Hodgkin’s disease is a type of lymphoma, which compromises the body’s immune system by affecting lymph nodes, lymph tissues, and other entities in the body responsible for fighting infection. According to the American Cancer Society, 8,200 new cases of the disease were diagnosed in the United States last year, with about 1,300 deaths. It is most common in people aged 15 to 40 and in those older than 55. Between 10 and 15 percent of all cases are found in children and teens.

At focus in the study, Phase II Study of Weekly Gemcitabine and Vinorelbine for Children with Recurrent or Refractory Hodgkin’s Disease: A Children’s Oncology Group Report, was a drug combination known as GV (Gemcitabine and Vinorelbine). Previous studies have shown that GV has been well tolerated by adults with breast cancer and non-small cell lung cancer. Investigators found that when children and young adults with Hodgkin’s disease that was recurrent or treatment resistant were administered GV, the response was greater than reported for either drug by itself. Predominant side effects were hematologic in nature and primarily consisted of decreased bone marrow activity, which results in fewer platelets and red and white blood cells.

The research looked at 30 patients with a median age of 17, who were heavily treated in their initial stage of Hodgkin’s disease. A median of five, 21-day cycles of GV was administered to each patient. Results showed 19 of 25 patients had measurable responses, with six having complete response, 11 having a very good partial response and two had a partial response. And while the one-year, event-free and overall survival rates measured 59.5 percent and 86 percent respectively, the study team notes that further evaluation of GV for this population of patients is warranted.

Dr. Drachtman, who is also a professor of pediatrics at UMDNJ-Robert Wood Johnson Medical School, and his study colleagues are part of the Children’s Oncology Group, which is the world’s largest cooperative pediatric cancer research organization.

Along with Drachtman, the author team consists of Peter D. Cole, MD, Albert Einstein College of Medicine, Montefiore Medical Center; Cindy L. Schwartz, MD, Brown Medical School, Hasbro Children’s Hospital; Pedro A. de Alarcon, MD, University of Illinois College of Medicine at Peoria, St. Jude Children’s Research Hospital; Lu Chen, PhD, Children’s Oncology Group; and Tanya M. Trippett, MD, Memorial Sloan-Kettering Cancer Center.

The research, which was presented in part as a poster presentation at the American Society of Hematology Annual Meeting in December 2007, was supported in part by a National Cancer Institute Grant (CA98543) and the Damon Runyon Cancer Research Foundation (CI-16-03).

About The Cancer Institute of New Jersey

The Cancer Institute of New Jersey is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center, and is dedicated to improving the prevention, detection, treatment and care of patients with cancer. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice quite literally bringing research to life. The Cancer Institute of New Jersey is a center of excellence of UMDNJ-Robert Wood Johnson Medical School. To support CINJ, please call the Cancer Institute of New Jersey Foundation at 1-888-333-CINJ.

The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, Jersey Shore University Medical Center. Affiliate Hospitals: Bayshore Community Hospital, CentraState Healthcare System, Cooper University Hospital*, JFK Medical Center, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate.

“I have always viewed healthcare as a fundamental issue of human rights. It is estimated that about one-third of cancers can be cured if detected and treated early,” said Robinson. “It is up to all of us — governments, non-governmental organizations, cancer survivors, all concerned individuals — to see that detection and treatment are offered to as much of the world’s population as possible. Through the LIVESTRONG Global Cancer Summit we will make great strides towards making this a reality.”

Lance Armstrong Foundation President and CEO Doug Ulman said, “Mary Robinson embodies the LIVESTRONG spirit of selfless service and leadership for the sake of positive change in our world. She has been a tireless advocate for issues at the intersection of health and human rights throughout her career — and we share the view that cancer control is at its core an issue of human rights.”

The LIVESTRONG Global Cancer Summit will make the case for urgent action to address the global cancer burden and introduce new commitments for cancer control by bringing together world leaders, corporations, non-governmental organizations and advocates in an unprecedented show of solidarity. Australian Prime Minister Kevin Rudd, Mexican President Felipe Calderon Hinojosa and former U.S. President Bill Clinton are included in the list of leaders expressing support for the Campaign and Summit, along with the Irish government and the Irish Cancer Society. The LAF is also in ongoing conversations with the Kingdom of Jordan and representatives of other nations about substantial new commitments.

Commitments are critical to avoid a looming public health catastrophe. Cancer kills more people every year than AIDS, tuberculosis and malaria combined. It is estimated that cancer will be the leading cause of death worldwide by 2010. However, many governments devote few resources to fighting cancer and collect little information about its causes and effects. The LAF is working with world leaders to focus on developing international partnerships, cancer advocacy, research and data collection.

“In 2010, cancer will be the leading cause of death worldwide. The LIVESTRONG Global Cancer Summit is an invaluable opportunity to stand up for the 28 million cancer survivors worldwide and to create a unified effort to control cancer through new commitments to action. This is not just a job for governments and medical researchers — it’s everyone’s job,” Ulman said.

The secondary purpose of the Summit is to build a global grassroots advocacy movement to influence global action in the fight against cancer. Participation in the Summit is by invitation only. LAF has outlined a commitment process that all world leaders and representatives from non-governmental organizations and corporations are required to complete to be eligible for invitation. For more information about the LIVESTRONG Global Cancer Campaign or the commitment process, visit http://www.LIVESTRONG.org.

