June 2009
Odds and Ends
An ESUN Resource
Oncolytics Biotech Present Positive Phase II Sarcoma Trial Results at ASCO Annual Meeting
On May 30th, Oncolytics Biotech Inc. announced interim results of a Phase II study of intravenous REOLYSIN® in patients with sarcomas metastatic to the lung. The results were presented at the American Society of Clinical Oncology (ASCO) annual meeting. The presentation, entitled "A Phase II Study of Intravenous REOLYSIN (Wild-type Reovirus) in the Treatment of Patients with Bone and Soft Tissue Sarcomas Metastatic to the Lung" was delivered by Dr. Monica Mita, the study’s principal investigator at the Institute of Drug Development (IDD), the Cancer Therapy and Research Center at the University of Texas Health Science Center (UTHSC), San Antonio, Texas.
The interim results demonstrated that the treatment has been well tolerated, with 15 of 36, or 42% of evaluable patients experiencing stable disease (SD) for more than 16 weeks, including five patients who have had SD for more than 24 weeks. One patient had SD for more than 80 weeks. Oncolytics reported on May 12, 2009, that full enrolment of 52 patients was completed, at which time nine patients were continuing on study. "The ASCO data are very encouraging, both in terms of efficacy in patients with sarcoma, and in those with other tumor histologies in whom the IDD group are investigating various REOLYSIN regimens," said Dr. Frank Giles, Director, IDD, and Deputy Director, CTRC at UTHSCSA.
Novel cancer gene accelerates or stops tumor growth
Researchers at the Hospital for Sick Children and the University of Toronto have found a gene that plays a crucial role in the development of rhabdomyosarcoma. The gene is called integrin-linked kinase (ILK) and is unique in that it can act as both a tumor suppressor and a tumor promoter. The study is published in the June issue of The Journal of Clinical Investigation.
Rhabdomyosarcoma (RMS) comes in two forms: embryonal RMS and alveolar RMS. Scientists have found that in patients with embryonal RMS, the ILK gene acted like the brakes and high levels of ILK suppressed tumor growth. However, in patients with alveolar RMS, ILK acted like the gas pedal, promoting the growth of tumors. “Think of tumor growth as a car; most genes either act to drive the growth, or to put the brakes on it. We were surprised to find that in patients who had different types of rhabdomyosarcoma, ILK could act as either the brake pedal or the accelerator," said Dr. David Malkin, a professor in the Department of Paediatrics at the University of Toronto, pediatric oncologist and senior scientist at the Hospital for Sick Children.
"Having found that ILK could act both as a tumor suppressor and a promoter, we needed to find out what was causing the gene to change its behaviour," said Adam Durbin, lead author of the study and a University of Toronto MD/PhD student. "We determined that it must be something that ILK was communicating with." The researchers found the culprit was another protein in the cell called JNK1 (pronounced "Junk-1"), which can act to control cell growth and cell death. The scientists determined that the levels of this protein dictated whether the ILK gene acted like the gas pedal or the brakes.
By understanding the mechanism behind this interaction, the scientists hope to be able to improve treatment options for RMS patients. In their study, the scientists found the gas pedal could be destroyed by knocking out the gene using genetic manipulation in mice. The researchers say new drug treatments for RMS may not be too far off in the future. There are drugs in early clinical trials that are currently being tested for their ability to turn off or inhibit ILK in other cancers. However to turn on ILK, new drugs would need to be developed. "A significant element of this study is that ILK is not unique to RMS; this gene is found in many other types of cancers," said Malkin. "The key would be to try to find the right way to kill the gas pedal and not the brakes."
Lifelong Cancer Incidence in 47,697 Patients Treated for Childhood Cancer in the Nordic Countries
The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. In this study, the authors obtained a cohort of 47,697 children and adolescents aged 0–19 years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943–2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). They used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. They also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. The results were as follows: A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60–69 years. For children treated in the prechemotherapy era (1943–1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975–2005). The authors conclude: Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.
