients were treated with radiation therapy at 49 sites between 1986 and 2006. Of the 35 patients for whom records were available, 14 received radiation treatment to the primary tumor or tumor resection bed. Within this group, 8 patients had unresectable tumors and 6 underwent surgical resection with either gross residual disease left behind/positive margin (n = 3) or multiple positive lymph nodes (n = 3). The other 21 patients had only been treated at the sites of distant metastasis, predominantly the liver or bone.

Nearly all of the patients (n = 13) in the group treated for a primary tumor were chemotherapy naive, and the majority (n = 20) of those who received radiation treatment to metastatic sites had undergone at least 1 course of cytotoxic chemotherapy. The median dose delivered to the primary and metastatic sites was 58.4 and 24.6 Gy, respectively, and 32 patients in this cohort were treated for symptoms or for progressive disease.

Follow-up computed tomography scans were performed to evaluate the disease in 23 patients who received treatment at 26 sites — 10 to the primary tumor and 16 to metastatic sites. Of this group, 13% had a complete response, 26% had a partial response, 56% had stable disease, and 4% had progressive disease.

Higher Doses for Improved Response

There was a definite dose-related response, Dr. Ben-Josef said. For the purposes of comparison, all radiation doses were converted to a 2 Gy/fraction biologically equivalent dose (BED). The interval to radiographic disease progression was determined for patients receiving either greater than or less than the median BED2Gy of 49.6. The authors observed a significant difference between these 2 groups (P < .01), and all cases of radiographic progression occurred in patients who had received a radiation dose of 32 BED2Gy or less.

"We need to use higher doses to achieve a better response rate," said Dr. Josef. "We recommend sophisticated planning techniques, as well as appropriate dose fractionation regimens."

There is a potential for adverse events, especially with more aggressive therapy. "We don't want to harm patients, of course, but our data showed a dose-response-related response to therapy," Dr. Josef explained.

There were 2 cases of acute grade 4 toxicities, and 3 late toxicities (2 that were grade 3 and 1 that was grade 5); all toxicities occurred in patients who had undergone both an open surgical procedure and radiation therapy to the primary site. All 5 patients received a radiation dose of more than 50.4 Gy.

The median overall survival was 2 years and, at the time this analysis was conducted, 30 of the patients had died. Although there were no significant differences between patients who were treated at a primary site and those treated at a metastatic site, and there was a trend for improved 1-year survival in those treated at the primary site (86% vs 62%).

"Survival was not the primary focus of our study, but we can say that the patients had a rather long survival," said Dr. Josef.

The authors have disclosed no relevant financial relationships.

Int J Radiat Oncol Biol Phys. 2009;75:1196-2000. Abstract

STATINS FOR ELEVATED CRP

November 25, 2009 (Orlando, Florida) — Treating healthy women with low LDL cholesterol but elevated high-sensitivity C-reactive protein (hsCRP) levels with rosuvastatin (Crestor, AstraZeneca) cuts their risk of cardiovascular events in half, according to a new analysis of Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER).

The reduction in risk is consistent with the reduction observed in the overall trial, and with the 42% benefit observed in men.

"The prespecified gender-specific analyses from JUPITER are crucial for writing evidence-based guidelines," lead JUPITER investigator Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) told heartwire . "We now know that many men and women who are outside current guidelines are in fact at substantive vascular risk if hsCRP is elevated, and we now have clear evidence that statin therapy can markedly reduce that risk."

The sex-specific analysis was presented here at the American Heart Association 2009 Scientific Sessions.

46% Reduction in Risk of Cardiovascular Events

Briefly, the overall JUPITER trial consisted of 17 802 healthy men and women assigned to rosuvastatin 20 mg or placebo. It was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL cholesterol levels but elevated CRP levels (>2.0 mg/L). As reported by heartwire , treatment with rosuvastatin significantly reduced the primary composite end point 44% compared with placebo.

