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The Lancet Oncology

Friday, October 23, 2009

Phase III DECISION trial Evaluates Sorafenib in Patients with Non-Responsive Thyroid Cancer

Earlier this month recruitment has begun to enroll patients in an international Phase III trial to evaluate sorafenib (Nexavar®) tablets for the treatment of patients with radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer (papillary, follicular and Hurthle cell). The study is scheduled to start later this month at sites in the United States, Europe, Asia, and Japan. The study is schedules to complete in November 2011.

Thyroid cancer, one of the few cancers that has increased in incidence over the past several years. According to the American Cancer Society, it is the sixth most common cancer and about three times as many women as men get thyroid cancer. Information from the World Health Organization (Globocan 2002 database) indicates that there are more than 140,000 new cases of thyroid cancer and more than 35,000 people die worldwide each year.

"Patients with thyroid cancer who failed to respond to surgical or radiotherapies, have limited treatment options to help them manage their disease," said Dimitris Voliotis, vice president, Nexavar clinical development, Bayer HealthCare Pharmaceuticals. "Recognizing this unmet need, we are evaluating Nexavar in this special patient population."

Phase III Trial Design
The DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial is an international, multicenter, randomized, placebo-controlled study that will enroll approximately 400 patients with locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer (papillary, follicular and Hurthle cell) who have received no prior systemic therapy.

Patients will be randomized to receive 400 mg of oral sorafenib twice daily or matching placebo. Patients will continue on treatment until disease progression, toxicity, non-compliance or withdrawal of consent. At the time of progression, patients receiving placebo will have an option to cross over to sorafenib at the discretion of the investigator, based on the patient's clinical status. The primary endpoint of the study is progression-free survival as defined by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints include overall survival, time to progression and response rate. The safety and tolerability of the two treatment groups will also be compared.

Phase II Trial Results
This Phase III trial initiative was started based on the results from Phase II clinical trials evaluating sorafenib in patients with advanced thyroid cancer.

Updated results from a single institution, investigator sponsored Phase II open-label study in 55 patients with metastatic, iodine refractory, thyroid cancer treated with Sorafenib r 400 mg twice daily were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 29-June 3, 2009 Orlando, FL, by Marcia Brose, M.D., Ph.D., an assistant professor of Hematology/Oncology and Otorhinolaryngology in the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, U.S.A. In 50 evaluable patients, 18 (36%) had a partial response per RECIST criteria.

The survival results on the first 30 patients enrolled into the study demonstrated that across all histologies the median progression-free survival (PFS) was 63 weeks and the median overall survival was 140 weeks. The most common adverse events (AE) seen in the trial were hand-foot skin reaction, rash, fatigue, stomatitis/mucositis, weight loss, and musculoskeletal pain, and were predominantly grade 1 or 2. Dr. Brose and Martin J. Schlumberger, Institut Gustave-Roussy, Villejuif, France, are the lead investigators on the Phase III trial.

"Based on the positive signal generated in the Phase II trial, the initiation of this Phase III represents progress in exploring the full potential of Nexavar in a variety of treatment settings and tumor types," noted Todd Yancey, M.D., vice president of clinical development at Onyx. "Building on our successful foundation of treating unresectable liver cancer and advanced kidney cancer, we are hopeful that this Phase III trial will lead to a new treatment option for patients with non-responsive thyroid cancer."

A Differentiated Mechanism of Action
Sorafenib is one of the first of a new class of drugs. In preclinical studies, the drug has shown to block a variety of multiple kinases. Multiple kinase inhibition works at multiple levels of signaling pathways in tumor cells and tumor vasculature - important processes that enable cancer growth. These targets include Raf kinase, VEGFR-1, 2 and 3 (Vascular Endothelial Growth Factor Receptor), PDGFR-B (Platelet Derived Growth Factor Receptor), KIT, FLT-3 and RET.

Sorafenib is currently approved in more than 80 countries for the treatment of patients with hepatocellular carcinoma (HCC), or liver cancer, and in more than 90 countries for the treatment of patients with advanced renal cell carcinoma (RCC), or kidney cancer. Even though these indications are well established, the utility of sorafenib continues to be evaluated in these tumor types, with ongoing studies examining special patient populations and long-term use.

Data on these indications was presented at Europe’s largest cancer congress, the ECCO 15 – ESMO 34 meeting in Berlin (Germany) and included results from two Phase III studies evaluating sorafenib in HCC and six studies examining sorafenib in RCC. During the same meeting, phase II study data of single-agent sorafenib in patients with thyroid cancer was also presented (Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 9:00 a.m.-5:00 p.m. Hall 14.1)

Ongoing trials
In addition to its current indications, sorafenib continues to be evaluated as a single agent or combination treatment in a wide range of cancers, including breast cancer and as an adjuvant therapy for kidney cancer and liver cancer.

Data from a recently unblinded Phase II trial evaluating the safety and efficacy of Nexavar as a potential treatment for breast cancer will be presented during an oral session at ECCO-ESMO. This trial examined sorafenib compared to placebo in combination with the oral chemotherapeutic agent, capecitabine, in patients with locally advanced or metastatic breast cancer. (Late-breaking presentation 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1)

Sorafenib is also being evaluated as a single agent or combination treatment in a wide range of cancers, including breast cancer, colorectal cancer, lung cancer, ovarian cancer, and as an adjuvant therapy for liver cancer.

Sorafenib (Nexavar®) is being co-developed by Bayer HealthCare AG and Onyx Pharmaceuticals, Inc.

