	Founded in 1898 by Dr Roswell Park, Roswell Park Cancer Institute (RPCI) is the oldest dedicated comprehensive cancer center in the country. In 1974, the Buffalo, New York, facility was 1 of the first 3 institutions to be National Cancer Institute (NCI)-designated as a comprehensive cancer center.

	“Roswell Park [Cancer Institute] has been ahead of its time from the very start,” said president and CEO Donald L. Trump, MD. “Our founder, a distinguished surgeon who was recruited to the University at Buffalo in 1893, articulated what is now understood as the underlying philosophy of modern comprehensive cancer, centers: namely, the critical need to bring together multidisciplinary teams of scientists and clinicians to develop an understanding of cancer and to translate that understanding from the laboratory to clinical practice.”

	More than a century after opening its doors, RPCI clinicians and scientists continue to apply this philosophy to every aspect of patient care, research, and education.

	It would be an understatement to say that RPCI has been successful in this pursuit. As an internationally renowned center for groundbreaking research for more than a century, RPCI has been at the forefront of scientific discoveries that have ultimately changed the course of cancer screening, prevention, and treatment 

	Not satisfied to rest on its laurels, RPCI has recently opened the Center for Immunotherapy, in which its faculty plays a major role in the development and clinical evaluation of vaccines and monoclonal antibodies for cancer treatment.

		Roswell Park Comprehensive Cancer Center Timeline

 — Roswell Park Cancer Center (RPCI) is founded.

— RPCI develops the world’s first chemotherapy research program.

— RPCI scientists pioneer photodynamic therapy.

— RPCI is one of the first 3 cancer centers approved as a National Cancer Institute designated comprehensive cancer center.

— RPCI scientists discover the prostate-specific antigen (PSA) molecule and, in subsequent years, pioneer the PSA screening test.

— RPCI scientists pioneer the combination of 5-fluorouracil and leucovorin as a treatment for colorectal cancer.

		Alex Adjei, MD, PhD Recognized for Scientific Excellence

	The Roswell Park Approach: Partnerships Near and Far

	RPCI’s commitment to converting its scientific discoveries into real-world products and applications is, in part, evidenced by its 400 active, funded research projects. RPCI’s research work is organized broadly into 6 major programs that form the foundation for the RPCI Cancer Center Support Grant, awarded by the NCI and funded continuously since 1974 (see “Cancer Center Support Grant”).

	RPCI Deputy Director Candace Johnson, PhD, attributed the center’s success in translating novel therapies from the lab to clinical practice to a number of factors. She explained that the center enjoys the dual benefit of being a freestanding facility with several affiliate sites, while also reaping the rewards of active, long-term collaborative relationships with the University at Buffalo, the Hauptman- Woodward Medical Research Institute, and numerous national and international entities. The result, she said, is a “seamless sharing of resources and talent,” the fruits of which are translated into real-world applications, such as several biotech spin-off companies that form strategic partnerships with investigators and cancer centers worldwide.

	The foundation of RPCI’s research and clinical programs is a state-of-the-art campus with laboratory research, educational, and patient care facilities (both inpatient and ambulatory). With the 2006 opening of the RPCI Center for Genetics and Pharmacology—one of the nation’s few Leadership in Energy and Environmental Design-certified research facilities&mdash;more than 400 faculty, staff, and graduate students are afforded access to the latest in laboratory technology and design. RPCI’s new on-site Clinical Research Center houses the institute’s investigator-initiated phase I clinical research program, where patients can be specially monitored during ambulatory administration of new cancer therapies.

	Among the newest and most exciting research focal points is RPCI’s recently expanded drug discovery effort. “The focus is on working to establish new paradigms for novel agents,” said Johnson, “and the key is our ability to employ an innovative approach to genetics in cancer research: namely, identifying the unique genetic signatures of specific tumors and applying that information to our drug discovery efforts.”

	“Our founder... articulated what is now understood as the underlying philosophy of modern comprehensive cancer centers: namely, the critical need to bring together multidisciplinary teams of scientists and clinicians to develop an understanding of cancer and to translate that understanding from the laboratory to clinical practice.”

	Such efforts, which represent a significant move toward highly individualized treatment, can take 1 of 2 forms. “We can discover a new cancer/tumor target and then synthesize a new drug that will be effective against that target,” Johnson explained. “Or we can screen any or all of the thousands of existing drugs to identify agents that might have efficacy against that new tumor target.” She went on to note that the basic science conducted at RPCI can then be funneled through the biotech spinoff companies to expedite the transition from bench to bedside.

	The institute’s immunotherapy program serves as an example of this multifaceted approach to research. “We’re looking at the immune system in the hopes of identifying areas we can exploit via antibodies,” said Johnson. These investigations will bring together studies in immunotherapy and classic small-molecule drug development to tackle problems related not only to cancer therapy but also to prevention.

	On the surgical front, RPCI clinicians are making strides toward providing patients with more precise, less invasive surgical options. The RPCI robotic program serves as a prime example.

		Roswell Park Comprehensive Cancer Center Timeline Continued

 — RPCI establishes one of the nation’s first long-term survivors’ clinics for childhood cancer patients.

— RPCI is a member of the international team of scientists that produces the landmark studies of the Human Genome Project.

— Dr Khurshid Guru is appointed director of RPCI’s Center for Robotic Surgery.

— RPCI opens the Center for Genetics and Pharmacology.

— RPCI’s Clinical Research Center opens.

— RPCI opens its Center for Immunotherapy.

	RPCI’s reputation as a center of excellence for robot-assisted surgery is known internationally. In 2004 the center became the first in western New York to offer state-of-the-art robot-assisted surgery to prostate cancer patients. Only one year later, RPCI surgeons performed their last open prostatectomies.

		Six major National Cancer Institute—funded programs form the basis for Roswell Park Cancer Institute’s Cancer Center Support Grant:

			Cell Stress and Biophysical Therapies Program

			Drug Development and Experimental Therapeutics Program

			Molecular Epidemiology and Functional Genomics

			Tumor Immunology and Immunotherapy Program

		Through the RPCI Graduate Division of the University at Buffalo, RPCI offers an interdisciplinary Master of Science program, as well as doctoral programs in the areas of cancer pathology and prevention, cellular and molecular biology, immunology, molecular and cellular biophysics and biochemistry, and molecular pharmacology and cancer therapeutics. More than 250 clinical residents, oncology fellows, and visiting MDs are trained through these programs every year, in addition to approximately 70 postdoctoral research fellows and 165 predoctoral graduate students.