In this latest analysis, Ridker, along with Dr Samia Mora (Brigham and Women's Hospital), presented data on 6801 women in the JUPITER trial. Like the overall findings, treatment with rosuvastatin 20 mg significantly reduced the relative risk of the primary end point--a composite of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, and death from cardiovascular causes--by 46%. The largest reduction observed was in the need for revascularization, which was reduced 76% compared with placebo.

Ridker said there are virtually no primary-prevention studies in women, and this trial supports the use of statins based on a marker of inflammation. He noted that the recently updated Canadian lipid guidelines reflect the JUPITER trial data, a change reported by heartwire , and now recommend hsCRP evaluation for those at "intermediate risk."

JUPITER was supported by AstraZeneca. Ridker reports having received research grant support from AstraZeneca, Merck, Abbott, Roche, and Sanofi-Aventis, and consulting or lecture fees from AstraZeneca, Novartis, Merck, Merck-Schering Plough, Sanofi-Aventis, ISIS, Dade-Behring, and Vascular Biogenics; he is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease, which have been licensed to several entities, including AstraZeneca.

A BETTER TEST TO DETECT T790M MUTATION

December 3, 2009 (Kissimmee, Florida) — A locked nucleic acid test can detect the epidermal growth-factor receptor (EGFR) T790M mutation in lung cancer patients better than standard sequencing, according to a new retrospective review study presented here at the Association for Molecular Pathology (AMP) 2009 Annual Meeting.

"While mutations of the [EGFR] predict sensitivity to tyrosine kinase inhibitors [TKIs] in patients with lung adenocarcinoma, these patients often go on to develop resistance to these drugs, to EGFR [TKIs], within 6 to 12 months," explained lead investigator Maria Arcila, MD, from the Department of Molecular Pathology at Memorial Sloan-Kettering Cancer Center in New York City, during a poster presentation.

She reported that although up to 50% of this patient population has shown a secondary EGFR mutation (T790M) in their tumor tissue, previous studies suggest that this number might actually be much higher.

"Standard sequencing techniques may lead to many T790M mutations going undetected," said Dr. Arcila. "We wanted to know, if we used a more sensitive method, whether those patients did have the mutation and we just weren't seeing it — that it could be that the cells that have the mutations are just very diluted within the other tumor cells."

T790M Resistance: As High as 72%?

For this study, Dr. Arcila and her team retrospectively reviewed 39 tumor samples that were tested by standard sequencing from August 2008 to May 2009. DNA from these samples was gathered from biopsies of patients with metastatic or recurrent lung adenocarcinomas.

A total of 18 of the 24 stored mutation-negative samples were retested using a "locked nucleic acid to develop a higher-sensitivity PCR sequencing assay to allow the detection of EGFR T790M in patients with a low mutant allele burden," according to the presentation. "This step was designed to suppress the amplification of nonmutant DNA," explained Dr. Arcila.

Results showed that 15 of the standard sequencing samples (38%) were found to be positive for the T790M mutation on initial testing.

The locked nucleic acid test detected the mutation in another 10 cases (56%). In addition, "the detection sensitivity of similar locked nucleic acid assays for specific point mutations, based on serial dilutions of mutated heterozygous cell lines mixed with a normal control sample, was at least 0.1%," reported Dr. Arcila.

She added that "since 56% of the cases that were negative by conventional sequencing were positive with a more sensitive assay, we estimate that the prevalence of the T790M resistance mutation in patients with established EGFR TKI resistance may be as high as 72%, which is significantly higher than the 50% usually reported in the literature."

Dr. Arcila said that her team was a little surprised that the assay worked so well. "We did think that these mutations were not being detected easily because standard PCR is known to have a very low sensitivity. But that the assay is able to pick up mutations at such a low, low dilution level was nice to see."

"I'd say the number 1 take-away message is the fact that these mutations are more common than people actually think and the improved detection by higher-sensitivity methods, such as nucleic acid, may have significant clinical implications," said Dr. Arcila. "After detection, these patients could then be treated with something else or be assigned to other clinical trials that they could benefit from."