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New Report Details the Benefits of Health Insurance Reform for Women with Breast Cancer

As Americans mark this year the 25th anniversary of October as the National Breast Cancer Awareness Month, Secretary of Health and Human Services Kathleen Sebelius released a new report, Health Insurance Reform and Breast Cancer: Making the Health Care System Work for Women. The report details how health insurance reform will help women diagnosed with breast cancer.

Breast cancer patients face great uncertainty in the current health care system. Women diagnosed with breast cancer, whether insured or not, face significant and sometimes devastating hurdles to receiving timely, affordable treatment

Commenting on breast cancer and how this adversely impacts patients and their family, Secretary Sebelius noted: “Thousands of women and their families are impacted by breast cancer. We are fighting for health reform that will help improve treatment for women with breast cancer and doing all we can to encourage women to take the simple steps that can help prevent this disease.”

The new report highlights the problems in the health care status quo that significantly impact women who are diagnosed with breast cancer or are breast cancer survivors. The report notes:
  • According to the American Cancer Society, Breast cancer is the second leading type of cancer among women. The disease will affect one in eight American women during their lifetime, with treatment costs totaling $7 Billion in 2007. Older women are more likely to develop breast cancer, as well as women who are obese and those who have a history of cancer in their family. This year alone, an estimated 192,370 American women will be diagnosed with breast cancer and 40,170 will die from the disease, making it the second leading cause of cancer deaths in women.
  • The affordability of treatment is often a concern for women diagnosed with breast cancer. Rising health care costs have left a growing number of Americans either uninsured or with less meaningful coverage than they need and deserve. The results of a recent survey estimated that 72 million, or 41%, of nonelderly adults have accumulated medical debt or had difficulty paying medical bills in the past year – and 61% of those experiencing difficulty paying medical bills had health insurance. Breast cancer patients with employer-based insurance had total out-of-pocket costs averaging $6,250 in 2007, higher than out-of-pocket spending for patients with asthma, diabetes, chronic obstructive pulmonary disease (COPD), or high blood pressure.
  • Breast cancer patients, even when in remission, are unlikely to find meaningful insurance coverage in the individual insurance market. A full 11 percent of individuals with any cancer said they could not obtain health coverage in the individual insurance market.
“Today, breast cancer patients incur thousands of dollars in debt, and breast cancer survivors struggle to get the affordable care they need,” Sebelius added. “Health insurance reform will bring costs down, make care more affordable and prevent insurance companies from discriminating against breast cancer survivors.”

For more information:

Wednesday, October 21, 2009

A New Treatment for Advanced Kidney Cancer

The U.S. Food and Drug Administration earlier this week approved pazopanib (Votrient®, GW786034; GlaxoSmithKline), the sixth drug to be approved for kidney cancer since 2005.

Pazopanib, is an oral medication that selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptor (PDGF-R), which may result in inhibition of angiogenesis, or growth of new blood vessels, in tumors in which these receptors are upregulated. All solid tumors need blood vessels to survive, and by stopping or slowing this process, Pazopanib and similar drugs medicines in this category, may halt the progression of tumor growth

Pazopanib is intended for people with advanced renal cell carcinoma (RCC), a type of kidney cancer in which the cancerous cells are found in the lining of very small tubes (tubules) in the kidney. This form of cancer is common type of kidney cancer and accounts for approximately nine out of ten cases. In 2009, approximately 49,000 people were diagnosed with renal cell carcinoma and 11,000 people died from the disease.

“The last five years have seen dramatic improvements in treatment options for patients with kidney cancer. Before 2005, the options available offered only limited effectiveness,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. The five other drugs approved for kidney cancer and their approval dates include sorafenib (December 2005), sunitinib (January 2006), temsirolimus (May 2007), everolimus (March 2009), and bevacizumab (July 2009).

The safety and effectiveness of pazopanib was evaluated in a 435-patient phase III study that examined a patient’s progression-free survival (PFS) – the length of time, following enrollment in the study, before the tumor began growing again or before the patient died. Progression-free survival averaged 9.2 months for patients receiving pazopanib compared to 4.2 months for patients who did not receive the drug.

Patients were randomly assigned on a 2-to-1 basis to receive either pazopanib or placebo. Pazopanib reduced the risk of disease progression or death by 54% (hazard ratio = 0.46 with 95% confidence interval 0.34 to 0.62; P<0.0000001). The overall response rate in the pazopanib arm for the overall study population was 30% with duration of response of 59 weeks. When specific patient groups were evaluated, those with no prior drug treatment experienced 11.1 months of median PFS with pazopanib versus 2.8 months with placebo.

Patients who had previously received cytokine-based treatment showed 7.4 months of median PFS with pazopanib versus 4.2 months with placebo. These results were featured in an oral presentation at the annual American Society for Clinical Oncology (ASCO) meeting in Orlando, Florida. Adverse reactions included diarrhea (incidence ≥20%) , high blood pressure, hair color changes, nausea, loss of appetite, vomiting, fatigue, weakness, abdominal pain and headache.

Pazopanib can also cause severe and fatal liver toxicity. Health care professionals should order blood tests to monitor liver function before and during treatment with the drug. Since pazopanib can harm a fetus, it should not be used during pregnancy.

“The study shows that pazopanib significantly improved PFS for patients regardless of whether or not they had prior therapy. While there have been many treatment advances for patients with advanced kidney cancer, there is still a need for medicines that are effective and well-tolerated,”said Dr. Cora N. Sternberg, Department of Medical Oncology, San Camillo and ForlaniniHospitals, Rome, Italy.
“Additionally, patients did not experience a significant decline in health-related quality of life with no significant differences between pazopanib and placebo.”

