ACCOMPLISHMENTS AND FUTURE PLANS
Symptom Management
Symptom Management studies utilize pharmacologic interventions to reduce the morbidity of cancer and its treatments, emphasizing novel uses of conventional agents as well as botanical and natural compounds in the following areas: appetite and weight loss (megestrol acetate, oxandrolone), cognitive function (donepezil [Aricept], ginkgo biloba), fatigue (coenzyme Q10), hot flashes (St. John’s Wort, soy isoflavones, venlafaxine [Effexor]), and mucositis/esophagitis (megestrol acetate, oxandrolone). Hypothesis-driven prospective Phase II and III clinical trials are being conducted in these areas by the CCCWFU and its CCOP Research Base. Each symptom management study is a Wake Forest investigator-initiated, hypothesis-driven trial based on preliminary data derived from the literature or translated from our own preclinical laboratory research data. The completed, ongoing, and planned studies described in this section represent the largest oncology clinical trials effort of any Cancer Center in the U.S. attempting to prove or disprove the efficacy, and describe the toxicity, of botanicals and natural products to relieve cancer or treatment-associated symptoms. Symptom management research is multidisciplinary/intraprogrammatic as well as interprogrammatic. The leaders of this thematic area of research include Edward Shaw, M.D. (radiation oncologist, Director of the Clinical Research Program), Nancy Avis, Ph.D. (public health scientist, Director of the Cancer Control Program), Michelle Naughton, Ph.D. (public health scientist, member of the Cancer Control Program), Glenn Lesser, M.D. (medical oncologist, member of the Clinical Research Program), Stephen Rapp, Ph.D. (neuropsychologist, member of the Clinical Research Program), Richard McQuellon, Ph.D. (psycho-oncologist), Ralph D’Agostino, Ph.D. (biostatistician, Director of the Cancer Center’s Biostatistical Shared Resource), Doug Case, Ph.D. (biostatistician, member of the Clinical Research Program), Mara Vitolins, R.D., Ph.D. (registered dietician, public health scientist, member of the Cancer Control Program), and Audrey Bell-Farrow, M.B.A., M.H.A. (Director, Cancer Center’s Clinical Research Management Shared Resource). Most of these individuals constitute the Executive Steering Committee of the Cancer Center’s CCOP Research Base. They meet monthly, reviewing ongoing trials and planning future studies in symptom management. Every study in this area has a team of co-investigators, including an oncologist and member of the Clinical Research Program, a public health scientist, and a biostatistician who are members of the Cancer Control Program. Over the last five years, some symptom management studies have been completed; the majority, however, are ongoing with the next generation already in development, as summarized herein.
Anorexia/weight loss studies
Two separate but related Phase III prospective randomized double blind placebo controlled studies have been completed in the area of appetite and weight loss. CCCWFU 98199 randomized lung cancer patients undergoing curative (>50Gy) external beam radiation therapy (RT) with or without chemotherapy to either800mg megestrol acetate (Megace OS) elixir or placebo elixir. CCCWFU 97300 was a similar study (megestrol acetate vs placebo) but was for head/neck cancer patients undergoing curative RT. The data from these studies have been combined for presentation/publication. The primary outcome was weight. Patients receiving megestrol acetate has significantly less weight loss (mean weight loss from time RT started to 12weeks following end of RT was <1 pound) compared to the control (mean weight loss ~12 pounds). One of the secondary endpoints, the anorexia subscore from the FAACT, was also significantly reduced (i.e., anorexia decreased) in treated patients compared to controls. No severe adverse thromboembolic events were reported in the megestrol acetate group. The study demonstrated the benefit of prophylactic megestrol acetate in lung and head/neck cancer patients undergoing curative RT in terms of quality of life and weight.