Early but Promising Results

"This study really represents many of the studies that were presented here [at the meeting], in that it addresses an important problem in medicine — one that's related to understanding better treatment response in developing the best possible diagnostics," said AMP program chair Timothy O'Leary, MD, PhD, new editor (beginning in January) of The Journal of Molecular Diagnostics, which is published by the AMP and the American Society for Investigative Pathology. Dr. O'Leary was not involved with this study.

He noted that the investigators "have done a very careful study of several techniques and it suggests that there are, which is always true in the field, improvements that can be made in the diagnostic methods that will eventually, presumably, devise better selections of patients for treatment."

"Overall, I think the results they found are very promising. They are early and it is a relatively small number of patients. It's not something that folks should necessarily be running out to do. Nonetheless, it looks like an approach that offers promise and is absolutely worth investigating further in larger numbers of patients," concluded Dr. O'Leary.

Dr. Arcila and Dr. O'Leary have disclosed no relevant financial relationships.

Association for Molecular Pathology (AMP) 2009 Annual Meeting: Abstract ST21. Presented November 20, 2009.

CONTROVERSY OVER MAMMOGRAPHY CONTINUES

December 2, 2009 (Chicago, Illinois) — The low doses of radiation associated with annual screening mammography could be placing high-risk women in even more jeopardy of developing breast cancer, particularly if they start screening at a young age or have frequent exposure, according to new research presented here at the Radiological Society of North America 95th Scientific Assembly and Annual Meeting.

A meta-analysis of 6 studies found that women with BRCA1 or BCRA2 gene mutations or a family history of breast cancer who were exposed to radiation, either from mammography or chest x-rays, before the age of 20 had a risk for breast cancer that was 2.5 times higher than their counterparts who were not exposed to radiation (95% confidence interval [CI], 1.9 - 3.2).

The analysis, which examined 9420 high-risk women, also found that 5 or more mammograms increased risk 2.5-fold (95% CI, 1.6 - 3.9), Marijke C. Jansen-van der Weide, PhD, from the University Medical Center Groningen in the Netherlands, reported.

Overall, exposure to low-dose radiation increased breast cancer risk by a nonsignificant 1.5 times, compared with no exposure, Dr. Jansen-van der Weide said.

The mean age of the women in the analysis was 45 years. The cumulative dose of radiation they received ranged from 0.3 to 24 mSv.

"The take-home message here is that high-risk women who are younger should be careful about mammography screening," she told Medscape Radiology. "Because they are young, they also have dense breasts, which poses a problem with mammography. They should explore alternative screening methods."

The average woman has a 10% chance of developing breast cancer during her lifetime. In comparison, women who are carriers of the BRCA1 gene mutation have a 57% chance, and BRCA2 carriers have a 49% chance of developing breast cancer. Screening these women must start at an early age, since many will get breast cancer in their 30s or 40s, Dr. Jansen-van der Weide said.

Magnetic resonance imaging (MRI) could be one alternative for these women, although it has its own problems, she suggested. "MRI is not as readily available, it takes more time, and it is associated with many more false-positives. This is why it is so important for high-risk women to discuss the issue with their doctor and, together, work out a screening strategy."

She emphasized that screening mammography is not a problem for high-risk women 30 years and older. "Screening these high-risk women is still very important, but we must think about alternative nonionizing techniques at younger ages," she said.

"From our study results, we are talking about women below the age of 20, which is very young. We are also talking about 5 or more exposures. So if a woman starts at 25 and then gets 5 or more mammograms by the time she is 30, her risk will be increased. Up to the age of 30, women should be careful. After 30, perhaps she could do mammography screening every other year; that is one idea. We only used 6 studies in our analysis and we need more prospective studies to find out more about this."

The dangers of radiation in younger women have been well recognized, affirmed Allen G. Meek, MD, from State University of Stony Brook in New York, who moderated the scientific session.

"The general consensus is that the immature breast is more susceptible to ionizing radiation, so I certainly think that low-dose radiation is an issue."