	In less than 3 years, the percentage of kidney, bladder, and prostate cancer surgeries performed with robotics increased from 50% to 95%; RPCI surgeons now have more than 1500 such procedures to their credit. Particularly noteworthy has been the leadership of Khurshid Guru, MD, associate professor of Urologic Surgery and Oncology, in developing one of the world’s first programs in robot-assisted cystectomies. Guru has performed more than 200 such procedures since 2005 and, today, nearly all cystectomies performed at RPCI are robot-assisted.

	The hub of RPCI’s burgeoning robotic surgery program is its Center for Robotic Surgery, equipped with 2 state-of-the-art da Vinci robotic systems and an adjoining teaching laboratory (see “The Nuts and Bolts of Robot-Assisted Surgery”). According to Guru, the Center for Robotic Surgery’s director, it is what happens in the teaching laboratory that sets Roswell apart from other centers that offer robot-assisted surgery.

	Trump described RPCI’s 2005 recruitment of Guru as a huge step forward for the RPCI. “As one of the world’s first clinicians to develop a technique to remove the bladder and construct the urinary diversion robotically, Dr Guru has performed more of these cystectomy procedures than anyone in the world and has pioneered several advanced robotassisted techniques,” said Trump.

	But while most people are eager to tout the high-tech capabilities of robot-assisted surgery, “they rarely address one of its major limitations: a very sharp learning curve,” said Guru, noting that dangerous errors can and do occur without proper training.

	Guru and his colleagues wasted no time taking their place at the forefront of training for robotassisted surgery and now lead a worldwide consortium for developing these training programs. RPCI is, in fact, one of the first centers to have developed a robotic curriculum, has created the world’s first virtual robotic training and research program, and is the first center to develop a video- based textbook on robotic surgery.

			The Nuts and Bolts of Robot-Assisted Surgery

			From her seat at a console, a surgeon operates the controls that guide a robot’s 4 arms, designed to mimic the movements of conventional surgery, but with slim robotic arms and wrists that swivel 360 degrees. As the robotic arms grasp a camera and surgical instruments that are inserted into the body through small keyhole incisions, the system provides her with a 10x magnified view of the operating field. The instruments move easily and precisely through tight spaces while eliminating any normal hand tremor.

			Robot-assisted surgery combines the skill, experience, and judgment of the surgeon with the superhuman flexibility and precision of robotic and computer technology, eliminating limitations and barriers such as those imposed by hand size, degree of dexterity, and visual restrictions.

			Patients consistently report high satisfaction with robot-assisted procedures, reaping the benefits of smaller incisions, less blood loss, and less pain than that experienced with open surgery, and, importantly, shorter hospital stays and faster recovery times.

	Surgeons come to RPCI’s Center for Robotics from around the world to participate in 16 hours of hands-on training on the robotic surgical simulator (RoSS), developed at RPCI. “Dr Guru partnered with the scientists at the University of Buffalo’s biomedical engineering department to produce exact clinical fields that create realistic intraoperative experiences, including complications,” said Trump. “He then went on to found a company to produce the software that controls the robot.”

	RPCI’s training center is funded by 4 foundations and investigators are now beginning to assess the results of such training, as well as the potential benefits of being able to “warm up” on the simulator before operating on patients. “The technology is improving and the applications are expanding to gynecologic, colorectal, thoracic, and head/neck cancers, as well as some noncancerous conditions,” said Guru. “But allowing the technology to ‘outrun’ the training will be like letting the tail wag the dog,” he cautioned.

	Small but Mighty: A Culture of Excellence

Articles

Founded in 1898 by Dr Roswell Park, Roswell Park Cancer Institute (RPCI) is the oldest dedicated comprehensive cancer center in the country

Roswell Park Cancer Institute: A History of Initiative and Innovation

 Investigators have reported an increased risk of invasive breast cancer in postmenopausal women who are or were cigarette smokers, particularly those who smoked with high intensity and for a long time. The results are from an analysis of 79,990 women aged 50 to 79 years who were enrolled in the prospective Women’s Health Initiative Observational Study from 1993 through 1998. The federally funded study was undertaken to examine major causes of morbidity and mortality in postmenopausal women. Overall, 3250 cases of invasive breast cancer were identified during 10.3 years of follow-up.

	The data also showed an increased breast cancer risk in nonsmokers with extensive exposure to passive smoking. However, the authors said that the link between passive smoking and breast cancer risk is suggestive rather than definitive and requires corroboration from other studies.

	“Our findings highlight the need for interventions to prevent the initiation of smoking, especially at an early age, and to encourage smoking cessation at all ages,” reported Juhua Luo, MD, of West Virginia University in Morgantown, and colleagues.

	The researchers conducted their analysis to determine the associations between active smoking, passive smoking, and breast cancer in postmenopausal women. Information on active smoking included smoking status; women who were current or former smokers were also asked when they started smoking, how many cigarettes they smoked per day, and how many years they had smoked. Former smokers were asked at what age they quit smoking. Questions on passive smoking focused on whether the participants resided in smoking households as children and/or as adults and whether there was smoking at their workplace.

	Recent cohort studies have shown an increased risk of breast cancer in women who started smoking at a young age or who smoked for several years, noted Luo and associates. An increased risk of breast cancer in women exposed to passive smoking has also been suggested; however, research to date has generally involved incomplete assessment of exposure information.

	The present analysis revealed that current smokers had a 16% increased risk of developing breast cancer after menopause and former smokers had a 9% increased risk. The increased risk was especially pronounced “with smoking of high intensity, of long duration, and [that] started at an early age.”

	“Our findings highlight the need for interventions to prevent the initiation of smoking, especially at an early age, and to encourage smoking cessation at all ages.”

	Among former smokers, there was a significant inverse association between the time since quitting and breast cancer risk. Also, the increased risk of breast cancer persevered for as long as 20 years after smoking cessation.