Following its successes in Australia, California and Mexico, the LIVESTRONG Global Cancer Campaign will head to Europe for the Giro d’Italia (May 9-31), the Tour de France (July 4-26), the Tour of Ireland (Aug. 19-23) and the LIVESTRONG Global Cancer Summit in Ireland (Aug. 24-26), as well as other locations to be announced soon.

About the Lance Armstrong Foundation

At the Lance Armstrong Foundation, we fight for the 28 million people around the world living with cancer today. There can be — and should be — life after cancer for more people. That’s why we kick in at the moment of diagnosis, giving people the resources and support they need to fight cancer head-on. We find innovative ways to raise awareness, fund research and end the stigma about cancer that many survivors face. We connect people and communities to drive social change, and we call for state, national and world leaders to help fight this disease.

The article describes a screening program to identify women from underserved communities who are at a high risk of developing breast or ovarian cancer; a pilot clinical research initiative sponsored by The Lynne Cohen Cancer Screening and symposium Project for High Risk Women.

Despite the advances in cancer diagnosis, treatment, and survival, racial and ethnic minorities suffer disproportionately from cancer. Ethnic and racial minorities are often less likely to take part in screening programs than Caucasian patients.

The pilot project will constitute the core of a broad-based screening program in New York City and, ultimately, a world class Clinical service targeted to women at high risk for cancer, in particular, women of minority ethnic groups.

Dr Franco M. Muggia, Director of Medical Oncology at NYU’s Langone medical Center will conduct the study at the Kaplan Cancer Center facilities. At Bellevue Hospital, the advanced services will be offered to 75 to 100 women who do not have access to normal medical screenings. Women referred to the program will receive state-of-the-art preventive care and early detection screening.

“Following a detailed family and personal history intake and physical exam, each woman on their initial visit is categorised into low (standard), high, and indeterminate risk groups. Women found to be at high risk of developing breast and/or ovarian cancer were referred for further testing, additional screening measures, or participation in chemoprevention trials” states Muggia.

Often women will not undergo screening procedures because of economic concerns, this program however, is completely free.

Continued and sustained efforts are needed on all fronts (education, practice, and research, policy) to improve the poor cancer-related outcomes for ethnic minorities.

Author:

Franco Muggia: Division of Medical Oncology, NYU Langone Cancer Institute, New York, NY 10016, USA.

ecancer is the online open-access peer-reviewed journal from the European Institute of Oncology in Milan, Italy.

The hollow gold nanospheres developed in the laboratory of Jin Zhang, a professor of chemistry and biochemistry at UCSC, have a unique set of properties, including strong, narrow, and tunable absorption of light. Zhang is collaborating with researchers at the University of Texas M. D. Anderson Cancer Center, who have used the new nanostructures to target tumors for photothermal cancer therapy. They reported good results from preclinical studies earlier this year (Clinical Cancer Research, February 1, 2009).

Zhang described his lab’s work on the hollow gold nanospheres in a talk on Sunday, March 22, at the annual meeting of the American Chemical Society in Salt Lake City.

“What makes this structure special is the combination of the spherical shape, the small size, and the strong absorption in visible and near infrared light,” Zhang said. “The absorption is not only strong, it is also narrow and tunable. All of these properties are important for cancer treatment.”

Zhang’s lab is able to control the synthesis of the hollow gold nanospheres to produce particles with consistent size and optical properties. The hollow particles can be made in sizes ranging from 20 to 70 nanometers in diameter, which is an ideal range for biological applications that require particles to be incorporated into living cells. The optical properties can be tuned by varying the particle size and wall thickness.

In the cancer studies, led by Chun Li of the M. D. Anderson Cancer Center, researchers attached a short peptide to the nanospheres that enabled the particles to bind to tumor cells. After injecting the nanospheres into mice with melanoma, the researchers irradiated the animals’ tumors with near-infrared light from a laser, heating the gold nanospheres and selectively killing the cancer cells to which the particles were bound.

Cancer therapy was not the goal, however, when Zhang’s lab began working several years ago on the synthesis and characterization of hollow gold nanospheres. Zhang has studied a wide range of metal nanostructures to optimize their properties for surface-enhanced Raman scattering (SERS). SERS is a powerful optical technique that can be used for sensitive detection of biological molecules and other applications.

Adam Schwartzberg, then a graduate student in Zhang’s lab at UCSC, initially set out to reproduce work reported by Chinese researchers in 2005. In the process, he perfected the synthesis of the hollow gold nanospheres, then demonstrated and characterized their SERS activity.

“This process is able to produce SERS-active nanoparticles that are significantly smaller than traditional nanoparticle structures used for SERS, providing a sensor element that can be more easily incorporated into cells for localized intracellular measurements,” Schwartzberg, now at UC Berkeley, reported in a 2006 paper published in Analytical Chemistry.

The collaboration with Li began when Zhang heard him speak at a conference about using solid nanoparticles for photothermal cancer therapy. Zhang immediately saw the advantages of the hollow gold nanospheres for this technique. Li uses near-infrared light in the procedure because it provides good tissue penetration. But the solid gold nanoparticles he was using do not absorb near-infrared light efficiently. Zhang told Li he could synthesize hollow gold nanospheres that absorb light most efficiently at precisely the wavelength (800 nanometers) emitted by Li’s near-infrared laser.