The drug has also been associated with heart rhythm irregularities. Patients receiving pazopanib should be monitored with periodic electrocardiograms, which measure heart rhythm, and blood tests to monitor electrolytes since an electrolyte imbalance can lead to an irregular heart rhythm.

Pazopanib has a broad clinical program across multiple tumor types. Study details are available at www.clinicaltrials.gov. Programs currently underway in advanced RCC include a head-to-head comparison trial with sunitinib in patients with no prior drug treatment. More than 2,000 patients have been treated to date in clinical trials.

Commenting on the approval of pazopanib in RCC, Paolo Paoletti, Senior Vice President, R&D Oncology Unit noted: “We’re extremely pleased to see the progress in developing pazopanib for advanced kidney cancer, but this represents just one type of cancer in need of new treatments. Our global studies using pazopanib are designed to find new ways to use a proven mechanism to fight a diverse group of cancers. This further demonstrates our efforts to discover new medicines that provide tangible clinical benefits for patients."

For more information
Illustration courtesy of the American Society of Clinical Oncology.

Saturday, October 3, 2009

New Drug May Offer Hope for Adrenocortical Carcinoma Patients

TGen Clinical Research Services (TCRS) at Scottsdale Healthcare in Scottsdale, Arizona, recently announced the start of a clinical trial for a drug designed to combat adrenocortical carcinoma (ACC), a rare but deadly cancer that forms in the cortex (steroid hormone-producing tissue) of the adrenal glands, a small organ on top of each kidney that makes steroid hormones, adrenaline, and noradrenaline.

The adrenal glands are responsible for making several critical hormones, including cortisol, which the body needs in order to respond to stress and which helps to maintain normal blood sugar levels in children.

Adrenal carcinoma (ACC) affects 1 to 2 per million population annually and may be curable if treated at an early stage. Radical surgical excision is the treatment of choice for localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%. Retrospective studies have identified two important prognostic factors: completeness of resection and stage of disease. The most common sites of metastases are the peritoneum, lung, liver, and bone.

Other than surgery, the only treatment for ACC is the exacting use of a compound called mitotane (Lysodren®, Bristol-Myers Squibb), a chemical relative of DDT, which the U.S. banned as an insecticide in 1972, systemic chemotherapy, or (for localized lesions) radiation therapy.

While use of mitotane in ACC patients reduces tumors, it also diminishes adrenal gland function, requiring patients to take hormone replacements for the rest of their lives. In addition, mitotane must be administered for at least three months in order to reach a therapeutic level. Even then, it has proved effective in about 22% of ACC cases. When given with other chemotherapy drugs, the effectiveness of mitotane may be improved, but patients often suffer debilitating side effects.
Clinicians at TGen Clinical Research Services (TCRS), a strategic alliance between the Translational Genomics Research Institute (TGen) and Scottsdale Healthcare, hope that a new compound, OSI-906, a small molecule IGF-1R inhibitor that blocks the chemical pathway that otherwise allows the ACC tumors to grow out of control.

The drug candidate is developed by OSI Pharmaceuticals Inc. of Melville, N.Y., and will stop ACC tumor growth — perhaps even promote tumor shrinkage — without the toxic side effects of current chemotherapies. The trial will focus on patients with inoperable tumors who have relapsed or failed to respond to conventional therapies.

IGF-1R inhibitor
OSI-906 is a potent, selective orally active inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) which has been viewed as an important therapeutic target due to its involvement in the growth and proliferation in a variety of human cancers, including adrenocortical carcinoma (ACC), ovarian and non-small cell lung cancers.

The new drug candidate stimulates proliferation, enables onogenic transformation, and suppresses apoptosis. Inhibitors of IGF-1R are expected to have broad utility in oncology since the over-expression of IGF-1R and/or its ligands or the down-regulation of ligand binding proteins occurs in numerous human malignancies including lung, colon, breast, prostate, brain and skin cancers. In addition, signaling through the IGF system has been implicated in protecting tumor cells from apoptosis induced by anti-cancer treatments such as cytotoxic agents and EGFR inhibitors. Scientists therefore believe that OSI-906 may be useful both as a single agent and in combination with other targeted therapies such as erlotinib (Tarceva® marketed by Genentech Bioncology and OSI Pharmaceuticals).

Ongoing research
During the 2009 annual meeting of ASCO, the American Society of Clinical Oncology, a number of abstracts were published with IGF-1R inhibitors in a range of cancers, making a case for insulin growth factor receptor (IGF-1R) inhibitors as a potential target for cancer therapeutics. So far, the data presented at ASCO has been very preliminary and isolated responses were seen.
In addition to OSI (OSI-906), a number of pharmaceutical and research companies have active, ongoing research programs in the clinic. Many other companies are involved in preliminary research in different stages in different cancers (Exelixis/XL228, Amgen/AMG-479, Roche/R1507, Pfizer/CP-751,871/Figitumumab, BMS/BMS-754807, Merck/MK-0646, and Imclone/Lilly/IMC A12). Others companies, including Sanofi-Aventis, Novartis, Eisai, Biogen Idec, are interested to see how this new class pans out.

OSI-906 trial
A clinical trial of OSI-906 is expected to last several years and include 135 patients, with 30-40 enrolled at TCRS. As there is no standard therapy available, two-thirds of the patients will receive the drug OSI-906 while one-third receives a placebo. Sites elsewhere in the U.S., as well as in Europe and Australia, are expected to enroll patients over the coming months.

“The trial is major step toward helping patients with ACC, who often face radical surgery as part of their treatment,” said Dr. Michael J. Demeure, who will oversee the trial locally. Dr. Demeure is a TGen Senior Investigator and a Scottsdale Healthcare surgeon experienced in removing ACC tumors.