	The researchers also found that nonsmoking women who had been exposed to extensive passive smoking had a 32% increased risk of breast cancer. Extensive exposure was defined as exposure during childhood ≥10 years, exposure as an adult at home ≥20 years, and exposure as an adult at work ≥10 years. The authors noted that since the risk of breast cancer was confined to the most extensive passive smoking category with a lack of a clear dose response, the association with passive smoking is only suggestive pending confirmation in additional studies.

	Finally, current smoking was more strongly associated with lobular cancer than with ductal cancer and with tumors that were hormone receptorpositive (for both estrogen and progesterone) than the other 3 combinations of receptor status.

	Luo and colleagues said that the results underscore the need for interventions to prevent women from smoking altogether and the need for interventions to promote smoking cessation at all ages. Future studies should seek to explain how genetic polymorphisms and other risk factors modify the impact of tobacco exposure on breast cancer risk.

	Luo J, Margolis KL, Wactawski-Wende J, et al. Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study. 

Investigators have reported an increased risk of invasive breast cancer in postmenopausal women who are or were cigarette smokers

Smoking Increases Breast Cancer Risk in Postmenopausal Women

Nephron-sparing surgery is more effective than radical nephrectomy for preserving long-term renal function in patients with renal tumors >4 cm, a German team has found. Importantly, nephron-sparing surgery seems to be the superior approach, irrespective of the patient’s age.

	Frederik C. Roos, MD, from Johannes Gutenberg University in Mainz, Germany, and colleagues examined functional outcome in patients undergoing elective treatment for unilateral renal tumors >4 cm. The study included 81 “younger” patients who were aged <55 years and 85 “older” patients aged >65 years.

	Overall, 84.5% of younger and 75.8% of older patients maintained good long-term renal function with nephron-sparing surgery. The researchers pointed out that this is important given that loss of renal function is associated with increased cardiac mortality, decreased physiological reserves in multiple organ systems, and a higher incidence of cardiovascular disease.

	Renal cell carcinoma primarily affects individuals in their 60s and 70s. Nephron-sparing surgery has been the mainstay of treatment in patients presenting with renal tumors ≤4 cm and is recommended for cT1b lesions at high-volume cancer centers. There are, however, limited data on oncologic or perioperative outcomes in elderly patients undergoing elective nephronsparing surgery for renal tumors >4 cm compared with radical nephrectomy.

	Roos and colleagues believed that open radical nephrectomy was overused in older patients in order to minimize operating time, even in patients with small tumors (cT1a), and thus decided to examine whether elderly patients would benefit from nephron-sparing surgery. The median length of follow-up in their study was 5.69 years for younger patients and 5.48 years for older patients. Renal function and perioperative morbidity were co-primary endpoints. Overall survival (OS) was a secondary endpoint.

	When deciding between radical nephrectomy and nephronsparing surgery in renal tumors >4 cm, clinicians need to carefully consider tumor characteristics, comorbidities, biological age, and the patient’s own wishes.

	Results showed that the incidence of new onset of chronic kidney disease in younger patients was 31.1% after radical nephrectomy and 15.5% after nephron-sparing surgery. The corresponding figures in older patients were 50.9% and 24.2%, respectively. Chronic kidney disease was defined as a glomerular filtration rate <60 mL/min/1.73m

. Complications occurred in 34.5% of younger patients and 25.8% of older patients (P = .656).

	OS did not differ significantly between the 2 procedures in young (P = .655) and older patients (P = .058). The authors suggested that the lack of a difference in OS between younger and older patients may be due to “an underpowered statistical analysis for OS and a lack of follow-up in both age groups mainly after radical nephrectomy.”

	Roos and associates emphasized that when deciding between radical nephrectomy and nephronsparing surgery in renal tumors >4 cm, clinicians need to carefully consider multiple factors. These include tumor characteristics, comorbidities, biological age, and the patient’s own wishes and social support. If nephron-sparing surgery is deemed feasible in a given patient, it is preferable to radical nephrectomy for both younger and older patients.

	Eventually, minimally invasive techniques, including robotassisted laparoscopy and thermal ablation, may have expanded indications to include the treatment of patients with more severe comorbidities and tumors >4 cm, they added.

	Roos FC, Brenner W, Jäger W, et al. Perioperative morbidity and renal function in young and elderly patients undergoing elective nephron-sparing surgery or radical nephrectomy for renal tumours larger than 4 cm. 

 2011. Feb;107(4):554-61. doi: 10.1111/j.1464- 410X.2010.09516.x. Epub ahead of print, August 12, 2010.

Nephronsparing surgery seems to be superior to radical nephrectomy, irrespective of the patient's age

Nephron-Sparing Surgery Leads to Better Functional Outcomes for Large Renal Tumors

	New data suggest that individuals who drink moderate amounts of alcohol, defined as 2 or 3 drinks a day, have an increased likelihood of developing colorectal cancer. The findings also support prior evidence of a causal relationship between a high alcohol intake and increased colorectal cancer risk.

	Veronika Fedirko, MD, of the International Agency for Research on Cancer (IARC) in Lyon, France, and colleagues conducted a metaanalysis involving 27 cohort and 34 case-control studies published before May 2010 on alcohol consumption and colorectal cancer.

	“The results from this largescale meta-analysis have important public health implications, given the large number of women and, especially, men consuming alcohol and the high incidence of colorectal cancer worldwide and in developed countries, in particular,” reported Fedirko and colleagues.

	According to the World Health Organization (WHO), roughly 2 billion people worldwide consume alcohol beverages—an average of 6.2 liters of ethanol per adult per year&mdash;on a regular basis.

	The IARC has concluded that alcohol consumption is related to colorectal cancer. However, several questions remain unanswered, including the dose-risk relationship of alcohol and colorectal cancer. It is also unclear whether the effect of alcohol varies for colon and rectal anatomical subsites and whether the effect varies by sex and geographical region.

	All studies in the meta-analysis included results for at least 3 categories of alcohol consumption. Light alcohol drinking was defined as the consumption of ≤1 drink per day (≤12.5 g/day of ethanol), moderate drinking as 2 or 3 drinks/day (12.6 to 49.9 g/day of ethanol), and heavy drinking as the consumption of ≥4 drinks/day (≥50 g/day of ethanol).

	“The results from this large-scale meta-analysis have important public health implications, given the large number of women and, especially, men consuming alcohol and the high incidence of colorectal cancer worldwide and in developed countries, in particular.”

