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:

• Health Insurance Reform and Breast Cancer: Making the Health Care System Work for Women
• American Cancer Society: Breast Cancer Facts and Figures 2009-2010.
• Horner MJ, Ries LAG, Krapcho M et al (eds). SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD.
• Centers for Disease Control and Prevention. Screening to Prevent Cancer Deaths.

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

• Sternberg CN, Szczylik C, Lee E, Salman PV, et al. A Randomized, Double-blind Phase III Study of Pazopanib in Treatment-naive and Cytokine-pretreated Patients with Advanced Renal Cell Carcinoma (RCC). Abstract #5021 Presented at the 2009 American Society of Clinical Oncology annual meeting.
• Hutson TE, Figlin RA. Novel therapeutics for metastatic renal cell carcinoma. Cancer. 2009 May 15;115(10 Suppl):2361-7. Review.
• Hutson TE, Figlin RA, et al Targeted Therapies for Metastatic Renal Cell Carcinoma: An Overview of Toxicity and Dosing Strategies. The Oncologist. 2008; 13: 1084-1096.
• Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008 Feb;17(2):253-61. Review.
• Sonpavde G and Hutson T. Pazopanib: A Novel Multitargeted Tyrosine Kinase Inhibitor. Curr Oncol Rep. 2007;Mar9(2):115-9.
• Parkin M, Bray F et al. Global Cancer Statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108.

Illustration courtesy of the American Society of Clinical Oncology.

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:

• Scottsdale Clinical Research Institute
• Scottsdale Healthcare Foundation
• Virginia G. Piper Cancer Center
• TGen Clinical Research Services

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:

• Nanda A, Chen MH, Braccioforte MH, Moran BJ, D'Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA. 2009 Aug 26;302(8):866-73.
• Moyad MA, Sonnleithner M. Prostate cancer and coronary heart disease: correlation or coincidence? Urol Clin North Am. 2004 May;31(2):207-12

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.”

For more information:

• European Partnership for Action Against Cancer

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:

• Fallowfield LJ, Bliss JM, Porter LS, Price MH, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006 Feb 20;24(6):910-7

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

• Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review. Cancer Treat Rev. 2008 Apr;34(2):157-74. Epub 2007 Dec 31. Review.
• Spicer J, Ellis P. Towards optimal endocrine therapy for hormone-sensitive breast cancer: initial versus sequential adjuvant aromatase inhibition.
  Cancer Lett. 2007 Apr 1 8;248(2):165-74. Epub 2006 Aug 21. Review.

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:

• EMEA - Public Summary of Positive Opinion for Orphan Designation of
  pralatrexate for the treatment of peripheral T-cell lymphoma
  (nodal, other extranodal and leukaemic/disseminated)

Also read these PubMed abstracts:

• O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009 Sep 10;27(26):4357-64. Epub 2009 Aug 3.
• Mould DR, Sweeney K, Duffull SB, Neylon E, et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther. 2009 Aug;86(2):190-6. Epub 2009 May 27.
• Marneros AG, Grossman ME, Silvers DN, Husain S, et al. Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood. 2009 Jun 18;113(25):6338-41. Epub 2009 Apr 23.
• Rueda A, Casanova M, Quero C, Medina-Pérez A. Pralatrexate, a new hope for aggressive T-cell lymphomas? Clin Transl Oncol. 2009 Apr;11(4):215-20. Review.

International Trial Shows Aspirin Protects Against Colorectal Cancer

A daily dose of aspirin can prevent the occurrence of cancer in people with a genetic predisposition towards Lynch syndrome, a condition which accounts for around five percent of all colon cancers, a scientist told the audience 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 in Berlin, Germany.

Professor John Burn, from the Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK, said that he believed that he and his colleagues might have uncovered a simple way of controlling cancer stem cells, which are essential to the formation of malignant tumors.

The clinical trial, which involved 1071 carriers of the Lynch syndrome mutation in 42 centers worldwide, randomized participants to a daily dose of 600mg aspirin and/or 30g Novelose®, a resistant starch that escapes digestion in the small intestine. “Although there were many reports that aspirin might have a beneficial effect in a range of cancers,” said Prof Burn, “they were from case control and epidemiological studies. We decided that the only way to achieve conclusive proof was to undertake a randomized trial in a high risk population.”