He agreed that women should consider the risks and benefits and discuss them with their doctor. "The benefit is to catch the cancer earlier; the risk is you may be inducing the cancer."

Dr. Meek told Medscape Radiology that the study will make people more conscious about using a nonionizing method such as MRI. He suggested that mammograms not be done in women younger than 25 or 30 years, and then after the age of 30, a strategy might be to do a mammogram every other year, alternating with MRI.

"We know that the BRCA gene is a radiation repair gene, and when you are missing that, you have a decreased capacity for radiation repair, which will make you more susceptible to the low dose of radiation with mammography. We think this might be the biological basis for what this study found."

Dr. Jansen-van der Weide and Dr. Meek have disclosed no relevant financial relationships.

Radiological Society of North America (RSNA) 95th Scientific Assembly and Annual Meeting: Abstract RO22-04. Presented November 30, 2009.

NOVEL CHANGES IN CT OF LIVER METASTASES WITH AVASTIN

December 2, 2009 — In patients with colorectal liver metastases who were treated with bevacizumab (Avastin) in combination with chemotherapy, computed tomography (CT) scans showed changes in the metastases that predicted survival.

The changes that showed up on the CT scans are described as "novel" by researchers writing in the December 2 issue of the Journal of the American Medical Association.

They describe how the metastases changed from "heterogeneous masses with ill-defined margins into homogeneously hypoattenuating lesions with sharp borders, . . . which in some cases could mimic a cyst." These changes, on responding to treatment, "likely reflect the replacement of treated tumor by fibroconnective tissue rather than tumor necrosis," the researchers add.

Patients with an "optimal morphologic response" to preoperative therapy on the CT scans showed improved overall survival. The association between the CT changes and overall survival was statistically significant, the team reports.

In contrast, there was no correlation between survival and assessment by the traditional size-based radiological criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), which were designed to assess tumor volume reduction after cytotoxic chemotherapy.

"Patients with an optimal morphology response can be reassured that they are benefiting from treatment, even if the tumor isn't shrinking by standard size criteria," said corresponding author Jean Nicholas Vauthey, MD, from the Department of Surgical Oncology at the University of Texas M.D. Anderson Cancer Centre in Houston. "For patients with a cancer that is responding to therapy, there are more options for subsequently using less intense therapies that improve the patients' quality of life," he told Medscape Oncology.

Retrospective Study

The results come from a retrospective study that analyzed 234 colorectal liver metastases from 50 patients who underwent hepatic resection and who had received preoperative treatment with bevacizumab and chemotherapy. All patients underwent routine CT scanning at the start and end of the preoperative treatment.

In addition, the researchers analyzed CT scans for a separate validation cohort of 82 patients with unresectable colorectal liver metastases treated with bevacizumab-containing chemotherapy.

Patients in both cohorts who showed an optimal morphologic response to preoperative therapy on the CT scans had improved overall survival.

Among the patients who underwent hepatic resection, median overall survival was not reached in those who showed an optimal morphologic response; the median overall survival was 25 months for patients who had no or an incomplete morphological response (P = .03). In the nonsurgical validation cohort, the median overall survival was 31 months in patients with an optimal morphological response and 19 months in those who had no or an incomplete morphological response (P = .009).

In addition, the morphological response assessed on CT scans correlated with pathologic response, stratified as complete, major, or minor response. Again, the RECIST criteria did not correlate with pathologic response.

"Thus, our results indicate that morphological response may be a useful, noninvasive surrogate marker of pathological response and improved survival in patients with colorectal metastases receiving a bevacizumab-containing regimen," the authors conclude.

Dr. Vauthey explained that bevacizumab is used in about 80% of patients as part of their initial therapy for metastatic disease. The morphological changes in the metastases seen on the CT scan are "more pronounced" after treatment with chemotherapy that includes bevacizumab, he said, adding that, "in our experience, this response pattern is less common" in patients treated with other biological agents.

Dr. Vauthey reports receiving grants and honoraria from Sanofi-Aventis, Genentech, and Roche. Several coauthors have disclosed relevant financial relationships, as listed in the paper.

