Cancer Prevention and Control Program

clinical trials

Research Advances

CPC researchers contribute to the body of knowledge in a variety of ways, helping to identify new ways to treat tobacco addiction - one of the primary causes of cancer, ease the pain and side effects of cancer therapy, and improve detection and prevention capabilities.

Following are some of the advances made in the Program's main areas of concentration:

Chemoprevention Clinical Trials
As the research base for the Cancer Prevention Network and the North Central Cancer Treatment Group, as well as many organically-funded projects, Mayo Clinic Cancer Center investigators are able to conduct a wide range of clinical trials across the continuum of cancer care, including preventive efforts. Some accomplishments in this area include Paul Limburg, M.D., leading the Adenoma Prevention with Celecoxib (APC) trial, showing celecoxib doses of 200 mg/day and 400 mg/day were associated with 33 percent and 45 percent proportional reductions, respectively, in the risk for recurrent adenomas by year 3 of follow-up.

Dr. Limburg was also the lead investigator on a randomized, controlled trial of selenomethionine 200 micrograms four times a day and/or celecoxib 200 mg/day for 10 months that was conducted in Linxian, People's Republic of China, wherein esophageal squamous cell carcinoma incidence rates are among the highest in the world. This study showed that selenomethionine favorably affected dysplasia grade among 115 subjects with mild esophageal squamous dysplasia at baseline, but not among 123 subjects with moderate esophageal squamous dysplasia at baseline. In contrast, celecoxib had no apparent affect on dysplasia grade.

Virender Sharma, M.D., and Kenneth Wang, M.D., were the first and second authors, respectively, on a recent report from a 1-year follow-up study of Barrett's esophagus patients treated with balloon-based, radio-frequency ablation at eight participating study centers. In the initial dosimetry phase (n=32), there were no dose-related serious adverse events; in the subsequent effectiveness phase (n=70), treatment resulted in a complete response (i.e., all biopsy specimens negative for Barrett's esophagus at 12 months) in 70 percent of participants. Importantly, no strictures or buried glandular mucosa were observed in either study phase, among 4,306 biopsy fragments evaluated.

In another set of experiments designed to clarify NSAID-related chemoprevention mechanisms, In another effort, Frank Sinicrope, M.D., studied the effects of sulindac sulfide on MAPK activation, COX-2 expression and apoptosis induction in HCA-7 human colon cancer cells. Sulindac sulfide treatment was associated with activation of ERKp44/42 and p38 MAPK in a dosage- and time-dependent manner, and also activated upstream MEK. Similar results were seen in HCT-15 cells and also with the selective COX-2 inhibitor NS398. ERKp44/42 and p38 activation were accompanied by an induction of COX-2 protein expression. Selective inhibitors of sulindac sulfide-induced ERKp44/42 (PD98059) and p38 MAPK (SB203580) activation also suppressed the induction of COX-2 by this NSAID. Furthermore, both MAPK inhibitors significantly augmented sulindac sulfide-induced apoptosis, as did suppression of constitutive COX-2 using antisense oligonucleotides.

Major conclusions drawn from this study, suggesting a novel strategy for the prevention or treatment of colorectal cancer, were: MEK/ERK and p38 MAPK activation mediate COX-2 induction by sulindac sulfide Selective inhibitors of these MAPKs potentiate apoptosis induction by this NSAID

Symptom Control and Side Effect Research
A significant advance in patient care was achieved via multiple studies by CPC members on treatment-induced mucosal injury including a controlled trial which demonstrated that oral cryotherapy could reduce 5FU-induced mucositis by 50 percent. This procedure has become incorporated into clinical practice, and it now has become more firmly established with recent multiple confirmatory presentations studies by other investigators, endorsement by an international guideline committee, and incorporation into National Comprehensive Cancer Network mucositis guidelines, thus benefiting thousands of cancer patients.