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is a rare type type of inherited cancer of the digestive tract that increases a patient’s risk of cancer, particularly the colon and rectum. People with Lynch syndrome have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women carriers also have a high risk of developing endometrial and ovarian cancers.

These patients tend to develop cancer quickly, so the scientists expected to see answers at an early stage. The first results were disappointing, however; at an average of 29 months after randomization the scientists saw no evidence of the benefits of aspirin in the high-risk population studied.

“Our original design allowed for long term post trial follow-up,” noted Prof Burn. “We have managed to track down most of those who completed the trial – around 75% of the original consent cohort – with information extending up to 10 years from randomization. We found that, around four years after randomization, there was a divergence in the incidence of cancers between the aspirin and placebo groups. To date, there have been only six colon cancers in the aspirin group as opposed to 16 who took placebo. There is also a reduction in endometrial cancer. This is a statistically significant result and we are delighted – all the more so because we stopped giving the aspirin after four years, yet the effect is continuing, and is directly correlated with the duration of aspirin use on the trial.”

Although scientists believe that diet is a major factor in the prevention of colorectal cancers, there are no randomized trial data which can prove it, since running proper, controlled trials of diet is extremely difficult. However, there is a strong inverse relationship between colon cancer and how much starch people eat. Resistant starch, after escaping digestion in the upper gut, is fermented in the colon and forms short chain fatty acids, which are powerful anti-cancer agents.

“Our very large colon probably evolved to capture such nutrients from our forefathers’ diets,” explained Prof Burn. “Because we were giving starch as well as aspirin we would also have expected to see a decrease in cancers in the placebo group. However, there could be a number of reasons for this result – perhaps patients didn’t take the starch every day, or that it simply wasn’t resistant enough.”

There were minor problems due to aspirin side effects; out of over 1000 people, 11 in the aspirin group had notable gastro-intestinal bleeds or ulcers as opposed to nine in the placebo group. But this was counter-balanced by fewer strokes and heart attacks in the aspirin group.

The mechanism by which aspirin protects against cancer has yet to be elucidated, but the scientists believe that cancer stem cells are involved. “We do not think that the mechanisms discussed to date are likely to provide an explanation,” said Prof Burn. “For example, the inflammatory enzyme COX2(Cyclooxygenase-2), a protein that acts as an enzyme and specifically catalyzes the production of certain chemical messengers called prostaglandins, is over-expressed in early cancer, but our results suggest an effect that predates the cancer, and may even predate the adenoma which precedes it. We believe that aspirin may have an effect on the survival of aberrant stem cells in the colon. These cancer stem cells are normally resistant to chemotherapy, but if a stem cell mutates but does not reveal its potential until an adenoma is formed, and if aspirin reduced the chances of such cells surviving, this would explain our results.”

The team intends to undertake a further study to see whether a smaller dose of aspirin would have the same beneficial effect or not. “We are planning to ask people with Lynch syndrome to agree to ‘toss a coin’ and take, say, either one or two aspirin tablets per day. Then we can see whether the people on the lower dose have the same protection, with fewer side effects. The problem is that, to have a significant result, this will need about 10 times as many people as we needed for our first trial, but the good news is that everyone gets treated,” said Prof Burn.

For more information:

• Abstract no: 6000, Gastro-intestinal malignancies, colorectal cancer session, Monday 11.00 hrs CEST (Hall 2)

Also read these PubMed abstracts:

• Hua A, Mackenzie GG, Rigas B. The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin. Int J Oncol. 2009 Oct;35(4):837-44.
• Barry EL, Sansbury LB, Grau MV, Ali IU, Tsang S, et al. Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial. Cancer Epidemiol Biomarkers Prev. 2009 Sep 15. [Epub ahead of print]
• Lang DL. Aspirin as Colorectal Cancer Adjuvant Therapy. Gastroenterology. 2009 Aug 22. [Epub ahead of print]
• Neugut AI. Aspirin as adjuvant therapy for colorectal cancer: a promising new twist for an old drug. JAMA. 2009 Aug 12;302(6):688-9
• Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology. 2008 Jan;134(1):21-8. Epub 2007 Sep 26.

The Experience and Impact of Teenage Cancer Diagnosis Reveals Major Struggle

New research provides unique insight into what it is like for teenagers and young people to go through the process of obtaining a cancer diagnosis, revealing stories of prolonged suffering, acute distress and intense frustration for some over their symptoms not being taken seriously.