“The heat that kills the cancer cells depends on light absorption by the metal nanoparticles, so more efficient absorption of the light is better,” Zhang said. “The hollow gold nanospheres were 50 times more effective than solid gold nanoparticles for light absorption in the near-infrared.”

Zhang’s group has been exploring other nanostructures that can be synthesized using the same techniques. For example, graduate student Tammy Olson has designed hollow double-nanoshell structures of gold and silver, which show enhanced SERS activities compared to the hollow gold nanospheres.

The ability to tune the optical properties of the hollow nanospheres makes them highly versatile, Zhang said. “It is a unique structure that offers true advantages over other nanostructures, so it has a lot of potential,” he said.

Source: Tim Stephens
University of California – Santa Cruz

In an accompanying Reflection and Reaction comment, Karol Sikora (CancerPartnersUK) states that, despite the tripling of investment in cancer care in the UK over the past decade, these findings show that there has been no striking improvement in cancer survival. According to a Leading Edge editorial published with the Article by The Lancet Oncology, the evidence shows that: “We are at best keeping track with improvements elsewhere rather than closing the gap.” The editorial adds that the cancer plan’s stated aim – of having five year cancer survival rates comparable with the best in Europe by 2010 – is looking optimistic.

In 2000, when the NHS cancer plan for England was introduced, Britain had one of the poorest levels of cancer survival in Europe. The plan was designed to improve 5-year survival rates for cancer, so they would compare with the best in Europe by 2010. In Wales there was no comparable cancer initiative until 2006, thus providing an opportunity to compare survival trends in England and Wales and assess the effectiveness of the English cancer plan.

In this study, Michel Coleman from the Cancer Research UK Cancer Survival Group London School of Hygiene and Tropical Medicine in London, UK, and colleagues report the national and regional survival trends in 2•2 million adults diagnosed with 21 common cancers in England and Wales and followed up to 2007. They analysed trends in short-term survival for patients diagnosed before the cancer plan (1996-2000), during initialisation (2001-03), and after implementation (2004-06).

Overall, 1-year survival* improved for most cancers in England and Wales between 1996 and 2006. Findings showed a slightly faster improvement in 1-year survival in Wales than in England between 1996 and 2003, but this was reversed after 2004 when annual trends in survival were more favourable in England than in Wales. For cancers of the stomach, colon, rectum, uterus, ovary, and kidney, survival trends in England improved after 2001, even without screening or the widespread use of effective new treatments. By contrast, bladder cancer, Hodgkin’s lymphoma, and leukaemia all showed a fall in survival.

However, differences in 3-year survival patterns between England and Wales were less obvious, with no difference in survival trends at 3 years or more for patients diagnosed up to 2003, and slightly faster increase in survival in England than in Wales between 2001-03 and 2004-06.The authors also note continued wide regional variation in survival, with more affluent southern regions having generally higher survival than the average survival for England.

They suggest that the improvements in survival trends in England since 2004 might be related to the cancer plan, but caution that it is not known whether the various initiatives in the cancer plan were fully implemented by that time. They conclude by calling for detailed analysis of the effect of more specific measures in the cancer plan, such as shorter waiting times and the creation of multidisciplinary teams, on cancer survival.

Mike Richards, the National Cancer Director for England, questions whether Wales is an appropriate control group for assessing progress in England in a second accompanying Reflection and Reaction comment. He points out that both countries took very similar approaches to cancer control by implementing cancer strategies that have worked at different times. He suggests that the differences in trends between the countries in 2001-03 and 2004-06 reflect Wales moving forward faster in the earlier years as a result of the Cameron report in 1996, and survival improving more quickly in England after 2000 as a result of the cancer plan.

Sikora also argues that the modest improvement in survival is because of: “a whole system fault within the NHS with serial delays, poor access and serious under-capacity.” He concludes: “We need to derive value from cancer services by increasing access and quality but not cost”. The Lancet Oncology editorial concludes that: “Perhaps the time has come to consider rather more fundamental changes to the NHS than are offered in the cancer plan if England is to truly offer world-class healthcare.”

*1-year survival can be considered to reflect early or late diagnosis of cancer, and 3-year and 5-year survival to reflect both early diagnosis and the effect of treatment.

Tony Kirby
Press Officer
The Lancet
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At the same time, FNA is less costly, less invasive, and produces fewer complications. It’s an easier procedure for patients, and it produces results for clinicians more rapidly. These facts have prompted some cancer centers to continue to rely on FNA, especially in cases where tumors are small and palpable, while recognizing the diagnostic method’s limitations.

“The benefits of FNA are that it is easier for the patient, and it produces less pain and less trauma to the breast. The risk of infection is also higher with core biopsy,” said Britt-Marie Ljung, MD, professor of pathology at the University of California, San Francisco, and codirector of the UCSF division of cytopathology.

“If a cytopathologist or pathologist is present at the biopsy, results from an FNA can be available almost immediately, and certainly the same day as the procedure,” Dr. Ljung said. A core biopsy, however, usually requires at least two days for a definitive diagnosis.

In a multidisciplinary team setting, where results can be immediately communicated to a woman’s healthcare team (oncologist, radiologist, surgeon), an FNA diagnosis can mean that treatment planning begins right away, according to Dr. Ljung, who discussed FNA at the 2008 Breast Imaging and Cancer: Multidisciplinary Approach to Breast Cancer Symposium hosted by UCSF.

Faster treatment planning can help reduce worry for patients and streamline medical care, especially in cases that meet the triple test: Clinical, radiographic, and pathology results are concordant.