	Compared with nondrinkers or occasional alcohol drinkers, moderate and heavy drinking were associated with a 21% and 52% increased risk of colorectal cancer, respectively. Light alcohol consumption was not associated with an increased cancer risk. The investigators also found that the association of alcohol drinking with colorectal cancer did not differ by colon and rectal anatomic subsites.

	The association between alcohol drinking and colorectal cancer risk was slightly stronger among Asian populations. The authors suggested that this finding may be a function of the high prevalence among Asians of the slow-metabolizing variant of aldehyde dehydrogenase enzyme, which is associated with increased blood levels of acetaldehyde after alcohol ingestion. Nongenetic factors, such as body composition, may also play a role.

	Fedirko and colleagues said that the findings mean that public health recommendations for colorectal cancer prevention should include limiting consumption of alcoholic beverages. However, the results need to be interpreted with caution given that high alcohol intake may be associated with behaviors that predispose to colorectal cancer, such as cigarette smoking, unhealthy diet, and low physical activity.

Fedirko V, Tramacere I, Bagnardi V, et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response metaanalysis of published studies. 

 2011 Feb 9. doi:10.1093/annonc/ mdq653. [Epub ahead of print]

New data suggest that individuals who drink moderate amounts of alcohol have an increased likelihood of developing colorectal cancer

Two or More Drinks a Day Increases Colorectal Cancer Risk

Analysis of a National Cancer Institute (NCI) database suggests that using age 70 as the cutoff for cervical cancer screening might omit women who account for a growing proportion of the at-risk population. More than 12% of newly diagnosed cervical cancers occurred in women aged 70 to 85 years during 2000 to 2006. The rate was similar to the incidence in younger women who are more often associated with the cancer. Among older women, about 60% of cervical cancer diagnoses occurred at later disease stages, which have fewer treatment options.

	“On the basis of these findings, it is fair to ask whether the current screening schedule for cervical cancer is contributing to the cervical cancer distribution pattern,” said Malgorzata E. Skaznik-Wikiel, MD, an oncologist at Magee-Womens Hospital in Pittsburgh, Pennsylvania. “The findings also question whether we need a more structured cervical cancer screening program for women over the age of 70.”

	Skaznik-Wikiel made the comments during a presentation at the recent Society of Gynecologic Oncologists meeting in Orlando, Florida.

	Current clinical guidelines recommend discontinuation of cervical cancer screening with Pap tests in women aged >65 years who meet certain criteria: 3 consecutive normal Pap tests, no history of abnormal tests in the past 10 years, and no history of cervical dysplasia or neoplasia.

	To examine the recommendations within the context of contemporary epidemiologic trends, Skaznik-Wikiel and colleagues analyzed data from the NCI Surveillance, Epidemiology and End Results (SEER) program. They found that women aged 70 to 85 years accounted for 12.18% of the 18,000 new cases of cervical cancer during 2000 to 2006. The percentage was similar to the rates of 12.55% to 14.99% among women aged 35 to 49 years.

	The stage distribution of cervical cancer varied between older and younger women. Among women aged <30 years, stage IA1 was most common (38%) and stage IA1-IB comprised three-quarters of all cases. In contrast, stage IIIB was most common among women aged >69 years (19%), and advanced stages (IIB-IVB) accounted for 59% of all diagnoses in that age group.

	Skaznik-Wikiel said that several factors, which conspire to create an age-incidence disparity, confound current cervical cancer screening recommendations for older women:

		Inaccurate results (both false-positive and falsenegative), which are more likely in older women because of sampling issues and because of age-related cellular changes that resemble neoplasia

		The changing epidemiology of human papillomavirus (HPV) infection, whose rates of infection decline in women aged 30 to 70 years but then begin to increase

	“Women older than 65 account for 13% of the US population but 25% of new cervical cancer diagnoses,” said Skaznik-Wikiel.

More than 12% of newly diagnosed cervical cancers occurred in women aged 70 to 85 years during 2000 to 2006

Age Cutoff for Pap Tests Questioned

	Investigators in a cooperative group trial reported that modifications in a chemoradiation regimen for locally advanced vulvar cancer boosted both clinical and pathologic complete response rates compared with historical results.

	About two-thirds of patients had clinical complete responses and more than half had no evidence of disease on pathologic examination. That compared with 48% of patients who had no gross residual disease in the Gynecologic Oncology Group (GOG) 101 trial, which established a widely used chemoradiation regimen. The new trial, GOG 205, employed a higher dose of radiation but a less-intense fractionation schedule than used in GOG 101, according to details presented at the recent Society of Gynecologic Oncologists meeting in Orlando, Florida.

	“Although there is still considerable room for improvement, the results of GOG 205 would indicate that this is a reasonable standard for [the] treatment of locally advanced squamous cell carcinoma of the vulva and should be the treatment program for future comparisons in prospective trials,” said David H. Moore, MD, a gynecologic oncologist at the St. Francis Medical Group in Indianapolis, Indiana.

	In response to questions that followed his presentation, Moore declined to call the regimen the standard of care and instead referred to it as a standard.

	Investigators in GOG 101 evaluated concurrent preoperative chemoradiation with cisplatin and 5-FU. Patients received a total radiation dose of 4760 cGy, delivered twice daily during chemotherapy. Additionally, patients had a drug holiday between the first and second cycles of therapy.

	"Although there is still considerable room for improvement, the results of GOG 205 would indicate that this is a reasonable standard for [the] treatment of locally advanced squamous cell carcinoma of the vulva and should be the treatment program for future comparisons in prospective trials."

	In GOG 205, patients received a total radiation dose of 5760 cGy administered in single daily fractions. Chemotherapy consisted of weekly cisplatin at a dose of 40 mg/m2. Investigators also eliminated the treatment break. The primary endpoint was pathologic complete response, which occurred in half of the 58 patients enrolled in GOG 205. Additionally, 37 (64%) of the patients had clinical complete responses. The principal toxicities were hematologic adverse events, radiation-related dermatitis, pain, and metabolic disturbances.

	Responding to another question, Moore suggested that the increased radiation dose probably accounted for most of the improvement in GOG 205 compared with GOG 101. Elimination of the treatment break also might have made a difference.

