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.

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:

• Hurt RD, Krook JE, Croghan IT, Loprinzi CL, Sloan JA, Novotny PJ, Kardinal CG, Knost JA, Tirona MT, Addo F, Morton RF, Michalak JC, Schaefer PL, Porter PA, Stella PJ. Nicotine patch therapy based on smoking rate followed by bupropion for prevention of relapse to smoking. Journal of Clinical Oncology. 21(5):914-20, 2003.
• Croghan GA, Sloan JA, Croghan IT, Novotny P, Hurt RD, DeKrey WL, Mailliard JA, Ebbert LP, Swan DK, Walsh DJ, Wiesenfeld M, Levitt R, Stella P, Johnson PA, Tschetter LK, Loprinzi CL. Comparison of nicotine patch alone versus nicotine nasal spray alone versus a combination for treating smokers: a minimal intervention, randomized multicenter trial in a nonspecialized setting. Nicotine & Tobacco Research. 5(2):181-7, 2003.
• Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR, for the Varenicline Phase 3 Study Group. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs. placebo or sustained-release bupropion for smoking cessation. A randomized controlled trial. JAMA. 2006:296(1):56-63.
• Ebbert JO, Dale LC, Patten CA, Croghan IT, Schroeder DR, Moyer TP, Hurt RD. Effect of high-dose nicotine patch therapy on tobacco withdrawl symptoms among smokeless tobacco users. Nicotine & Tobacco Research. 2007:9(1):43-52.
• Sood A, Ebbert JO, Schroeder DR, Croghan IT, Sood R, Vander Weg MW, Wong GY, Hays JT. Gabapentin for smoking cessation: a preliminary investigation of efficacy. Nicotine & Tobacco Research. 2007:9(2):291-98.
• Muggli ME, LeGresley EM, Hurt RD. Big tobacco is watching: British American Tobacco's surveillance and information concealment at the Guildford depository. Lancet. 363:1812-19.
• Warner DO, Patten CA, Ames SC, Offord KP, Schroeder DR. Effect of nicotine replacement therapy on stress and smoking behavior in surgical patients. Anesthesiology. 2005; 102(6):1138-46.
• Hurt RD, Patten CA, Offord KP, Croghan IT, Decker PA, Morris RA, Hays JT. Treating nondepressed smokers with alcohol dependence in sustained full remission: nicotine patch therapy tailored to baseline serum cotinine. Journal of Studies on Alcohol. 2005:506-16.
• Alberts SR, Novotny PJ, Sloan JA, Danella J, Bostwick DG, Sebo TJ, Blute ML, Fitch TR, Levitt R, Lieberman R, Loprinzi CL. Flutamide in men with prostatic intraepithelial neoplasia: a randomized, placebo-controlled chemoprevention trial. American Journal of Therapeutics. 2006, 13:291-97.
• Reid JM, Mandrekar SJ, Carlson EC, Harmsen WS, Green EM, McGovern RM, Szabo E, Ames MM, Boring D, Limburg PJ; Cancer Prevention Network. Comparative bioavailability of sulindac in capsule and tablet formulations. Cancer Epidemiolology Biomarkers & Prevention. 2008 Mar;17(3):674-9.
• Alberts SR, Novotny PJ, Sloan JA, Danella J, Bostwick DG, Sebo TJ, Blute ML,Fitch TR, Levitt R, Lieberman R, Loprinzi CL. Flutamide in men with prostatic intraepithelial neoplasia: a randomized, placebo-controlled chemoprevention trial. American Journal of Therapeutics. 2006 Jul-Aug;13(4):291-7.
• Limburg PJ, Wei W, Ahnen DJ, Qiao Y, Hawk ET, Wang G, Giffen CA, Wang G, Roth MJ, Lu N, Korn EL, Ma Y, Caldwell KL, Dong Z, Taylor PR, Dawsey SM. Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib. Gastroenterology. 2005 Sep;129(3):863-73.
• Sinicrope FA, Half E, Morris JS, Lynch PM, Morrow JD, Levin B, Hawk ET, Cohen DS, Ayers GD, Stephens LC; Familial Adenomatous Polyposis Study Group. Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients. Cancer Epidemiology Biomarkers & Prevention. 2004 Jun;13(6):920-7.
• Jatoi A, Rowland K, Loprinzi CL, Sloan JA, Dakhil SR, MacDonald N, Gagnon B, Novotny PJ, Mailliard JA, Bushey TI, Nair S, Christensen B; North Central Cancer Treatment Group. An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort. Journal of Clinical Oncology. 15;22(12):2469-76, 2004.
• Witzig TE, Silberstein PT, Loprinzi CL, Sloan JA, Novotny PJ, Mailliard JA, Rowland KM, Alberts SR, Krook JE, Levitt R, Morton RF: A Phase III randomized double-blind study of epoetin alfa versus placebo in anemic patients with cancer undergoing chemotherapy. Journal of Clinical Oncology. 23(12):2606-17.
• Steensma DP, Molina R, Sloan JA, Nikcevich DA, Schaefer PL, Rowland KM, Dentchev T, Novotny PJ, Tschetter LK, Alberts SR, Hogan TF, Law A, Loprinzi C. Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer. Journal of Clinical Oncology. 24(7):1079-88, 2006
• Loprinzi CL, Levitt R, Barton D, Sloan JA, Dakhil SR, Nikcevich DA, Bearden JD, Mailliard JA, Tschetter LK, Fitch TR, Kugler JW. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. Journal of Clinical Oncology. 24(9):1409-14, 2006
• Pockaj BA, Gallager JG, Loprinzi CL, Stella PJ, Barton DL, Sloan JA, Lavasseur BI, Rao RM, Fitch TR, Rowland KM, Novotny PJ, Flynn PJ, Richelson E, Fauq AH. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. Journal of Clinical Oncology. 24(18):2836-41, June 2006.
• Loprinzi CL, Kugler JW, Barton DL, Dueck AC, Tschetter LK, Nelimark RA, Porteza Balcueva E, Burger KN, Novotny PJ, Carlson MD, Fletcher Duane S, Corso SW, Johnson DB, Jaslowski AJ. Phase III trial of gabapentin alone or in conjunction with an anti-depressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. Journal of Clinical Oncology. 2007; 25(3):308-12.
• Croghan IV, Hurt RD, Dakhil SR, Croghan GA, Sloan JA, Novotny PJ, Rowland KM, Bernath A, Loots ML, Le-Lindqwister NA, Tschetter LK, Garneau SC, Flynn KA, Ebbert LP, Wender DB, Loprinzi CL. Randomized comparison of a nicotine inhaler and bupropion for smoking cessation and relapse prevention. Mayo Clinic Proceedings. 2007; 82(2):186-95.
• Barton DL, Wender DB, Sloan JA, Dalton TJ, Balcueva EP, Atherton PJ, Bernath AM, DeKrey WL, Larson T, Bearden JD, Carpenter PC, Loprinzi CL. Randomized controlled trial to evaluate transdermal testosterone in female cancer survivors with decreased libido; North Central Cancer Treatment Group Protocol N02C3. JNCI. 2007; 99(9):672-9.
• Halyard MY, Jatoi A, Sloan JA, Bearden JD III, Vora SA, Atherton PJ, Perez EA, Soori G, Zalduendo AC, Zhu A, Stella PJ, Loprinzi CL. Does zinc sulfate prevent therapy-induced taste alterations in head and neck cancer patients? Results of phase III double-blind, placebo-controlled trial from the North Central Cancer Treatment Group (N01C4). International Journal of Radiation Oncolology, Biology and Physics. 2007; 67(5):1318-22.