JAMA. 2009;302:2338-2344.

WHAT'S HOT AT ASH 2009 (BENDAMUSTINE)

December 1, 2009 — This year's American Society of Hematology (ASH) 51st Annual Meeting, being held in New Orleans, Louisiana, looks like it will be even bigger than the 50th anniversary meeting last year; registrations are already at an all time high. To whet the appetite of our readers, Medscape Oncology asked the cochairs of the scientific program to highlight presentations that they feel are particularly noteworthy or potentially practice-changing.

Richard Van Etten, MD, PhD, chief of hematology/oncology and director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts, highlighted hot topics within the hematological malignancies field, and Joel Anne Chasis, MD, associate professor of hematology/oncology at the University of California, San Francisco and a staff scientist at the Lawrence Berkeley National Laboratory, discussed hot topics related to nonmalignant hematology.

Progress in Lymphoma

In the lymphoma field, new data on bendamustine will attract a lot of attention, Dr. Van Etten predicted. Results from a phase 3 study (abstract 405) show that when bendamustine was used with rituximab in the first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas, it "beat the standard in the field," he said, which is rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin] and prednisolone).

Bendamustine is an old drug that was used more than 30 years ago in Germany, but it got a new lease on life last year when it was approved (as Treanda, Cephalon) by the US Food and Drug Administration for first-line use in chronic lymphocytic leukemia (CLL), Dr. Van Etten explained in an interview. The new study used first-line bendamustine in B-cell non-Hodgkin's lymphoma, and the results showed improved progression-free survival and tolerability. These new data for bendamustine are potentially practice-changing, he said.

A new standard of care in early-stage Hodgkin's lymphoma has been established by the final analysis of the German Hodgkin Study Group, say the researchers (abstract 716). The best results were seen with a combination of chemotherapy with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) followed by 20 Gy involved-field radiotherapy. There has been an ongoing debate about whether using chemotherapy or radiotherapy, or both, is the best approach, Dr. Van Etten explained. These new results show that a combination of the 2 is the best option in patients with early-phase disease with a favorable prognosis, and "it looks as if it will become a standard," he told Medscape Oncology.

There will be several important updates to immunotherapy for lymphoma with monoclonal antibodies presented at the meeting. The standard therapy in the field is the anti-CD20 monoclonal rituximab (Rituxan, Genentech/Roche). A new agent that works in a similar manner, also an anti-CD20 monoclonal antibody, is ofatumumab (GlaxoSmithKline). This drug has just been approved for use in relapsed or refractory CLL, and is now being investigated in a more up-front setting, Dr. Van Etten explained. Phase 2 data from a trial in previously untreated CLL patients show that ofatumumab given in combination with fludarabine and cyclophosphamide is "highly active" (abstract 207).

Another agent, GA101 (also know as RO5072759), from the same manufacturer, Genentech, is being billed as "son of rituximab." It is being investigated in relapsed/refractory CLL (abstract 884). "These are early days," Dr. Van Etten said, "but it will be interesting to follow this one."

New Treatment Approaches in Myeloma

A new approach to initial therapy for myeloma in elderly patients comes from an Italian study in which researchers used a 4-drug combination of bortezomib (Velcade, Millennium Pharmaceuticals), melphalan, prednisone, and thalidomide (VMPT). Up to now, the most recent standard for initial therapy has been the 3-drug regimen of bortezomib, melphalan, and prednisone (VMP). This is the first report to show superiority with a 4-drug combination, say the researchers (abstract 128). Dr. Van Etten pointed out that this is unique to elderly patients with myeloma; "you would tend not to give melphalan to a younger patient because it might compromise your ability to harvest stem cells." But in elderly patients with myeloma, these new data will lead to a change in initial therapy, he predicted.

An interesting new product on the horizon is pomalidomide, the newest immunomodulatory agent to have shown activity in multiple myeloma. Data from a small trial show that it is active and well tolerated in multiple myeloma patients who are refractory to lenalidomide (abstract 429).

