Tuesday, August 16, 2011
New analysis indicates that risk of bladder cancer from smoking greater than previously reported
CHICAGO – An analysis of data that includes nearly 500,000 individuals indicates that the risk of bladder cancer among smokers is higher than reported from previous population data, and that the risk for women smokers is comparable with that of men, according to a study in the August 17 issue of JAMA.
More than 350,000 individuals are diagnosed with bladder cancer per year worldwide, including more than 70,000 per year in the United States. Tobacco smoking is the best established risk factor for bladder cancer in both men and women, with previous studies indicating that current cigarette smoking triples bladder cancer risk relative to never smoking, according to background information in the article. "However, the composition of cigarettes has changed during the past 50 years, leading to a reduction in tar and nicotine concentrations in cigarette smoke, but also to an apparent increase in the concentration of specific carcinogens, including beta-napthylamine, a known bladder carcinogen …," the authors write. They add that changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer.
Neal D. Freedman, Ph.D., M.P.H., of the National Cancer Institute, Department of Health and Human Services, Rockville, Md., and colleagues conducted a study to examine the association between tobacco smoking and bladder cancer using data from men (n = 281,394) and women (n = 186,134) in the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study, who completed a lifestyle questionnaire and were followed up between October 1995 and December 2006. Previous studies of smoking and incident bladder cancer were identified by systematic review of the available literature.
During the course of follow-up, 3,896 men and 627 women were newly diagnosed with bladder cancer. Cigarette smoking was a significant risk factor for bladder cancer in both sexes. Relative to never smokers, former and current smokers had increased risk of bladder cancer in both men and women. Analysis of the data indicated that former smokers had a 2.2 times increased risk of bladder cancer and that for current smokers, the risk was about 4 times higher, relative to never smokers. "In contrast, the summary risk estimate for current smoking in 7 previous studies (initiated between 1963 and 1987) was 2.94," the authors write.
Ever smoking explained a similar proportion of bladder cancer in both sexes, with population attributable risks of 50 percent in men and 52 percent in women.
The researchers write that factors that may have strengthened the cigarette smoking-bladder cancer association include changes in the constituents of cigarette smoke (such as increased concentrations of beta-napthylamine), and increased awareness of bladder cancer risk in smokers, which may prompt earlier diagnostic workup.
"These results support the hypothesis that the risk of bladder cancer associated with cigarette smoking has increased with time in the United States, perhaps a reflection of changing cigarette composition. Prevention efforts should continue to focus on reducing the prevalence of cigarette smoking."
Friday, August 12, 2011
NEW TREATMENT OPTION FOR ADVANCED PROSTATE CANCER
Prostate cancer that has become resistant to hormone treatment and that does not respond to radiation or chemotherapy requires new methods of treatment. By attacking stem cell-like cells in prostate cancer, researchers at Lund University are working on a project to develop a new treatment option.
A successful interdisciplinary project is underway between two research groups, in which senior researcher Rebecka Hellsten and Professor Anders Bjartell at the Faculty of Medicine’s division for Urological Cancer Research, Skåne University Hospital in Malmö, and Professor Olov Sterner and Assistant Professor Martin Johansson at the Lund University division of Organic Chemistry recently published their latest research findings in the scientific online journal PLoS ONE.
“Prostatic tumours are thought to consist only of about 0.1 per cent cancer stem cells, but if you are not successful in eradicating that tumour cell population, there is a risk of subsequent uncontrolled growth of the tumour. The cancer stem cells are often unresponsive to both hormonal treatment and to chemotherapy, so it is essential to develop a direct treatment towards all types of cancer cells”, says Anders Bjartell.
Exploring the tumour biology of prostate cancer, the research group have now observed that the protein STAT3 is active in the stem cell-like cells. In their previous studies, they have proven that the natural compound galiellalactone affects STAT3 and has inhibitory effects on the growth of prostate cancer.