“For breast cancer, the benefits of FNA are that it is a fast and reliable method,” said medical oncologist Pamela Munster, MD, an associate professor at UCSF and director of early phase clinical trials. “In some situations, core biopsy is not needed.”

While the accuracy of results from core biopsy and FNA are both operator-dependent, the training and expertise of the clinician performing FNA is of special concern, according to Dr. Ljung. Th e presence of a pathologist or cytopathologist reduces the number of insufficient samples and improves accuracy of results. At UCSF, where cytopathologists are closely involved in FNA diagnosis, the false-negative rate is only 2%, Dr. Ljung said.

However, studies of FNA in other settings have found sensitivities that range from 43.8% to 95%, while specific cities ranged from 89.8% to 100%, according to the Diagnostic Cytopathology article. By contrast, studies have found that sensitivities for core biopsy ranged from 94% to 99%, and specific cities from 99% to 100%.

When is FNA most appropriate?
Oncologist Yelena Novik, MD, an assistant professor of medicine at the New York University Cancer Institute, noted that when a woman has a small palpable breast cancer, FNA is an entirely reasonable choice. In these cases, because the tumor is palpable, there’s usually little question of whether it is invasive. “It’s a double win: The patient gets a procedure that’s less painful and less invasive, and the surgeon gets the most important information rapidly,” she said.

Yet in cases where in situ disease is suspected, core biopsy would be preferred. The same is true for cases in which a woman presents with a larger palpable lump. In these cases, it’s possible that the patient will need neoadjuvant therapy before surgery, such as chemotherapy or hormonal therapy. Her breast tissue needs to be tested for estrogen and progesterone receptors as well as HER2 status in order to choose the best treatment. “In these cases, a core biopsy is in the best interest of the patient because it gets a bigger piece of tissue and the pathologist has more material to work with,” Dr. Novick said.

“The biggest shortcoming of FNA is biological and not anatomical,” explained Baljit Singh, MD, director of breast pathology at NYU. “Treatment options today are essentially a function of a tumor’s receptor status, and all these are assessed by immunohistochemical stains on invasive cancer. While immunohistochemical stains can be done on FNA smears, the techniques are not developed or standardized at most labs, including commercial labs.”

However, Dr. Ljung explained that if cell blocks are prepared from FNA material, which is routinely done at UCSF, receptor and HER2-neu status can be assessed with routine techniques standardized for histopathology specimens.

Dr. Singh emphasized that it’s important that FNA be done when it’s appropriate and in a multidisciplinary setting, where the triple test can easily be applied. If the clinical, radiological, and pathological exams all agree, there’s little question about a woman’s treatment aft er FNA of a small palpable mass. Yet if the triple test is discordant, a more invasive procedure is usually necessary. “With a multidisciplinary team that applies the triple test, there’s much less risk of a false diagnosis,” Dr. Singh said.

Fine-needle aspiration for soft-tissue metastases
At the same time, FNA can also be a good choice for metastatic disease in patients with breast cancer, according to Dr. Ljung. “FNA is very effective in sampling suspicious masses in the supraclavicular neck and axillary area, in addition to local recurrence in the breast and chest wall and some distant body sites,” she said. John W. Park, MD, associate professor of medicine and attending medical oncologist at the University of California, San Francisco, noted that there’s been an increasing trend to use FNA when breast cancer has metastasized to the lung, liver, and other soft -tissue sites. But that’s not a hard and fast rule. Whether FNA is used is dependent on the site as well as clinical and radiographic findings about the tumor, he said.

FNA does not usually require sophisticated equipment or image guidance and is thus less costly. Because a smaller needle is used, it causes less trauma to the breast and is an obvious benefit for patients—especially when their tumors are small or look like they may be cysts. Dr. Ljung noted that 80% to 90% of all breast lumps are benign, so FNA can be a good choice when there’s reason to suspect no malignancy. In these cases, FNA can provide a speedier answer for a woman undergoing biopsy, and an easier recovery. “And if the woman has to undergo another biopsy down the line, she is less likely to be fearful about it,” she said.

In the end, however, whether an FNA is used for breast biopsy is a matter of performing a cost-benefit analysis. Which type of biopsy is more likely to serve the patient and improve outcomes? “It’s a more patient-friendly procedure, and thus has some advantages, but it’s not necessarily appropriate in all cases,” Dr. Park said.

Anthracycline cardiotoxicity has been of clinical concern for more than 3 decades. Many hundreds of papers have been written about this unusual form of toxic cardiomyopathy, and yet, we are still putting pieces of the puzzle together. Our cumulative knowledge helps us to predict the risk of cardiac damage with fair accuracy for most patients, but others demonstrate an unpredictable sensitivity to anthracyclines and suffer devastating consequences. Strategies to prevent anthracycline cardiotoxicity have been developed but are underutilized.

Then, just as we thought we had reached a plateau in our knowledge base, new agents entered the scene, and we are now challenged by complex interactions between these agents and the anthracyclines. While evolving treatment strategies may someday render anthracyclines less essential (perhaps presaged by the Breast Cancer International Research Group [BCIRG] 006 results),[1] for a variety of cancers the proven oncologic efficacy of anthracyclines remains robust. The timely review by Hershman and Shao in this issue of ONCOLOGY adds perspective with regard to breast cancer, but the quandary of anthracycline cardiotoxicity is still with us, and is likely to remain so for the foreseeable future.