The study, presented by British researchers 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 in Berlin, Germany, is the first to have asked young people with cancer about their experiences from the time of first symptoms to diagnosis and provides lessons for catching the disease earlier and improving the care and experience of patients in this age group, about whom little is known.

Cancer is rare in teenagers and young people, with those aged between 15 and 24 years accounting for less than two percent of all cancer cases worldwide. But the rates are twice as high as they are in children and the disease is the most frequent cause of death in this age group after accidents. The long-term outcome for some tumor types is thought to be relatively poor compared with that for children and adults and delay in diagnosis is thought to be one of the key factors in this. The problem of diagnostic delay is widely acknowledged but is perhaps the least understood aspect of the young person’s cancer journey.

“While being diagnosed with a potentially life-threatening disease is a distressing experience for any patient, a cancer diagnosis, and the process leading up to it, can have a particularly poignant impact on teenagers because that stage of development already presents significant challenges in developing independence, identity and in coping with the world. Research in this area has been limited and better understanding of the complexities of their experience in the pre-diagnostic period is crucial if we are to provide the most comprehensive and sensitive care and improve their outcomes,” said one of the study’s researchers, Ms Susie Pearce, a health service researcher for young people with cancer at University College Hospital in London.

The researchers conducted narrative interviews with 24 young people aged between 16 and 24, two to four months after they had been diagnosed with solid tumors in one of four major centers in England. The medical notes of each participant were also analyzed in the study.

While the individual experiences varied in terms of how their symptoms evolved and were responded to, several common themes emerged. Key findings included a pattern of young voices not being heard, delays in diagnosis and a misconception among young people and society as a whole that young people don’t get cancer.

“While symptoms in some young people were promptly recognized by GPs and referred to specialists quickly, other patients recounted tales of protracted periods of suffering, with rationalization of their own symptoms or numerous disappointing visits to doctors and hospitals before the cancer was diagnosed,” said Pearce, adding that the time period between first symptoms and diagnosis ranged from eight weeks to 11 years.

Examples of symptoms being missed by general practitioners or accident and emergency doctors included being told it is normal to be tired, that symptoms are due to menstrual problems, fluid on the knee, irritable bowel syndrome, excess weight or lack of exercise.

“One consistent thread through these stories is young people’s perception that they were not being listened to and that cancer was being ruled out on age alone,” explained Pearce. “For instance, one eventually thought she was going mad after three months of headaches and 12 visits to the GP and A&E. Finally, after breaking down at the GP’s surgery, she was referred to the specialist and was later diagnosed with neuroblastoma. It seemed that extreme levels of worry and distress had to be reached before the right course of action was taken.”

In another case, a 22-year-old young woman who was diagnosed with colon cancer that had spread to the liver recounted a frustrating battle to be taken seriously after nine or ten years of suspicious symptoms such as food aversion, abdominal pain, frequent diarrhea and rectal bleeding from the age of 14 and two separate diagnoses of familial adenomatous polyposis, or FAP, a hereditary syndrome that carries a very high risk of colon cancer.

“Basically because I grew up with the symptoms no-one went ding din ding… red light warning, we need to do something about this,” she told the researchers. “I said ‘look, this is ridiculous. I am passing blood a lot, diarrhoea, tummy ache. I want to get it sorted because it’s ruining, not ruining but it’s taking over my life’ …They look at you and they say you are too young for this. If you are old, they will do something about it.”

Pearce noted: “She felt quite strongly that if she had been 40 or 50 her symptoms would have been picked up on at a very early stage and she would have been fine, but lots of cues were missed because nobody was thinking that she could have colon cancer.” Sadly, after her participation in the study, this young woman died.

In another example, a 23-year-old young woman who was diagnosed with ovarian cancer 10 months after her first symptoms said: “I wish they had just listened to me in the beginning. I’d like them more aware so you can’t just be shoved away out the door. It’s your life … it’s your whole world they are talking about and they are not taking it seriously.”

The researchers found that the reaction of others, particularly parents, was important in determining how long the patients were willing to put up with symptoms and how assertive they were at pushing for an answer to their concerns.

“There seemed to be a trigger point at which further help was sought. That threshold came when normal physical, social and emotional functioning became impossible and the symptoms could no longer be dismissed as normal,” Ms Pearce said. “Prompting, confirmation and support from others was crucial in the acknowledgment of threat and seriousness of the need for action.”