It’s a big operation requiring a large incision because these tumors can be the size of a football. Unfortunately many patients’ tumors have spread so we can’t remove it all, so new treatments are needed.’’ Demeure explained. “This unique partnership between Scottsdale Healthcare and TGen allows us to bring the newest and most promising treatments to patients with cancer right here in Arizona.”

The TCRS clinic in the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea is the first site worldwide approved for these clinical trials.

"Being the first site in the world for clinical trials of this drug adds to the long list of ‘firsts’ for the Virginia G. Piper Cancer Center,” said Mark Slater, Ph.D., vice president of research. "Scottsdale Healthcare’s collaborations with world-class physicians and scientists are helping pave the way for exciting new cancer treatments to benefit patients with cancer everywhere.”

Although the disease is very rare, Demeure said that developing a new drugs against this orphan indication is worth the effort and expense. “Patients with rare tumors have unique challenges. Often it is difficult for them to find a doctor who even knows about their disease,” he said. “What we learn taking care of those patients with ACC could help us learn how to take care of others with rare tumors.’’

The clinical trial follows nearly 3 1/2 years of research at TGen, initiated through the efforts of patient advocate and ACC survivor, Mr. Troy Richards.

Richards, a Scottsdale resident, has battled ACC since 1999. To combat what little research he saw being done on the disease, he began the Advancing Treatments for Adrenocortical Carcinoma (ATAC) fund, which helped finance the ACC Research Program at TGen.

"The ACC project at TGen has finally given those of us with the disease hope for better treatments, and maybe one day a cure,” said Mr. Richards. “It is my hope that this program can serve as a model for other rare diseases, and that patients will realize they do have the power to make a difference.”

Dr. Kimberly Bussey, a TGen Associate Investigator and Lead Investigator for TGen’s Adrenocortical Carcinoma Research Program, said, “Troy brings a sense of urgency and a connection to the ACC patient community that made this trial possible. This is a huge accomplishment for the ACC Research Program at TGen and a great testament to what patient-advocated research can accomplish in a short period of time.”

We are eagerly awaiting the opening of this study,” said Dr. Maqbool Halepota, an oncologist with the Palo Verde Hematology/Oncology group based at the Virginia G. Piper Cancer Center at Scottsdale Healthcare. “I firmly believe that targeted therapies are the future of cancer care, and our partnership with TCRS allows patients in the Phoenix area access to many innovative trials.”

For additional information:

New Findings Could Be Practice-changing for the Treatment of Locally Advanced Soft Tissue Sarcoma

Patients with soft-tissue sarcomas at high risk of spreading were 30% more likely to be alive and cancer free almost three years after starting treatment if their tumours were heated at the time they received chemotherapy, according to new research. The finding bolsters the case for intensifying exploration of the strategy in other types of cancer.

The study, which found that the addition of the innovative heat technique more than doubled the proportion of patients whose tumors responded to chemotherapy without increasing toxicity, is also the first to show that any treatment other than surgery followed by radiation can prolong survival of this type of patient.

“These findings provide a new standard treatment option and we believe they are likely to change the way many specialists treat these tumors,” said the study’s leader, Professor Rolf Issels, a professor of medical oncology at Klinikum Grosshadern Medical Center at the University of Munich in Germany, who presented the results in Berlin, Germany, at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24), meeting in Berlin, Germany.

“But the implications of these findings are more far-reaching,” Issels said. “This is also the first clear evidence that targeted heat therapy adds to chemotherapy. We expect our findings will encourage other researchers to test the approach in other locally advanced cancers. Targeted heat therapy has already shown promise in recurrent breast and locally advanced cervical cancer in combination with radiation and studies combining it with chemotherapy in other localized tumors such as those in the pancreas and rectum are ongoing.”

Soft tissue sarcomas involve cancer that starts in the soft, supporting tissues of the body, such as muscle, fat, blood vessels, nerves, tendons, tissue around the joints and deep layers of the skin. They are relatively rare, accounting for about three percent of all cancers, but are more common in children and young adults. Surgery is the primary treatment, but sometimes these tumors are difficult to remove completely, so they are often also treated with radiotherapy and sometimes chemotherapy. However, in cases where the disease is localized, the benefits of chemotherapy have been shown to be limited. In high-risk patients, any relapse usually occurs within two or three years. Survival varies widely depending on the location and severity of the tumor, with abdominal sarcomas being the most deadly.

The phase III study involved 341 patients being treated at several centers in Europe and the United States between July 1997 and November 2006 for locally advanced soft tissue sarcomas that were at high risk of recurrence and spread. More than half of the tumors were located in the abdomen, while the rest were in the arms and legs. All patients were given chemotherapy before and after surgery and radiotherapy.

Half were randomly given targeted heat treatment along with the chemotherapy. The technique, known as regional hyperthermia, uses focused electromagnetic energy to warm the tissue in and around the tumor to between 40 and 43 degrees Celsius (104 – 109.4 degrees Fahrenheit). The heat not only kills cancer cells, but it also seems to make chemotherapy work better by making cancer cells more sensitive. It also improves blood flow, which allows chemotherapy to be more effective.

After an average follow-up of 34 months, only 153 patients (44.9%) in total had died. The improvement in overall survival was not statistically meaningful when all patients were analyzed, but an analysis of the 269 who completed the full treatment of either four cycles of initial chemotherapy alone or four chemotherapy cycles and eight heat treatments found that those who got the heat therapy were 44% less likely to die during the follow-up period than those who got chemotherapy alone.