Future plans for anorexia/weight loss research are focused on planning for the next study in irradiated lung and head/neck cancer patients. At this time, another Phase III prospective randomized study is being contemplated, randomizing patients between 20 cc (800 mg) standard megestrol acetate (Megace OS) elixir versus 5 cc (625 mg) megestrol acetate ES elixir, a new highly concentrated formulation of megestrol acetate manufactured by Par Pharmaceuticals. Megace ES uses nanocrystal technology (i.e., a nanoparticulate drug delivery system which enhances the bioavailability of poorly water-soluble compounds) to improve the rate of dissolution and the bioavailability of the medication. While there are Phase II data in the AIDS population of its efficacy, there are no Phase I, II or III data in cancer patients. We hypothesize that Megace ES will be more effective, less toxic, and easier to tolerate than Megace OS.
Another area for anorexia/weight loss research is in chemotherapy patients. Oxandrolone (Oxandrin), an anabolic steroid, has been utilized in AIDS patients with anorexia/cachexia, demonstrating a reduction in weight loss (or actual weight gain), an increase in lean body mass, but little to no improvement in appetite, as opposed to megestrol acetate, which is an appetite stimulant that induces weight gain, usually fat/fluid, with a reduction in lean body mass. A Phase III prospective randomized study of Oxandrin and Megace for patients with solid tumors undergoing chemotherapy is ongoing in our CCOP Research Base (Glenn Lesser, M.D., member of the Clinical Research Program, is PI; Michelle Naughton, Ph.D., member of the Cancer Control Program, is co-PI). Patients undergoing chemotherapy who have >5% body weight loss in the prior 3 months (or >3% weight loss in the prior month) are randomized to either 800 mg megestrol acetate (Megace OS) elixer or oxandrolone (Oxandrin) 10 mg po bid. The primary endpoint, body composition, is assessed by bioimpedance analysis. Weight and quality of life are secondary endpoints. Thus far, about 80 of a planned160 patients have been accrued. The successor trial in this patient population will take the best arm of the ongoing trial (megestrol acetate or oxandrolone) compared to the combination of megestrol acetate and oxandrolone, based on the hypothesis that these agents combined optimize appetite stimulation and lean body mass weight gain.
Cognitive function and quality of life studies
Each year, about 15, 000 patients are diagnosed with a primary brain tumor, and another 150, 000 or more with metastatic brain disease, most of whom will undergo multimodality treatment including surgery, radiation therapy (RT), and chemotherapy. The most common primary brain tumor is glioblastoma multiforme (GBM). With surgery, RT, and temozolomide chemotherapy during/following RT, the median survival time is now ~15 months. Similar improvements in outcome have resulted from the addition of stereotactic radiosurgery to whole brain RT for brain metastases; median survival time is ~6 months. In fact, the 2-yearsurvival rate for prognostically favorable subsets of patients with GBM or brain metastases is ~20-40%.Although the incidence of overt dementia is only 10% in long-term (>6 month) survivors of multimodality therapy that includes whole- or partial brain RT, when formal neurocognitive testing is performed in these patients to assess attention and concentration, memory, language and executive function, >90% demonstrate significant abnormalities. In addition, fatigue and mood disturbances (depression and anxiety in particular) are common. These observations have resulted in a new interprogrammatic research effort at Wake Forest, radiation-induced brain injury (RIBI), involving the Clinical Research, Cancer Control, and DNA Damage and Cellular Defense Programs, catalyzed by the Cancer Center and its Brain Tumor Center of Excellence. The RIBI effort is led by Mike Robbins, Ph.D., section head of radiation biology and a member of the DNA Damage and Cellular Defense Program. A substantial basic science effort in RIBI has evolved since Dr. Robbins’ targeted recruitment in 2001. Pathophysiological observations from preclinical and clinical research on the late effects of ionizing radiation on the brain and other normal tissues, carried out in part by Dr. Robbins, indicate that the expression of radiation-induced normal tissue injury involves complex and dynamic interactions between several cell types within a particular organ. Radiation not only causes acute cell death, but also induces an intrinsic recovery/repair response in the form of specific cytokines and may initiate secondary reactive processes that result in the generation of a persistent oxidative stress and/or chronic inflammation. This new paradigm offers an exciting approach to radiation-induced normal tissue morbidity in which radiation injury can be modulated by the application of therapies directed at altering steps in the cascade of events leading to the clinical expression of normal tissue injury.
