SAFETY STANDARDS FOR CHEMOTHERAPY APPLICATION

October 5, 2009 — National standards for safe administration of chemotherapy drugs in the outpatient setting have been issued for the first time in the United States.

Details are outlined in a paper published online September 28 in the Journal of Clinical Oncology.

"Because of the complexity of chemotherapy administration and the risk of severe adverse effects, standardizing care in settings where chemotherapy is delivered is essential," the authors write.

The new standards, compiled by the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS), aim to reduce the risk for errors and provide a framework for best practices in cancer care.

Both societies have also developed additional materials to assist in the implementation of the new standards (available online at www.asco.org/safety and www.ons.org/clinical). These guides should help oncology practices review and develop the policies and procedures needed to adhere to the new standards, they add.

"Administration of chemotherapy is a complex process, and safety challenges will only grow as the number and complexity of chemotherapeutic regimens increase and as oral chemotherapy drugs become more commonplace," lead author Joseph Jacobson, MD, said in a statement. Dr. Jacobson is the immediate past president of ASCO's Quality of Care Committee, and chair of the Department of Medicine at the North Shore Cancer Center in Salem, Massachusetts.

The new standards were developed by a multidisciplinary workgroup made up of oncologists, nurses, pharmacists, social workers, practice administrators, and patient advocates. A draft of the document was made available for comment for 6 weeks, during which time more than 300 comments from members of the public were submitted.

Electronic Records May Improve Safety

ASCO and ONS recommend increased use of electronic medical record systems, which they believe might improve safety and quality of outpatient chemotherapy administration. E-prescribing, for example, could prove to be a tool for reducing errors in chemotherapy ordering, because automated systems can reduce errors in regimen selection in a busy clinical setting, the authors explain.

"By automating processes related to prescribing and administering chemotherapy, safety checks can be built in along the way," said Marty Polovich, MN, RN, AOCN, cochair of this project and second author on the paper.

"However, we don't believe that patient safety has to wait for electronic systems," she added. "Implementing these standards is a step toward ensuring that patients receive their anticancer therapies as intended, no matter the type or size of setting in which they are treated."

J Clin Oncol. Published online September 28, 2009. Abstract

HYPOGLYCEMIA INCREASES MI RISK

October 5, 2009 (Vienna, Austria) — A new case-control study has shown that an episode of hypoglycemia in diabetes patients is associated with a higher risk of MI for the following two weeks and possibly for a few months afterward. Dr Donald R Miller (Boston University School of Public Health, MA) reported the findings at the European Association for the Study of Diabetes (EASD) 2009 Meeting last week.

"We found an increased risk [of MI] in the short term from hypoglycemia, and there's a hint of long-term increased risk--those were the two questions we addressed," Miller told heartwire . However, he added, "I'd say the long-term risk is very small and may not be there, because it's certainly within the range of controlled confounding."

He and his colleagues say further and more detailed studies are needed to better measure the risks and identify conditions whereby hypoglycemia may lead to MI. These risks, they add, should be taken into account by doctors during the management of diabetes, with appropriate choice of therapies and treatment goals to minimize the likelihood of hypoglycemia occurring.

Risk of MI Increased 65% Within Two Weeks of Hypoglycemic Episode

Miller said he had been interested in whether hypoglycemia could precipitate cardiovascular disease events for a number of years, but it "really was ignited by the [Action to Control Cardiovascular Risk in Diabetes] ACCORD and then the [Veterans Affairs Diabetes Trial] VADT results that highlight the risks that may be there."

The ACCORD study was halted prematurely last year because of an increased risk of death in diabetes patients who underwent intensive blood glucose lowering. And VADT showed that intensive blood glucose lowering had no significant effect on the rates of cardiovascular events, death, or microvascular complications. In addition, the Action in Diabetes and Vascular Disease (ADVANCE) trial showed a reduction in the progression of albuminuria with intensive glucose control but no effect on cardiovascular-event rates.

Miller and colleagues thus set out to examine whether hypoglycemia is a precipitating factor for MI, and if so, by how much it might increase the risk within a short period of time. They also looked at whether predisposition for or history of hypoglycemia is associated with a higher risk of MI.

Using data from the Diabetes Epidemiology Cohorts of the Veterans Affairs (VA) system, they looked at the medical records of all VA patients with diabetes from 2000 to 2004 who had had at least two years of VA care and no prior MI, acute coronary syndrome, or cardiac surgery. Hypoglycemia was confirmed from medical records at any encounter, whether it was outpatient clinic, emergency room, or in an inpatient setting. Cases were defined as the first hospital MI, and controls were chosen by random selection.

They found a 65% increased odds of MI associated with hypoglycemia within the previous two weeks, even after adjustment for potential confounding factors. And a lower, but still slightly elevated, risk of MI, of around 20%, was seen for hypoglycemia events within the previous six months.

Miller and colleagues found only small differences relating to insulin use compared with no insulin use and a slightly higher risk of MI associated with inpatient hypoglycemia compared with hypoglycemia recorded in other settings. They also found a small 10% increased risk of MI for hypoglycemia in the more distant past.

Miller told heartwire : "My message is: pay attention to treatments that may increase the risk of hypoglycemia, because it has risks that have not been recognized up to this point and should be considered in the balance of risks/benefits for diabetes therapies." Tailoring therapy to the individual is the best approach, he concluded.

There was much debate at the EASD meeting last week on what the ideal glycated hemoglobin A_1c (HbA_1c) goal should be, and this subject will be covered in more detail in a future report on heartwire .