The patients receiving the targeted heat therapy fared better on all outcome measurements,” Issels noted. “Almost three years after starting treatment, they were 42% less likely to experience a recurrence of their cancer at the same site or to die than those who were getting chemotherapy alone, surviving an estimated 120 months before local progression of their disease, compared with an estimated 75 months. Similarly, the average length of time that patients remained disease free was 32 months in the group that got both treatments, compared with 18 months in the group that got chemotherapy alone – an improvement of 30%.”

At two years, 76 percent of the patients in the heat therapy group were still alive without local progression of their cancer, compared with 61 percent in the chemotherapy alone group. The proportion of patients who experienced tumor shrinkage rose from 12.7% in the chemotherapy alone group to 28.8%, while the proportion of patients who saw their tumor grow was 6.8% in the heat therapy group, compared with 20% in the chemotherapy alone group.

The most frequent side effect of the heat therapy was mild to moderate discomfort, reported in 45% of patients. The most serious side effect was severe burns, seen in one patient (0.6%). Blisters occurred in 17.8%.

“This strategy has been in development for about 20 years, with about 150 leading groups studying it, but the clear results of this trial show that the field has now matured to the point where we must step up efforts to explore its potential to offer an entirely new way of treating locally advanced disease in several major cancers,” explained Issels. “That will take investment from public funders to underwrite trials that investigate, for instance, whether it will be possible to reduce the dose of chemotherapy drugs by boosting their effectiveness with targeted heat therapy and whether the technique can enhance the effectiveness of newer targeted drugs.”

"Other questions remaining include whether targeted heat therapy can play a role in stimulating the immune system to more effectively attack cancer," Issels said, adding that "studies of heat shock protein therapy indicate that they may activate the immune system against the disease."

The study was funded by the German Cancer Foundation, Deutsche Krebshilfe and the Helmholtz Assocation, Germany’s largest scientific organization.

For more information:
  • Abstract no: 1 LBA. Presidential session II, Tuesday 12.15-14.15 hrs CEST (Hall 1)

Comprehensive Study Shows Prostate Cancer Patients on Hormone Therapy are at Greater Risk for Heart Disease

New research has found that hormone therapy used to treat men with advanced prostate cancer is associated with an increased chance of developing various heart problems. Some choices of therapy appear, however, to be less risky than others.

Researchers told Europe’s biggest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that the findings of their study, the largest and most comprehensive to date on the issue, indicate that doctors need to start considering heart-related side effects when they prescribe endocrine therapy for prostate cancer and might want to refer patients to a cardiologist before starting treatment.

A few smaller studies have indicated that some types of hormone therapy increase the risk of coronary heart disease and heart attacks in prostate cancer patients, but others have found no increased risk. This is the first large study to investigate how the broader range of hormone therapies affect a wider range of heart problems and provides for the first time a detailed picture of the impact of each sort of hormone therapy on individual types of heart trouble.

“If we have observed a causative effect, then for all hormone therapies put together, we estimate that compared with what’s normal in the general population, about 10 extra ischemic heart disease events a year will appear for every 1,000 prostate cancer patients treated with such drugs,” said the study’s leader, Ms Mieke Van Hemelrijck, a PhD student and cancer epidemiologist at King’s College in London.

“However, not all types of therapy were associated with the risk of heart problems to the same degree. We found that drugs which block testosterone from binding to the prostate cells were associated with the least heart risk, while those that reduce the production of testosterone were associated with a higher risk. This may have implications for treatment choice.”

Prostate cancer is diagnosed in more than 670,000 men each year worldwide, making it the second most common cancer among men worldwide, after lung cancer. Hormone therapy is a mainstay of treatment when the cancer is locally advanced and when it has spread to more distant parts of the body, but is increasingly being used in earlier stages of the disease. It involves either removing the testicles to eliminate the main source of testosterone production, injections of gonadotropin releasing hormone agonists to dramatically reduce the production of testosterone from the testicles or anti-androgen pills, which do not reduce the amount of testosterone produced but block it from attaching the prostate cells. Doctors sometimes use a combination of those approaches.

In the study, researchers analyzed the link in 30,642 Swedish men with locally advanced or metastatic prostate cancer who had received hormone therapy as primary treatment for their disease between 1997 and 2006. The men were followed for an average of three years. The researchers calculated the risk of developing ischemic heart disease, heart attacks, arrhythmia and heart failure requiring hospitalization as well as the risk of dying from these heart diseases by comparing the rates among the cancer patients with what’s normal in the general Swedish population. Most patients got one of the three hormone treatment choices, but 38% got a combination of the two types of drugs.

“We found that prostate cancer patients treated with hormone therapy had an elevated risk of developing all of the individual types of heart problems and that they were more likely than normal to die from those causes,” Van Hemelrijck noted, adding that the problems started happening within a few months of initiating treatment.

Overall, prostate cancer patients treated with hormone therapy had a 24% increased risk of a non-fatal heart attack, a 19% increased risk of arrhythmia, a 31% increased risk of ischemic heart disease and a 26% increased risk of heart failure. The risk of a fatal heart attack was increased by 28%, the risk of dying from heart disease by 21%, the risk of heart failure death was increased by 26% and the risk of fatal arrhythmia was increased by 5%.

“In a more detailed analysis by type of hormone therapy, the lowest increase in risk for ischemic heart disease, heart attack and heart failure was seen in the group taking anti-androgen therapy, and we saw no increase in risk of death from heart disease in this group,” Van Hemelrijck explained. “Patients on gonadotropin releasing hormone agonist therapy had the highest risk of these problems.”