Cumulative Damage
Anthracycline cardiotoxicity might be more understandable if it could be recognized in its early stages, and if it consistently produced the same degree of cardiac dysfunction in all exposed patients. The unfortunate limitation of trying to use ejection fraction to monitor patients during treatment is that systolic dysfunction is a late finding, and substantial irreversible damage on the cellular level has already occurred by the time decreases in ejection fraction are appreciated. By then, we have missed our window of opportunity to use preventive measures.

The fact that anthracycline cardiotoxicity is cumulative-dose–related suggests that damage starts with the first administration, and additional exposure—as far as the heart is concerned—is an additive stress. Indeed, data from endomyocardial biopsies has confirmed cell death at cumulative dosages below those associated with ejection fraction decreases.

In the modern era of cardiac imaging and biomarkers, it should be possible to recognize early toxicity noninvasively, but we have not yet reached that juncture. Progress is being made on this front: In a study of 204 patients, early increase in troponin?I was found to significantly predict a drop in left-ventricular ejection fraction at 7 months.[2] Given what we now know about the pathophysiology, it seems increasingly likely that acute manifestations of anthracycline cardiotoxicity are directly and causally linked to the late cardiomyopathy that previously had been thought of as a separate entity. Even with this knowledge, problems remain.

More Sensitive Detection Techniques
After the myocyte insult occurs, subtle changes in cardiac performance and hemodynamics gradually ensue. This may provide an opportunity for early detection prior to the onset of symptoms or frank systolic dysfunction. Echocardiography is able to detect several parameters of left-ventricular dysfunction beyond ejection fraction. Indeed, diastolic function and indirect measurements of elevated left-atrial pressure that generally precede a fall in systolic function in a variety of conditions can be detected.

Yet, how are we to use these more sensitive techniques? If we limit anthracyclines in those with any marker for toxicity, are we compromising the oncologic treatment? Newer nonanthracycline regimens make this less likely for some tumors, but the concern still exists. Perhaps the most useful scenario would be to institute cardioprotection earlier for the high-risk or compromised patient identified by early-detection techniques.

Complicating Factors
Part of the problem, of course, is that doxorubicin does not affect all hearts equally, and notwithstanding the tremendous strides made in the early recognition of cardiac damage, early toxicity is often silent. These facts conspire to confuse us and give us a false level of security with regard to some of our patients.

Our dilemma is in recognizing that the cardiotoxicity taking place is, at least in part, related to the considerable cardiac reserves, without which we could not run marathons, and perhaps would have difficulty living at high altitudes. After more than 30 years, our current tools for assessing toxicity still incorporate a decline in ejection fraction to an abnormal value or a decrease in the ejection fraction compared with the baseline level. It is now known that in cases of subclinical cardiotoxicity, the heart compensates, and that changes in the ejection fraction do not reflect this early compensation. Only when sufficient damage has taken place do we see declines in the ejection fraction, and this may be a relatively late sequela of the initial damage.

This helps to explain why traditional cardiac risk factors increase the likelihood of anthracycline-related damage. Conditions such as advancing age, hypertension, and diabetes (all associated with increased left-ventricular wall stress and elevated filling pressures) have necessitated tapping into those cardiac reserves, thus leaving the heart more vulnerable to any additional insult, including anthracycline administration.

Anthracycline-Trastuzumab Interactions
The interaction of anthracyclines with other breast cancer agents such as trastuzumab (Herceptin) adds yet another layer of complexity. By itself, trastuzumab causes a cardiomyopathy that appears to be fundamentally different from that of anthracyclines; there is no relationship with cumulative dose, there are minimal pathologic changes by electron microscopy, and cardiac dysfunction is largely reversible.[3] Unfortunately, the clinical manifestations of congestive heart failure or decreased ejection fraction are indistinguishable from those caused by doxorubicin. Algorithms for dealing with this on a practical level involve serial imaging studies and are probably overly conservative, but are based on the clinical trials that included both agents.

As Hershman and Shao note, the trastuzumab interaction is unique in its mechanism. Trastuzumab appears to prevent the myocyte’s adaptive response to and repair of anthracycline injury. This explains why trastuzumab, in the absence of anthracycline, is generally benign, but when given concurrently with anthracyclines, markedly increases the risk of cardiomyopathy.[4] Analysis of the adjuvant trastuzumab trials further suggests that the timing between anthracycline and trastuzumab administration also may be a factor in the expression of cardiotoxicity.

The incidence of congestive heart failure in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31[5] and BCIRG 006[1] trials (both gave trastuzumab 21 days postanthracycline) was 4% and 2%, respectively. The HERceptin Adjuvant (HERA) trial (89 days between agents) reported an incidence of 0.6%.[6] In the smaller Finland Herceptin (FinHer) trial, trastuzumab was given prior to anthracycline, and the incidence of heart failure was 0%.[7] Flushing out these types of interactions will be an important component of minimizing anthracycline toxicity, especially as a multitude of newer agents become available.

Conclusions
In the end, we can safely treat the majority of our patients with anthracyclines by assessing their pretreatment risk, monitoring them during their treatment, and incorporating strategies to mitigate toxicity for higher-risk individuals or those in whom a greater anthracycline dose is essential. For the present, anthracyclines remain an integral part of the oncologic armamentarium. The common goal of oncologists and cardiologists must be to optimize cancer survival; we strive to kill the cancer while at the same time minimizing the destruction of myocytes and the dysfunction of cardiac contractile elements.