Through the development of new specific STAT3-inhibitors with galiellalactone as a model, the researchers hope to develop targeted therapies that attack the stem cell-like cancer cells in prostate cancer and prevent the tumour from growing and spreading.
Monday, August 8, 2011
Men Have Overly Optimistic Expectations About Recovery from Prostate Cancer Surgery
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Nearly half of men undergoing surgery for prostate cancer expect better recovery from the side effects of the surgery than they actually attain one year after the operation, a University of Michigan Comprehensive Cancer Center study finds.
In addition, prior to surgery, a small proportion of men had expected to have better urinary continence and sexual functions a year after the surgery than they had before it – the exact opposite of what typically happens.
“This is a belief that does not reflect preoperative counseling which, on the contrary, alerts men to urinary and sexual problems after surgery,” says study author Daniela Wittmann, M.S.W, sexual health coordinator at the U-M prostate cancer survivorship program.
The study, published in the August issue of the Journal of Urology, surveyed 152 men undergoing radical prostatectomy, an operation to remove the prostate. All of the men filled out questionnaires before surgery, after receiving preoperative counseling. The questions asked the men about their expectations of urinary, bowel, hormonal and sexual function a year after the surgery.
The study showed that for the most part, men’s expectations of hormonal and bowel function matched what happened one year after surgery. But, when it came to urinary incontinence only 36 percent of the men’s expectations corresponded to what happened one year post-surgery.
In addition, only 40 percent of men found what they expected for sexual function to be true one year post-surgery.
Also, 46 percent of the men found worse than expected outcomes in urinary incontinence and 44 percent of men found worse than expected outcomes in sexual function one year after surgery.
"When we provide preoperative education, we can only inform men in terms of overall statistics. We can't predict for the individual,” explains Wittmann. “This may mean that, if in doubt, people tend toward being hopeful and optimistic, perhaps overly optimistic.”
The researchers suggest that it is important to provide men with tools for urinary and sexual recovery after surgery and with support that will lead to the best possible outcome.
Patients who undergo surgery for prostate cancer at U-M participate in the prostate cancer survivorship program. The program includes partners as well. It is designed to provide men with excellent surgical care along with tailored, couples-oriented support both before and after surgery to help ease recovery from the side-effects of surgery.
“Although preoperative education is very important and should be explicit about the general expectations regarding outcomes, we also need to help men and their partners with the recovery process after surgery in order to help them regain their intimate lives,” says Wittmann.
Nearly half of men undergoing surgery for prostate cancer expect better recovery from the side effects of the surgery than they actually attain one year after the operation, a University of Michigan Comprehensive Cancer Center study finds.
In addition, prior to surgery, a small proportion of men had expected to have better urinary continence and sexual functions a year after the surgery than they had before it – the exact opposite of what typically happens.
“This is a belief that does not reflect preoperative counseling which, on the contrary, alerts men to urinary and sexual problems after surgery,” says study author Daniela Wittmann, M.S.W, sexual health coordinator at the U-M prostate cancer survivorship program.
The study, published in the August issue of the Journal of Urology, surveyed 152 men undergoing radical prostatectomy, an operation to remove the prostate. All of the men filled out questionnaires before surgery, after receiving preoperative counseling. The questions asked the men about their expectations of urinary, bowel, hormonal and sexual function a year after the surgery.
The study showed that for the most part, men’s expectations of hormonal and bowel function matched what happened one year after surgery. But, when it came to urinary incontinence only 36 percent of the men’s expectations corresponded to what happened one year post-surgery.
In addition, only 40 percent of men found what they expected for sexual function to be true one year post-surgery.
Also, 46 percent of the men found worse than expected outcomes in urinary incontinence and 44 percent of men found worse than expected outcomes in sexual function one year after surgery.
"When we provide preoperative education, we can only inform men in terms of overall statistics. We can't predict for the individual,” explains Wittmann. “This may mean that, if in doubt, people tend toward being hopeful and optimistic, perhaps overly optimistic.”
The researchers suggest that it is important to provide men with tools for urinary and sexual recovery after surgery and with support that will lead to the best possible outcome.