The sense of relief once they had arrived in specialist care was striking. They felt they were in safe hands, with experts whom they now had confidence in, the study found. However, some said their struggle to get to that point prompted them to lose trust in their GP or the hospital Accident & Emergency system and that they would be reluctant to seek the help of those professionals again.

“The stories related here are, sadly, far from unique. Doctors should be making urgent referrals when children or young people come to see them several times with the same problem and persistent parental anxiety should be sufficient reason for referral,” Pearce said, adding that the study recommends research into interventions such as education in schools and universities and better education of health professionals, including school nurses, university health centers and general practitioners so that classic signs are investigated properly and promptly.

The 23-year-old ovarian cancer patient’s advice to young people was: “Listen to your intuition and be strong. If you think something is wrong just keep pushing.”

The study was funded by CLIC Sargent, the UK-based children and young people’s cancer charity.

For more information:

• Abstract no: 4170. Experiences of Care proffered papers session, Tuesday 09.00 hrs CEST (Hall 10)

Also read these PubMed abstracts:

• Gurney JG, Krull KR, Kadan-Lottick N, Nicholson HS, Nathan PC, Zebrack B, Tersak JM, Ness KK. Social outcomes in the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009 May 10;27(14):2390-5. Epub 2009 Feb 17. Review.
• Zeltzer LK, Recklitis C, Buchbinder D, Zebrack B, et al. Psychological status in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2009 May 10;27(14):2396-404. Epub 2009 Mar 2
• Stein KD, Syrjala KL, Andrykowski MA. Physical and psychological long-term and late effects of cancer. Cancer. 2008 Jun 1;112(11 Suppl):2577-92. Review.
• Zeltzer LK, Lu Q, Leisenring W, Tsao JC, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):435-46
• Zebrack BJ, Zevon MA, Turk N, Nagarajan R, et al, Psychological distress in long-term survivors of solid tumors diagnosed in childhood: a report from the childhood cancer survivor study. Pediatr Blood Cancer. 2007 Jul;49(1):47-51
• Turner J, Clavarino A, Yates P, Hargraves M, Connors V, Hausmann S. Development of a resource for parents with advanced cancer: what do parents want?
  Palliat Support Care. 2007 Jun;5(2):135-45.
• Van Dijk J, Imhof SM, Moll AC, Ringens PJ, Cohen-Kettenis PT, Rijmen F, Huisman J. Quality of life of adult retinoblastoma survivors in the Netherlands.
  Health Qual Life Outcomes. 2007 Jun 4;5:30.
• Abrams AN, Hazen EP, Penson RT. Psychosocial issues in adolescents with cancer.
  Cancer Treat Rev. 2007 Nov;33(7):622-30. Epub 2007 Apr 16. Review.
• Upton P, Eiser C. School experiences after treatment for a brain tumour.
  Child Care Health Dev. 2006 Jan;32(1):9-17.
• Stam H, Grootenhuis MA, Brons PP, Caron HN, Last BF. Health-related quality of life in children and emotional reactions of parents following completion of cancer treatment.
  Pediatr Blood Cancer. 2006 Sep;47(3):312-9.

Novel Cancer Drug Test May Results in Safer and More Effective Clinical Trials

A group of scientists from Hamburg may have taken a big step towards more effective cancer drug development. Dr Ilona Schonn, Director of Cell Culture Research at Indivumed GmbH, a company specialized in the analysis and procurement of highly standardized tissue samples and data of tumor patients, told the audience at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that they had developed a preclinical drug test platform that would enable researchers to analyze tumor tissue for individual patient drug responses on the molecular level.

To date most tests for drug metabolism and toxicity testing have used tissue slices of normal organs like liver, kidney and lung. The new test was created specifically for oncology drug testing and uses tumor tissues from colorectal and lung cancer patients.

A major problem of drug development at present is the inability to extrapolate response in preclinical cell models to patients. “Approximately 90% of clinical trials fail because the drugs used are too ineffective or too toxic,” explained Dr Schonn. “Not only does this result in unacceptably high costs for drug development, but it also exposes patients to risks from toxicity or simply wastes their time in testing a substance which proves to be ineffective.”

The problem arises from the fact that patients respond individually to drugs. In addition, each tumor consists of a variety of different cancer cells that interact in different ways with the framework of individual non-tumor cells, resulting in highly variable growth behavior and response to drugs. Dr Schonn and her team set out to try to develop a drug test that would eliminate these problems and provide an accurate model of individual patient response.