A Pilot Study Evaluating the Safety and Efficacy of Modafinil for Cancer-Related Fatigue
Fatigue is a common symptom that lowers the quality of life of patients with cancer, affecting between 60% and 90% of patients. Relatively few options are available for the treatment of this debilitating condition. Modafinil, a psychostimulant developed for the treatment of narcolepsy, has been used to treat fatigue in other diseases such as multiple sclerosis, but little data support its use in cancer patients. The primary objective of this open-label pilot study was to evaluate the safety, and efficacy of modafinil in improving cancer-related fatigue (CRF) as measured by the Brief Fatigue Inventory (BFI). The effect of this agent on depression, quality of life, functional status, and cognitive function was also assessed. Modafinil was self-administered at a dose of 100mg/d during weeks 1–2, and 200mg during weeks 3–4. Assessments were performed at baseline, 2, and 4 weeks. The results were as follows: BFI score was improved in 46% of patients at 2 weeks and 75% at 4 weeks (p=0.025). Hospital Anxiety and Depression Scale scores declined at 2 and 4 weeks (p<0.001). Most scales for neurocognitive function were unchanged. Score for all Functional Assessment of Cancer Therapy-Brain (FACT-BR) subscales (measuring quality of life), except social/family well-being, were improved (p<0.05) at 2 and 4 weeks. Significant changes in Eastern Cooperative Oncology Group (ECOG) performance status were noted, with 40% of patients improving at least one level. Modafinil was well-tolerated with only one patient discontinuing treatment due to drug-related toxicity. The authors conclude: Modafinil was well-tolerated and effective for fatigue in patients with cancer. Improvements were also seen in mood, quality of life, and functional status.
The use of herbal medicines by people with cancer: a qualitative study
Between 7% and 48% of cancer patients report taking herbal medicines after diagnosis. Because of the possibility of unwanted side effects or interactions with conventional treatments, people with cancer are generally advised to tell the professionals treating them if they are taking any form of herbal medicines. But studies suggest that only about half do so and that the professionals themselves have at best very limited knowledge and feel unable to give informed advice. This study is intended to inform the future development of information resources for cancer patients, survivors and healthcare professionals including tools for use before or during consultation to make it easier for patients to mention, and for healthcare professionals to ask about, use of herbal medications.
This is a three-phase study. In phase 1, a systematic review of the literature on self-medication with herbal medicines among UK populations living with cancer will establish the current evidence base on use of herbal medicine, sources of information, characteristics and motivations. This will allow the investigators to better understand what aspects need further investigation and inform the topic guide for a qualitative study (phase 2). Six focus groups of six to eight cancer patients who have used at least one herbal preparation since diagnosis will explore behavior, beliefs, knowledge, information sources and needs in an informal conversational setting. Informed by the findings of the systematic review and qualitative study, in phase 3 the investigators will construct and pilot a questionnaire for a future large-scale survey to quantify and prioritize people's beliefs, needs and information preferences.
Wales Publishes New National Cancer Standards For Sarcoma Services
New standards to improve access to diagnosis and treatment of sarcomas have been published by the Welsh Assembly Government. The new standards, which have been developed by the Cancer Services Co-ordinating Group with a multi-professional group of cancer specialists and patients, take into account the latest NICE guidance which emphasizes the importance of earlier diagnosis in order to improve survival. The standards aim to improve the co-ordination of care with clearly designated diagnostic clinics which will speed up diagnosis. For those patients found to have sarcoma, a rapid onward referral, as part of a clinical pathway, to an appropriate specialist team will ensure prompt treatment by experts in this rare disease. The National Health Service in Wales must submit plans to the Assembly Government by the end of September on how it will achieve the new standards by June 2012. The National Cancer Standards for Sarcoma Services are available on the Welsh Assembly Government Website.