Investigators in a cooperative group trial reported that modifications in a chemoradiation regimen for locally advanced vulvar cancer boosted both clinical and pathologic complete response rates

Tinkering With Regimen Leads to Better Outcomes in Vulvar Cancer

	The results of a small clinical trial showed that low-level expression of a microRNA correlated with improved progression-free survival (PFS) in women with advanced ovarian cancer treated with chemotherapy plus the angiogenesis inhibitor bevacizumab.

	Patients with low microRNA-378 (miR-378) expression had a median PFS of 9.2 months, more than double the 4.2-month PFS among patients with normal miR-378 expression (P = .035). No patient with normal miR-378 expression survived progression-free for as long as 6 months, said John K. Chan, MD, at the recent Society of Gynecologic Oncologists meeting in Orlando, Florida.

	“Our data suggest that miR-378 is associated with treatment response after bevacizumab and chemotherapy in recurrent ovarian cancer,” said Chan, an oncologist at the University of California, San Francisco. “Differential microRNA expression may have clinical utility in determining response to novel therapeutics.”

	MicroRNA is noncoding, singlestranded RNA involved in the regulation of gene expression. Some studies have suggested that microRNA expression may predict response to chemotherapy and influence cancer survival. However, no studies had examined associations between microRNA expression and biologic therapy, said Chan.

	Using clinical and genetic information from the National Institutes of Health’s Cancer Genome Atlas, investigators identified 34 patients with recurrent serous ovarian cancer treated with chemotherapy and bevacizumab at recurrence. A search of the 800 microRNAs in the atlas revealed 33 that exhibited at least a twofold differential expression in tumors versus normal tissue from the same patient. The list of candidate microRNAs was subsequently whittled down to 5.

	Comparing expression of the 5 microRNAs with clinical data, Chan and colleagues found that miR-378 expression had the strongest association with response to bevacizumab. Six of 10 patients with low-level expression had a progression-free interval of at least 6 months, compared with none of the 24 patients with normal miR-378 expression (P <.001).

	Additional analyses showed that miR-378 expression was specific to bevacizumab and PFS. Differential expression of the microRNA did not predict response to chemotherapy or overall survival. In a multivariate analysis, only 2 factors remained significant as predictors of response to bevacizumab: the treatment-free interval of the last therapy before bevacizumab (P = .03) and miR-378 expression (P = .02).

	Chan said that future studies will include examination of miR-378 gene targets that might influence response to bevacizumab. The microRNA is thought to affect expression of several genes involved in tumor angiogenesis.

The results of a small clinical trial showed that low-level expression of a microRNA correlated with improved progression-free survival

MicroRNA May Predict Response to Bevacizumab

Results of a phase II cooperative-group trial showed that the targeted agent cetuximab demonstrated minimal activity in patients with advanced, platinum-resistant cervical cancer. No patient had an objective response, and fewer than 15% of patients survived for at least 6 months when treated with the inhibitor of epidermal growth factor receptor (EGFR). A possible suggestion of activity in squamous cell histology tumors offered the only encouragement from an otherwise negative study.

	“Although the overall level of activity in the current report does not justify a phase III trial of cetuximab in heavily pretreated, advanced, and recurrent cervical cancer, the current data cannot rule out potential activity of cetuximab in patients harboring cervical tumors with squamous cell histology,” said Alessandro D. Santin, MD, a gynecologic oncologist at Yale University, in a presentation at the recent Society of Gynecologic Oncologists recent meeting in Orlando, Florida.

	EGFR is overexpressed in several types of malignancy, including cervical cancer, providing a rationale for evaluating anti-EGFR therapy in the disease. The Gynecologic Oncology Group chose patients with previously treated, metastatic cervical cancer for the clinical evaluation of cetuximab. Eligible patients had recurrent or metastatic cervical cancer with a treatment history of 1 or 2 prior regimens, 1 of which had to be platinum-based. Cetuximab therapy began with a 400-mg loading dose, followed by 250 mg weekly until progression. The primary endpoint was 6-month survival.

	Investigators enrolled 35 patients. The trial design required 7 objective responses and for 7 patients to survive progression-free for 6 months or longer as the minimum activity to justify a phase III trial.

	Santin reported that no patient had an objective response, and 5 (14.2%) patients survived at least 6 months during treatment with cetuximab. The median progression-free survival (PFS) was 1.97 months, and median overall survival was 6.7 months.

	Analysis of response and survival by tumor histology showed that all 5 patients who survived a PFS of at least 6 months had squamous cell histology. In contrast, none of 11 patients with adenosquamous cell or adenocarcinoma histology survived without progression for 6 months.

Results of a phase II cooperative-group trial showed that the targeted agent cetuximab demonstrated minimal activity in patients with advanced, platinum-resistant cervical cancer

Study Indicates Cetuximab Provides No Benefit in Advanced Cervical Cancer

 (noun). A situation that requires a choice between options that are or seem mutually exclusive. 

Thorndike-Barnhart Comprehensive Desk Dictionary (1962)

	The current question facing patients, physicians, payers, and society is: Can we truly afford to provide each patient diagnosed with cancer comprehensive, state-of-the-art care until death? Or can we afford not to?

	In 1971, President Richard M. Nixon declared war on an enemy that each year claimed the second largest number of lives in the United States: a disease called cancer. At the time, little was known about the cause and biologic mechanisms of cancer, yet there was a national consensus that more information was needed to achieve victory over this dreaded disease. Consequently, President Nixon signed into law the National Cancer Act, which gave the National Cancer Institute (NCI) privileged autonomy and funding separate from the National Institutes of Health.

	As we celebrate the 40th anniversary of its signing, the National Cancer Act’s “societal benefits” remain in question, according to a comprehensive review published recently (

 2011;331[6024]:1539). President Nixon would be pleased to know that there is little doubt regarding the clinical benefits that have stemmed from the National Cancer Act. The incidence of cancer started dropping in 1990 and continues to do so, as do the overall mortality rates among patients with cancer. Surveillance, Epidemiology, and End Results (SEER) data confirm that age-adjusted death rates have dropped from over 200 per 100,000 pre-1971 to 178 per 100,000 in 2007. The prevalence of cancer has increased significantly as well, primarily due to the increased survivorship as a result of more effective therapies. Vincent T. DeVita, Jr, MD, former director of NCI, recently stated, “The War on Cancer did everything it was supposed to do…. Every benchmark of the mandate—better understanding of the biology, improved survival, lower incidence&mdash;was hit.”