“Based on freshly cultivated intact tissue from surgically treated cancer patients we are now able to analyze numerous tumors from different patients, to identify differences in drug response between those patients, and to understand variations of response in cell subtypes within one tumor,” said Dr Schonn.

The new test allows scientists to translate findings from commonly used cell lines to a preclinical model which is as close as possible to using the same drug in the clinical setting, thus enabling a better estimate of the number of patients who are likely to respond to the treatment. It also helps to identify biomarkers that can predict drug response for patients entering a clinical trial, allowing researchers to include only those patients whose participation will provide a significant answer to the question being asked.

“Together with all the clinical patient data and several analytical test systems such as signaling pathway analysis, we have been able to characterize individual tumors in more detail. This will improve the understanding of drug effects and treatments, a step forward towards the goal of individualized cancer therapy,” she said. “The test is of particular interest to pharmaceutical companies because it allows the analysis of samples from meaningful number of patients with different tumors in a short period of time, and can, therefore, accelerate progression of a potential new treatment to clinical trials.”

In addition, it can help gain more knowledge about the mode of action of a new compound in patients, and identify optimal disease areas, for example tumors with particular mutations or over-expression of target receptors, and dosage.

To date the test has only been validated in colon, non-small cell lung (NSCLC), and breast cancer tumors but there is no reason to think that it would not be equally accurate in other solid tumor types, the scientists say.

“Because the test allows us to maintain the complex environment of the primary cancer tumor, we believe that it holds out great promise for the quick and effective elucidation of response to anticancer drugs,” said Dr Schonn. “We hope to be able to apply it to a growing number of drugs emerging from the labs of pharmaceutical companies to help to shorten development time and to make clinical trials both more efficient and safer for patients.”

The test can analyze numerous tumors from different patients, identify the patients’ diverse reactions to the test compounds and elucidate their varying effects on cell subtypes within the same tumor. Says Prof Dr Hartmut Juhl, CEO and founder of Indivumed. “In the long run, our test paves the way to personalized medicine, because it helps to understand and to embrace the individual reactions of the patients to a certain therapy.”

For more information:

• Abstract no: 1013, Basic Science/Translational Research poster discussion, Wednesday 17.00 – 18.00 hrs CEST (Hall 14.2)

Ultrasound can Predict Tumor Burden and Survival in Melanoma Patients, Sparing Unnecessary Surgery

Ultrasound can predict tumor burden and survival in melanoma patients. Researchers have shown for the first time that patterns of ultrasound signals can be used to identify whether or not cancer has started to spread in melanoma patients, and to what extent. The discovery enables doctors to decide on how much surgery, if any, is required and to predict the patient’s probable survival.

Dr Christiane Voit told Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany: “We have identified two ultrasound patterns of lymph node metastasis in melanoma patients which can identify correctly any amount of tumor cells in the sentinel lymph nodes in 75-90% of cases before proceeding to surgery on the sentinel lymph nodes.”

Voit, who is a dermatologist and head of the diagnostic unit at the Skin Cancer Centre at Charité – Universitätsmedizin Berlin, the Medical University of Berlin, said that although her research needs to be confirmed in multi-centre, randomized clinical trials, it had the potential to spare patients unnecessary surgery, especially if it was combined with ultrasound-guided fine needle biopsy of lymph nodes rather than conventional surgery.

Since 2001 Dr Voit and her colleagues in Germany and The Netherlands have included 850 melanoma patients in a prospective study to investigate the use of ultrasound in diagnosis and treatment planning. They have already demonstrated that ultrasound-guided fine needle biopsy of sentinel nodes before conventional sentinel node surgery can identify up to 65% of patients in whom the cancer has started to spread. The study presented today shows how far ultrasound patterns correlate with disease progression, tumor burden, survival and prognosis in the first 400 of these patients with stage I/II melanoma and with the longest follow-up.

Before having sentinel node surgery the patients were investigated using ultrasound, and these results were checked against the results of the subsequent surgery. The researchers found that two ultrasound patterns together could correctly identify the amount of cancer cells in the lymph nodes in 80% of cases.