Developments in Leukemia

Two conclusions from a trial in childhood acute lymphoblastic leukemia (abstract 321) are potentially practice-changing, Dr. Van Etten noted. Individualizing the dose of asparaginase on the basis of pharmacokinetic measurements produced superior results to those seen with a fixed-dose regimen, and "everybody should now start doing this," he said. The same trial also showed superior results with dexamethasone, compared with prednisone, when added to asparaginase.

In the treatment of acute myeloid leukemia (AML), several new compounds with activity against FLT3 mutations are piquing the interest of researchers. These FLT3 mutations occur in about a third of patients with AML, are associated with a poor prognosis, and represent a new therapeutic target, Dr. Van Etten explained. "We haven't had a new target in AML for 30 years, so there are a lot of eyes on this," he added.

One of these products is lestaurtinib (under development by Cephalon), a multitargeted kinase inhibitor with potent activity against FLT3, which was tested as a salvage treatment for patients with FLT3-mutant AML in first relapse (abstract 788). The results are negative, but Dr. Van Etten said they beg the question: "Is it the therapeutic approach that has failed, or is it rather this particular drug at this dose?"

A similar product is midostaurin (under development by Novartis), which is currently in a large phase 3 clinical trial. Results from a preliminary phase 2b study with follow-up of more than 1000 days suggest that this product, together with chemotherapy, "might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3-mutant AML patients in first complete remission," say the researchers (abstract 634).

Further back in development is AC220 (under development by Ambit Biosciences), which is described as a second-generation FLT3 receptor tyrosine kinase inhibitor. It might be more potent and specific; the data to be presented are the first results in humans (abstract 636).

In chronic myeloid leukemia (CML), the introduction of imatinib (Gleevec, Novartis) has revolutionized treatment, but "we are now realizing that it is probably not curing most patients," Dr. Van Etten noted.

New data from the Stop Imatinib (STIM) study show that when CML patients who had achieved a molecular response on imatinib stopped taking the drug, nearly 60% relapsed. The relapse came quickly — within 6 months, Dr. Van Etten said, although the remainder of patients remained in remission (abstract 859).

Long-term data on imatinib from the IRIS trial now go out to 8 years, and show that 45% of patients are no longer taking the drug, for a variety of reasons, including adverse effects, unsatisfactory therapeutic outcome (which can include developing resistance to the drug), changing to another drug, and death (abstract 1126).

As a result, there is a lot of interest in the follow-on compounds — nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb), Dr. Van Etten explained. Both of these are currently approved for use in second-line therapy for CML in patients who have been treated with other therapies, including imatinib, but both drugs are now being investigated in the first-line treatment of CML.

New data for first-line nilotinib treatment come from the ENESTnd trial (abstract LBA-1). This trial showed that a complete cytogenic response at 1 year was achieved by 78% patients receiving nilotinib and by 65% receiving imatinib, and that the rate of progression to the accelerated phase or blast crisis was significantly lower with nilotinib (<1%>

Another approach in the treatment of CML is the addition of interferon therapy to imatinib, Dr. Van Etten noted. Interferon was the treatment of choice before imatinib arrived, and there is interest in combing the 2 products. However, the data on this so far are conflicting, and updates from 2 ongoing studies are showing opposite results. A French group has reported achieving a higher rate of complete molecular response in patients who received both interferon and imatinib as initial treatment (abstract 340), but a German study did not see this (abstract 862). "This raises the question of whether this is a real effect or not," Dr. Van Etten noted. He mentioned that there is a difference in the type of interferon product — the French group used pegylated interferon alpha-2a (Pegasys) but the German group did not — which could have affected both disease response and patient compliance.

New Anticoagulant Might Replace Older Products

Data on a new anticoagulant have the potential to be practice-changing, Dr. Chasis said in an interview; they suggest that dabigatran (Pradaxa, Boehringer Ingelheim) could offer a replacement for older products.