Patients who undergo surgery for prostate cancer at U-M participate in the prostate cancer survivorship program. The program includes partners as well. It is designed to provide men with excellent surgical care along with tailored, couples-oriented support both before and after surgery to help ease recovery from the side-effects of surgery.
“Although preoperative education is very important and should be explicit about the general expectations regarding outcomes, we also need to help men and their partners with the recovery process after surgery in order to help them regain their intimate lives,” says Wittmann.
Improved radical surgery techniques provide positive outcomes for bladder cancer patients
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Bladder cancer patients who have radical surgery at university hospitals can benefit from excellent local control of the disease, acceptable clinical outcomes and low death rates, according to research in the August issue of the urology journal BJUI.
Researchers studied 2,287 patients who had radical cystectomy surgery, where the bladder is removed, together with nearby tissue and organs as required. The surgery was performed at eight Canadian academic centres between 1998 and 2008.
The study found that there were three independent factors, apart from pathological stage at surgery, that influenced survival rates. Patients who smoked had lower survival rates, while patients who had pelvic lymphadenectomy - lymph nodes removed from the pelvic area - had higher survival rates, as did patients who received adjuvant chemotherapy, which aims to destroy microscopic cancer cells left after surgery.
However, the researchers found that neoadjuvant chemotherapy - which is often recommended prior to surgery to improve outcomes - tends to be under utilised for bladder cancer in Canada.
"Recent advances in combined radiation with chemotherapy have challenged the role of radical cystectomy (RC) with pelvic lymphadenectomy, which is used to treat muscle invasive and refractory non-muscle invasive bladder cancer" says co-author Dr Wassim Kassouf, from McGill University Health Centre, Quebec, Canada.
"These bladder-preservation strategies are potentially attractive in terms of health-related quality of life and cancer outcomes, but they only tend to work in highly selected patients.
"Advances in RC surgery have improved surgical care and techniques and reduced complications and mortality rates. The aim of our study was to evaluate a contemporary series of patients with bladder cancer to assess the clinical outcomes and identify any variables that affected their long-term health."
Key findings of the study included:
- 79% of the patients were male, the median age was 68 and the average follow-up of live patients was just over 29 months. 66% reported a family history of tobacco smoking.
- More than three-quarters of the patients had high-grade tumours. Pathological specimen examination revealed no evidence of cancer in 7% of patients, muscle invasive disease in 73% and positive nodal involvement in 25%.
- Adjuvant chemotherapy was offered to 19% of patients and neoadjuvant chemotherapy to just over 3%.
- All patients had previously undergone transurethral resection of bladder tumours and the median time from this to RC surgery was 49 days. This is similar to waiting times reported in international studies conducted in Sweden (49 days), the USA (42 days) and Germany (54 days).
- The 30, 60 and 90-day death rates were 1.3%, 2.6% and 3.2% respectively. Cancer returned in 33% of patients within a median of 10 months. Local recurrence rates were 6% in the overall group and 4% in the organ-confirmed node-negative group.
- The five-year overall, recurrence-free and cancer-specific survival rates were 57%, 48% and 67% respectively.
Multivariate analysis showed that lower pathological stage, negative surgical margins, receipt of adjuvant chemotherapy, performance of pelvic lymphadenectomy and an absence of smoking were associated with prolonged disease-specific and overall survival.
"Our study shows that very good results can be achieved when RC is performed at academic centres within a universal healthcare system and that it remains an effective clinical option for treating patients with bladder cancer" says Dr Kassouf.
Bladder cancer patients who have radical surgery at university hospitals can benefit from excellent local control of the disease, acceptable clinical outcomes and low death rates, according to research in the August issue of the urology journal BJUI.
Researchers studied 2,287 patients who had radical cystectomy surgery, where the bladder is removed, together with nearby tissue and organs as required. The surgery was performed at eight Canadian academic centres between 1998 and 2008.
The study found that there were three independent factors, apart from pathological stage at surgery, that influenced survival rates. Patients who smoked had lower survival rates, while patients who had pelvic lymphadenectomy - lymph nodes removed from the pelvic area - had higher survival rates, as did patients who received adjuvant chemotherapy, which aims to destroy microscopic cancer cells left after surgery.
However, the researchers found that neoadjuvant chemotherapy - which is often recommended prior to surgery to improve outcomes - tends to be under utilised for bladder cancer in Canada.
"Recent advances in combined radiation with chemotherapy have challenged the role of radical cystectomy (RC) with pelvic lymphadenectomy, which is used to treat muscle invasive and refractory non-muscle invasive bladder cancer" says co-author Dr Wassim Kassouf, from McGill University Health Centre, Quebec, Canada.
"These bladder-preservation strategies are potentially attractive in terms of health-related quality of life and cancer outcomes, but they only tend to work in highly selected patients.
"Advances in RC surgery have improved surgical care and techniques and reduced complications and mortality rates. The aim of our study was to evaluate a contemporary series of patients with bladder cancer to assess the clinical outcomes and identify any variables that affected their long-term health."
Key findings of the study included:
- 79% of the patients were male, the median age was 68 and the average follow-up of live patients was just over 29 months. 66% reported a family history of tobacco smoking.
- More than three-quarters of the patients had high-grade tumours. Pathological specimen examination revealed no evidence of cancer in 7% of patients, muscle invasive disease in 73% and positive nodal involvement in 25%.
- Adjuvant chemotherapy was offered to 19% of patients and neoadjuvant chemotherapy to just over 3%.
- All patients had previously undergone transurethral resection of bladder tumours and the median time from this to RC surgery was 49 days. This is similar to waiting times reported in international studies conducted in Sweden (49 days), the USA (42 days) and Germany (54 days).
- The 30, 60 and 90-day death rates were 1.3%, 2.6% and 3.2% respectively. Cancer returned in 33% of patients within a median of 10 months. Local recurrence rates were 6% in the overall group and 4% in the organ-confirmed node-negative group.
- The five-year overall, recurrence-free and cancer-specific survival rates were 57%, 48% and 67% respectively.
Multivariate analysis showed that lower pathological stage, negative surgical margins, receipt of adjuvant chemotherapy, performance of pelvic lymphadenectomy and an absence of smoking were associated with prolonged disease-specific and overall survival.
"Our study shows that very good results can be achieved when RC is performed at academic centres within a universal healthcare system and that it remains an effective clinical option for treating patients with bladder cancer" says Dr Kassouf.
Tuesday, July 26, 2011
Hormone therapy may be hazardous for men with heart conditions
Adding hormone therapy to radiation therapy has been proven in randomized clinical trials to improve overall survival for men with intermediate- and high-risk prostate cancer. However, adding hormone therapy may reduce overall survival in men with pre-existing heart conditions, even if they have high-risk prostate cancer according to a new study just published online in advance of print in the International Journal of Radiation Oncology•Biology•Physics, the official scientific journal of ASTRO.
From 1991 to 2006, 14,594 men with prostate cancer were treated with brachytherapy-based radiation therapy. Of these, 1,378 (9.4 percent) had a history of congestive heart failure or myocardial infarction. Among these men with heart conditions, 22.6 percent received supplemental external beam radiation therapy and 42.9 percent received four months of androgen deprivation therapy to reduce testosterone in their bodies, which can help the cancer grow.
For the entire group of men with a history of heart problems, adding hormone therapy led to a significant increase in overall mortality. For men with pre-existing heart conditions and high-risk prostate cancer, researchers found that by 5 years, 31.8 percent of the men who received hormones had died compared to 19.5 percent of the men who did not receive hormone therapy.
"We found that for men with localized prostate cancer and a history of heart problems, treatment with hormones plus radiation was associated with a higher all-cause mortality than treatment with radiation alone, even for patients with high-risk malignant disease," Paul L. Nguyen, M.D., lead author of the study and a radiation oncologist at the Dana-Farber/Brigham and Women's Cancer Center in Boston, said. "Despite Phase III data supporting hormone therapy use for men with high-risk disease, the subgroup of men with a history of heart disease may be harmed by hormone therapy."