A balloon shape ultrasound pattern with or without loss of central echoes (where the lymph node has lost central echoes or still has some residual central echoes, but these are wandering toward the rim, giving an asymmetrical shape to the centre) was an indicator in up to 83% of cases of a large amount of cancer cells in the sentinel node. “This ultrasound pattern was a late sign, only occurring in cases of advanced metastasis,” said Voit.

A pattern of peripheral perfusion (where small blood vessels start to surround the lymph node) was an early sign of a small number of cancer cells present. “The early signs are signs of first disruption of the normal lymph node architecture by an early stage metastasis. The most important one is peripheral perfusion, which shows angiogenesis (the formation of new blood vessels) is occurring,” she explained.

The researchers found that these two ultrasound patterns could predict overall survival. Estimates for overall survival after five years for patients with stage I/II is between 50-90% depending on the state of the tumour. Dr Voit found that 93% of patients with neither of these ultrasound patterns, 87% of patients with peripheral perfusion, and 56% of patients with balloon shapes with or without loss of central echoes, survived for at least five years; survival without cancer spreading to other parts of the body was 74%, 60% and 26% respectively.

Dr Voit said: “For the first time we have established that ultrasound patterns can be used as criteria for diagnosing disease progression and tumor burden. Balloon shaped lymph nodes with or without loss of central echoes and peripheral perfusion are independent prognostic factors for survival.”

Discovering if cancer has spread to the lymph nodes is the most important factor influencing the prognosis and treatment of melanoma patients. Doctors usually cut out one or two key lymph nodes, called sentinel nodes, and use these as an indicator of whether or not the cancer has spread to the other lymph nodes. If the sentinel node is free of cancer, patients don’t need to have more extensive lymph node removal.

However, only 20% of patients who have a sentinel node biopsy have cancer that has spread there, and so the operation, which can be accompanied by side effects such as chronic swelling and seroma, is unnecessary for 80% of patients. Using ultrasound first to detect the presence or not of sentinel node metastases could be a non-invasive way of limiting the numbers of patients who require subsequent surgery or simply watchful follow-up care.

For more information:

• Abstract no: 9303. Melanoma session, Wednesday 14.45-17.00 hrs CEST (Hall 7)

Also read these PubMed abstracts:

• Voit C, Kron M, Schäfer G, Schoengen A, Audring H, Lukowsky A, Schwürzer-Voit M, Sterry W, Winter H, Rademaker J. Ultrasound-guided fine needle aspiration cytology prior to sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol. 2006 Dec;13(12):1682-9.
• Voit CA, Schäfer-Hesterberg G, Kron M, van Akkooi AC, Rademaker J, Lukowsky A, Schoengen A, Schwürzer-Voit M, Sterry W, Krause M, Röwert-Huber J, Eggermont AM.
  Impact of molecular staging methods in primary melanoma: reverse-transcriptase polymerase chain reaction (RT-PCR) of ultrasound-guided aspirate of the sentinel node does not improve diagnostic accuracy, but RT-PCR of peripheral blood does predict survival. J Clin Oncol. 2008 Dec 10;26(35):5742-7. Epub 2008 Nov 3.

Images courtesy American Society of Clinical oncology (ASCO).

Sorafenib (Nexavar®) Significantly Improves the Length of Time Before Breast Cancer Worsens: Results From First, Large Randomized Trial

Approximately 30 studies evaluating the use of sorafenib (Nexavar®, Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals)tablets across tumor types – as a single agent or in combination with other therapies – were presented at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin.

“The presentations at the ECCO/ESMO conference continue to build on our large body of data in unresectable liver cancer and advanced kidney cancer where sorafenib has a proven track record,” said Dimitris Voliotis, Vice President, Global Clinical Development Oncology. “Additionally, we are very enthusiastic about the presented Phase 2 studies evaluating the safety and efficacy of sorafenbib in other tumor types, including breast and thyroid cancers.”

One of the first of a series of trials to investigate the use of sorafenib – a targeted anti-cancer drug – for the treatment of advanced breast cancer has found that if it is combined with the chemotherapy drug, capecitabine (Xeloda®, Roche, Basel, Switzerland), it makes a significant difference to the time women live without their disease worsening.