Selected for presentation at the plenary session is a large trial that shows that, in the treatment of acute venous thromboembolism, fixed-dose dabigatran is similar in efficacy and safety, including bleeding, to the older product, warfarin (abstract 1). "This suggests that dabigatran could offer a potential replacement for warfarin, which would be welcome news for both patients and physicians," Dr. Chasis said, because warfarin requires regular monitoring, but dabigatran does not. "It would ease the burden on the physicians," she added.

Improvements in Transfusions?

A practical clinical message comes from the FOCUS trial (abstract LBA-6), which investigated the use of blood transfusions in cardiovascular patients who had undergone hip-fracture repair. "These cardiovascular patients are particularly vulnerable to anemia, so they are given blood transfusions, with the trigger being a set hemoglobin level," Dr. Chasis explained. She added, however, that this indication for transfusion has been controversial. "In a surprise to us all, the results from the new trial show that there are no adverse effects to waiting until a patient becomes symptomatic before transfusing," she told Medscape Oncology.

Also concerning blood transfusions is translational research that could eventually lead to a reduction of transfusion-related acute lung injury (TRALI), which is the single most important cause of transfusion-related mortality. TRALI is known to be caused by HNA-3a-specific antibodies, and about 4% to 5% of the general population is at risk because they are HNA-3a-negative. The new research comes from a genome-wide survey that found a single-nucleotide polymorphism, which correlates with the HNS-3a-negative phenotype (abstract LBA-4). The hope is that this research will eventually lead to strategies to screen individuals for the HNA-3a-negative phenotype and to screen donated blood for the presence of HNA-3a-specific antibodies, which are capable of causing TRALI, Dr. Chasis explained.

Progress in Platelet Disorders

Treatment of chronic immune thrombocytopenia has been improved with the recent introduction of 2 agents, romiplostim (Nplate, Amgen) and eltrombopag (Revolade, GlaxoSmithKline). Long-term data for these agents going out to 5 years for romiplostim (abstract 681) and out to 2 years for eltrombopag (abstract 682) will be presented. "These longer-term data have not shown any new safety issues, which is reassuring," Dr. Chasis said. In addition, data from a year-long study with a 6-month extension follow-up show that romiplostim significantly reduces the incidence of splenectomy and treatment failure, compared with the standard of care (abstract 679).

Essential thrombocythemia gets a boost with a new mouse model of the disease (abstract 226). "These patients are at an increased risk of thrombosis because they have dysfunctional platelets," Dr. Chasis explained. "This research may help us to understand why the platelets are dysfunctional," she continued, and unraveling the mechanism involved might lead, in the future, to new therapeutic approaches to this disease.

Dr. Van Etten and Dr. Chasis have disclosed no relevant financial relationships.

A NOVEL INDICATION FOR CETUXIMAB

NEW YORK (Reuters Health) Nov 25 - Treatment with cetuximab (Erbitux) significantly improves the signs and symptoms of Menetrier's disease, sometimes leading to near-resolution, the findings of a small study show.

"Because no other medical therapies have shown to be consistently beneficial, cetuximab should be considered as first-line therapy for Menetrier's disease," senior author Dr. Robert J. Coffey and colleagues at the Vanderbilt University School of Medicine in Nashville conclude.

Also known as hypoproteinemic hypertrophic gastropathy, Menetrier's disease is a rare premalignant hyperproliferative disorder of the stomach with no known cure other than gastrectomy.

The disease is characterized by enlarged gastric folds, decreased acid production, excess mucus secretion, and hypoalbuminemia. Symptoms may include abdominal pain, nausea and vomiting, peripheral edema, and chronic gastric blood loss.

Evidence from both mice and humans indicates that the histologic abnormalities are associated with increases in transforming growth factor (TGF)-alpha. Cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor, inhibits binding of TGF-alpha.

In the November 25th issue of Science Translational Medicine, the researchers report that their treatment of one patient with cetuximab led to marked clinical and biochemical improvement.

Based on that success, they administered a one-month course of treatment to nine patients (ages 29 to 79) with severe Menetrier's disease, all of whom were considering gastrectomy. (The disease is so rare, notes an editorial commentary, that it took the researchers eight years to assemble these nine patients.)