He added, "Future research is necessary to understand the mechanisms of this effect. In the meantime, I encourage men with prostate cancer and a history of heart disease to talk to their doctor about the benefits and risks of hormone therapy."
From 1991 to 2006, 14,594 men with prostate cancer were treated with brachytherapy-based radiation therapy. Of these, 1,378 (9.4 percent) had a history of congestive heart failure or myocardial infarction. Among these men with heart conditions, 22.6 percent received supplemental external beam radiation therapy and 42.9 percent received four months of androgen deprivation therapy to reduce testosterone in their bodies, which can help the cancer grow.
For the entire group of men with a history of heart problems, adding hormone therapy led to a significant increase in overall mortality. For men with pre-existing heart conditions and high-risk prostate cancer, researchers found that by 5 years, 31.8 percent of the men who received hormones had died compared to 19.5 percent of the men who did not receive hormone therapy.
"We found that for men with localized prostate cancer and a history of heart problems, treatment with hormones plus radiation was associated with a higher all-cause mortality than treatment with radiation alone, even for patients with high-risk malignant disease," Paul L. Nguyen, M.D., lead author of the study and a radiation oncologist at the Dana-Farber/Brigham and Women's Cancer Center in Boston, said. "Despite Phase III data supporting hormone therapy use for men with high-risk disease, the subgroup of men with a history of heart disease may be harmed by hormone therapy."
He added, "Future research is necessary to understand the mechanisms of this effect. In the meantime, I encourage men with prostate cancer and a history of heart disease to talk to their doctor about the benefits and risks of hormone therapy."
Monday, July 11, 2011
Nearly all patients with high-grade bladder cancer do not receive guideline-recommended care
A study at UCLA's Jonsson Comprehensive Cancer Center found that nearly all patients with high-grade, non-invasive bladder cancer are not receiving the guideline-recommended care that would best protect them from recurrence, a finding that researchers characterized as alarming.
In fact, out of the 4,545 bladder cancer patients included in the study, only one received the comprehensive care recommended by the American Urology Association and the National Comprehensive Cancer Network.
Receiving the recommended comprehensive care for high-grade bladder cancer is critical because it can significantly minimize the likelihood that patients will die from their cancer, said Dr. Karim Chamie, a postdoctoral fellow in urologic oncology and health services research and lead author of the study.
"We were surprised by the findings in this study, particularly in an era when many suggest that doctors over-treat patients and do too much in the name of practicing defensive medicine," Chamie said. "This study suggests quite the contrary, that we don't do enough for patients with bladder cancer. If this was a report card on bladder cancer care in America, I'd say we're earning a failing grade."
The study is published July 11, 2011 in the early online edition of CANCER, a peer-reviewed journal of the American Cancer Society.
The study then investigated the cause of poor compliance. What they found was that non-compliance knew no boundaries and that patient-level factors such as age, race, ethnicity or socioeconomic status had very little impact. Instead, non-compliance with guideline-recommended care was primarily attributed to urologists. The patients in the study were elderly, but capable of withstanding these simple measures.
"It wasn't their age, race, ZIP code or how wealthy they were. It all came down to who their doctor was," Chamie said
Dr. Mark S. Litwin, professor of urology and public health and senior author of the study, said it's not clear why physicians are not routinely following established guidelines for care.
"It is puzzling, because strong evidence supports those guidelines," Litwin said. "But this is a wake-up call to all physicians caring for patients with bladder cancer. We know definitively what constitutes high-quality care. Now we just need to make sure it happens."
Patients with primary high-grade bladder cancer, which has not yet invaded the muscle of the bladder, have a 50 to 70 percent chance of their cancer coming back in the bladder following treatment. They also have a 30 to 50 percent chance of the cancer becoming more aggressive and invading into the muscle, where it is much harder to treat. Once the cancer invades the muscle, the bladder and surrounding organs must be removed and both the quality and the quantity of the patient's life are significantly impacted, Chamie said.