For instance, the increased heart failure risk for anti-androgens was 5%, compared with 34% for gonadotropin releasing hormone agonists and the increased ischemic heart disease risk was 13% in the anti-androgen group, compared with 30% in the gonadotropin releasing hormone agonist therapy group.

“The finding that anti-androgens carry the least heart risk supports the view that circulating testosterone may protect the heart. The association with heart risk when the testicles were removed was close to that seen with the gonadotropin releasing hormone agonist therapy,” Van Hemelrijck added.

The increased risk of heart events requiring hospitalization was less pronounced in patients who already had heart disease before hormone treatment, with a 17% risk increase for a new ischemic heart disease event among those with a history of heart disease, compared with a 41% increase among men who didn’t have any heart trouble before hormone treatment, for instance. Van Hemelrijck said that could be because the men who already had heart disease were likely to be taking heart medications that protected them from further heart risk imposed by the endocrine treatment.

“We now need studies verifying the association and exploring plausible biological mechanisms. Then we would know how to best use these treatments according to a patient’s history of various types of heart disease and whether it would be a good idea to give patients heart medicines to counteract these side effects,” Van Hemelrijck concluded.

The study was funded by the Swedish Research Council, the Stockholm Cancer Society and Cancer Research UK.

For more information:
  • Abstract no: 0272. Presidential session, Tuesday 12.15 hrs CEST (Hall 1)

Also read these PubMed Abstracts:

Illustration courtesy of the American Society of Clinical Oncology.

New Cancer Research Priorities Needed to Correct Imbalance that Leaves Important Questions Neglected

Cancer research is too focused on new drug development, while not enough money and effort is being devoted to pursuing important advances in knowledge likely to have the biggest impact on combating the disease in the next few decades, a leading research policy expert says, adding that a major shift in research priorities will be crucial to the ability to cope with the coming wave of cancer cases.

Professor Richard Sullivan of the King’s Health Partners Integrated Cancer Centre in London told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that studies aiming to improve surgery, pathology and diagnostic and staging imaging, as well as a radical rethink of the approach to prevention research, must become the focus of public- and federally-funded cancer research now. The global public sector spend on cancer research was about €14 billion a year in 2004/05, the latest year for which figures are available. Non-commercial funders in Europe spent just over €3 billion on cancer research in 2004/05.

“An analysis we have just completed shows that, on average, European public funders are spending 74% of their money on fundamental biology and drug development research and that well over 70% of the cancer research initiatives at the European level are aimed at the same areas,” noted Prof Sullivan, who is also chairman of the European Cancer Research Managers Forum, which studies cancer research and funding in Europe.

“In the United States, the imbalance is even greater. There is no shortage of cancer drugs coming through pipeline and the whole area of drug research is quite healthy. What we need is a reapportioning of budgets from the charitable sector and public funders to carve out space for these other areas of cancer research that are largely invisible to a lot of policymakers."

“This is a deeply unfashionable view and the easy way out is to say that we must just ask for more money, but the reality is that we’ve got to prioritise,” Prof Sullivan said. “Most of the new medicines are having a small impact on the big picture of cancer burden at the moment, extending life by a few months. Research in this area is already heavily funded and that will continue regardless, as will the investments in fundamental cancer biology.”

The World Health Organization predicts that the number of people worldwide living with cancer will rise from about 28 million today to about 75 million in 2030. Detecting cancer early enough to treat it successfully and improving our understanding of how to make primary prevention strategies work hold the potential for the greatest gains, he said.

“This demands an overhaul of prevention research. You can take the quite reasonable view that we know the risk factors now. What we don’t understand is how to take that research on prevention and apply it in populations because we don’t understand the behaviour of those groups or how that might change over the next 20 or 30 years. For instance, how do we address the fact that many men across Europe will put up with rectal bleeding for a year before going to see a doctor? This is very important because cancer is not just about genes, it is predominantly about culture.”

"Cancer researchers must now be more imaginative and collaborate across unusual disciplinary boundaries to embrace behavioural engineering, population psychology, evolutionary biology, novel sociological methods and ideas such as cultural transmission theory – the study of how behaviours are learned and transmitted between generations," Sullivan explained

“Research in these novel areas addresses questions that can never be answered with classical epidemiological studies or standard social science questionnaires – we’ve reached the limits of enquiry with many standard approaches. There are people doing fantastic work that could be extremely useful not only to cancer research, but to medicine in general and most medics and researchers are completely ignorant about their existence and what they can do for medicine. It is a huge untapped area with massive potential to make a difference,” Prof Sullivan said.

The growing scale of cancer in developing countries also presents an imminent challenge for cancer research, he said. More than half of all cancer diagnoses occur in developing countries, which will bear a large majority of the global burden before long. Keeping the research focus as it is in developed countries will not address the problem in the developing and transitional countries because drug development is not going to be the answer. Surgery and radiotherapy are the most important approaches for reducing the global cancer burden and financial support for programmes that bring those treatments to developing countries is still very poor.

The argument is always made that there is enough to deal with in developing countries with the infectious disease challenges, but chronic disease is a major, often unrecognised problem and we can’t afford to wait any longer. Like it or not, developed countries have a responsibility to investigate which cancer control approaches are exportable and to support those institutions working in these areas,” he said.

Governments, research charities and European funders need to recognise the importance of shifting the focus to a new approach to prevention research and more investment in non-drug treatment research, but it will be largely up to cancer researchers to drive the change, Prof Sullivan said.

“There has already recently been a major shift in Europe toward hospital-university alliances driving the agenda. They need to start banging on the doors of the non-government organisations and the federal funders, lobbying hard and proving that it’s important to give attention to these neglected areas of cancer research.”