To further emphasize the importance of this research theme, the Cochrane group published a review of preventive interventions with respect to mucositis, and oral cryotherapy was cited by the Cochrane Reports in 2001 as the only evidenced-based effective intervention. At a mucositis presentation at the 2005 American Society of Clinical Oncology annual meeting, the discussant reiterated that the most cost effective intervention for mucositis remains oral cryotherapy.

CPC researchers have continued evaluating methods for alleviating mucosal injury caused by cancer therapy. More recently, James Martenson Jr., M.D., led a trial evaluating glutamine versus a placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. This negative study was published in the Journal of Clinical Oncology. Jeff Sloan, Ph.D., and colleagues also reviewed Mayo's mucositis data, demonstrating sex differences in 5-FU-induced stomatitis, with women having more trouble than men. This was also published in the Journal of Clinical Oncology.

A number of Mayo investigator-led studies have helped to clarify the roles and delineate the limitations of the use of potential orexigenic agents for treating cancer-associated anorexia/cachexia in clinical practice. This includes the use of progestational drugs and corticosteroids, which have verified activity in alleviating cancer anorexia; and many other agents, which looked promising in preliminary trials but, subsequently, did not appear beneficial in randomized trials.

In another line of investigation, CPC researchers have sought to find more and better ways to treat hot flashes. In the past five years, the group published manuscripts regarding three randomized clinical trials:

A Phase III trial evaluating black cohosh, led by Barbara Pockaj, M.D., and Charles Loprinzi, M.D., in a placebo-controlled manner, based on promising appearing pilot information. It did not demonstrate any benefit for black cohosh and was recently published in the Journal of Clinical Oncology.

A comparison between venlafaxine and intramuscular medroxyprogesterone acetate (MPA), led by Dr Loprinzi, demonstrating that MPA reduced hot flashes better. This also was published in the Journal of Clinical Oncology.

Another study led by Dr Loprinzi, involving women who had inadequate hot flash control despite the use of a newer antidepressant. This trial randomized 115 women to receive gabapentin alone versus gabapentin with continuation of the antidepressant they had been receiving. It demonstrated that the continuation of the antidepressant with gabapentin was no better than gabapentin alone. This was chosen for an oral presentation at the 2006 ASCO annual meeting and was published in the Journal of Clinical Oncology.

In addition, CPC investigators have conducted multiple pilot trials to screen for promising agents, including the following: mirtazapine, paroxetine - in men with prostate cancer, black cohosh, citalopram, dehydroepiandrosterone, bupropion, aprepitant, levetiracetam, desipramine and flaxseed. Of these, subsequent placebo-controlled trials, based on the positive nature of the pilot trial data, were conducted with black cohosh and citalopram, while plans are in process to also study flaxseed in a randomized controlled trial.

Dr. Loprinzi led an effort to conduct an individual patient pooled analysis of all of the published placebo-controlled trials, which evaluated newer antidepressants or gabapentin and which included daily hot flash diaries. Results, demonstrating that these drugs were efficacious, were chosen for presentation at the 2008 ASCO annual meeting. In addition, Dr. Loprinzi and colleagues conducted an individual patient analysis of multiple Mayo hot flash studies to examine whether a history of breast cancer or use of tamoxifen-influenced therapies would alleviate hot flashes. Results, demonstrating that neither of these situations influenced the efficacy of hot flash therapies, were also chosen for presentation at the 2008 ASCO annual meeting.

The discovery that newer antidepressants can control hot flashes has drastically impacted practice in the treatment of this symptom and has also led the way for other investigators to perform Phase III trials to evaluate new agents. As a result, multiple review articles and book chapters have been written on non-estrogenic alternatives to managing hot flashes and have impacted oncology, nursing, and primary care practice.