Chamie said that, at diagnosis, about 75 percent of bladder patients have disease that has not invaded the muscle. So treating those patients with the guideline-recommended care to help minimize recurrences and prevent invasion of the tumor into the muscle could help a large number of patients.
The recommended medical guidelines call for injecting a cancer-killing drug directly into the bladder to minimize recurrence and progression. They also recommend an intense follow-up schedule, including the repeated use of a scope to evaluate the bladder from the inside, a procedure called cystoscopy, and a urine test that is similar to a pap smear every three months to check for abnormal cells.
Only one patient in the study, which analyzed date from Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, was given the recommended care. The study also found that nearly half of urologists treating these patients had not performed at least one cystoscopy, one urine test, and one infusion of the cancer-killing drug into the bladder.
To rectify the situation, Chamie and Litwin suggest a quality-improvement initiative and or changes to physician reimbursements. To complicate matters, despite the poor compliance rate, bladder cancer is the most expensive malignancy to treat on a per-patient level. While improving compliance with changes to physician reimbursement or a quality improvement initiative will increase healthcare costs in the short term, preventing recurrences or progression of the cancer likely will cut costs in the long term.
"We have to improve compliance and there are two ways to do that: Modify our reimbursement schedules to provide incentives to doctors to follow the guidelines, or go out and interact and educate the community urologists - who are delivering the vast majority of bladder cancer care - on the importance of providing compliant care," Chamie said. "Unlike some patients diagnosed with bladder cancer after having it spread to other sites when it's too late to treat effectively, or those with low-grade tumors that are not likely to ever be aggressive, this is a potentially curable cohort of patients. If we don't do a good enough job treating these cancers, we're going to lose these patients."
In fact, out of the 4,545 bladder cancer patients included in the study, only one received the comprehensive care recommended by the American Urology Association and the National Comprehensive Cancer Network.
Receiving the recommended comprehensive care for high-grade bladder cancer is critical because it can significantly minimize the likelihood that patients will die from their cancer, said Dr. Karim Chamie, a postdoctoral fellow in urologic oncology and health services research and lead author of the study.
"We were surprised by the findings in this study, particularly in an era when many suggest that doctors over-treat patients and do too much in the name of practicing defensive medicine," Chamie said. "This study suggests quite the contrary, that we don't do enough for patients with bladder cancer. If this was a report card on bladder cancer care in America, I'd say we're earning a failing grade."
The study is published July 11, 2011 in the early online edition of CANCER, a peer-reviewed journal of the American Cancer Society.
The study then investigated the cause of poor compliance. What they found was that non-compliance knew no boundaries and that patient-level factors such as age, race, ethnicity or socioeconomic status had very little impact. Instead, non-compliance with guideline-recommended care was primarily attributed to urologists. The patients in the study were elderly, but capable of withstanding these simple measures.
"It wasn't their age, race, ZIP code or how wealthy they were. It all came down to who their doctor was," Chamie said
Dr. Mark S. Litwin, professor of urology and public health and senior author of the study, said it's not clear why physicians are not routinely following established guidelines for care.
"It is puzzling, because strong evidence supports those guidelines," Litwin said. "But this is a wake-up call to all physicians caring for patients with bladder cancer. We know definitively what constitutes high-quality care. Now we just need to make sure it happens."
Patients with primary high-grade bladder cancer, which has not yet invaded the muscle of the bladder, have a 50 to 70 percent chance of their cancer coming back in the bladder following treatment. They also have a 30 to 50 percent chance of the cancer becoming more aggressive and invading into the muscle, where it is much harder to treat. Once the cancer invades the muscle, the bladder and surrounding organs must be removed and both the quality and the quantity of the patient's life are significantly impacted, Chamie said.