	Despite the progress made in the War on Cancer, a President has another important duty: namely, to protect the integrity of our national economy. Data published in 1965 by the Centers for Medicare & Medicaid Services showed healthcare expenditures to be 5% of gross domestic product (GDP). Since then, healthcare expenditures have outpaced growth in GDP and are rapidly approaching 20%—a growth rate considered unsustainable by everyone on both sides of the aisle.

	The cost of cancer care is increasing dramatically in large part due to the fruits of the National Cancer Act. Until 1996, the standard use of 5-fluorouracil and leucovorin for metastatic colon cancer resulted in a median response rate of 12 months at a cost of $100 for 6 months of therapy. While a better understanding of the molecular basis of metastatic colon cancer has led to the development of new agents that have significantly increased patients’ median survival (now 21 months), these advances also come at a remarkable increase in cost. For example, the aggregate cost of treating metastatic colon cancer can easily exceed $150,000 for an additional year of survival, compared with 5-fluorouracil and leucovorin alone. Today, translational medicine is transforming outcomes for cancer patients. Recent drug approvals like sipuleucel-T (Provenge) for metastatic prostate cancer and ipilimumab (Yervoy) for metastatic melanoma significantly increase survival, but at a cost in excess of $100,000 for a single course of therapy.

	Economists use the term “moral hazard” to describe situations where consumers insulated from risk behave differently than those who bear the full risk. We often see this behavior in healthcare when insured patients who only pay a portion of the cost of treatment (ie, copays) actually drive up the demand for more—and even more expensive&mdash;care compared to patients who have to bear the full cost of care. To combat the effects of this type of moral hazard, the current healthcare dialogue now includes discussions with patients about things such as when the appropriate time is to initiate palliative care. Such discussions are designed, in part, to avoid unnecessary expenditures. In the UK, this dialogue has been elevated to the point where governmental agencies evaluate the costeffectiveness of a given therapy to determine if it is worth the investment, and then possibly deny the therapy even if it prolongs survival.

	One wonders what President Nixon would have done if he knew his actions would dramatically improve the outcomes for cancer patients, but at the same time put the nation at risk of becoming fiscally unsound and uncompetitive on a global scale, largely due to the dramatic increase of cancer care expenditures. Yogi Berra, the great philosopher and former New York Yankee, once said, “When you come to a fork in the road, take it.” We are clearly at a fork in the road. Do we limit access to lifeextending care or spend ourselves into insolvency? It is no longer President Nixon’s dilemma, it is ours.

	Hopefully, the broad use of evidence-based guidelines and the continued efforts in translational medicine to find cures—and not just therapies that extend survival&mdash;will allow every cancer patient to benefit from the intent of the National Cancer Act without the risk of a moral dilemma.

Can we truly afford to provide each patient diagnosed with cancer comprehensive, state-of-the-art care until death? Or can we afford not to?

President Nixon's Dilemma

Translational medicine is currently the focus of much attention in the medical and research community and is the wave of the foreseeable future. “Translational medicine” is a catchphrase for the attempt to improve communication between basic science and clinical medicine so as to accelerate the development of drugs that attack key targets involved in diseases. This involves a multidisciplinary effort with continuous feedback, collaboration, and data-sharing.

	Vast amounts of money are being spent in this effort by the federal government and pharmaceutical companies. The Translational Research Working Group (TRWG) was established to work with the cancer research community to develop recommendations about how the National Cancer Institute could best organize its efforts to further translational research. The TRWG defined a translational continuum and developed a “roadmap” to create a stronger research infrastructure to accelerate the clinical research enterprise. The field has moved forward with its own journal—the 

	Efforts in translational medicine have paid off in the development of cancer treatments like imatinib (Gleevec) for chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs) and trastuzumab (Herceptin) for HER2/

-positive breast cancer. Both imatinib and trastuzumab have in fact revolutionized treatment of these respective cancers and are lifesaving for patients who previously had no good treatment options.

	According to researchers, prostate cancer poses a major challenge for those involved in translational medicine, mainly due to its heterogeneity. However, progress is being made on several fronts.

According to Robert DiPaola, MD, of The Cancer Institute of New Jersey at Robert Wood Johnson Medical School in New Brunswick, New Jersey, the field of prostate cancer is advancing due to a greater synergy between basic research and clinical science, aided by the discovery of molecular pathways, genetic alterations, mechanisms of drug resistance, and findings based on the clinical effectiveness of specific therapies.

	DiPaola reviewed advances in characterization of targets and the pathways that drive prostate cancer in terms of discovering targets for drug development. He also discussed oncogenic targets, such as growth signaling pathways and apoptosis, and said that a more recent focus for drug development is nononcogenic stress response targets.

	“Prostate cancer is a heterogeneous disease, making it difficult to personalize treatment,” he said. “The identification of new targets, made possible by sophisticated DNA microarrays from prostate cancer specimens, will move the field forward.” Some new targets include TMPRSS22- ERG, RAF, P13K, RAS/RAF, Rb, and SRC.

	Fusions of the androgen-responsive gene TMPRSS22-ERG with transcription factors ERG or ETV1 (both members of the ETS family of transcription factors) have been identified in prostate tumors. Fusions of TMPRSS22-ERG occur in about 50% of invasive cancers, and fusions involving TMPRSS22 with other ETS family proteins occur in an additional 10% of prostate cancers. Genetic rearrangements have been found in 1% to 2% of prostate cancer specimens. In these tumors, DiPaola explained, RAF overexpression seems to be the driving molecular event. This suggests a potential role for small-molecule RAF inhibitors in this subset of patients.

	Transcriptome and mutation analysis CNA data have identified P13 kinase (P13K), RAS/RAF, and Rb as oncogenic targets. Overexpression of these genes is predictive of biochemical recurrence following radical prostatectomy.

	"The identification of new targets, made possible by sophisticated DNA microarrays from prostate cancer specimens, will move the field forward."

	Based on this research, DiPaola said that there is now a rationale for the combination of targeted therapies in the treatment of prostate cancer. During the past 10 years, there has been a 143% increase in options for treating prostate cancer, and there are now more than 800 agents in clinical development. In general, combination therapies fall into 3 strategies: identification and maximum inhibition of pathways (eg, synthetic lethal screens); inhibition of compensatory pathways; and targeting resistance of “successful” agents.