UCLA Pediatric Cancer Doctor Wins Research Award from Today’s and Tomorrow’s Children Fund
Dr. Noah Federman, assistant professor of pediatric hematology/oncology and director of the Pediatric Bone and Soft Tissue Sarcoma Program at Mattel Children’s Hospital UCLA, has been selected as the winner of the fourth annual Today's and Tomorrow's Children Fund Faculty Presentation Award. The prize honors compelling presentations made by UCLA faculty members engaged in pediatric research. The group will present him with a gift of $130,000 at a luncheon in July.
Federman's award-winning lecture, "Fighting Cancer in Children Using Nanotechnology," described the development of using targeted nanoparticles to treat pediatric sarcomas. Over the past several years, Federman has built an impressive clinical and research program collaborating with the UCLA adult sarcoma program and the UCLA Jonsson Comprehensive Cancer Center. His translational research developing nanoparticles to specifically target pediatric cancers represents a novel approach that could lead to a breakthrough in the way aggressive childhood cancers are treated.
Organized in 2006, Today's and Tomorrow's Children Fund is a fundraising group that supports pediatric research at Mattel Children's Hospital UCLA. The group currently includes 30 volunteer members from the community. UCLA faculty members are selected to present their research projects to the group members, who then select the winning presentation. Ultimately, the group hopes to expand its membership and to provide an annual award of $1 million to one or more pediatric researchers.
A Multidisciplinary Approach to Retroperitoneal Sarcomas: Current State-of-the-Art
Retroperitoneal sarcomas are complex, heterogeneous cancers requiring expert multidisciplinary care. The most common types of retroperitoneal sarcoma are liposarcomas and leiomyosarcomas. This review article covers the current state of the art treatment for these sarcomas. It notes that surgery is critical to treatment of the disease and requires an aggressive approach, including multivisceral resection. Even in advanced disease, surgery may provide useful palliation for patients with slow-growing disease. Radiotherapy (RT) has a definite role in reducing relapse, although prospective trials of adjuvant or neoadjuvant RT specifically for retroperitoneal sarcomas must be undertaken. The article indicates that chemotherapy has a limited role in the adjuvant setting for most forms of retroperitoneal sarcoma but has an increasing role in advanced disease. Finally, it notes that novel therapeutic agents that target MDM2 and CDK4 offer promise for subsets of these diseases.
LIFE RAFT GROUP ANNOUNCES GIST COLLABORATIVE
On May 28, 2009, the Life Raft Group (LRG) announced the long-awaited launch of the GIST Collaborate Tissue Bank. The non-profit LRG is dedicated to “providing support, through information, education, and innovative research to patients with a rare cancer called GIST (Gastrointestinal Stromal Tumor).” To this end, LRG has created partnerships with sarcoma researchers around the world to create a GIST clinical database that includes tissue samples from GIST patients as well as detailed patient histories. The link between patient data and tissue samples provides invaluable information to researchers that has never been available on a large scale.
Lead researcher and professor of pathology at Stanford, Dr Matt van de Rijn, says, “Scientists studying tissue usually have limited information about that patient’s clinical history. Being able to examine tissue in one patient over time and compare that to tissues from other patients with similar disease progression patterns will significantly accelerate our understanding of the underlying mechanisms of GIST.” The tissue and data will be stored at the Stanford University School of Medicine.
The tissue samples are typically collected during surgical procedures and are stored in paraffin tissue blocks at the hospitals performing the surgeries. The key to getting the tissue bank project off the ground was to engage GIST patients in the tissue collection process, an act which Jerry Cudzil, LRG Board President, hopes will be “empowering for patients and family dealing with a life-threatening disease.”
Because GIST is rare, the current challenge is to obtain larger numbers of samples. The database currently includes over 1,100 entries. As patient outreach continues, we can hope to see this unique database serve as the foundation for ground-breaking research into the mechanisms of GIST and lead to the first cure for this rare sarcoma.