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TEAM Study of Adjuvant Endocrine Treatment for Breast Cancer Reveals the Cost of Patient Non-compliance

The largest study in the world of treatments for post menopausal, hormone positive breast cancer has shown that patients who continue to take exemestane or tamoxifen do significantly better than patients who start to take one drug (or tamoxifen followed exemestane) but then stop.

Professor Cornelis van de Velde, principal investigator at the central data office for TEAM (tamoxifen exemestane adjuvant multinational) trial told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that differences in compliance between the nine countries involved in the trial shed light on the role that it played in patient outcome.

In the Dutch/Belgian part of the TEAM trial, more patients were node positive compared to those in other countries (and were therefore at higher risk of recurrences), because the existing Dutch treatment guidelines (which have since been changed) indicated that only ‘high risk’ patients should receive chemotherapy, endocrine treatment or both. Yet despite this handicap, recurrences of breast cancer in The Netherlands and Belgium were 12% for patients using tamoxifen and 9% of patients using exemestane compared to 8% and 7% internationally. This is probably due to better compliance with treatment in The Netherlands, which was significantly better than in other countries.

“Across the whole study, up to a cut-off point of two years nine months, non-compliance amongst women on tamoxifen was 19.8% and 12.9% for women on exemestane. However, these percentages were considerably lower in the Dutch/Belgian part of the TEAM trial where non-compliance was 14% for tamoxifen and 9% for exemestane Patients who stopped study treatment (tamoxifen or exemestane) had significantly higher chance of a recurrence; the chance was between four and five times higher among this group than among those who continued their treatment. This underlines the need for good information for patients concerning the side-effects of drugs and treatment efficacy,” said Prof van de Velde, who is Professor of Surgery at the Leiden University Medical Centre (Leiden, The Netherlands) and President of the European Society of Surgical Oncology. Compliance with medication in the TEAM study was lower than in any previous study of adjuvant aromatase inhibitors.

The TEAM study is a randomised phase III clinical trial comparing the efficacy of the aromatase inhibitor exemestane versus the current “gold standard” treatment tamoxifen as adjuvant endocrine therapies for hormone sensitive early breast cancer in postmenopausal women. After two years nine months a total of 9,779 women had been included in the trial from nine countries: France (1230 patients), Germany (1480), Greece (211), Japan (184), The Netherlands (2753), Belgium (414), UK/Ireland (1275), and the USA (2232).

The trial was started in 2001 but in 2004, based on results from another trial (Intergroup Exemestane Study) that showed a significant survival advantage for patients on exemestane, the TEAM study was changed so that patients receiving tamoxifen were switched to exemestane after having been in the trial for between two and a half to three years. The results presented today relate to data on disease-free survival in patients on the trial for no longer than two years nine months and they focus particularly on issues of compliance in the Dutch/Belgian TEAM patients, as well as on side effects, and disease-free and overall survival across the whole of the study.

Prof van de Velde noted: “Adverse side effects were the main reasons why patients discontinued their treatment – about half of all patients who discontinued did so because of side effects. Out of all the patients in the study, 6.3% discontinued tamoxifen and 4.4% discontinued exemestane because of side effects."

Adverse side effects included heart, skin, hormonal, digestive, metabolic, neurological, muscle and skeletal problems. Exemestane was associated with significantly higher rates of arthralgia, carpal tunnel syndrome, diarrhoea and high cholesterol levels, but with significantly lower rates of hot flushes, vaginal bleeding and discharge, and thromboembolism than tamoxifen. Fractures and heart problems were similar between the two groups.

“The safety profile has been better for exemestane than for tamoxifen and I think this is a contributory factor to the lower discontinuation rates amongst the patients on exemestane,” Van de Velde said.

After two and three-quarter years of follow-up, among the women on exemestane there were 11% fewer cases of a local recurrence of the tumour, distant metastases, breast cancer in the other breast (contralateral breast cancer) and deaths occurring without a relapse of the disease,than among the women on tamoxifen (352 in the exemestane patients and 388 in the tamoxifen patients). There were no differences between the two groups for time to contralateral breast cancer or overall survival, and no unexpected safety issues were reported. Patients aged 70 or over and women with breast cancer that had spread to only one to three lymph nodes had a significantly better disease-free survival on exemestane than on tamoxifen.

“The current analysis covers a short period of time with relatively few deaths occurring and this makes it difficult to see significant differences between the two groups. However, the data from TEAM indicate that early use of exemestane in these high risk patients appears to be safe and a more effective endocrine treatment than tamoxifen for reducing breast cancer recurrence,” said Prof van de Velde. “The study is continuing and the next end point has already been reached, so that we now have enough events to conclude whether starting with tamoxifen and switching to exemestane is better or worse than starting with exemestane. These results will be presented at the San Antonio breast cancer symposium in December.”

For more information:
  • Abstract no: 2BA. Presidential session, Tuesday 12.30-14.30 hrs CEST (Hall 1)

Also read these PubMed Abstracts:

Post-menopausal Early Breast Cancer Patients May Benefit From Switching to Exemestane After Two Years of Treatment with Tamoxifen

New research has found that switching post-menopausal women with early breast cancer to the drug exemestane (Aromasin®, Pfizer, USA) after two or three years of tamoxifen rather than keeping them on tamoxifen for five years improves the chance of remaining cancer free and reduces the risk of death for at least the next six years.