	The hallmarks of targets for cancer therapy have been cell survival, proliferation, and immune evasion. New nononcogenic targets have been identified, including the following new stress phenotypes: mitotic stress, metabolic stress, proteotoxic stress, oxidative stress, and DNA damage stress.

	Most of the drugs studied in clinical trials of castration-resistant prostate cancer (CRPC) are aimed at oncogenic targets. Some examples of targets and drugs aimed at those targets are P13K (everolimus and deforolimus); VEGF/ VEGFR (sorafenib, sunitinib, and bevacizumab); Bcl-2 (oblimersen, ABT-263); insulin growth factor (IMC A-12); and androgen receptor (AR)/ CYP17 (abiraterone, MDV3100, and immune targets [sipuleucel-T, PROST-VAC, ipilimumab, MDX-1106]).

	Novel agents targeted to self-sufficiency in growth signal and evading apoptosis—both oncogenic targets&mdash;are under development. These include abiraterone and MDV3100. The PTEN gene is lost or mutated in 0% to 80% of prostate cancers, activating P13K/AKT, which DiPaola said supports further studies of P13K and AKT inhibitors in prostate cancer. Other novel agents are aimed at evading apoptosis. BH3 mimetics in early stages of clinical development include ABT- 264, AT-101, PARP inhibitors, and GX-15070.

	DiPaola said that this type of research was showcased at the recent ASCO Genitourinary Cancers Symposium (ASCO GU) held in Orlando, Florida, in February, where 3 different poster presentations focused on early studies of AT-101. A phase II trial evaluated AT-101 to abrogate Bcl- 2-mediated resistance in patients with newly diagnosed androgen-dependent prostate cancer (Abstract 173). A randomized, double-blind, phase II study evaluated docetaxel and prednisone combined with AT-101 or placebo as first-line therapy for CRPC (Abstract 125). A phase I trial looked at the combination of AT-101 plus paclitaxel plus carboplatin in solid tumors and prostate cancer (Abstract 169). A different recent study looked at Bcl-2 inhibition with ABT 263/737 in prostate cancer, DiPaola said.

Regarding nononcogenic stress response targets, DiPaola said that they can be identified by synthetic lethal screens. Examples of targets identified by synthetic lethal screens include the use of PARP inhibitors targeted to tumors with BRCA1 and BRCA2 mutations, mitotic stress, mitochondrial metabolism, and reactive oxygen species generation.

	A more definitive example of a nononcogenic target is autophagy, DiPaola noted. “We were focused on apoptosis for a long time, and now it turns out that autophagy is an important survival mechanism in prostate cancer,” he said. Autophagy refers to how a cell deals with oxidative, metabolic, and proteotoxic stress. If autophagy is present, cells can withstand a great degree of stress. There are not many drugs to act on this pathway, but hydroxychloroquinolone is being studied in this regard.

	A poster presented at ASCO GU focused on patients with a rising PSA after primary therapy for prostate cancer with no evidence of metastasis who were treated with hydroxychloroquinolone (Abstract 164), with the rationale that blocking autophagy would be beneficial. The authors said that the drug appeared to have some activity in PSA progression, including increasing PSA doubling time and reducing PSA, but further study using higher doses is needed.

	The novel agent ABT-737 induces autophagy, and preclinical data suggest that when this drug is combined with hydroxychloroquinolone the effect is strong. There are at least 4 other ongoing trials that are targeting autophagy.

	“The bottom line is that we have moved the field forward by characterizing prostate cancer and discovering new oncogenic and nononcogenic targets for drug development,” said DiPaola. “Now the research needs to be done.”

	Schlom listed the following takeaway points from the vaccine trials:

		Vaccines as monotherapy do not appear to influence time to progression, but they do improve survival. Vaccines appear to change the growth rate of the tumor, Schlom noted. “We propose that if you get to the patient early on [with a vaccine], you can change the growth rate of the tumor and improve survival,” he said.

		Vaccines have little toxicity, according to the 2 phase III trials of sipuleucel-T and the 2 phase II trials of PSA-TRICOM. Schlom said, “This is important and often overlooked.”

		It takes time for the vaccine to exert its effect. Unlike other therapies, vaccines do not act directly on tumor cells; they activate the host immune system. Thus, unlike other prostate cancer therapies, continued boosting by vaccine should enhance therapeutic efficacy without enhanced toxicity. “This may well be the reason delayed efficacy of vaccines are observed,” he noted. “At times, vaccine therapy may be withdrawn prematurely due to disease progression, not allowing the additional immune stimulation of booster vaccines to take effect.”

		Unlike chemotherapy, after vaccination the vaccine-activated immune response endures. This may in turn slow the growth rate of the tumor, but may not be strong enough to eliminate tumor mass. This fits in with the observed lack of difference between vaccine and placebo in time to progression but with meaningful and statistically significant differences in OS.

		The long-lived immune response induced by vaccines can have a robust effect on concomitant or subsequent therapies for prostate cancer.

Several combination studies of vaccines plus other therapies are ongoing or are in the planning stages. One completed study has utilized PSA-TRICOM alone or with ipilimumab. An ongoing study is comparing the effect of Quadramet (153 Sm chelate) alone versus Quadramet plus vaccine in men with prostate cancer and bone metastases. A multicenter trial has just been initiated in patients with metastatic prostate cancer that is comparing docetaxel/prednisone alone versus 3 months of PSA-TRICOM vaccine followed by docetaxel/prednisone. Moreover, an ongoing trial in advanced prostate cancer patients is comparing flutamide plus or minus vaccine.

	In summary, combination therapy with vaccine and other agents that either stimulate the immune system or suppress inhibitory factors, or the eventual use of combinations of vaccines, suggests that vaccines may have a role both as monotherapy in early-stage disease and in numerous types of combination therapies for patients with later-stage disease.

Jeffrey Schlom, PhD, of the NCI’s Center for Cancer Research in Bethesda, Maryland, is involved in research on vaccines for prostate cancer. He reviewed phase III studies of sipuleucel-T (Provenge), the first FDA-approved vaccine for prostate cancer, which is made from the patient’s own antigen-presenting cells and a tumor antigen, and phase II trials of an off-the-shelf vaccine under development by NCI called PSA-TRICOM.