Chamie said that, at diagnosis, about 75 percent of bladder patients have disease that has not invaded the muscle. So treating those patients with the guideline-recommended care to help minimize recurrences and prevent invasion of the tumor into the muscle could help a large number of patients.
The recommended medical guidelines call for injecting a cancer-killing drug directly into the bladder to minimize recurrence and progression. They also recommend an intense follow-up schedule, including the repeated use of a scope to evaluate the bladder from the inside, a procedure called cystoscopy, and a urine test that is similar to a pap smear every three months to check for abnormal cells.
Only one patient in the study, which analyzed date from Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, was given the recommended care. The study also found that nearly half of urologists treating these patients had not performed at least one cystoscopy, one urine test, and one infusion of the cancer-killing drug into the bladder.
To rectify the situation, Chamie and Litwin suggest a quality-improvement initiative and or changes to physician reimbursements. To complicate matters, despite the poor compliance rate, bladder cancer is the most expensive malignancy to treat on a per-patient level. While improving compliance with changes to physician reimbursement or a quality improvement initiative will increase healthcare costs in the short term, preventing recurrences or progression of the cancer likely will cut costs in the long term.
"We have to improve compliance and there are two ways to do that: Modify our reimbursement schedules to provide incentives to doctors to follow the guidelines, or go out and interact and educate the community urologists - who are delivering the vast majority of bladder cancer care - on the importance of providing compliant care," Chamie said. "Unlike some patients diagnosed with bladder cancer after having it spread to other sites when it's too late to treat effectively, or those with low-grade tumors that are not likely to ever be aggressive, this is a potentially curable cohort of patients. If we don't do a good enough job treating these cancers, we're going to lose these patients."
Wednesday, June 29, 2011
MAKE BLADDER CANCER CELLS MORE SUSCEPTIBLE TO CHEMOTHERAPY
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Improving efficacy of drugs would boost post-surgery survivorship
Researchers at the UC Davis Cancer Center have discovered a way of sensitizing muscle-invasive bladder cancer cells so that they succumb to the toxic effects of chemotherapy. The finding adds to mounting evidence that tiny strands of RNA — called microRNA — play key roles in some of the deadliest types of cancer.
In the current study, published online June 28 in International Journal of Cancer, researchers boosted the production of a microRNA found in bladder cancer cell lines — encoded for by the gene miR-34a — and found that this resulted in more of the cells being killed by cisplatin, a chemotherapy drug used to treat many types of cancer.
Ralph deVere White
"When we took the bladder cancer cell lines and activated miR-34a, they were more responsive to chemotherapy," said Ralph deVere White, UC Davis Cancer Center director and professor of urology.
The study establishes, for the first time, a link between sensitivity of bladder cancer cells to chemotherapy and the expression of miR-34a. It suggests that miR-34a may be used as a predictor of response to chemotherapy, as well as a target for new drugs.
Currently, about 50 percent of patients with advanced bladder cancer will survive five years after diagnosis. Although clinical trials have demonstrated that chemotherapy before surgery can improve survival rates, it is rarely used because fewer than 50 percent of patients will respond favorably. Without knowing which patients will improve as a result of chemotherapy, physicians are generally reluctant to use a treatment that can cause their patients to suffer significant side effects.
"So, now we have to prove that it works to predict chemotherapy response in patients," deVere White said. To that end, UC Davis has entered into a partnership with Israel-based Rosetta Genomics to develop a microRNA profile for muscle-invasive bladder cancer that may be used to predict response to chemotherapy.
As part of the current study, deVere White and his colleagues studied 27 patients and found that many who expressed lower levels of miR-34a subsequently did not respond to the combined chemotherapy-surgery treatment. Because the finding was not statistically significant, however, further work in this area is needed.
The team also studied tumor samples taken from eight of the patients who did not respond to chemotherapy. They compared the expression of miR-34a before and after chemotherapy.
"We wanted to see, if you looked at the patient's tissue before chemotherapy, were there differentially expressed microRNAs in the patients who responded to the drugs versus those that didn't respond," deVere White explained.