Soft Tissue Sarcoma Trials: One Size No Longer Fits All
In this Editorial article, Jaap Verweij of the Erasmus University Medical Center in Rotterdam, introduces five (5) feature articles in the Journal of Clinical Oncology, Vol. 27, 2009. What the articles have in common, he says, is that they all support changes to the design of sarcoma clinical trials. Current practice is to pool soft tissue sarcomas together in clinical trials. The effect is that all sarcomas are treated as if they are biologically the same when, according to the author, they are not.
Sarcoma-related trials must be modified in significant ways, the author states, in recognition of growing evidence that sarcomas are very different at the cellular level and thus need to be treated according to subtype-specific mutations. Verweij notes “Such cancer cell-specific treatment will obviously depend on the molecular characteristic that, in the case of soft tissue sarcomas, may not be shared by all of the subtypes and would thus require subtype-specific trials and treatments.”
Verweij summarizes the findings of studies of imatinib in GIST; sorafenib; sunitinib; pazopanib; and the use of “alternate end points” other than tumor regression. He then goes on to say that “the literature is filling up with evidence that even for cytoxic drugs, different soft tissue sarcoma subtypes have different treatment sensitivity.”
Verweij concludes:
So what should soft tissue sarcoma trials look like in the future?
- For screening phase II trials, it is important to stratify for histologic subtypes. Whether a Bayesian model can be used depends on the absolute guarantee of the functionality of the molecular abnormality targeted, which unfortunately most often is still lacking. Given the relative rarity of soft tissue sarcomas, the above means that it is likely these studies will have to be performed in a cooperative group setting or an even larger network.
- Given the tumor-inhibitory action of drugs in development, for screening phase II trials we should select an end point other than tumor regression. Freedom of progression seems more appropriate, and there are several ways to assess this. This means that evidence of tumor progression will have to be provided at study entry, a concept challenging for investigators, but not infeasible.
- In phase II and/or phase III trials, we should collect samples for pharmacokinetics to define if minimal drug concentrations have to be pursued.
- In all studies, we should collect tissue samples for molecular profiling to help identify the benefiting populations.
Care of the Caregiver: Stress and Dysregulation of Inflammatory Control in Cancer Caregivers
Authors Susan Lutgendorf and Mark Laudenslager collaborate on a discussion of a study by Marin Rohleder, et al. The article, “Biological cost of caring for a cancer patient: Dysregulation of pro- and anti-inflammatory signaling pathways” by Rohleder, et al, finds that, in addition to experiencing emotional and physiological responses to stress, caregivers of cancer patients are at risk of “increasing inflammation and dysregulation of inflammatory control” Inflammation is a contributor to other health problems, including heart disease, with long-term effects.
The authors note that family members often fill the role of caregiver, taking on the many day-to-day tasks associated with managing cancer treatment in addition to their other family and work responsibilities. Multiple references are provided documenting caregiver responses to the added stress, including exhaustion, depression and fatigue. They are often faced with financial difficulties, social isolation and career concerns as well. According to the authors, this study “demonstrates how high levels of chronic stress associated with caring for a glioblastoma patient may be translated into general dysregulation of inflammatory control by the hypothalamic-pituitary-adrenal axis, particularly at a cellular level.”
They conclude with a recommendation for additional research into how much biological damage occurs and whether this damage can be reversed. They also offer their support for the US Surgeon General’s suggestions for improvements in interventions available to caregivers and stress “the importance of attention to caregiver distress by medical providers.”
This article is recommended as a good reference point for those interested in studying the relationship between caregiver health and patient outcomes.
REFERENCES
1. Rohleder N, Marin TJ, Ma R, et al: Biological cost of caring for a cancer
patient: Dysregulation of pro- and anti-inflammatory signaling pathways. J Clin
Oncol 2009 doi:10.1200/JCO.2008.18.7435
V6N3 ESUN Copyright © 2009 Liddy Shriver Sarcoma Initiative.