	“At NCI, we are focusing on developing an off-the-shelf vaccine to be used early in the course of prostate cancer in patients with low tumor burden,” Schlom said.

	Why is immunization an attractive strategy for prostate cancer? He said, “Immune targeting of prostate cancer has reached a tipping point in terms of agents and strategies leading to patient benefit, with great potential for the use of vaccines in combination with chemotherapy, radiation, hormone therapy, and/or small molecule-targeted therapeutic agents.”

	Sipuleucel-T was recently approved by the FDA for treatment of metastatic castrationresistant prostate cancer (CRPC), based on phase III trials. In 1 randomized phase III trial, median overall survival (OS) was 25.8 months for men treated with the vaccine versus 21.7 months for placebo, representing a survival difference of 4.1 months (P = .032). Schlom pointed out that there was no difference between the 2 arms in time to progression, which gives an indication of how vaccines exert their effects.

	“The results of this phase III trial were virtually identical to a previous phase III trial of sipuleucel-T where the primary endpoint was time to progression and was not reached, but the vaccine demonstrated a clear statistically significant difference from placebo in median overall survival,” Schlom said.

	Sipuleucel-T is a unique vaccine platform in which the patient’s own leukapheresed product is sent to a central laboratory for processing. There the patient’s own antigen-presenting cells are incubated with a fusion protein. The vaccine is then shipped back to the treating site where it is reinfused. This process happens every 2 weeks for a total of 3 treatments. Schlom emphasized that the interval between processing of the vaccine and administration of therapy is short and the treatment has little toxicity.

	PROSTVAC is a second vaccine that is undergoing evaluation in the setting of metastatic CRPC. This off-the-shelf vector vaccine consists of a prime-boost regimen of 2 different viruses (ie, recombinant vaccinia prime and usually 5 to 6 recombinant fowlpox boosters), each containing transgenes for PSA and 3 costimulatory molecules (TRICOM) aimed at boosting the immune system.

	"At times, vaccine therapy may be withdrawn prematurely due to disease progression, not allowing the additional immune stimulation of booster vaccines to take effect."

	In 1 randomized, placebo-controlled phase II trial, PSA-TRICOM (ie, PROSTVAC) achieved 3-year OS of 30% versus 17% of controls. Median OS was 8.1 months longer in those treated with PSA-TRICOM (25.1 months vs 16.6 months, respectively). That trial was conducted at 43 centers and included 125 patients with metastatic CRPC.

	“An important point is that there was no difference between the treatment arms in time to progression—similar to the sipuleucel-T trials&mdash;and the vaccine had little toxicity,” Schlom stated.

	A second single-arm trial that included 32 patients with metastatic CRPC found that, similar to the randomized phase II trial, PSA-TRICOM achieved median OS of 26.6 months, which was 9.2 months longer than survival of these patients predicted by the Halabi nomogram, a tool used to predict the aggressiveness of metastatic prostate cancer. Investigators from the same institution treated patients with docetaxel alone and reported median OS similar to that predicted by the Halabi nomogram.

	Schlom pointed out that patients treated with PSA-TRICOM in the single-arm phase II trial had a median OS similar to that predicted by Halabi if the Halabi Predictive Score (HPS) was ≤18 months, while those with more indolent disease and tumor burden (ie, HPS of >18 months) had a median OS far better than that predicted by HPS.

	The Androgen Receptor in Prostate Cancer

Prostate cancers of all stages are exquisitely dependent on the activity of the AR, explained Karen E. Knudsen, PhD, of the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania. Androgen ablation is considered first-line therapy for cancers that have spread beyond the prostate. Knudsen said that despite available therapies, CRPC can develop, and there is no effective therapy for it.

	Experts agree that despite hormonal therapy, a proportion of CRPCs emerge due to recurrent activation of the AR. One of the events that drives CRPC is AR deregulation. Tumors with a high level of AR are associated with an increase in mortality and disease progression. Mechanisms responsible for activation of the AR receptor fall into 3 different categories: those that directly affect AR modulation, those that involve alterations in AR cofactors, or those that promote intratumor ligand synthesis.

	“The most frequently observed mechanism [of AR reactivation] to date involves upregulation of AR levels,” Knudsen said. But she added that the mechanisms that underlie AR deregulation are not well understood.

	Knudsen and colleagues have identified retinoblastoma tumor suppressor (Rb) as a mechanism that controls AR levels, AR signaling, and the transition to CRPC.

	“Retinoblastoma tumor suppressor constrains the transition to CRPC by supporting Rb function,” she said. “Perturbation of Rb function is a key driver of human CRPC development. Further analysis suggests that the Rb gene locus may be a major mechanism involved in Rb disruption.” Clinical studies also suggest that loss of Rb function is associated with poor outcome in men with prostate cancer.

	“Taken together, these observations suggest that a new paradigm is emerging for the role of Rb in prostate cancer progression,” she said.

	"The present studies support the hypothesis that pharmacologic awakening of Rb activity in Rb-positive tumors could be clinically beneficial."

	Knudsen posed 3 questions: (1) How relevant/frequent is Rb loss? (2) How can it be detected? and (3) Is this a new opportunity for therapeutic intervention?

	She said that the 159 gene signature for Rb loss can be detected by immunohistochemistry, and it is frequently seen in CRPC. Rb loss of function is enriched in CRPC. Patients that scored as having Rb loss of function had reduced progression-free survival. Knudsen believes that Rb loss presents a new opportunity for therapeutic interventions.

	Rb status should be considered in the management of prostate cancer, she said. Studies are needed to determine whether Rb status should be developed as a measure for predicting poor response to androgendeprivation therapy and AR-directed therapeutics.

	“The present studies support the hypothesis that pharmacologic awakening of Rb activity in Rb-positive tumors could be clinically beneficial,” Knudsen explained. “Human tissue explants are being used to study this hypothesis using a Pfizer CDK4 inhibitor: PD 0332991. These studies show that Rb-enriched tumors respond to CDK4 inhibitors.”

	Knudsen and her colleagues are also testing the hypothesis that Rb-deficient tumors are hypersensitive to selected chemotherapy agents.

Translational medicine is currently the focus of much attention in the medical and research community and is the wave of the foreseeable future

April 2011 | Oncology & Biotech News