These findings have confirmed that the strategy of switching to exemestane mid-way through the five-year tamoxifen treatment plan provides a clear and durable benefit for relapse and overall survival,” the study’s leader, Professor Charles Coombes, head of oncology at Imperial College in London, told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany. “We found that six years after changing treatment, women who got exemestane were 18% more likely to remain disease free and were 14% less likely to die than those who stayed on tamoxifen.”

Breast cancer is the leading cancer in women, with 1.29 million cases diagnosed worldwide every year. About 75% of breast cancers are oestrogen-receptor positive, meaning that oestrogen plays in important role in promoting the growth. Such tumours are usually treated with anti-oestrogen drugs.

Tamoxifen, also known by the trade names Nolvadex, Istubal, and Valodex, is the oldest of these. The drug blocks the tumour’s ability to use oestrogen and is the standard treatment after surgery in women who have early-stage breast cancer. It is normally taken for five years.

Exemestane belongs to a newer class of anti-oestrogen drugs known as aromatase inhibitors, which interfere with the function of aromatase, an enzyme responsible for the production of oestrogen. Aromatase inhibitors are accepted as an alternative to tamoxifen for post-menopausal women, but the question of how best to use these drugs remains under investigation.

The study tested whether switching to exemestane after two or three years of tamoxifen was more effective in the long term than continuing with tamoxifen for the remainder of the five years of treatment. The results presented in Berlin update findings reported previously, providing evidence based on a longer follow-up to produce a more robust estimate of the strategy’s effect on survival and disease recurrence and give a clearer picture of the long-term side effects.

“Our earlier analysis, based on a shorter follow-up, had shown a clear relapse advantage but until now, the magnitude and duration of the overall survival benefit had been uncertain. These updated results show that the relapse improvement does not seem to diminish over time and have clarified that the survival advantage is robust and enduring.”

The study, which has the longest follow-up of any trial to date investigating the impact of switching from tamoxifen to an aromatase inhibitor, involved 4,724 postmenopausal women from 37 countries with oestrogen-receptor-positive or unknown receptor status breast cancer who had their tumours cut out and had remained disease free after two or three years on tamoxifen. About half continued with tamoxifen until they had completed a total of five years of treatment, while the other half were switched to exemestane for the remaining period of treatment. The women were followed for an average of 91 months.

The 18% improvement in disease-free survival is derived from a hazard ratio of 0.82, while the 14% improvement in overall survival is calculated from a hazard ratio of 0.86.

“Practice changed in many countries after our early findings were released in 2004, from using five years of tamoxifen to the current recommended treatment strategy of switching these patients to exemestane or another aromatase inhibitor after two or three years of tamoxifen. The issue that has yet to be clarified is whether starting with tamoxifen and then switching is better than starting with an aromatase inhibitor,” Coombes said.

Cancer Research UK and Pfizer Ltd., which makes exemestane, funded the study.

For more information:
  • Abstract no: 5010. Breast Cancer proffered papers session, Tuesday 09.00-11.00 hrs CEST (Hall 1)

Also read these PubMed Abstracts

Thursday, October 1, 2009

Pralatrexate Approved by FDA as the First Drug for Treatment of Peripheral T-cell Lymphoma

The U.S. Food and Drug Administration (FDA) approved pralatrexate (Folotyn®, Allos Therapeutics), the first treatment for a form of cancer known as Peripheral T-cell Lymphoma (PTCL), an often aggressive type of non-Hodgkins lymphoma.

Pralatrexate, also known as 10-propargyl-10-deazaaminopterin, is a folate analog inhibitor of dihydrofolate reductase studied for the treatment of cancer. The drug candidate was approved under the FDA's accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. It is approved for patients who have relapsed, or have not responded well to other forms of chemotherapy.

Lymphoma is a cancer of the lymphatic system, which is part of the immune system. There are many types of lymphoma: one type is called Hodgkin's disease, and the rest are called non-Hodgkin's lymphomas. PTCL involves a type of white blood cell called T-cells. It is a relatively rare disease, occurring in less than 9,500 patients each year in the United States.

“Folotyn's approval demonstrates FDA's commitment to the rapid approval of drugs for rare and uncommon diseases,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

When studying a new drug, it can take time to learn whether a drug actually provides real improvement for patients – such as living longer or feeling better. This real improvement is known as a “clinical outcome.” In 1992 FDA instituted accelerated approvals which allow earlier approval of drugs based on a surrogate endpoint, a laboratory measurement or physical sign that can serve as an indirect or substitute measurement for clinical outcomes.

In the case of pralatrexate, this meant the FDA approved the drug based on evidence that it reduces tumor size, because tumor shrinkage is considered reasonably likely to predict a clinical benefit such as extending the survival of cancer patients. Tumor shrinkage was seen on imaging scans in one study. Of 109 patients with PTCL in the trial, 27% had reduction in tumor size.
To speed the drug's availability, pralatrexate was granted priority review, ensuring a review within six months rather than 10 months for a standard review. The drug was also designated as an orphan drug, which provides a variety of financial incentives to manufacturers that develop drugs for a small number of patients with a rare disorder.

The most common adverse reactions seen with pralatrexate were irritation or sores of the mucous membranes such as the lips, the mouth, and the digestive tract, low platelet cell counts, low white blood cell counts, fever, nausea, and fatigue.

Pralatrexate can harm a fetus. Therefore, women should avoid becoming pregnant while being treated with this drug and pregnant women should be informed of the potential risk.
Patients treated with pralatrexate should take folate and vitamin B12 supplements to reduce mucous membrane irritation.

Pralatrexate is manufactured by Allos Therapeutics Inc. of Westminster, Colorado (USA). As a condition of accelerated approval, Allos will conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer.

For more information:
Also read these PubMed abstracts: