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The Lancet Oncology

Monday, July 13, 2009

Erlotinib Improves Overall Survival After Initial Chemotherapy in Patients with Advanced Lung Cancer

Results from SATURN, a pivotal Phase III study, met a key secondary endpoint of extending overall survival in patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib (Tarceva®, Genentech/Roche; OSI) immediately after their initial chemotherapy. A statistically significant improvement in overall survival was seen in the pre-planned final analysis of the total patient population in the study. The new data will be presented during the 13th World Conference on Lung Cancer to be held July 31 – August 4, 2009 in San Francisco.

Lung cancer is the most common cancer worldwide with 1.5 million new cases annually and NSCLC accounts for 85 – 90% of all lung cancers. Non-small cell lung cancer (NSCLC) progresses rapidly and survival rates are generally very poor. Most people are diagnosed with advanced stage disease and less than 5% of these advanced NSCLC patients survive for five years. Extending the time patients live and managing side effects are key treatment goals.

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States. In 2009, approximately 159,000 Americans will die from the disease.
Treating patients immediately following first-line chemotherapy versus waiting for the cancer to grow or spread before giving additional treatment represents a new approach in advanced NSCLC.

A new approach
Erlotinib is, as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor, different from conventional chemotherapies.
Over-expression of EGFR is common in several solid tumors, such as colorectal cancer, lung carcinomas, and cancers of the head and neck. It correlates with increased metastasis, decreased survival and a poor prognosis. EGFR protects malignant tumors cells from the cytotoxic effects of chemotherapy and radiotherapy, making these treatments less effective.

HER1 and EGFR receptors are directly involved in inter-cellular signaling in systems governing cell division and proliferation. By interfering with the function of these receptors, which are highly active and often over-expressed in rapidly dividing tumor cells, erlotinib inhibits EGFR-receptor tyrosine kinase activity, and may help to initiate pathways of apoptotic cell death. The interference with the cell signaling pathways involved in cell proliferation represents a novel approach to the treatment of solid tumors.

Today, erlotinib is the first and only EGFR oral targeted agent in second line with a proven and significant survival and symptom benefit in a broad range of patients with advanced lung cancer without the side effects associated with chemotherapy. The drug has been approved in the EU since September 2005 and in the US since November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Patient benefit
In the landmark registration study BR.21, a randomised controlled phase III clinical trial comparing erlotinib with placebo/best supportive care in patients with locally advanced or metastatic non-small lung cancer which took place in 17 countries around the world, erlotinib delivered effectiveness comparable to chemotherapy and significantly improves overall quality of life.

The registration study underlined that more patients on erlotinib had improvement in cough, pain, shortness of breath and overall physical function versus patients on placebo. In addition erlotinib did not induce the distressing side-effects associated with chemotherapy, such as nausea and vomiting. An added benefit, improving adherence, is that erlotinib is convenient as patients can take a tablet once a day at home rather than receive intravenous treatments in a hospital.

Global trial
SATURN, a global multicentre, double blind, randomized, prospective phase III study was designed to evaluate the efficacy of erlotinib vs. placebo in patients with advanced, recurrent or metastatic NSCLC who had not progressed following first line platinum-based chemotherapy. The study involved more than 880 patients from approximately 160 centers; 438 received erlotinib and 451 placebo.

The study met its primary endpoint demonstrating a statistically significant extension of the time patients live without their disease worsening; there was a 41% increase compared with placebo (hazard ratio= 0.71, p-value <0.0001).>

“This study has now not only confirmed that immediate treatment with Tarceva after initial chemotherapy delayed the progression of disease, but also importantly helped patients in the study live longer,” said Professor Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, Milan and principal investigator of the SATURN study. “This is good news for doctors and their patients since advanced lung cancer is one of the most challenging cancers to treat and is often associated with a very short life-expectancy.”

Commenting on the study, William M. Burns, CEO Division Roche Pharmaceuticals said, “This is the second set of data from large studies that has shown Tarceva helps patients with advanced lung cancer to live longer. These results confirm that Tarceva has an important role to play in improving the lives of patients earlier in the management of this devastating disease.”

Erlotinib is already a well established treatment in second-line management of advanced NSCLC after the failure of chemotherapy and is proven to extend survival for a broad range of patients in this setting. Most recently, presentation of the SATURN primary endpoint data analysis at ASCO 2009 showed that patients who received treatment with erlotinib immediately after initial chemotherapy if their cancer had not progressed had a 41% improvement in the length of time they lived without their disease getting worse compared to placebo.

Outcome confirmed
During the Annual Society of Clinical Oncology (ASCO) Vincent A. Miller, MD., a medical oncologist from the Memorial Sloan-Kettering Cancer Center, presented results from the phase III ATLAS study supported findings in the SATURN study.

The ATLAS study, a global multicentre, randomised, double blind, placebo controlled study that enrolled 1,160 patients with locally advanced, recurrent or metastatic NSCLC, was designed to evaluate bevacizumab (Avastin®, Genentech/Roche) in combination with erlotinib (150 mg daily) versus bevacizumab alone, following bevacizumab in combination with a platin-containing doublet chemotherapy, in patients with stage IIIb/IV NSCLC.

The study showed that combined treatment with bevacizumab and erlotinib, immediately following initial therapy with bevacizumab plus chemotherapy was highly effective and significantly delayed disease progression for patients with advanced NSCLC, without the need for chemotherapy.

The positive results from these trials were encouraging because previous Phase III studies in which erlotinib was used as first-line therapy in combination with cytotoxic drugs (the TRIBUTE and TALENT studies) failed to demonstrate a survival advantage when erlotinib was added to conventional treatment regimens.

The overall survival data fron SATURN will be used to support the European and US applications for use of erlotinib as a first-line maintenance treatment for patients with advanced NSCLC. These applications were made to the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in March 2009 and are based on the pivotal Phase III SATURN trial. The FDA Prescription Drug User Fee Act (PDUFA) review date will be on or about January 18, 2010.

Commenting on the overal product development, Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals, Roche's US partner, said:"We are pleased with the launch of Tarceva in the U.S. to date and we continue to believe that Tarceva will emerge as a fundamentally important new agent in changing the paradigm for the treatment of cancer patients around the world. With our partners, Genentech and Roche, we are committed to executing a post-approval development plan, studying Tarceva in earlier stage lung cancer patients, in patients with other tumor types and combinations with other targeted therapies."

For more information:

ASCO 2009 Annual meeting:

Also read these PubMed abstracts:

Information for your patient:

Images courtesy American Society of Clinical oncology (ASCO)

Sunday, July 12, 2009

Pemetrexed First Agent Approved in Europe as Maintenance Therapy for Advanced, Nonsquamous Non-Small Cell Lung Cancer

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has granted approval for the use of pemetrexed for injection (Alimta ®, Eli Lilly and Company) as monotherapy for maintenance treatment of patients with other than predominantly squamous cell histology in locally-advanced or metastatic non-small cell lung cancer (NSCLC), whose disease has not progressed immediately following platinum-based chemotherapy. This approval is based on data that showed pemetrexed improved overall survival in other than predominantly squamous NSCLC patients in the maintenance setting.

Globally, lung cancer is the most common form of cancer and the biggest killer, causing 1.3 million cancer deaths annually. This is more than breast, colon and prostate cancer taken together. About 85 - 90 percent of all lung cancers are non-small cell lung cancer (NSCLC). Survival rates are very poor.

Major disease forms
Non-small cell lung cancer (NSCLC) is defined as a group of histologies, that is, tumor types differentiated by cellular structure. The most predominant is squamous cell carcinoma (also known as epidermoid carcinoma) which accounts for 30 - 40% of all NSCLC cases. Formed from round cells that replace damaged cells along the epithelium of the main, lobar or segmental bronchi, this disease is a relatively slow growing carcinoma with a relatively good prognosis. Recurrence rates for resected squamous cell carcinoma are relatively low compared top other types of NSCLC, with distant metastases less common given the same treatment at the same stage.

Also referred to as nonsquamous histology, adenocarcinoma, which account for more than half of all NSCLC diagnoses, usually arises from mucus-producing cells of the lung. Aproximately two-thirds of adenocarcinomas develop in the outer regions of the lung, while the remaining one-third develop centrally. The majority of adenocarcinomas are asymptomatic until they have progressed to an advanced stage. As a consequence, the prognosis is generally worse compared to that of squamous cell carcinoma. On the other hand, once diagnosed, adenocarcinomas generally respond better to treatment than other NSCLC histologies.

Squamous cell carcinoma tends to metastasize in the bone, adrenal glands, liver, small intestines and brain. Because this disease is almost always caused by smoking, occurrence has decreased over the past 30 - 35 years.

Other types of NSCLC include bronchoalveolar carcinoma (BAC), a subclassification of adenocarcinoma with distinct clinical and pathologic properties and large cell carcinoma.

The majority of patients with NSCLC eventually develop metastatic disease or disease that is not a candidate for surgical interventions. this makes them potential candidates for systemic therapies. However, the decision on whether a patient receives therapy, greatly depends upon a number of factors, including the disease stage. In general, the more advanced the disease is, the more likely that a physician will prescribe a drug therapy.

Staging of Lung Cancer
Lung Cancer is often classified according to the American Joint Commitee on Cancer (AJCC) TNM staging system, and has five-tier staging, starting at 0 and rising to the severity of stage IV.

The primary T1 tumor, generally smaller than 3 centimeter, is usually easy to define on computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET).

TNM stage T3 tumors include tumors of any size with direct extension into the chest wall, diaphragm, mediastinal pleura or pericardium. Stage T4 tumors invade the mediastinum, great vessels, trachea, oesophagus and vertebral bodies.

Lung cancer in metastatic stage becomes aggressive. In this stage a therapy to shrink tumour size, stabilize the disease and relieve debilitating symptoms, with minimal toxic effects of the drug is required. Pemetrexed is the most promising molecule in that aspect. The drug provides better survival, progression free time and response and has superior tolerability than other cytotoxic drugs used for the same condition.

Mechanism of action
Pemetrexed is a multitargeted antifolate currently approved for first-line treatment of advanced, other than predominantly squamous NSCLC in combination with a platinum-based chemotherapy, and as a single agent in the second-line setting for advanced, other than predominantly squamous NSCLC patients with recurrent disease. Pemetrexed is chemically similar to folic acid and is in the class ofchenotheray drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).

Improve Overall Survival in a Maintenance Setting
The concept of maintenance therapy represents a paradigm shift in the treatment of advanced, other than predominantly squamous NSCLC.
Traditionally, patients who respond to first-line chemotherapy are monitored until the disease recurs and are then treated with a second-line regimen. In maintenance therapy, rather than halting further treatment until disease progression, patients who respond to a first-line therapy are treated immediately with a maintenance regimen.

"The idea behind ALIMTA as maintenance therapy for nonsquamous, non-small cell lung cancer is to treat patients immediately following their initial course of therapy, in an effort to prolong survival," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader at Lilly. "The study that led to this approval was the first that showed improved overall survival in the maintenance setting for NSCLC. This was also the third trial to show the benefit of tailoring ALIMTA treatment to the nonsquamous NSCLC patient population."

Overall survival data for pemetrexed as a maintenance therapy for NSCLC was presented on May 31, 2009, at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) by Chandra P Belani M.D.

The trial compared efficacy with respect to overall survival of pemetrexed plus best supportive care versus placebo plus best supportive care in 663 patients with stage IIIB/IV NSCLC whose disease had not progressed after four cycles of platinum-based induction chemotherapy. Pemetrexed was not included among the induction regimens studied in the maintenance trial. The trial supported two previous studies looking at the use of histology to tailor treatment for patients with advanced, other than predominantly squamous NSCLC.

Patients in the trial were treated with pemetrexed (500 mg/m2 on day one of each 21-day cycle) plus best supportive care or placebo plus best supportive care. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Pemetrexed was initially approved by the FDA in 2004 for the treatment of mesothelioma, with subsequent approval for second-line treatment of NSCLC.

This latest approval for pemetrexed - the fourth in Europe - follows an initial positive opinion issued by the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) on May 29, 2009, and the recent approval by the U.S. Food and Drug Administration (FDA) of pemetrexed for maintenance therapy in advanced, nonsquamous NSCLC patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Apart from the existing approvals in the EU and U.S. for the use of pemetrexed in the treatment of patients with locally-advanced or metastatic other than predominantly squamous NSCLC, pemetrexed is also approved, in combination with cisplatin, in both the EU and U.S. for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

For more information:
Also read these PubMed abstracts:

How to help your patients:

  • Encourage your patients to have an open, honest talk with you. Tell them that they should feel free to ask any question that’s on their mind, no matter how small it might seem. Also, encourage your patients to talk to other healthcare professionals, including nurses, social workers, and other members of the healthcare team.
Patient resources:

Images courtesy American Society of Clinical oncology (ASCO)

Saturday, July 11, 2009

Study Points to Possible Reasons Why African-Americans Fare Worse With Cancer.

Among man and women with sex-specific cancers, including breast, ovarian, and prostate cancer, African Americans have a higher mortality rate than Caucasian. This is the conclusion of an analysis of clinical trial data which implicates biological factors behind worse outcomes for African-Americans.

After analyzing almost 20,000 patient records from the Southwest Oncology Group's (SOG) database of clinical trials finds, the researchers, for the first time, noted potential biological factors as an explanation why African-American patients with sex-specific cancers tend to die earlier than patients of other races. This despite identical medical treatment regimens for all patients involved and enrollment in the same phase III SWOG trials with uniform stage, treatment, and follow-up. Other confounding socioeconomic factors were also controlled.

Breast cancer
In unrelated earlier studies, observed variations in breast cancer survival by racial/ethnic background had been attributed to a number of varying factors, including differences in clinical and pathologic disease features at diagnosis and economic resource inequities that may affect treatment access and quality.

Whether African-American women have biologically more aggressive breast carcinoma compared with women of other races and whether race acts as a significant independent prognostic factor for was a question that for many years remained unanswered. The general consensus was that race could be a surrogate for socioeconomic status (SES). Researchers in often concluded that a mortality deficit for African-American women relative to Caucasian women, was due to greater mortality from noncancer causes among African-Americans. A retrospective literature review in 2002 by Cross et al demonstrated that while socioeconomic factors replaced race as a predictor of worse outcome after women were diagnosed with breast carcinomas, black women generally presented more advanced disease that appeared more aggressive biologically at a younger age compared with white women.

Prostate cancer
Similar racial/ethnic disparities have been observed in prostate cancer rates. Large population-based cross-sectional studies show the highest incidence and mortality rates among African-Americans followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders. In many studies African-Americans men have two- to fivefold increased risk of prostate cancer deaths in comparison to non-Hispanic Whites across all levels of their socioeconomic status (SES). Based on these results, many researchers felt that socioeconomic status alone could account for the greater burden of prostate cancer among African-American men.

Non Sex-specific cancers
Furthermore, various key studies into other major cancers, including non sex-specific cancer such as colon cancer, generally attributed to the disparity in survival in racial/ethnic settings to a number of varying causes, including diagnosis at later disease stage and other unfavorable disease features, inadequate treatment, and socioeconomic factors.

After analyzing the results of the Eastern Cooperative Oncology Group's E3200 trial, Dr Paul Catalano, D.Sc.,of the Harvard School of Public Health and the Dana-Farber Cancer Institute in Boston found that African Americans with metastatic colorectal cancer (MCC) do not fare as well as Caucasians when, in a specific treatment, bevacizumab (Avastin), a targeted vascular endothelial growth factor inhibitor, is added to the FOLFOX regimen.

In analyzing the data accumulated in the trial that included 713 Caucasians and 66 African Americans, Dr. Catalano and colleagues determined that, in the E3200 trial, African Americans had a lower objective response rate - 3% versus 12.5% (P=0.02), a non-significant shorter time of progression-free survival (P=0.08) and a significantly shorter overall survival (10.2 months versus 11.8 months, (P=0.03). They noted that and this difference remained after adjustment for treatment, gender, age and performance status.

Analytical outcome
The SOG analyses for the first time, shows overwhelming evidence pointing to biological or host genetic factors as the potential source of the survival gap between African Americans and Caucasian patients.

Of 19 457 patients registered, 2308 (11.9%, range = 3.9%–21.6%) were African American. After adjustment for prognostic factors, African American race was associated with increased mortality in patients with early-stage premenopausal breast cancer (hazard ratio [HR] for death = 1.41, 95% confidence interval [CI] = 1.10 to 1.82; P = .007), early-stage postmenopausal breast cancer (HR for death = 1.49, 95% CI = 1.28 to 1.73; P < .001), advanced-stage ovarian cancer (HR for death = 1.61, 95% CI = 1.18 to 2.18; P = .002), and advanced-stage prostate cancer (HR for death = 1.21, 95% CI = 1.08 to 1.37; P = .001).

No statistically significant association between race and survival for lung cancer, colon cancer, lymphoma, leukemia, or myeloma was observed. Additional adjustments for socioeconomic status did not substantially change these observations. Ten-year (and median) overall survival rates for African American vs all other patients were 68% (not reached) vs 77% (not reached), respectively, for early-stage, premenopausal breast cancer; 52% (10.2 years) vs 62% (13.5 years) for early-stage, postmenopausal breast cancer; 13% (1.3 years) vs 17% (2.3 years) for advanced ovarian cancer; and 6% (2.2 years) vs 9% (2.7 years) for advanced prostate cancer.

Access to Quality treatment
"When you look at the dialogue about the issue of race and cancer survival that's gone on over the years," says the paper's lead author, Kathy Albain, M.D., a breast and lung cancer specialist at Loyola University's Cardinal Bernardin Cancer Center, "it always seems to come down to general conclusions that African-Americans may in part have poorer access to quality treatment, may be diagnosed in later stages, and may not have the same standard of care delivered as Caucasian patients, leading to a disparity in survival."

The study, published online by the Journal of the National Cancer Institute (JNCI), found that when treatment was uniform and differences in tumor prognostic factors, demographics, and socioeconomic status were controlled, there was in fact no statistically significant difference in survival based on race for a number of other cancers -- lung, colon, lymphoma, leukemia, and multiple myeloma.

"The good news is that for most common cancers," Albain says, "if you get good treatment, your survival is the same regardless of race. But this is not the case for breast, ovarian, and prostate cancers."

Even with good treatment by the same doctors, African-American patients with one of these three cancers faced a significantly higher risk of death than did other patients, ranging from a 21% higher risk for those with prostate cancer to a 61% higher risk for ovarian cancer patients.
The elimination of treatment and socioeconomic factors as the cause of this higher mortality "implicates biology," says study co-author Dawn L. Hershman, M.D., of the Columbia University College of Physicians and Surgeons.

"There may be differences in genetic factors by race that alter the metabolism of chemotherapy drugs or that make cancers more resistant or more aggressive," she adds.

Earlier this year, Hershman, et al published a smaller study that found that, at least with breast cancer, disparities in survival based on race persist even after adjusting for differences in treatment. That study, published in the May 2009 issue of Journal of Clinical Oncology, analyzed data on 634 breast cancer patients.

"Our study of multiple cancers is distinguished from others that have looked at race-based disparities by its size and by the source of its data," says Joseph Unger of the Southwest Oncology Group's Statistical Center, who was statistician and co-author on the new JNCI study.
The study analyzed records from 35 clinical trials - going back as far as 1974 - that had been conducted by the Southwest Oncology Group, an NCI-sponsored cooperative group headquartered at the University of Michigan. Using data from clinical trials, which are already controlled for a range of potentially confounding factors such as differences in diagnosis, treatment, and follow-up, helps throw the remaining factors into sharper relief, according to Frank L. Meyskens, Jr., M.D.

"It's because of the similar way that people are treated on clinical trials that these differences are even detectable," he says. Meyskens is associate chair for Cancer Control and Prevention for the Southwest Oncology Group and director of the University of California-Irvine's Chao Family Comprehensive Cancer Center.

Long term prediction
The urgency of addressing the reasons for racial disparities in outcomes - both sociological and biological - is amplified by another recent study in the Journal of Clinical Oncology. In this study, Benjamin Smith and colleagues predict that cancer incidence among minorities will nearly double in the coming decades, increasing 99% by 2030 compared to an expected 31% increase among whites. Overall, from 2010 to 2030, the percentage of all cancers diagnosed in older adults will increase from 61% to 70%, and the percentage of all cancers diagnosed in minorities will increase from 21% to 28%

Disparities in Cancer Care
In 2008, the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who treat people with cancer, published a ‘Disparities in Cancer Care’ policy statement that recommends a set of strategies designed to address the disparities of cancer care experienced by underserved and minority populations.

The recommendations offered by ASCO suggest that strategies should focus on education, prevention, diagnosis, and treatment and should discuss issues regarding the resources and funding routinely available, talk about misconceptions regarding clinical trials and cancer research, address lack of minority representation among oncologists. The authors of the ASCO policy statement feel that addressing these topics, coupled with improved access to care, are likely to yield improved outcomes for minority cancer patients.

"The elimination of socioeconomic and healthcare access disparities must be a priority in the United States," says Lisa Newman, M.D., director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center. "However, Dr. Albain's landmark study demonstrates that further investigation of race- or ethnicity-associated differences in primary tumor biology is also important."

John Crowley, Ph.D., of the Southwest Oncology Group Statistical Center and Charles A. Coltman, M.D., of the University of Texas Health Science Center were also coauthors of the study, which was funded by the National Cancer Institute.

The Southwest Oncology Group is one of the largest cancer clinical trials cooperative groups, with a network of almost 5,000 physician-researchers practicing at more than 500 institutions, including 19 of the National Cancer Institute-designated cancer centers. The Group is headquartered at the University of Michigan in Ann Arbor, Mich. The Group has an operations office in San Antonio, Texas and a statistical center in Seattle, Washington.

For more information:

Also read these PubMed Abstracts:

Images courtesy American Society of Clinical oncology (ASCO)

Thursday, July 9, 2009

Americans Fear Paying for Cancer Treatment As Much As Dying of the Disease

A recent survey commissioned by The Community Oncology Alliance (COA), a non-profit organization dedicated solely to community oncology, underscores concerns Americans have about the cost of cancer detection and treatment.

While cancer death rates in the U.S. have declined due to earlier detection, the quality of treatment, and the accessibility of cancer care, the American Cancer Society reports that men still have an approximately one in two lifetime risk of developing cancer, with a risk of one in three for women. According to the American Society of Clinical Oncology (ASCO) advances have come with significant increases in the cost of cancer care, which, in the United States, are growing more rapidly than the overall economy. The considerable financial burden for patients and family members is a major concern noted my healthcare professionals.

To address the concerns, the American Society of Clinical Oncology (ASCO) established a Cost of Care Task Force. The Task Force has developed a Guidance Statement on the Cost of Cancer Care which provides a concise overview of the economic issues facing stakeholders in the cancer community. It also recommends that steps be taken to address immediate needs, including recognition that patient-physician discussions regarding the cost of care are an important component of high-quality care, the design of educational and support tools for oncology providers to promote effective communication about costs with patients, and the development of resources to help educate patients about the high cost of cancer care to help guide their decision making regarding treatment options.

Public Concern
The Community Oncology Alliance announced results of a national survey that reveals the inability to pay for cancer care is among the top fears about the disease. Seven out of ten reports being very concerned about paying for cancer treatment if they developed the disease (69%), the same proportion who are very concerned about dying of it (68%). Only the cancer consequences of having a poor quality of life (75%) and being in pain (72%) evoke slightly more concern.

COA commissioned Opinion Research Corporation to survey a statistically representative sample of 1,022 adult Americans 18 years of age or older. The survey was conducted June 26-30, 2009.

The participant speak from experience: 79% of the survey respondents reported having a family member or friend diagnosed with cancer. Other top concerns regarding a cancer diagnosis include being unable to work (61%) and leaving their families in debt (59%).

Lack of confidence
"The need for healthcare reform is especially critical for cancer care," explained Patrick Cobb, M.D., president of COA and managing partner of Hematology-Oncology Centers of the Northern Rockies in Billings, Montana. "The increasing cost of drugs, declining Medicare reimbursement, and current financial crisis have created a 'perfect storm' that jeopardizes community cancer clinics, where most Americans with cancer are treated."

The survey reveals a lack of confidence in the cancer healthcare payment system, including both private insurance plans and the Medicare system. Less than half (45%) believe their private insurance plans would cover the full cost of cancer treatment, while only 25% believe Medicare would cover treatment costs. Only 41% believe they would be covered for care in a community cancer clinic, where 84% of cancer treatment actually occurs.

Cobb continued, "Though the U.S. has the best cancer care delivery system in the world, the system is now in first-stage crisis because Medicare has substantially cut payments for cancer drugs and essential services. Oncologists are spending an inordinate amount of time dealing with patient financial issues, including trying to find ways of navigating the insurance maze and identifying drug and co-payment assistance for patients in need. Community cancer clinics have had to close satellite facilities and cut staff. Smaller clinics are struggling to operate and more will close."

Inability to cover the costs
The survey found that most Americans say they could not afford the typical monthly cost of cancer treatment not covered by insurance plans. Only a third (37%) say they could pay up to $1,000 per month towards their cancer care not covered by insurance plans. And only 16% say they could pay up to $2,500 per month towards cancer care.

"Monthly out-of-pocket costs for cancer care and treatment, not covered by private insurance plans or Medicare, can easily run to $1,000 or more," explained Dr. Cobb. "For many cancer patients, the costs of diagnostic imaging, surgery and expensive cancer medications, especially in the first few months of treatment, can add up to well beyond $2,500 per month."

To pay for cancer care, Americans report they would take a variety of dire steps. Nearly seven out of ten (66%) report they would go on government assistance to pay the cost of cancer treatment. Four out of ten or more would sell their cars (48%) or their homes (38%), would borrow the money (44%) or declare bankruptcy (40%). Fully one third (33%) say they would simply stop the cancer treatment.

Most (85%) of Americans believe a government-run health plan would have significant disadvantages for cancer care, compared to their own current insurance plans. They see higher taxes as the mostly likely disadvantage of a government-run health plan (74%), while more than half cite negative impacts on treatment and quality of care: longer wait for medical appointments (62%), less coverage of expensive cancer medications or treatments (60%), less coverage of cancer detection and diagnostic tests (54%) and lower quality of care in general (56%).

"The need for healthcare reform is especially critical to cancer care," said Ted Okon, executive director of COA. "However, the proposals currently under consideration by Congress and the Administration to reform the healthcare payment system do not take into account the special circumstances and requirements of cancer care. What is needed is a substantive program developed with the involvement of oncologists to enhance the delivery of quality cancer care."

Aggressive Solutions Needed
Recently, H.R. 2872, the "Medicare Quality Cancer Care Demonstration Act of 2009," was introduced into the House of Representatives by U.S. Representatives Artur Davis (D-AL), Steve Israel (D-NY) and Mary Jo Kilroy (D-OH). H.R. 2872 is a bill that will authorize Congress to direct the Centers for Medicare & Medicaid Services (CMS) to implement the Quality Cancer Care Demonstration (QCCD) project. The QCCD, a landmark initiative to transform the payment system for cancer care, will focus on patients covered by Medicare (approximately 45% of cancer patients), involving the collection of data and implementation of a patient-centric program that enhances quality cancer care while controlling costs.

"The Quality Cancer Care Demonstration project offers a means of moving forward immediately, and an architecture for a solution to the current crisis in cancer care," Cobb noted.

Earlier this year, Sen. Arlen Specter (D-PA) introduced into the U.S. Senate S. 1221, "The Medicare Prompt Pay Correction Act," as the companion to the H.R. 1392. Both seek to address problems with Medicare reimbursement for cancer drugs and help alleviate a national problem affecting the delivery of cancer care treatment to patients, almost all of whom are treated in community oncology clinics close to their homes.

In addition to these developments, the Guidance Statement developed by ASCO’s Cost of Care Task Force recommends that the organization will be more involved in the development of policy positions to address the underlying factors contributing to the increased cost of cancer care. Doing so will require a clear understanding of the factors that drive these costs, as well as potential modifications to the current cancer care system to ensure that all Americans have access to high-quality, cost-effective care.

For more information:

Physician Resources:Cursief

Also read the following PubMed abstracts:

How to help your patients:

Wednesday, July 8, 2009

Consensus Panel Sees Little Evidence of a Beneficial Effect from Blood Transfusions

An exhaustive review and analysis of the medical literature by a panel of experts at the 1st International Consensus Conference on Transfusion and Outcomes (ICCTO) held in April 2009 in Phoenix (Arizona, USA) concluded that there is little evidence to support a beneficial effect from the greatest number of blood transfusions currently being given to patients.

The vast majority of studies show an association between red blood cell transfusions and higher rates of complications such as heart attack, stroke, lung injury, infection and kidney failure and death.

The ICCTO conference brought together 15 leading international physicians and scientists in the fields of anesthesiology, intensive care, hematology, oncology, surgery, and patient blood management, and was monitored by the Food and Drug Administration, the American and the Australian Red Cross, the Joint Commission, along with government health officials, and other organizations.

"The results of the conference firmly establish the view that, rather than being a benign procedure, blood transfusion is associated with increased risk of medical complications," said Aryeh Shander, M.D., Chief of the Department of Anesthesiology, Critical Care Medicine, Pain Management and Hyperbaric Medicine at Englewood Hospital and Medical Center in Englewood, NJ and a founding member of the Society for the Advancement of Blood Management (SABM).

A review of available statistical data shows that allogeneic blood transfusion improves outcomes in only 11% of clinical scenarios for patients without trauma or active hemorrhage.

"The evidence tells us to restrict the practice of transfusion and to avoid unnecessarily transplanting stored blood that could harm a patient's recovery," Shander noted.

Transfusion and safety
Safety concerns with blood transfusions initially came to the public's awareness with the realization that infectious agents such as HIV could be transmitted via blood transfusion. Careful screening and testing have resulted in the risk of known infectious agents being transmitted via blood being reduced to extremely low levels. Since then, concern has emerged amongst many in the medical profession that transfusion itself may be a risk factor for adverse patient outcomes. It has been known for some time that blood undergoes many physical and chemical changes during storage, losing its ability to supply oxygen to vital organs and triggering inflammatory and immune reactions when transfused. It is now thought by some that these storage-related problems may result in negative outcomes to patients.

The 1st International Consensus Conference on Transfusion and Outcomes (ICCTO) was organized by two professional medical societies, the USA based Society for the Advancement of Blood Management (SABM) and the international Medical Society for Blood Management (MSBM). Both educational organizations comprise networks of practitioners from a wide variety of medical and scientific disciplines who are dedicated to improving patient outcomes and the advancement of optimal patient blood management in clinical practice through education, cooperation and research. The societies facilitate cooperation among existing and future patient blood management/blood conservation, bloodless medicine and surgery programs as well as enhance the clinical and scientific aspects of transfusion practice.

During the consensus conference leading physicians and scientists from around the world reviewed more than 550 articles and case studies published over the last 13 years. They arrived at a consensus about transfusion and its relation to patient outcomes. The overwhelming majority of evidence supports the view that, rather than being the benign procedure many view it as, blood transfusion is associated with increased risk of infection and medical complications.

Comments Shander. “The time has come for the medical community at large to use patient blood management to improve patient outcomes by avoiding unwarranted and unnecessary blood transfusions.”

Efficacy assessment
Blood transfusion came into medical use decades ago, however, it has never been subject to the same rigorous safety and efficacy assessment process applied today to other drugs and treatments before they are approved for use. This has resulted in a great deal of uncertainty and lack of knowledge among physicians as to whether a patient should or should not be transfused. As a consequence, there is enormous variation in transfusion practice between countries, states within countries, hospitals and even between clinicians within the same institution.

The accepted ‘consensus conference’ process using the RAND-UCLA method was chosen to unravel some of this uncertainty. This method involves a comprehensive review of all published scientific studies on a treatment, after which a panel of experts assesses a series of patient scenarios using the scientific literature to determine whether the treatment has evidence to support that it will improve the patient's outcome.

The 1st International Consensus Conference on Transfusion and Outcomes (ICCTO) panelists also considered what has come to be known as the Bradford Hill Criteria for establishing causation, the process Sir Austin Bradford Hill and Sir Richard Doll used in the 1960s to establish that cigarette smoking caused such diseases as lung cancer and emphysema.

Long term review
The ICCTO literature review searched for all studies on blood transfusion and outcomes published in the last 13 years. 555 studies met study inclusion criteria and were analyzed by each panelist in preparation for the conference.

A great majority of these studies were initiated to investigate the benefits of transfusions, and instead either found no benefit or identified negative outcomes associated with blood transfusions. Only a small minority of clinical scenarios, were associated with suggested improved outcome.

The panel confined this initial ICCTO analysis to stable non-bleeding patients. Approximately sixty percent of the 90 million units collected around the globe each year (14 million units annually in the USA) are given to such patients.

"Given what we now know, donor transfusions should be limited only to surgery patients who are experiencing major bleeding that is difficult to control quickly," said James Isbister, MD, Clinical Professor of Medicine at the University of Sydney, and a founding member of MSBM. "We hope the conference will help all physicians and the public become aware of the many negative outcomes associated with transfusion, and call for blood management strategies to improve patient outcomes."

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Wednesday, July 1, 2009

A New and Advanced Imaging Technique Allows Researchers to Monitor Protein Changes in Mouse Tumors

A new imaging technique can monitor, in living mice, the HER2 protein found in above-normal amounts in many cases of breast cancer as well as some ovarian, prostate and lung cancers. This new approach, once validated in mice and pending further experiments, could provide a real-time noninvasive method for identifying tumors in women who express HER2 and who would be candidates for targeted therapy directed against this protein.

The new technique may also provide real-time information that will help clinicians optimize treatment for individual patients. The study by Kramer-Marek and colleagues, published in the July 2009 issue of The Journal of Nuclear Medicine, was conducted at the National Cancer Institute (NCI) and the National Institute of Biomedical Imaging and Bioengineering, both parts of the National Institutes of Health.