Risk of MI Associated With Episode of Hypoglycemia Within a Given Prior Period

Any hypoglycemia in specific periods	Cases (%)	Controls (%)	Adjusted risk of MI (95% CI)
Index date or day before	2.9	0.1	--
Prior 2 wk	1.1	0.3	1.65 (1.50–1.81)
Previous 5.5 mo	6.0	2.5	1.20 (1.15–1.25)
Previous 6 mo	4.8	2.1	1.11 (1.06–1.15)
Previous y	9.6	4.2	1.12 (1.08–1.16)

NEW ANALYSIS OF TEAM STUDY

September 29, 2009 (Berlin, Germany) — Adjuvant therapy with exemestane (Aromasin) appears to be more effective than tamoxifen in reducing disease recurrence in breast cancer patients, according to data presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

The conclusions come from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) study, the largest of 3 trials to compare the efficacy of an aromatase inhibitor with tamoxifen as initial endocrine therapy.

The analysis shows that in postmenopausal patients with early invasive hormone-receptor-positive breast cancer, initial adjuvant treatment with exemestane was superior to tamoxifen in improving disease-free survival and reducing disease recurrence.

"At 2.75 years, exemestane was associated with improved disease-free survival, time to distant metastasis, and recurrence-free survival," said lead author Cornelis van de Velde, MD, PhD, professor of surgery at Leiden University Medical Center in the Netherlands.

"The data are very impressive," said Chris Twelves, MD, clinical director and professor of clinical cancer pharmacology and oncology at the Institute of Cancer Therapeutics in West Yorkshire, United Kingdom. "This study is another demonstration of the superiority of [aromatase inhibitors], and does reinforce that we use them up front."

Analysis of TEAM Trial

The TEAM cohort consisted of 9779 postmenopausal patients with invasive estrogen-receptor-positive and/or progesterone-receptor-positive early breast cancer from 9 countries who were prospectively randomized to tamoxifen 20 mg/day or exemestane 25 mg/day. All patients had completed primary therapy of surgery and, if indicated, chemotherapy .

The original trial began in 2001, when the primary end point was disease-free survival. But in 2004, on the basis of results of the Intergroup Exemestane Study (IES), which showed a strong benefit for exemestane, the study was amended. All patients in the tamoxifen group were switched to exemestane at 2.5 to 3 years.

The modified study design, explained Dr. van de Velde, had 2 end points. The first compared disease-free survival in patients using either tamoxifen or exemestane for up to 2.75 years. The second end point compared disease-free survival in women using exemestane for 5 years with that in women using tamoxifen who switched to exemestane for a total of 5 years.

The current analysis focused on the first primary end point — disease-free survival after 2.75 years with tamoxifen or exemestane — with the censoring of events, said Dr. van de Velde.

Their results showed that, compared with tamoxifen, exemestane is associated with better disease-free survival (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.77 - 1.03; P = .12) and relapse-free survival (HR, 0.85%; 95% CI, 0.72 - 1.00; P = .056). Time to first distant metastasis was also better with exemestane (HR, 0.81; 95% CI, 0.67 - 0.98; P = .028).

Overall, there were 11% fewer cases of local recurrence, distant metastases, contralateral breast cancer, and deaths without disease relapse for patients in the exemestane group.

Discontinuation Rates Higher for Tamoxifen

In the TEAM study, a much higher rate of patients in the tamoxifen group discontinued their treatment (29.5%; n = 1434), than in the exemestane group (18.9%; n = 926). In addition, 754 tamoxifen patients made an early switch to exemestane.

"Discontinuation rates varied considerably by country, and this does deserve more attention," said Dr. van de Velde. "We need to inform patients of the side effects, but also the benefits of continuing their treatment. Noncompliance can confound the results of [aromatase inhibitor] trials."

There were no unexpected safety issues reported, but exemestane use was associated with significantly higher incidences of arthralgia, carpal tunnel syndrome, diarrhea, and hypercholesterolemia. The incidence rate for cardiac ischemia and infarction was similar between the groups.

IES Data Also Show Superiority

More data showing superiority of exemestane, but from a switching trial, come from a long-term follow-up of the IES, and were reported at the meeting by Charles Coombes, MD, PhD, FRCP, FMedSci, head of oncology at Imperial College in London, United Kingdom. Whereas the TEAM study set out to compare initial therapy with the 2 products, the IES compared switching to exemestane after 2 to 3 years of tamoxifen with staying on tamoxifen for the full 5 years. The new longer-term data confirm a significant 18% reduction in disease-free survival in the group that switched (HR, 0.82; P = .0009), and show a significant prolongation of overall survival, reducing the risk of dying by 14% (HR, 0.86; P = .04).

"These new longer-term follow-up data from the IES demonstrate a significant survival benefit for patients who switched to exemestane compared with those who stayed on tamoxifen," Dr. Coombes said in a statement. "These findings are important to patients and physicians alike, as they reaffirm their confidence in switching to exemestane after 2 to 3 years on tamoxifen."

The use of exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with estrogen-receptor-positive early breast cancer is an approved indication in both the United States and Europe.

Both the TEAM and the IES studies were funded by Pfizer, the manufacturer of exemestane.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstracts 2BA (TEAM study) and 5010 (IES study). Presented September 22, 2009.

BREAST CANCER DEATH RATE CONTINUE TO DROP

October 1, 2009 — Breast cancer death rates dropped 2%, continuing a decade-long decline, the American Cancer Society reports.

That means about 15,000 deaths were avoided in 2009 alone, the ACS estimates.

Breast cancer deaths declined among African-American women. But African-Americans are still 40% more likely to die of breast cancer than are white women in the U.S.

And although fewer white women are getting diagnosed with breast cancer, rates have remained stable among African-Americans.

"While there is much to celebrate in the fight against cancer, this report is also a strong reminder that far too many women still die of breast cancer," Elizabeth "Terry" T.H. Fontham, DrPH, ACS national volunteer president, says in a news release. "We need to make sure all women have access to information to help them reduce their risk and to resources to ensure early detection and the best possible treatment."

This year, nearly 200,000 U.S. women will be told they have breast cancer, the ACS estimates, and more than 40,000 women will die of the disease. After skin cancer, breast cancer is the most common cancer among U.S. women.

Breast cancer rates -- which reflect disease occurrence and how completely the population is screened -- differ among states and by race:

• The state with the lowest breast cancer rate for white women is Utah, with 111.5 cases per 100,000 women.
• The state with the lowest breast cancer rate for African-American women is New Mexico, with 60.9 cases per 100,000 women.
• The state with the highest breast cancer rate for white women is Hawaii, with 139.1 cases per 100,000 women.
• The state with the highest breast cancer rate for African-American women is Kentucky, with 127.3 cases per 100,000 women.

Even though white women are diagnosed with breast cancer at a higher rate than African-American women, they have a lower death rate. Death rates among white women range from 21.7 per 100,000 in Hawaii to 27.3 in New Jersey; among African-American women they range from 20.9 in Rhode Island to 40.0 in Louisiana.

This disparity is captured in another statistic: 90% of white women, but only 78% of African-American women, survive at least five years after their breast cancer diagnosis.

As of January 2006, when the latest figures were compiled, some 2.5 million U.S. women were breast cancer survivors. Most of them were cancer free.

The ACS report on breast cancer comes out every two years. Here are some other facts and figures from the current report, which compiles data from 2002 to 2006:

• 95% of breast cancer cases and 97% of breast cancer deaths were in women aged 40 and older.
• Half of women diagnosed with breast cancer are younger than 61.
• Breast cancer incidence dropped sharply from 2002 to 2003, particularly among women aged 50-69. Many experts think this is because of the sudden decline in postmenopausal hormone replacement therapy in 2002.

SOURCES:

American Cancer Society: "Breast Cancer Facts & Figures 2009-2010."

NOVEL AGENT FOR RELAPSED OVARIAN CANCER

October 2, 2009 (Berlin, Germany) — Although the data are early, farletuzumab appears to increase the duration of second remission in women with relapsed ovarian cancer. When combined with platinum and taxane, the objective response rate was significantly higher than that from historic data for platinum/taxane regimens alone.

According to the results of the open-label phase 2 trial, which were presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress, 73.5% of patients using combination therapy with farletuzumab achieved objective response. Median progression-free survival in this group was 10.3 months.

Farletuzumab is an investigational product under development by Morphotek. It is a humanized monoclonal antibody to folate receptor alpha, which is overexpressed in most epithelial ovarian cancers but largely absent in normal tissue. Efficacy was demonstrated in preclinical xenograft models of ovarian cancer, and activity was demonstrated in antibody-dependent cellular cytotoxicity assays.

In addition, a phase 1 trial conducted using farletuzumab as a single agent showed signs of efficacy, explained lead study author Deborah Armstrong, MD, associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland.

"The results of phase 1 trials found that it had a favorable safety profile up to 400 mg/m² IV given weekly, with 4 doses given," said Dr. Armstrong. "This was the highest dose tested; no maximum tolerated dose was identified. Radiolabelled farletuzumab also demonstrated tumor binding."

Current Study Details

The current study involved 54 patients with ovarian, fallopian tube, or primary peritoneal cancer, with disease that was evaluable by CA125 at baseline. Those with low-volume or symptomatic disease could go on single-agent farletuzumab until progression, whereas patients with symptomatic or large-volume disease continued with their original platinum/taxane regiment with farletuzumab for a target of 6 cycles.

"Patients on single-arm therapy who progressed could cross over, and those who had completed combination therapy could go on a maintenance farletuzumab trial," said Dr. Armstrong.

All patients received farletuzumab 100 mg/m² weekly, and those in the combination-therapy group received carboplatin AUC 5 or 6 every 21 days for 6 cycles, and either paclitaxel 175 m/m² over 3 hours or docetaxel 75 mg/m² every 3 weeks for 6 cycles.

Dr. Armstrong pointed out that the median length of the first progression-free interval was 15.5 months (range, 6.3–29.7). "Approximately one third of patients were in the 6- to 12-month range of progression-free interval, so about a third had relapsed within a fairly short time," she said.

Twenty-eight patients entered the single-agent group and, of this group, 21 continued on to combination therapy. At baseline, 26 patients entered the combination-therapy group, making a total of 47 patients treated with combination therapy. Of this group, 44 were evaluable for response.

Single-Agent Results

A total of 25 patients in the single-agent group completed at least 9 weeks of therapy. At week 7, day 43:

• 1 patient had more than a 75% decrease in CA125
• 1 patient had more than a 50% decrease in CA125
• 3 patients had more than a 25% decrease in CA125
• 13 patients were unchanged
• 6 patients had an increase in CA125 levels
• 1 patient was missing.

"Our summary from single-agent use is that additional studies are needed, and planned, to determine optimal use," said Dr. Armstrong.

Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST) showed no responses, but there was stable disease in 38.5% of the single-agent cohort and progressive disease in 53.8%; 7.7% of the group was not evaluable.

Combination Trial Results

In the combination group, 39 patients achieved a normal CA125 (88.6%). Of the 5 patients (11.4%) who did not normalize their CA125, 3 achieved a greater than 50% reduction.

Within this group, 4 patients are continuing on in the study and 9 (20.5%) have had a second progression-free survival interval that is longer than their first one.

"A few of the patients had second progression-free intervals that were substantially longer — 2 to 3 times longer than their first ones," she said. In other patients, the intervals were similar.

RECIST data were available for 43 patients (98%), and showed that a complete response was achieved by 7.0%, a partial response was achieved by 62.8%, stable disease was achieved by 23.2%, and disease progression was seen in 7.0%. The overall response rate was 69.8%.

Overall, the treatment regimen was very well tolerated, with infrequent grade 1 or 2 infusion reactions, Dr. Armstrong pointed out. There was no additive toxicity observed in the carboplatin/taxane group, but 5 serious adverse events were observed in 3 patients.

"Compared with historical progression-free intervals, farletuzumab increases the duration of the second progression-free interval when combined with carboplatin and taxane," she concluded. "Single-agent farletuzumab may stabilize disease for an indeterminate time."

Randomized clinic studies are being planned or are underway to test farletuzumab in platinum-sensitive and platinum-resistant relapsed ovarian cancer, Dr. Armstrong added.

The study was funded by Morphotek, the manufacturer of farletuzumab. Dr. Armstrong is an advisory board member for Morphotek, and her employer has received funding in support of research for the study.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 8000. Presented September 24, 2009.

MORE WOMEN CHOOSE TO REMOVE NON CANCEROUS BREAST

Prophylactic mastectomy is the removal of a healthy breast in order to reduce risks of developing breast cancer. According to the study’s results, the number of patients in New York State who had a healthy breast removed after a cancer diagnosis more than doubled between 1995 and 2005, even though the total number of women having mastectomies dropped by one-third. The rate of women who underwent the procedure without having any breast cancer at all only rose slightly during this period.

“It’s true that women who decide to have prophylactic mastectomies end up with a ‘virtually zero’ risk of having breast cancer. But my patients say, ‘It’s not even the medical issue; it’s the anxiety.’ They just don’t want to worry about getting it in the other breast some day,” explains breast cancer surgeon Rache Simmons, MD, FACS, of New York-Presbyterian Hospital/Weill Cornell Medical Center. “I have never had a patient regret that decision,” says Simmons, who was not involved in the study.

Simmons estimates that she performs 10 times as many double mastectomies in patients with one non-cancerous breast than she did 10 years ago. Part of the reason: the much wider availability and awareness of genetic testing for the BRCA1 and BRCA2 mutations, she tells WebMD. These gene mutations are associated with an 85% lifetime risk of developing breast cancer and a much higher chance of tumors appearing in both breasts, according to the American Cancer Society.

Greater social acceptance of double mastectomies and improved cosmetic surgery techniques are additional reasons for the growing numbers, says Simmons.

Of the 6,275 women who had prophylactic mastectomy in the study, 81% of them had been diagnosed with cancer in one breast. The rest had no personal history of breast cancer, suggesting they had high risk factors for breast cancer such strong family history and positive BRCA test results.

Prophylactic Mastectomy: No Improvement in Survival Rate

Despite dramatically lowering chances of future breast cancers from developing, prophylactic breast removal has not been shown to cut down a woman’s chances of dying from breast cancer – a distinction that study author Stephen B. Edge, MD, FACS makes to caution patients against choosing the surgery without careful consideration.

“Unfortunately, the cold hard fact is that the threat to their life comes from the cancer that they already have,” says Edge, who heads the department of breast surgery at Roswell Park Cancer Institute in Buffalo. He remarks that he is heartened to find it still relatively uncommon for women with no past breast cancers to undergo double mastectomies, in light of recent media coverage of celebrities who choose the dramatic procedure.

Women who are considering removing a healthy breast should weigh the pros and cons with the help of counseling in a breast cancer program that includes specialists in genetics, advises Edge. “People usually make good decisions when they’re well-informed,” he says.

Both Simmons and Edge agree that the best candidate for prophylactic removal of both breasts is a BRCA-positive woman who also has a strong family history of the disease, meaning she has several first- and second-degree relatives who were diagnosed at a young age.

The current study, published in the Sept. 28 online edition of the journal Cancer, used cancer data collected from New York state health records. The results showed that women who underwent double mastectomy to protect against further cancer development were more likely to be younger, white, and carry private health insurance than other breast cancer patients.

Edge attributes the overall drop in mastectomy rates seen over the past two decades in the study to the high success rate of surgical lump removal -- a less invasive, relatively conservative approach compared to extracting the entire breast. He says that lumpectomy yields a survival rate similar to mastectomy.

METFORMIN PROTECTS DIABETIC PATIENTS FROM CANCER

October 1, 2009 (Vienna, Austria) — Metformin was found to reduce risk in pancreatic and colon cancers in patients with type 2 diabetes in an epidemiologic study presented here at the European Association for the Study of Diabetes (EASD) 45th Annual Meeting.

"Our observational study shows the risk of developing cancer over 5 years with insulin and with metformin. We found that patients on insulin were twice as likely to develop colon carcinomas than those on metformin. With pancreatic cancer there is a major difference between the 2 — patients on insulin alone had 4.5 times the risk. These are remarkably big differences and it suggests that metformin could play a significant role in pancreatic cancer — a particularly lethal form of cancer," said study coauthor Dr. Edwin Gale, MD, from the Department of Diabetic Medicine and head of the Department of Clinical Science at the University of Bristol in the United Kingdom.

The retrospective cohort study drew information relating to the treatment of diabetic patients from 300 British general practice records. Patients were excluded if they had had previous cancer and data were only collected from patients treated after the year 2000. Insulin exposure was estimated by the number of prescriptions filled per year (categorized as <7,>15). The researchers analyzed data from 4829 patients taking insulin alone (11,415 patient-years), 5035 taking insulin plus metformin (15,725 patient-years), and 30,421 taking metformin alone (71,261 patient-years). The primary outcome measure was the diagnosis of the first solid tumor.

Crude cancer rates showed a notable 60 cancer events per 1000 patient-years in the group exposed to the highest amount of insulin alone, compared with 34 cancer events per 1000 patient-years in the insulin plus metformin group. After adjustment for age, sex, and smoking status, the same ratio was true for insulin plus metformin vs insulin alone (5.73 vs 3.20).

Craig Currie, PhD, a medical epidemiologist from Cardiff University in Wales, who coauthored the study, said: "In the insulin-only group, there was a distinct dose-response relationship, with a 6-fold increase in all forms of cancer in the highest group, compared with metformin monotherapy. This dose-response relationship brings us 1 step closer to suggesting a causal relationship, although further work needs to be done for a definitive answer. Metformin, on the other hand, does have important properties that appear to reduce cancer risk and we need to analyze these risks further," he told Medscape Diabetes & Endocrinology.

Chairing the session, current EASD president Ulf Smith, MD, from Sahlgrenska University Hospital in Göteborg, Sweden, acknowledged that further research is needed to determine whether the relationship with cancer rates is due to high insulin dose or to the insulin resistance that is associated with type 2 diabetes. "There are reasons to involve insulin resistance per se. Findings at a cellular level and in animals suggest insulin resistance may be an important factor in this. This epidemiological study shows an association but we need further study to be conclusive," he said.

"A really important conclusion is that metformin reduces cancer risk," Dr. Smith said. "The story with metformin is very exciting because clinical studies show that patients treated with chemotherapy for breast cancer do considerably better when metformin is added. Another extremely exciting paper this week shows that metformin also targets cancer stem cells that remain after chemotherapy and can cause metastases. We are now starting clinical studies in nondiabetic patients."

Acknowledging the advent of an exciting research agenda over the coming years, Dr. Gale said that "in the future, we need to look at the possibility of links between cell metabolism, cell turnover, and cancer, and possibly the nondiabetic use of metformin. Understanding more about the link between insulin resistance and cancer and moving toward targeted screening of high-risk groups could save thousands of lives."

Dr. Gale, Dr. Currie, and Dr. Smith have disclosed no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 45th Annual Meeting. Presented October 1, 2009.

NEW DATA FOR JAK2 KINASE

Cancer Research UK scientists identify a nuclear role for JAK2 in the phosphorylation of H3Y41

01.10.09

Category: Scientific News

Results reveal a direct mechanistic link between two genes, JAK2 and LMO2, involved in normal hematopoiesis and leukemia

Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in hematological malignancies. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signaling cascades. In the 27 September 2009 edition of Nature advanced access publication, Dr Tony Kouzarides of the Gurdon Institute and Department of Pathology and colleagues from University of Cambridge, UK, show that human JAK2 is present in the nucleus of hematopoietic cells and directly phosphorylates Tyr-41 (Y41) on histone H3. Heterochromatin protein 1α (HP1α), but not HP1β, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukemic cells decreases both the expression of the hematopoietic oncogene LMO2 and the phosphorylation of H3Y41 at its promoter, simultaneously increasing the binding of HP1α at the same site. These results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, JAK2 and LMO2, involved in normal hematopoiesis and leukemia.

The scientists found that the enzyme made by the JAK2 gene is also located inside the cell nucleus and plays an important role in controlling how genetic information is used by the cell. Previously, it was only known to be located on the inner surface of cells – acting as a messenger between the outside of the cell and the cell's nucleus. In this exciting research the authors have revealed new unidentified parts of the cell's messaging system that can lead to leukemia, giving scientists new opportunities to develop drugs to block it.

SORAFENIB AND CAPECITABINE FOR BREAST CANCER

Sorafenib significantly improves progression-free survival in advanced breast cancer when given in combination with capecitabine

30.09.09

Category: Scientific News

Results from first, large randomized trial are in

One of the first of a series of trials to investigate the use of sorafenib for the treatment of advanced breast cancer has found that if it is combined with capecitabine, it makes a significant difference to progression-free survival (PFS).

Principal investigator of the study, Prof. José Baselga, presented the results at Europe’s largest cancer congress, ECCO 15 – ESMO 34, in Berlin on Wednesday 23 September 2009. This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Study results showed that patients who received sorafenib plus capecitabine had a 74% improvement in PFS compared with those who received chemotherapy alone. This is a very positive result and the magnitude of the benefit is such that it suggests that this agent will be an important addition to the therapeutic armory in breast cancer.

Sorafenib is a potent multi-kinase inhibitor, which works by interfering with the growth of cancer cells and slowing the growth of new blood vessels within the tumor. Until now, it has only been used in the treatment of kidney and liver cancer.

Prof. Baselga and colleagues in Spain, France, and Brazil enrolled 229 patients with locally advanced or metastatic breast cancer in the double-blind, randomized phase II clinical trial between June 2007 and December 2008. They randomized the patients to receive capecitabine (1000 mg/m2 p.o. taken twice daily for 14 of every 21 days) and a placebo (114 women), or capecitabine and sorafenib (400 mg p.o. taken twice daily continuously) for 115 women.

The first results from the trial show that the average PFS was 6.4 months for women on capecitabine and sorafenib compared with 4.1 months for women taking the placebo. It is too early for data on overall survival to be available. The only death that occurred was in the placebo arm of the trial, attributed to the effect of capecitabine. The number of patients discontinuing treatment because of adverse side-effects was 9 (8%) in the placebo arm and 15 (13.4%) in the sorafenib arm. The regimen was tolerable and side-effects were mostly manageable. No new or unexpected side-effects were observed with this combination. The fact that this treatment could be taken orally may represent a unique and convenient treatment option for patients with breast cancer.

This trial is an example of a good academic and industry partnership. It was designed and conducted by the Spanish breast co-operative group SOLTI, with the participation of Brazilian and French groups. The trial was fully supported by Onyx and Bayer. Based on the encouraging data from this trial so far, Onyx and Bayer are evaluating various strategies for sorafenib in breast cancer. This trial is the first in a series of randomized phase II studies with sorafenib that are currently underway in breast cancer.

YONDELIS AND CAELYX COMBINATION APPROVED FOR RELAPSED PLATINUM SENSITIVE OVARIAN CANCER

EMEA extended indication of trabectedin in combination with pegylated liposomal doxorubicin to the treatment of patients with relapsed platinum-sensitive ovarian cancer

28.09.09

Category: Scientific News

Study results were first presented at the ESMO Congress in Stockholm

The European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) at its meeting on 21-24 September 2009, gave a positive opinion for applications for the extension of indication, adding new treatment option, for trabectedin, from Pharma Mar S.A. It extended the indication of trabectedin in combination with pegylated liposomal doxorubicin to the treatment of patients with relapsed platinum-sensitive ovarian cancer.

Results of the study entitled “A Randomized Phase III Study of Trabectedin with Pegylated Liposomal Doxorubicin (PLD) vs PLD in Relapsed, Recurrent Ovarian Cancer OVA-301” were presented by Dr B Monk during Presidential Symposium at the ESMO Congress in Stockholm (2008).

Trabectedin is currently indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents.

The EMEA has also completed a review on the risk of osteonecrosis of the jaw associated with the use of bisphosphonates. The CHMP was asked to give a scientific opinion on:

• the criteria that define osteonecrosis of the jaw related to bisphosphonates;
• how bisphosphonates may cause osteonecrosis of the jaw;
• whether the risk of osteonecrosis of the jaw is greater with some bisphosphonates or for some groups of patients;
• the measures that could be taken to minimise this risk.

The CHMP has concluded that there is an increased risk of osteonecrosis of the jaw in patients using these medicines. However, further studies should be carried out to better identify the factors that increase the risk and the measures needed to minimise it.

The review was carried out under Article 5(3) of Regulation (EC) 726/2004, opinion on any scientific matter concerning the evaluation of medicinal products for human use. Under this type of procedure the CHMP can give a scientific opinion on any matter concerning the evaluation of medicinal products for human use.

B. Monk: A Randomized Phase III Study of Trabectedin with Pegylated Liposomal Doxorubicin (PLD) vs PLD in Relapsed, Recurrent Ovarian Cancer OVA-301

WEEKLY PACLITAXEL FOR OVARIAN CANCER

Lancet. 2009 Sep 18. [Epub ahead of print]

Related Articles, LinkOut

Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.

Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K; for the Japanese Gynecologic Oncology Group.

Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

BACKGROUND: Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer. METHODS: Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS: 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups. INTERPRETATION: Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer. FUNDING: Bristol-Myers Squibb.

OBESITY AND CANCER

October 1, 2009 (Berlin, Germany) — During the past few decades, the percentage of overweight and obese adults and children has steadily increased, which in turn has elevated the risk for certain cancers. That increase in risk might be substantial, according to the results of a new modeling study presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

"In 2008, at least 124,000 new cancers in Europe may have been related to excess body weight," said study author Andrew Renehan, PhD, FRCS, FDS, a senior lecturer in cancer studies and surgery at the University of Manchester, United Kingdom

"I must emphasize that we are trying not to be sensationalist about this," he added. "These are very conservative estimates, and it's quite likely that the numbers are in fact higher."

This number has substantially increased in the past 5 years. In 2002, there were 70,288 new cases of cancer related to excess body weight (Renehan et al. Int J Cancer. Published online before print July 30, 2009).

The sex differences also show an increase over the past few years, Dr. Renehan noted. In 2002, it was estimated that new cancers attributed to excess body weight affected 2.5% of men and 4.1% of women. By 2008, these proportions had increased to 3.2% of men and 8.6% of women.

"The proportion of new cancers attributable to a [body mass index] above 25 kg/m² was highest among women in the Czech Republic, Latvia, Slovenia, and Bulgaria," Dr. Renehan said.

The analysis quantifies the burden of incident cancers attributable to excess body mass index in Europe, explained Dr. Renehan. The percentage of obesity-related cancers varied widely between the different countries, but the data were "broadly consistent" across geographic locations.

Percentages of Obesity-Related Cancers

Country	% in Men	% in Women
Denmark	2.4	2.1
United Kingdom	3.4	4.0
Germany	3.3	4.8
Czech Republic	3.5	8.2

Projected Figures Show Continuing Rise in New Cancers

In projecting the figures forward to 2008, the researchers took into account confounders such as rates of smoking and the use of hormone replacement therapy in postmenopausal women. Endometrial cancer (n = 33,421), postmenopausal breast cancer (n = 27,770), and colorectal cancer (n = 23,730) accounted for 65% of all cancers attributable to excess body weight.

After the Women's Health Initiative showed an association between hormone replacement therapy and risk for breast cancer, in 2002, the use of such therapy declined sharply. Hormone replacement therapy helped mask and dilute the effect of obesity on the incidence of breast cancer, Dr. Renehan explained.

But with fewer postmenopausal women using hormone therapy, the effect of excess weight on breast cancer risk is much clearer, he said. With declines in both smoking and the use of hormone replacement therapy, obesity could become the leading cause of cancer among European women.

With breast cancer and weight, there is no cutoff point, explained Jack Cuzick, PhD, head of the Department for Epidemiology, Mathematics and Statistics at the Wolfson Institute of Preventive Medicine in London, United Kingdom.

"There is a 1% increase in relative risk for every kilogram of excess weight," said Dr. Cuzick, who served as moderator for the session. "It's a continuum."

"People in Europe are gaining weight," said Dr. Renehan, "and it is projected to keep rising."

Multiple strategies are needed to circumvent the growing numbers of Europeans who are overweight and obese. There must be policy changes at national and international levels, lifestyle interventions, and new approaches, including pharmacologic interventions, he said. There is an "urgent need" to better understand the biologic and molecular mechanisms underpinning the link between obesity and different cancers.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 327. Presented September 24, 2009.

DEXAMETHASONE INSTEAD OF CRANIAL RADIATION FOR CHILDREN WITH ALL

September 30, 2009 — A dexamethasone-based protocol can cut the risk of relapse and improve survival in high-risk children with acute lymphoblastic leukemia (ALL), with fewer side effects than were associated with older regimens, new research shows.

The regimen, designated the Dutch Childhood Oncology Group (DCOG) ALL-9 protocol, achieved 5-year event-free survival rates of 84% for non-high risk patients and 72% for high-risk patients, according to a report in the September 10th online issue of The Lancet Oncology.

High-risk patients were those with white blood cell counts of 50,000/microliter or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement.

By comparison, the ALL-6 protocol against which ALL-9 was tested achieved a similar 5-year event free survival of 83% in its non-high-risk group in the late 1980s, but this rate was only 53% among high-risk patients. Lead author Dr. Anjo J. Veerman from VU University Medical Center, Amsterdam, The Netherlands, and colleagues explain that while ALL-9 is identical to ALL-6 for non-high risk patients, changes were made for high-risk patients, in the hopes of improving outcomes.

They emphasize that the improvement in the high-risk group was achieved without cranial irradiation and without the use of such toxic drugs as anthracyclines, cyclophosphamide, or epipodophyllotoxins.

The ALL-9 trial involved 859 children, ages 1 to 18 years, with de novo disease who were recruited between January 1997 and November 2004. Median follow up was 72.2 months.

In the non-high risk group, 601 children received induction with dexamethasone, vincristine, and L-asparaginase for 6 weeks, then medium-dose methotrexate for 3 weeks, and then maintenance therapy. The 258 high-risk patients received the same three drugs plus daunorubicin for induction for 6 weeks, then high-dose methotrexate for 8 weeks, and two intensification courses before maintenance therapy.

Triple intrathecal medication was given 13, 15, and 17 times in non-high risk, high risk, and central nervous system-affected patients, respectively.

In all patients, maintenance therapy — consisting of mercaptopurine and methotrexate alternating with dexamethasone and vincristine — was continued until 109 weeks.

The complete remission rates in the non-high risk and high risk groups were 98.5% and 96.9%, respectively. Five deaths in the non-high risk group and four in the high risk group occurred during induction therapy. Isolated central nervous system relapses were noted in 2.6% of patients.

On multivariate analysis, the strongest predictor of outcomes was the DNA index, followed by age, and then the white blood cell count, the authors note.

"The most radical feature of (the ALL-9) protocol is the omission of prophylactic cranial irradiation in all patients," Dr. Ching-Hon Pui, from St Jude Children's Research Hospital in Memphis, Tennessee, writes in a related editorial. "Not surprisingly, (the researchers) have reported only a few cases of osteonecrosis and only two cases of second malignancy."

"The vast majority of their patients are expected to survive with an excellent quality of life," Dr. Pui added.

Lancet Oncol. Published online September 10, 2009.

COMBINATION THERAPY FOR NEUROPATHIC PAIN

October 1, 2009 — Researchers looking for new ways to treat refractory neuropathic pain suggest that combining gabapentin with nortriptyline may be beneficial. They propose that adding an antidepressant to an anticonvulsant used for pain relief may ease difficult-to-treat neuropathic pain. Exploratory findings were published online September 30 in the Lancet.

"Given the challenges of neuropathic pain, polypharmacy is frequently used," lead investigator Ian Gilron, MD, from Queen's University in Kingston, Ontario, Canada, said during an interview. "But many combinations are not beneficial. We wanted to study this combination in a rational and evidence-based way," Dr. Gilron told Medscape Neurology.

The trial was investigator initiated and was supported by the Canadian Institutes of Health Research. Gabapentin (Neurontin, Pfizer) is a 3-alkylated analogue of γ aminobutyric acid. It was originally developed for the treatment of epilepsy but is widely used as a pain reliever.

Nortriptyline (Pamelor, Novartis) is a metabolite of amitriptyline and reportedly blocks norepinephrine, serotonin uptake, sodium channels, and N-methyl-D-aspartate glutamate receptors.

"This study is most welcome because improved treatment for patients with chronic types of pain is urgently needed," Dr. Troels Jensen and Dr. Nanna Brix Finnerup, from the Aarhus University Hospital in Denmark, said in an accompanying comment.

Neuropathic pain affects an estimated 3% of the general population, and a meta-analysis showed that less than two thirds of patients obtain sufficient pain relief (Pain. 2005;118:289–305).

At the recent American Academy of Pain Medicine annual meeting, experts discussed the challenges of refractory neuropathic pain. Session moderator Perry Fine, MD, from the University of Utah School of Medicine, Salt Lake City, emphasized the limits to what can be accomplished with current therapies.

Challenge of Treating Neuropathic Pain

"Generally, available drugs lack molecular specificity and simply act as antihyperalgesics," Dr. Jensen and Dr. Finnerup add in their article. Drugs that target specific parts of somatosensory processing are now in development and could be used for early treatment before neuroplastic changes have taken place.

However, once chronic pain has set in, with all of its associated biological, psychological, and social effects, Dr. Jensen and Dr. Finnerup suggest that 1 or even 2 drugs that target a specific mechanism are unlikely to cure the patient.

In this double-blind, double-dummy, crossover trial, investigators studied 56 patients. Participants had diabetic polyneuropathy or postherpetic neuralgia and a daily pain score of at least 4 on a scale of zero to 10.

Investigators randomly assigned patients in a 1:1:1 ratio. Participants received 1 of 3 sequences of daily oral gabapentin, nortriptyline, and a combination of both. During each 6-week treatment period, investigators titrated the drugs toward the maximum tolerated dose.

The primary outcome for the trial was mean daily pain at maximum tolerated dose. Analysis was by intention to treat.

Dr. Gilron and his team found that pain with combination therapy was significantly lower than with gabapentin (−0.9; 95% confidence interval [CI], −1.4 to −0.3; P = .001) or nortriptyline (−0.6; 95% CI, −1.1 to −0.1; P = .02) alone.

Pain at Maximum Tolerated Dose

Therapy	Mean Daily Pain	95% CI
Gabapentin	3.2	2.5 – 3.8
Nortriptyline	2.9	2.4 – 3.4
Combination	2.3	1.8 – 2.8

Investigators report no serious adverse events for any patients during the trial. The most common adverse effect was dry mouth, and the participants reported more weight gain in the gabapentin group.

"Combination therapy decreased pain, but it also decreased sleep interference without increasing side effects," Dr. Gilron said. He acknowledged that these promising results will need to be replicated at other centers.

"Gilron and colleagues' trial benefits from being an investigator-initiated study of 2 commonly used drugs for neuropathic pain," note Dr. Jensen and Dr. Finnerup. "This type of study is unfortunately rare because most drug studies are based on large sample sizes from many sites and financed by drug companies."

A drawback of the current study was that the investigators had to keep costs down and thus limited the number of participants. They used a crossover design in which each participant served as his or her own control.

The investigators also provide no data on the benefits of sequential vs simultaneous combination treatment. "In clinical practice, sequential treatment is most common," Dr. Jensen and Dr. Finnerup point out, "but in Gilron and colleagues' study, drugs in combination were given simultaneously."

This study was supported by the Canadian Institutes of Health Research. Lead author Dr. Ian Gilron and senior author Dr. Robyn Houlden have disclosed receiving financial support from Pfizer. Editorialist Dr. Troels Jensen has disclosed that he has received funding from Pfizer, Eli Lilly, and Grünenthal. Editorialist Dr. Nanna Brix Finnerup has disclosed receiving research support from UCB Nordic.

Lancet. Published online September 30, 2009.

DO NOT DISCONTINUE CHEMOTHERAPY IN METASTATIC COLORECTAL CANCER

J Clin Oncol. 2009 Sep 28. [Epub ahead of print]

Related Articles, LinkOut

Can Chemotherapy Be Discontinued in Unresectable Metastatic Colorectal Cancer? The GERCOR OPTIMOX2 Study.

Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A.

Hôpital Saint-Antoine and Hôpital La Pitié-Salpétrière, Assistance Publique Hôpitaux de Paris, Université Paris VI; L'Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S 893, Paris; Hôpital Privé Jean Mermoz, Lyon; Institut Sainte-Catherine, Avignon; Hôpital Montfermeil, Montfermeil; Hôpital Foch, Suresnes; Hôpital de Senlis, Senlis; Hôpital Drevon, Dijon; Clinique Victor-Hugo, Le Mans; and Clinique de Courlancy, Reims, France.

PURPOSE: This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC). RESULTS: Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively. CONCLUSION: The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.

CAELYX FOR AGGRESIVE FIBROMATOSIS

Eur J Cancer. 2009 Sep 18. [Epub ahead of print]

Related Articles, LinkOut

Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis.

Constantinidou A, Jones RL, Scurr M, Al-Muderis O, Judson I.

Sarcoma Unit, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, UK.

BACKGROUND: Aggressive fibromatosis (AF) or desmoid tumour is a monoclonal proliferation which is locally invasive but does not metastasize. If local treatment fails to control the disease, systemic treatment with anti-oestrogens, non-steroidal anti-inflammatory drugs (NSAIDs) or chemotherapy can be used. Recent reports indicate that pegylated liposomal doxorubicin (PLD) is effective. METHODS: Twelve patients with AF received PLD between February 2006 and May 2009. PLD was administered intravenously (iv) at 50mg/m(2) over 1h every 4weeks. RESULTS: The female/male ratio was 11:1 and median age at presentation was 29years (range 3-53). Objective response (PR) was achieved in 4 (36%) of 11 patients. In one case ongoing shrinkage of the tumour was observed for over 12 months and partial remission was achieved at 14months after the completion of treatment. Seven patients achieved stable disease. One patient is currently undergoing chemotherapy. Clinical benefit in terms of pain relief, improved mobility or cosmesis was observed in 11 patients. Nine patients (75%) had no evidence of progression at the end of this follow-up period and disease control has ranged from 7 to 39months with a median of 14months. The most severe toxicities observed were palmar-plantar erythema (4) and mucositis (3). In 6 cases (55%) toxicity resulted in dose reduction. CONCLUSION: This is the largest series of patients with AF receiving PLD reported to date. PLD as a single agent therapy has acceptable toxicity and highly promising activity in unresectable AF and may provide long-term clinical benefit in some patients.

TRASTUZUMAB AND ANASTARZOLE COMBINATION

J Clin Oncol. 2009 Sep 28. [Epub ahead of print]

Related Articles, Links

Trastuzumab Plus Anastrozole Versus Anastrozole Alone for the Treatment of Postmenopausal Women With Human Epidermal Growth Factor Receptor 2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Results From the Randomized Phase III TAnDEM Study.

Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A.

Chaim Sheba Medical Center, Tel Hashomer, Israel; Cross Cancer Institute, Edmonton, Alberta, Canada; Klinikum Mutterhaus der Borromäerinnen, Trier, Germany; Kidwai Memorial Institute of Oncology, Bangalore; Rajiv Gandhi Cancer Institute, New Delhi, India; Christie Hospital National Health Service Foundation Trust, Manchester; Royal Free Hospital, London, United Kingdom; Russian Cancer Research Center, Moscow, Russia; and F. Hoffmann-La Roche, Basel, Switzerland.

PURPOSE: TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. RESULTS: Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure. CONCLUSION: Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.

LAPATINIB AND LETROZOLE COMBINATION

J Clin Oncol. 2009 Sep 28. [Epub ahead of print]

Related Articles, LinkOut

Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer.

Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M.

Royal Marsden Hospital, London; GlaxoSmithKline, Middlesex, United Kingdom; Sammons Cancer Center, Dallas, TX; David Geffen School of Medicine; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Durham, NC; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; University Hospital J. Minjoz, L'Institut National de la Santé et de la Recherche Médicale Unit 645, Besançon; Institut Curie, Paris; Department of Medical Oncology, CRLC Val d'Aurelle, Montpellier, France; Cancer Research Center, Moscow; City Clinical Oncology Dispensary, St Petersburg, Russia; Instituto De Enfermedades Neoplasicas, Lima, Peru; and The All-Ireland Cooperative Oncology Research Group, Dublin, Ireland.

PURPOSE: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. RESULTS: In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >/= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION: This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.