Interventional approaches targeted at reducing the severity of radiation-induced acute and chronic inflammation in the brain, hypothesized to be involved in radiation-induced brain injury, including cognitive impairment, are being explored by the RIBI basic research team for future translation into the clinic. The basic science investigators include, in addition to Dr. Mike Robbins, David Riddle, Ph.D. and Judy Brunso-Bechtold, Ph.D., faculty in the Department of Neurobiology/Anatomy and new members of the Clinical Research Program, William Sonntag, Ph.D., faculty member in the Department of Physiology/Pharmacology and member of the Clinical Research Program, Debra Diz, Ph.D., faculty member in the Department of Physiology/Pharmacology, and William Brown, Ph.D., faculty member in the Division of Radiological Sciences and member of the Clinical Research Program. These translational basic scientists represent new internally recruited members to the Clinical Research Program. Their collaborative research focuses on the role of the brain renin-angiotensin system (RAS) in the pathogenesis of RIBI and to explore how angiotens in converting enzyme inhibitors such as captopril or ramipril and angiotensin II receptor antagonists modulate RIBI. Another theme is to define the role of the anti-inflammatory peroxisomal proliferator-activated receptor (PPAR) agonists in the pathobiology of RIBI. Dr. Robbins has a recently funded R01 grant exploring this question. Within the next few years, clinical trials utilizing modulators of the brain RAS as well as PPAR modulators will be developed for both neurotherapeutic and neurotherapeutic interventions for patients with RIBI or those at risk for developing such.
Two clinical trials, both Phase II studies in >6 month disease-free survivors of whole- or partial-brain RT in irradiated brain tumor patients have been completed. The first study was based on the clinical observation that patients with radiation-induced brain injury manifest a symptom complex that is similar to those suffering from mild to moderate Alzheimer’s disease. The intervention chosen for the study was donepezil (Aricept), anacetylcholinesterase inhibitor that is FDA-approved for Alzheimer’s disease. A Phase II open-label study in 35patients was conducted between 2001-2004 and found that health-related quality of life (decreased fatigue and improved mood) as well as several domains of cognitive function (attention and concentration, verbal memory, and verbal fluency) were improved with donepezil. The second completed study for survivors of brain radiation utilized the botanical product ginkgo biloba. Ginkgo is regulated as a drug by the German equivalent of the FDA and has been shown in randomized trials to improve cognition in patients with mild to moderate Alzheimer’s disease. Hypothesized mechanisms of action for ginkgo biloba included improved cerebral blood flow and reduced oxidative stress. The Phase II open-label ginkgo biloba study enrolled 34 patients in 2004-2005. The data have just been analyzed. Like donepezil, patients taking ginkgo biloba had improved health related quality of life (decreased fatigue and improved mood) as well as several domains of cognitive function (executive function, attention/concentration, verbal memory, and visual memory). Co-investigators in the study include Edward Shaw M.D., Robin Rosdhal R.N., L. Douglas Case Ph.D., Ralph D’Agostino Ph.D., Michelle Naughton Ph.D., Glenn Lesser M.D., Kevin McMullen M.D., Volker Stieber M.D., Mike Robbins Ph.D. and Stephen Rapp Ph.D.
Future plans for brain tumor QOL/cognition research includes conduct of a Phase III prospective randomized double blind placebo controlled study of donepezil in adult irradiated brain tumor survivors that will be conducted by the CCCWFU CCOP Research Base in conjunction with the M.D. Anderson Cancer Center’s CCOP Research Base. An R01 grant to support the study was submitted in 10/05 with Drs. Rapp and Shaw as co-PIs. A Lance Armstrong Foundation grant to fund an open-label Phase II study of donepezil in pediatric brain tumor survivors has just been awarded to Sharon Castellino, M.D. Dr. Castellino is a new faculty recruit to pediatric oncology, a member of the Clinical Research Program, and also a participant in the Wake Forest’s junior faculty mentoring program, with Dr. Ed Shaw, Program Leader for the Clinical Research Program, as her designated mentor.