We are not there yet, but we are making progress. For now, and for these reasons, we remain highly interested in the clinical spectrum of anthracycline cardiotoxicity.

Classification of Anthracycline-Induced Toxicity
As described by Hershman and Shao, AIC can be categorized as three distinct types: acute, early, and late. Acute AIC, occurring during the anthracycline infusion or within 1 week of therapy, is rare and reversible. It may present as transient arrhythmia, a pericarditis-myocarditis syndrome, or acute failure of the left ventricle.[6-8] Delayed AIC typically presents as a cardiomyopathy and has been reported in approximately 5% of patients.[9,10] It is classified as early subacute cardiotoxicity occurring < 1 year or late cardiotoxicity occurring > 1 year after the cessation of chemotherapy.[11] Late cardiotoxicity may not be apparent until years to decades after the administration of anthracyclines.[11,12] Patients typically have reduced left-ventricular mass, mass index, and ventricular compliance, with increasing susceptibility to cardiac stressors.[13] The majority of patients who develop early subacute cardiotoxicity will manifest late cardiotoxicity.[11,14]

While numerous studies have reported late AIC in patients exposed to the drug during childhood, the incidence in the adult population has been difficult to determine, as follow-up time and cardiac monitoring are inadequate in most clinical trials. Our group reported long-term AIC in 32 of 85 patients treated with sequential dose-dense and dose-intense doxorubicin, paclitaxel, and cyclophosphamide (ATC).[15] At a median follow-up of 7 years, the median absolute change in left-ventricular ejection fraction (LVEF), measured by multigated acquisition (MUGA) from baseline was 5.5%, and from the end of chemotherapy was ?2.0%. Four patients (12%) had an LVEF < 50%; two of the four patients had an LVEF < 50% at the end of chemotherapy. We concluded from this study that late asymptomatic decline in cardiac function is uncommon, and does not appear to significantly contribute to the morbidity or mortality of the regimen.

Monitoring of Cardiac Function
As Hershman and Shao note, echocardiogram (ECHO) and MUGA scans are standard methods used to monitor AIC. The authors refer to the limited applicability of MUGA scan for frequent monitoring as a result of cumulative radiation exposure; however, when a precisely reproducible measurement is required for patient management decisions or clinical trial monitoring, MUGA may be the method of choice.[16]

Serial MUGA assessments of LVEF vary between 2% and 4%, whereas serial ECHO assessments of LVEF vary between 13% and 17%. Several studies have reported a decrease in LVEF >?10 points from baseline or a fall below the institutional lower limit of normal as indicative of AIC.[17-20] However, such a drop is a late event and would not be detectable until significant cardiac damage has occurred.[21] Therefore, alternative methods of cardiac monitoring are being evaluated.

As described by Hershman and Shao, magnetic resonance imaging (MRI) is an alternative method used for assessment of myocardial function, perfusion, and tissue characterization. However, long-term data to support its use in this setting are lacking, especially with the limited availability of this technology.[22] Another modality under investigation is tissue doppler imaging (TDI), which allows the measurement of diastolic and systolic velocities of the ventricular walls and mitral annulus, and appears to be more reliable and less affected by loading conditions than conventional Doppler.[23] In a study by Tassan-Mangina et al, TDI confirmed the occurrence of early diastolic and late systolic impairment of left-ventricular function following moderate-dose anthracycline therapy.[23]

Hershman and Shao refer to troponin T and B-type natriuretic peptide (BNP) as potential biomarkers for earlier detection of cardiotoxicity. BNP levels were monitored for a small number of patients with acute leukemia treated with a daunorubicin-containing regimen; those who had abnormal BNP levels during subsequent stem-cell transplant developed heart failure, whereas those who had normal BNP levels did not.[24] Troponin levels were measured in 211 patients with breast cancer receiving high-dose therapy; abnormal levels predicted the development of future LVEF depression in a 12-month follow-up.[25]

Cardiac Risk Assessment and Management Recommendations
Although anthracyclines have served as the mainstay of effective cytotoxic therapy for breast cancer during the past 30 years, AIC remains a concern. Therefore, better methods for prevention, monitoring, and management of AIC are needed. When making treatment recommendations for breast cancer patients—especially those with early-stage disease—the presence of cardiac risk factors and strong cardiac family history need to be considered. Treatable cardiac risk factors such as hypetension, hyperlipidemia, and diabetes should be closely monitored and managed in an attempt to prevent additional cardiac injury.

In addition, long-term follow-up is needed to identify patients with subclinical late cardiac dysfunction, who may be at a higher risk for subsequent cardiac events. Patients with preexisting cardiac disease and poorly controlled risk factors may consider treatment with alternative non-anthracycline regimens with reported lower risk of cardiotoxicity.

As mentioned by Hershman and Shao, non-anthracycline-containing regimens have been evaluated for treatment of patients with early-stage breast cancer.[26,27] These non-anthracycline regimens appear to be comparable in efficacy and less cardiotoxic than the anthracycline regimens. While relatively short follow-up has been reported for these regimens, at very least they provide an alternative for breast cancer patients with a history of cardiac disease or cardiac risk factors. These nonanthracycline regimens should be discussed with patients as an alternative treatment, with acknowledgment of the relatively short duration of follow-up.