Patients were treated with a loading dose of IV cetuximab (400 mg/m2 of body surface area), followed by three weekly IV infusions of 250 mg/m2. One patient withdrew after the first dose due to concerns over potential side effects. A second patient withdrew after two infusions when persistent abdominal pain led to the diagnosis of gastric cancer.

The seven patients who completed the study showed significant improvement within days of starting treatment. By the end of the month, the primary outcomes - scores on the overall Quality of Life Index and the Health and Functioning subscale - were significantly improved. Furthermore, parietal cell mass had increased, mean gastric pH had fallen from 6.0 to 4.0, and there was a trend toward decreased stomach wall thickness (from 13.7 to 9.6 mm).

All seven patients chose to continue treatment (follow-up 8 to 40 months). Four had near-complete histologic resolution of their illness. Four patients elected to undergo gastrectomy despite improvement (including one with near-complete resolution), primarily over fears of gastric cancer and concerns about indefinite treatment with cetuximab. One patient had a dysplastic lesion more than a year after discontinuing treatment.

While treatment with cetuximab may help patients avoid gastrectomy altogether, the authors note that the drug might also be used as a "bridge" to improve the operative risk of poor surgical candidates.

Sci Transl Med 2009.

BRAIN METASTASES IN HER2+ BREAST CANCER

Int J Radiat Oncol Biol Phys. 2009 Nov 23. [Epub ahead of print]

The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death.

Niwińska A, Tacikowska M, Murawska M.

Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

PURPOSE: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). METHODS AND MATERIALS: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period. RESULTS: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). CONCLUSIONS: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

HER2+ IN METASTATIC BREAST CANCER

J Clin Oncol. 2009 Nov 23. [Epub ahead of print]

Prognosis of Women With Metastatic Breast Cancer by HER2 Status and Trastuzumab Treatment: An Institutional-Based Review.

Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH.

Departments of Breast Medical Oncology and Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and Department of Medical Oncology, Dubai Hospital, Dubai, United Arab Emirates.

PURPOSE: The purpose of this study was to determine whether trastuzumab improves prognosis of women with metastatic human epidermal growth factor receptor 2 (HER2)/neu -positive breast cancer beyond that of women with HER2/neu-negative disease. PATIENTS AND METHODS: Two thousand ninety-one women with metastatic breast cancer diagnosed from 1991 to 2007, with known HER2/neu status and who had not received trastuzumab in the adjuvant setting, were identified. Disease was classified into the following three groups: HER2/neu negative, HER2/neu positive without first-line trastuzumab treatment, and HER2/neu positive with first-line trastuzumab treatment. Overall survival (OS) was estimated using the Kaplan-Meier product-limit method and compared between groups with the log-rank test. Cox proportional hazards models were used to determine associations between OS and HER2/neu status after controlling for patient characteristics. RESULTS: One hundred eighteen patients (5.6%) had HER2/neu-positive disease without trastuzumab treatment, 191 (9.1%) had HER2/neu-positive disease and received trastuzumab treatment, and 1,782 (85.3%) had HER2/neu-negative disease. Median-follow-up was 16.9 months. One-year survival rates among patients with HER2/neu-negative disease, HER2/neu-positive disease and trastuzumab treatment, and HER2/neu-positive disease and no trastuzumab treatment were 75.1% (95% CI, 72.9% to 77.2%), 86.6% (95% CI, 80.8% to 90.8%), and 70.2% (95% CI, 60.3% to 78.1%), respectively. In a multivariable model, women with HER2/neu-positive disease who received trastuzumab had a 44% reduction in the risk of death compared with women with HER2/neu-negative disease (hazard ratio [HR] = 0.56; 95% CI, 0.45 to 0.69; P < .0001). This HR varied with time and was significant for the first 24 months and not significant after 24 months. CONCLUSION: Our results show that women with HER2/neu-positive disease who received trastuzumab had improved prognosis compared with women with HER2/neu-negative disease.