A growing transdisciplinary effort in human cognition is developing at Wake Forest involving four different groups, including the Women’s Health Center of Excellence (Cognitive Aging), Comparative Medicine (Menopause and Aging), Neurology and the Center on Aging (Vascular Dementia), and the Cancer Center (RIBI). Each group utilizes animal models (rodent and non-human primate), anatomic and functional imaging in animals and humans (MRI and PET), and therapeutic intervention human clinical trials. In December 2005, Nancy Avis, Ph.D., Director of the Cancer Center’s Cancer Control Program, and Dr. Ed Shaw, Director of the Clinical Research Program, hosted a half day retreat in which 20 representative investigators from these areas came together to share their research and identify areas for cross-disciplinary collaborative research projects focusing on human cognition and cancer: the interplay of aging, chemotherapy, hormones, menopause, and radiation. One outcome of the retreat was a proposal for a transdisciplinary program project grant with the theme of cognition across the life cycle in the breast cancer patient, including animal models, imaging, and clinical trials focusing on prevention/therapy.
Fatigue and Hot Flash Studies
Ongoing or planned clinical trials in the areas of fatigue and hot flashes utilize botanical/natural product interventions that are widely taken by cancer patients without hypothesis driven, evidence-based data to support their use. These are CCCWFU investigator-initiated intervention studies being conducted by the Cancer Center’s CCOP Research Base (described more fully in Section D2). Fatigue is the most common symptom experienced by cancer patients. Coenzyme Q10 is an antioxidant found ubiquitously in human heart, lung, kidney, and liver. Randomized clinical trials in congestive heart failure patients have shown improved cardiac pump function and reduced fatigue. CoQ10 also appears to have protective effects against anthracycline-induced cardiotoxicity. Preclinical studies have demonstrated that CoQ10 stabilizes red blood cell membranes, which led to our hypothesis that CoQ10 would minimize anemia and prevent fatigue in cancer patients. Glenn Lesser, M.D., medical oncologist and member of the Clinical Research Program, in conjunction with Michelle Naughton, Ph.D., public health scientist and member of the Cancer Control Program, are coinvestigators on a phase III prospective, randomized, placebo-controlled, double-blind study of CoQ10 in breast cancer patients undergoing adjuvant chemotherapy. The study is ongoing and has accrued about 60 of a planned 200 patients. It is funded by the NCI’s Office of Cancer Complementary and Alternative Medicine.
Future plans for hot flash research will focus on two studies which will open in the first quarter of2006. Dr. Naughton, in conjunction with Tony Miller, M.D., medical oncologist and member of the Clinical Research Program, are coinvestigators on a Phase I/II study of St. John’s Wort to alleviate hot flashes in postmenopausal women with a history of breast cancer. This study of breast cancer survivors hypothesizes that St. John’s Wort, a botanical with antidepressant effects in randomized clinical trials, will reduce hot flashes without the side effects typically seen with conventional antidepressants (e.g., SSRIs). Women on tamixofen will also have tamoxifen levels drawn prior to, during, and following St. John’s Wort use to see if this botanical, which is metabolized by the liver’s p450 system, reduces serum levels of tamoxifen. This aspect of the study was mandated by the Food and Drug Administration. For hot flashes in androgen deprived men with prostate cancer, Mara Vitolins, Ph.D., a registered dietician, public health scientist, and member of the Cancer Control Program, will conduct a four arm study (2x2 factorial design) of placebo, soy phytoestrogens, venlafaxine (Effexor, a commonly used SSRI antidepressant), and soy plus venlafaxine. The study hypothesizes that both soy and venlafaxine will be effective in reducing hot flash frequency, intensity and duration, with the combination of both interventions being most effective due to additive or synergistic effects. Both hot flash studies are funded by grants from the NCI’s Office of Cancer Complementary and Alternative Medicine.