Finally, the potential for delayed cardiotoxicity should continue to be evaluated in adjuvant and neoadjuvant clinical trials, particularly in light of the recent advances with dose-dense therapy as well as with adjuvant trastuzumab (Herceptin).

However, despite Medicare reimbursement in the United States for specific clinical settings, the clinical impact of PET/CT imaging has not been as significant in breast cancer as in other malignancies. In that context, the article by Almubarak, Osman, Marano, and Abraham provides a timely review of the topic. The authors essentially conclude that while the role of [18F]-fluorodeoxyglucose (FDG)-PET/CT imaging is limited in the initial diagnosis and staging of breast cancer, this modality can be useful in detecting suspected recurrence, assessing for distant metastases, and measuring treatment response to chemotherapy.

Importance of Early Detection
Breast cancer is a common cancer that will afflict one out of nine women during their lifetime. Although breast cancer has a high cure rate when detected early, metastatic breast cancer remains an incurable disease, which can be managed by a variety of relatively effective therapies, but with the eventual development of resistance and disease progression.

Mammography is credited with earlier detection and improved survival of women with breast cancer.[1] Because of the limited specificity of this test in some cases, many investigators are looking into second-line imaging techniques to avoid performing invasive procedures for diagnosis. Given the high accuracy and low morbidity of the various breast biopsy techniques, imaging tools would need to be highly accurate to influence management in this setting.

As pointed out by Almubarak and colleagues, PET imaging suffers from a lack of sensitivity for small breast tumors with a diameter less than 1 cm. In addition, some large tumors can be missed because of their low incorporation of FDG. Even relatively large lobular carcinomas and some estrogen receptor–sensitive breast cancers, for example, can sometimes have a very low FDG uptake,[2,3] and the sensitivity of FDG-PET imaging to detect axillary metastases with this histology is much lower than for invasive ductal carcinoma.[4]

Sensitivity vs Specificity
Conversely, since mammography is not highly sensitive either, tools such as magnetic resonance imaging (MRI) and positron-emission tomography (PET) have also been considered for screening high-risk women, particularly those with dense breasts. Although highly sensitive, MRI suffers from a lack of specificity, resulting in positive predictive values as low as 17% in this setting,[5] leading to many biopsies, which can create a strain on the capacity of breast imaging departments.

In this context, PET instruments with the capacity to detect very small tumors in the breast do exist (“positron emission mammography”).[6,7] However, given the close relationship between FDG uptake and tumor biology, as noted by Almubarak et al, it is possible and even likely that some breast cancers will be missed because of low FDG uptake.

An ongoing study scheduled for completion this year should provide further information on the potential benefits of this technology compared to MRI (clinicaltrials.org study #NCT00484614). Further studies are needed in this setting, and perhaps new radiopharmaceuticals will improve the accuracy of positron-emission tomography for the detection of primary breast cancer.

Role of PET
It is fair to say that at this stage, there is no clinical indication for the routine use of PET in the initial diagnosis of breast cancer. Due to its ability to evaluate breast tumor biochemistry, PET imaging may well provide additional prognostic data for women with breast cancer, but whether this information will be complementary or redundant to immunohistochemical findings and other molecular markers of poor prognosis from paraffin-embedded or frozen biopsy specimens remains to be established in the clinical setting.

Likewise, given the low morbidity and high accuracy of sentinel lymph node biopsy for the detection of axillary nodal metastases, there is no indication to perform PET or PET/CT imaging for axillary nodal staging. PET imaging is simply not sufficiently sensitive to detect nodal metastases in clinically negative axillae.[4,8] For detection of distant metastases in untreated patients, PET imaging is more accurate than other conventional imaging modalities, but the cost-effectiveness of using this procedure on a routine basis is not likely to be favorable.

PET/CT is perhaps best reserved for cases with equivocal conventional imaging results when the detection of distant metastases would alter management. PET/CT might be useful when selectively used in staging aggressive lesions such as triple-negative breast cancers, but further studies on this topic will be necessary. The uptake of FDG in primary tumors has been linked with tumor grade[2] and the presence of axillary or distant metastases.[9] Triple-negative tumors also tend to have higher FDG uptake.[10] A recent retrospective study conducted in women with inflammatory breast cancer showed that PET/CT imaging detected distant metastasis in 49% of cases, many of which were not detected by conventional staging.[11]

Troubleshooting Niche
There are certainly data in the literature to suggest that FDG-PET imaging is useful in restaging patients with a newly suspected recurrence based on clinical, laboratory, or radiologic findings. The detection of distant metastases in this setting can alter management, as local recurrence would be treated aggressively with surgery and/or radiation, whereas systemic treatment would be altered in the presence of metastatic disease.

Given the high clinical impact of PET imaging in the management of patients with recurrent breast cancer,[12] this tool fills a niche in troubleshooting many complex cases where recurrence is suspected clinically while conventional imaging remains negative or equivocal. Demonstrating this benefit in a prospective clinical trial remains difficult in light of the biologic heterogeneity of breast cancer and the number of treatment options that can be offered in various clinical scenarios. Although somewhat limited in high-quality prospective studies, current data support the selective use of PET/CT imaging in the diagnosis of recurrent breast cancer when the results are reasonably expected to affect clinical management.