Principal investigator of the study, Professor José Baselga told his audience: “This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Our results showed that patients who received sorafenib plus capecitabine had a 74% percent improvement in the time they lived without their disease worsening compared to those who received the chemotherapy alone. This is a very positive study and the magnitude of the benefit is such that it suggests that this agent will be an important addition to our 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, who is head of the oncology department at Vall d’Hebron University Hospital (Barcelona, Spain), president of ESMO (European Society for Medical Oncology) and a member of the ECCO (European CanCer Organization) executive committee, and his 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 pill taken twice daily for 14 of every 21 days) and a placebo (114 women), or capecitabine and sorafenib (400 mg pill taken twice daily continuously) for 115 women.

The very first results from the trial only became available in time for the ECCO 15 – ESMO 34 congress, and they show that the average progression free survival (the time that elapses without the cancer getting worse) was 6.4 months for women on capecitabine and sorafenib compared to 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 due to adverse side-effects was nine (8%) in the placebo arm and 15 (13.4%) in the sorafenib arm of the trial.

Prof Baselga said: “The regimen was tolerable and the 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 good academia and industry partnership. It was designed and conducted by the Spanish breast cooperative group SOLTI with the participation also 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 of a series of randomized phase II studies with sorafenib that are currently underway in breast cancer. Based on our results, we believe that the drug shows considerable promise for the treatment of the disease.”

For more information:

• Jose Baselga, M.D., Vall d'Hebron University Hospital in Barcelona, Spain. A double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (BC). Late-breaking abstract 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1

Other trial results:

Hepatocellular Carcinoma

• Jean-Luc Raoul, M.D., Centre Eugène Marquis, Rennes, France. Effect of Macroscopic Vascular Invasion (MVI), Extrahepatic Spread (EHS), and ECOG Performance Status (ECOG PS) on Outcome in Patients with Advanced Hepatocellular Carcinoma (HCC) Treated with Sorafenib: Analysis of Two Phase 3, Randomized Double-Blind Trials. Abstract 6621, Poster 309, Wednesday, September 23, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Josep Llovet, M.D., Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain. Efficacy and Safety of Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC): Collective Results from the Phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Asia-Pacific (AP) Trials. Abstract 6519, Poster 13, Tuesday, September 22, 2009, 8 a.m. – 11 a.m., Poster Discussion, 11:15 a.m. – 12:15 p.m., Central Lobby (Outside Hall 3)

Renal Cell Carcinoma

• Joachim Beck, M.D., Johannes-Gutenberg-Universität III. Medizinische Klinik, Mainz, Germany. Final Analysis of a Large Open-label, Noncomparative, Phase 3 Study of Sorafenib in European Patients with Advanced RCC (EU-ARCCS). Abstract 7137, Poster 150, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Hideyuki Akaza, M.D., Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. Efficacy and Safety of Long-term Use of Sorafenib: Final Report of a Phase II Trial of Sorafenib in Japanese Patients with Unresectable/Metastatic Renal Cell Carcinoma. Abstract 7147, Poster 160, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Ronald M. Bukowski, M.D., Cleveland Clinic Taussig Cancer Center, Cleveland, OH. Efficacy and Safety of Sorafenib in Patients with Advanced Clear-Cell Renal-Cell Carcinoma (RCC) with Bone Metastases: Results from the Phase III TARGET Study Abstract 7130, Poster 143, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Dirk Jäger, M.D., National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with Nexavar) Global Non-interventional Study: First interim results. Abstract 7128, Poster 141, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1

Thyroid Cancer

• Marcia Brose, M.D., Ph.D. Department of Medicine, Division of Hematology/Oncology and Department of Otorhinolaryngology: Head and Neck Surgery, Abrahamson Cancer Center of the University of Pennsylvania, Philadelphia, PA, U.S.A. Completion of a Phase II study of sorafenib for advanced thyroid cancer. Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 11 a.m. – 1:00 p.m. Hall 14.1

Highlights of Prescribing Information:

• Sorafenib (Nexavar ®)
• Capecitabine (Xeloda®)

Also read these Pubmed Abstracts:

• Higgins MJ, Forastiere A, Marur S. New directions in the systemic treatment of metastatic thyroid cancer. Oncology (Williston Park). 2009 Aug;23(9):768-75.
• Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs. 2009 Aug;20(7):616-24.
• Hill KL Jr, Lipson AC, Sheehan JM. Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma. J Neurosurg. 2009 Sep;111(3):497-503.
  Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I. Tyrosine kinase blockers: new hope for successful cancer therapy Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. Review.
• Schraml C, Schwenzer NF, Martirosian P, Bitzer M, et al. Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol. 2009 Oct;193(4):W301-7.
• Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):367-72.