Overexpression of HER2
The HER2 protein is overexpressed in approximately 20 percent to 25 percent of breast cancers. Numerous studies have shown that HER2 is associated with shorter disease-free and overall survival. In breast cancer, HER2 gene amplification was significantly associated with pathologic stage at diagnosis, axillary node involvement, and histologic subtype. In ovarian cancer HER2 has been associated with decreased overall survival and with an increase in relative risk of death.

Tumors that overexpress HER2 are more aggressive and more likely to recur than tumors that do not overexpress the protein. Targeted therapies directed against HER2 can slow or stop the growth of tumors that overexpress it.

Determining HER2
HER2 expression can be determined by any of several methods. The most commonly used methods include Fluorescence in situ hybridization or FISH, which detects gene amplification by measuring the number of copies of the HER2 gene in the nuclei of tumor cells and Immunohistochemistry or IHC, which measures the number of HER2 receptors on the cell surface and therefore detects receptor overexpression.

Chromogenic in situ hybridization or CISH, which measures gene amplification using a light microscope rather than a fluorescent microscope required for FISH and reverse-transcriptase polymerase chain reaction or RT-PCR, which detects HER2 gene amplification are among some other methods of HER2 testing whicj have been used increasingly in clinical studies and may eventually be incorporated into routine practice.

Not Perfect
In 2007, Wolff et al showed that Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) test results can be affected by testing conditions including the use of suboptimally fixed tissue, failure to use specified reagents, deviation from specific instructions, and failure to include appropriate controls. Therefore, in order to increase the accuracy of HER2 testing results, testing should be performed by laboratories with demonstrated aptitude in the specific test requested. Even if tested in these high-end laboratories, expression of HER2 in test samples may still not accurately represent HER2 expression in the tumor as a whole. Moreover, follow-up biopsies are not always routinely performed after the initial diagnosis, and there are no means to evaluate how long a targeted therapy takes to reach its target, how effective it is, and how long its effects last.

In this study, the researchers used an imaging compound that consists of a radioactive atom (fluorine-18) attached to an Affibody molecule, a small protein that binds strongly and specifically to HER2. Affibody molecules are developed by Affibody AB, (Bromma, Sweden), a Swedish biotech company focused on developing next generation products for therapy, diagnostic imaging, and other applications based on its unique proprietary Affibody® molecules and albumin binding technology platforms. The Affibody molecules are much smaller than antibodies and can reach the surface of tumors more easily. The radioactive atom allows the distribution of the Affibody molecules in the body to be analyzed by positron emission tomography (PET) imaging.

The researchers first used the radiolabeled Affibody molecule to visualize tumors that expressed HER2 in mice. The mice were injected under the skin with human breast cancer cells that varied in their levels of HER2 expression, from no expression to very high expression. After three to five weeks, when tumors had formed, the mice were injected with the Affibody molecule and PET images were recorded. The levels of HER2 expression as determined by PET were consistent with the levels measured in surgically removed samples of the same tumors using established laboratory techniques.

To determine whether their method could be used to monitor possible changes in HER2 expression in response to treatment, the team next injected the Affibody molecule into mice with tumors that expressed very high or high levels of HER2 and then treated them with the drug 17-DMAG, which is known to decrease HER2 expression. PET scans were performed before and after 17-DMAG treatment. The researchers found that HER2 levels were reduced by 71 percent in mice with tumors that expressed very high levels of HER2 and by 33 percent in mice with tumors that expressed high levels of HER2 in comparison with mice that did not receive 17-DMAG. The researchers confirmed these reductions by using established laboratory techniques to determine the concentrations of HER2 in the tumors after they were removed from the mice.

"Our work shows that PET imaging using Affibody molecules was sufficiently sensitive to detect a twofold to threefold decrease in HER2 expression," said senior author Jacek Capala, Ph.D., of NCI’s Center for Cancer Research. "Therefore, PET imaging may provide a considerable advantage over current methods. Our technique would allow a better selection of patients for HER2-targeted therapies and also early detection of tumors that either do not respond to or acquire resistance to these therapies."

"This approach might easily be extended to forms of cancer other than breast cancer," Capala continued. "Because Affibody molecules may be selected to target specific cell proteins, similar compounds can be developed to target proteins that are unique to other types of tumors."

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Images courtesy of Affibody AB.

Escalated Dose-Intensified Combined Modality Treatment Shows Survival Benefit In Patients With Early Unfavourable Hodgekin Lymphoma

With more than 7,500 participants from more than 100 European and non-European countries in attendance, the 14th congress of the European Hematology Association (EHA), which was held in Berlin, Germany, from June 4 – 7, 2009, proved record-breaking. The delegates gathered in Berlin to share the most recent developments in hematological research and improvements in care.

The program included sessions on clinical and laboratory hematology and covered all the major hematological subspecialties, including hemato-oncology, red cell disorders, hemostasis, thrombosis, pediatric hematology and transfusion medicine.

The program featured a session, presented by Prof. Peter Borchmann on behalf of the German Hodgkin Study Group / GHSG (abstract number 0553) discussing an analysis of Dose-Intensified Combined Modality Treatment In Patients With Early Unfavourable Hodgekin Lymphoma (HL).

As a result of intensified medical research, Hodgkin's lymphoma has become one of the most curable tumors in adults. Today, about 80% - 90% of patients experience long-term disease free survival (DFS). This is mainly the result of numerous large clinical trials initiated by the German Hodgkin Study Group and other organizations, taking place since the late 1970's, using risk-adapted, highly effective therapy modalities. From the late '70s nearly 15,000 patients have been randomized and treated in these prospectively randomized trials.

Risk Groups
Patients with Hodgkin lymphoma are divided in three risk groups according to the initial staging and additional clinical risk factors: early favorable, early unfavorable and advanced-stage risk groups.

Abstract 0553 (Interim Analysis of the GHSG HD14 Trial for Patients With Early Unfavourable HL) compared the results of the arms of the GHSG HD14 trial. The rational of this trial was to improve the prognosis of patients with early unfavorable disease by comparing the old standard treatment, 4 courses of ABVD (adriamycin, bleomycin, vinblastine, and dacarbacine) followed by localized radiotherapy (30 Gy IF-RT), with a more intensive chemotherapy regimen consisting of 2 cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by 2 cycles of ABVD and the same radiotherapy as in the standard arm.

Treatment-associated toxicities
A previous GHSG trial (GHSG HD11) compared 4 cycles of ABVD with BEACOPP, followed by either 30 or 20 Gy IF-RT. This trial showed no difference with respect to outcomes, and despite excellent initial remission rates, approximately 15% of patients with early unfavorable-stage HL relapsed within 5 years and another 5% suffered from progressive disease. Nevertheless, these good results of the GHSG trials are threatened by treatment-associated toxicities such as infertility, cardiopulmonary toxicity and secondary malignancies.

Improving trial results
The GHSG HD14 trial showed a significantly better outcome in terms of progression-free survival in the more intensive escalated BEACOPP regimen than the standard regimen of 4 cycles of ABVD in patients with early unfavorable Hodgkin's lymphoma (HL).
The study, conducted by the German Hodgkin Study Group (GHSG), included 1645 patients in 346 centres. These patients had early unfavorable Hodgkin's lymphoma, clinical stage 1 or 2 and risk factors, including large mediastinal mass, extranodal disease, high erythrocyte sedimentation rate, and 3 or more areas affected.

Interim analysis
After the third interim analysis with 1127 patients, researchers decided to terminate the GHSD HD14 trial early because of the significantly better outcome for patients treated with BEACOPP compared to ABVD. The interim results showed that progression free survival (PFS) was significantly better for patients treated with the hybrid regimen than for patients treated with 4 courses of ABVD. After 3 years, progression-free survival was observed in 97% of patients in the escalated BEACOPP group and 91% in the ABVD group.

Furthermore, the interim analysis showed freedom from treatment failure to be 95% in the escalated BEACOPP group versus 91% in the ABVD group. Overall, there were more patients with progressive disease, relapse and a higher mortality in those receiving 4 cycles of ABVD. These results prompted the GHSG to adopt a regimen of two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy radiotherapy as the new standard treatment for patients with early unfavorable Hodgkin's lymphoma.

Escalated BEACOPP, compared to standard BEACOPP, uses a higher doses of etoposide (200 vs 100 mg/m2), doxorubicin (35 vs 25 mg/m2), cyclophosphamide (1200 vs 650 mg/m2), with added granulocyte colony-stimulating factor support. Combined with local irradiation, the escalated regimen showed superior disease control compared with ABVD. Patients experienced more hematological adverse events in the escalated BEACOPP group compared to the ABVD group. This included leukopenia (22% vs , including 81%), thrombocytopenia (<1%>

Predisposition to Myeloproliferative Neoplasms
An unrelated presentation by Prof. Nick Cross, Salisbury, United Kingdom, discussed research aimed to understand what causes a group of related conditions known collectively as myeloproliferative neoplasms (abstract number 0555).

Researchers have found a common genetic 'signature' that predisposes to these disorders. The predisposition is relatively subtle and so it cannot by itself be used to predict whether anyone will develop disease or not, but it is an important step towards understanding why some people get cancer and why others do not. In the future it is possible that the abnormality we have found might be combined with other genetic and environmental risk factors to enable much better predictions of disease susceptibility to be made.

Myeloproliferative neoplasms or MPNs are conditions of the blood that are related to leukemia but in effect they are a very mild form that resembles the first steps towards cancer. They are characterised by the overproduction of red and white blood cells, which increases the risk of strokes and heart attacks. Many cases of MPDs are caused by a mutation in a gene called JAK2. When the JAK2 gene has mutated, it sends abnormal messages to the blood stem cells to produce more and more blood cells.

Scientists have found that a particular region of chromosome 9 that carries the JAK2 gene is predisposed to acquiring mutations, but only in individuals with a particular genetic makeup. It is likely that this finding will lead to a much better understanding of how the JAK2 gene mutations happen and why they lead to an increased risk of someone developing an MPD.

The study, carried out at the Wessex Regional Genetics Laboratory in Salisbury and the University of Southampton, has proved that people carrying this mutation-prone region of DNA on chromosome 9 that includes the JAK2 gene have triple the risk of developing an MPD. The chromosome 9 variant is present in 40% of the population in the United Kingdom but only 1 in 20,000 people develop an MPD each year. Nonetheless, the new research has confirmed that the inheritance of this genetic variant can contribute to inherited susceptibility to develop an MPD.The study found that the link was especially strong in polycythaemia vera (PV), one of the main three MPDs.

Professor Nick Cross, from the University of Southampton (University RoadSouthampton SO17 1BJ, United Kingdom, Tel. +44 (0)23 8059 5000, Fax +44 (0)23 8059 3131) who led the research team, said: “This research provides strong evidence that at least half of the cases of PV diagnosed each year are linked to an inherited genetic variant on chromosome 9. Whilst this risk is still very small it nonetheless confirms that individual susceptibility to acquiring cancer-causing mutations is linked to genetic inheritance. Now that we have this evidence we can carry out studies to determine exactly how the variant contributes to this risk.”

Dr Shabih Syed, Scientific Director at UK-based Leukaemia Research who sponsored the reserach, adds: “This is a very important step forward in our knowledge of the causes of myeloproliferative disorders. It helps us to understand why some people might be predisposed to acquiring genetic mutations that lead to cancers.”

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Illustrations courtesy of the European Hematology Association.