Assessing Response to Therapy
PET imaging can provide faster assessment of disease response to therapy. A PET scan performed after three cycles of chemotherapy is predictive of survival, as shown in some studies in the neoadjuvant[13] and metastatic settings.[14] This approach may reduce unnecessary treatments that may carry the risk of significant toxicity despite limited benefits to women with resistant cancers. It may also provide a quick surrogate indicator of response in clinical trials for the evaluation of new drugs.

In clinical practice, whether interventions guided by PET imaging translate into improved outcomes—ie, reduced toxicity and/or improved survival compared to traditional clinical and conventional imaging response assessment methods—will remain debated until large scale, well designed prospective studies address this question.[8] The lack of a definite cure for metastatic breast cancer creates challenges in identifying measurable endpoints for the use of imaging techniques in patients who are likely to be subjected to multiple rounds of diverse diagnostic and therapeutic procedures over several years.

Macclesfield, UK, Friday 13 March 2009: A new analysis of the ATAC (ARIMIDEX, Tamoxifen, Alone or in Combination) trial, presented today at the 11th International St Gallen Oncology Conference, Switzerland, shows that during the first two years after surgery, anastrozole is superior to tamoxifen at reducing the risk of breast cancer returning in postmenopausal women with hormone receptor positive early breast cancer (n=5,216).1 Anastrozole has consistently demonstrated superiority over tamoxifen, both during the five-year treatment period and beyond treatment completion.2 This latest analysis provides further reassurance that prescribing anastrozole from the start protects women in the crucial first two years when the risk of recurrence is highest, meaning that fewer patients have to be told the devastating news that their breast cancer has returned.

When breast cancer returns, particularly outside the breast at distant sites such as bone, liver or lung, it is no longer curable. Therefore protecting women from recurrence is the number one priority for doctors and is imperative to saving lives. Although the risk of recurrence can persist for up to at least 15 years,3 the risk is at its greatest within the first two years following surgery, as seen in the ATAC study where over half of all excess recurrences and deaths among patients taking tamoxifen occurred in the first two and a half years.2

This latest analysis confirms that in women who benefit from treatment with AIs (84% of the total ATAC population) anastrozole is even more effective at preventing all types of early recurrence (32%; 2 years post surgery) than previously seen in the broader study population (17%; 2.5 years post surgery).1

Professor Howell continued, “It is now standard practice to assess the hormone receptor status of breast tumours to guide the best course of treatment. ATAC is a ground breaking study which has led to a significant change in treatment strategies in breast cancer with aromatase inhibitors, such as anastrozole, now replacing tamoxifen as the standard of care for postmenopausal women with hormone receptor positive disease in many countries. These new findings confirm that in the women who receive it in routine clinical practice, anastrozole offers reassuring protection against their cancer returning at the time of greatest risk, giving women the best chance of continuing their lives cancer-free.”

The ATAC trial is one of the world’s largest and longest-running clinical studies in postmenopausal women with early breast cancer. With a median follow-up of 100 months – significantly longer than any other adjuvant AI trial – ATAC provides further information on the safety profile of anastrozole which remains predictable, with no long-term safety concerns. As a result of the weight of efficacy and safety evidence for anastrozole, it is now the most widely prescribed AI worldwide, with over twice as many prescriptions as the next most widely prescribed AI and over 4 million patient years’ experience.4 These new data will offer doctors treating hormone receptor positive postmenopausal early breast cancer further confidence that initial treatment with anastrozole offers women the best chance of staying recurrence free.

Anastrozole offers sustained protection against recurrence, demonstrating significantly superior disease free survival, time to recurrence, time to distant metastases and reduced incidence of contralateral breast cancer compared with tamoxifen – a benefit which increases over time and persists even after treatment ends.2

In ATAC, there were fewer recurrences in women with hormone receptor positive breast cancer treated with anastrozole (n= 2,618) than tamoxifen (n=2,598) at 2, 5 and 9 years post-surgery (91 vs 133; 245 vs 312; 385 vs 488 respectively).1

At a median follow-up of 2 years, compared to tamoxifen, anastrozole:1

- reduces the risk of all recurrences by 32% (HR 0.68 [0.52-0.88])
- reduces the risk of distant metastases by 21% (HR 0.79 [0.58-1.07])
- reduces the incidence of contralateral breast cancer by 78%.

ATAC Trial

The ARIMIDEX, Tamoxifen, Alone or in Combination (ATAC) trial is one of the world’s largest and longest-running clinical studies in postmenopausal women with early breast cancer. ATAC is designed to investigate the comparative efficacy and tolerability of two adjuvant therapies: ARIMIDEX (anastrozole) and tamoxifen.

This analysis of ATAC reinforces the significant superiority of ARIMIDEX over tamoxifen at reducing the risk of breast cancer returning (also known as ‘recurrence’) in postmenopausal women with hormone receptor positive early disease.1 The ATAC data also show that, even approximately four years after treatment completion, the absolute reduction in the risk of disease recurrence continues to increase with ARIMIDEX compared with tamoxifen.2

AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world’s leading pharmaceutical companies with healthcare sales of $26.47 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4 Good Index. http://www.astrazeneca.com

ARIMIDEX (anastrozole) is a trademark, the property of the AstraZeneca group of companies.

References

1. Howell A, Forbes J, Cuzick J et al. Initial adjuvant therapy with anastrozole – early and late event data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial in the hormone-responsive population. St Gallen 2009 Poster

2. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14(10): 2738-46

3. ATAC Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45-53

4. AstraZeneca IMS data on file