David Steensma, M.D. (Hematologic Malignancies Program), has taken the lead in this program to investigate the use of agents for treating anemia. The first such clinical trial (NCCTG 97-92-53) in our program, led by Thomas Witzig, M.D., compared erythropoietin to a placebo. This positive study was published in the Journal of Clinical Oncology. A subsequent protocol (N02C2), led by Dr. Steensma, was developed to randomly compare, after a three-week run in period, weekly treatment with erythropoietin versus treatment every three weeks at triple the weekly doses. The study accrued 330 patients and was published in the Journal of Clinical Oncology, demonstrating no significant differences in the two treatment arms.

 

Tobacco Dependence - Traditional Pharmacotherapy
Our first nicotine patch study in 1988 helped to establish the efficacy of this therapy, and in subsequent studies, we better defined the doses needed to adequately treat patients with tobacco dependence. We have also investigated other nicotine replacement therapies including the nicotine inhaler, nicotine nasal spray, nicotine gum, and nicotine lozenge as well as multiple non-nicotine medications. The CPC's research team of Richard Hurt, M.D., Lowell Dale, M.D., and Ivana Croghan, Ph.D., was the lead group for a pivotal trial that led to bupropion approval in 1997. Dr. Dale recently completed two studies testing the efficacy of the cannabinoid receptor inhibitor rimonabant in treating tobacco dependence, and in the past five years we have extended our close collaborations with our colleagues in the Department of Laboratory Medicine to develop the capabilities of assaying biological fluids for tobacco alkaloids. This began with work in the 1980s and 1990s using HPLC methodology to measure nicotine and cotinine in saliva, serum, and urine. This has evolved into more sophisticated assays using GC mass spectrometry.

Alcoholic Smokers
The prevalence of smoking in alcoholics is two to three times that of the general population. Drs. Hurt and I. Croghan in our group, with the collaboration of L. Joseph Melton III, M.D., produced a seminal paper with NIDA support which showed that the mortality following treatment for alcoholism was much higher than expected for the general population, but the extensive burden of tobacco-caused disease accounted for over 50 percent of all deaths, while alcohol-caused disease accounted for 34 percent. This paper has had a major impact on the addictions treatment field, which up until that time rarely addressed tobacco dependence in patients undergoing treatment for alcohol dependence. This led to an NIAAA-funded study, "Pharmacologic Relapse Prevention for Alcoholic Smokers," into which Drs. Hurt and I. Croghan, along with Christi Patten, Ph.D., and J. Taylor Hays, M.D., enrolled 195 recovering alcoholics and provided tailored nicotine replacement therapy for the first seven weeks, which proved quite effective.

Smokeless Tobacco Dependence
Smokeless tobacco use is a major health and addiction problem, particularly for adolescent and young adult males. According to the 1999 U.S. National Household Survey of Drug Abuse, an estimated 7.6 million people 12 years of age and older, currently use smokeless tobacco. Long-term smokeless tobacco use increases the risk of developing oral leukoplakia, oropharyngeal cancer, and periodontal diseases. While few intervention studies for smokeless tobacco users have been conducted, Jon Ebbert, M.D., has conducted a range of research projects over the past several years, leading to a broad experience in the clinical treatment of smokeless tobacco users. Dr. Ebbert and team have conducted a clinical trial investigating the efficacy of high dose nicotine patch therapy (up to 63 milligrams (mg)/day) in smokeless tobacco users. In this study, Drs. Ebbert and Patten, also validated a dependence measure for smokeless tobacco users, the Fagerström Test for Nicotine Dependence for smokeless tobacco users. Drs. Dale, Ebbert, I. Croghan, and Hurt have also conducted a study of bupropion SR for smokeless tobacco users, concluding that bupropion SR significantly decreased craving and weight gain over the treatment period, although it did not significantly increase tobacco abstinence rates among smokeless tobacco users.

 

In addition to these accomplishments, many other cancer prevention and control advances have been made by Mayo Clinic Cancer Center investigators. Below are some notable program-related publications of the Cancer Prevention and Symptom Control Program:


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