The team found that expression of miR-34a increased after treatment in only two of the eight cases, suggesting that gene expression levels remained low during treatment and confirming the link between low gene expression and failure to respond to treatment.
"The combined data indicate that the elevation of miR-34a expression levels prior to chemotherapy would be of benefit to muscle-invasive bladder cancer patients, particularly in a setting of low mi-R-34a expression," the authors write.
Since their discovery in 1993, microRNAs have been found to be involved in a number of types of cancer, heart disease and diseases of the nervous system. In 2007, deVere White was part of a team that identified miR-125b, a gene that encodes for a microRNA that jump starts prostate cancer cell growth midway through the disease process, eventually causing it to become fatal.
The microRNA studied here was also recently found to play a role in medulloblastoma, an aggressive type of brain cancer. MicroRNAs, which are usually 22 to 33 nucleotides in length, are known as post-transcriptional regulators. That means they work by turning genes on or off during the part of the protein synthesis process that involves making a strand of RNA from a DNA template. The human genome encodes for an estimated 1,000 microRNAs.
According to the authors, future studies involving miR-34a will focus on testing its ability to increase sensitivity to chemotherapy and analysis of miR-34a expression in patients with muscle-invasive bladder cancer. With the currently low chemotherapy success rate and poor five-year survival rate for patients with this disease, "such studies are clearly warranted," the authors write.
"If we can prove what is causing chemotherapy resistance in patients with muscle-invasive bladder cancer, American ingenuity will come up with ways to overcome it," predicted deVere White.
Improving efficacy of drugs would boost post-surgery survivorship
Researchers at the UC Davis Cancer Center have discovered a way of sensitizing muscle-invasive bladder cancer cells so that they succumb to the toxic effects of chemotherapy. The finding adds to mounting evidence that tiny strands of RNA — called microRNA — play key roles in some of the deadliest types of cancer.
In the current study, published online June 28 in International Journal of Cancer, researchers boosted the production of a microRNA found in bladder cancer cell lines — encoded for by the gene miR-34a — and found that this resulted in more of the cells being killed by cisplatin, a chemotherapy drug used to treat many types of cancer.
Ralph deVere White
"When we took the bladder cancer cell lines and activated miR-34a, they were more responsive to chemotherapy," said Ralph deVere White, UC Davis Cancer Center director and professor of urology.
The study establishes, for the first time, a link between sensitivity of bladder cancer cells to chemotherapy and the expression of miR-34a. It suggests that miR-34a may be used as a predictor of response to chemotherapy, as well as a target for new drugs.
Currently, about 50 percent of patients with advanced bladder cancer will survive five years after diagnosis. Although clinical trials have demonstrated that chemotherapy before surgery can improve survival rates, it is rarely used because fewer than 50 percent of patients will respond favorably. Without knowing which patients will improve as a result of chemotherapy, physicians are generally reluctant to use a treatment that can cause their patients to suffer significant side effects.
"So, now we have to prove that it works to predict chemotherapy response in patients," deVere White said. To that end, UC Davis has entered into a partnership with Israel-based Rosetta Genomics to develop a microRNA profile for muscle-invasive bladder cancer that may be used to predict response to chemotherapy.
As part of the current study, deVere White and his colleagues studied 27 patients and found that many who expressed lower levels of miR-34a subsequently did not respond to the combined chemotherapy-surgery treatment. Because the finding was not statistically significant, however, further work in this area is needed.
The team also studied tumor samples taken from eight of the patients who did not respond to chemotherapy. They compared the expression of miR-34a before and after chemotherapy.
"We wanted to see, if you looked at the patient's tissue before chemotherapy, were there differentially expressed microRNAs in the patients who responded to the drugs versus those that didn't respond," deVere White explained.
The team found that expression of miR-34a increased after treatment in only two of the eight cases, suggesting that gene expression levels remained low during treatment and confirming the link between low gene expression and failure to respond to treatment.
"The combined data indicate that the elevation of miR-34a expression levels prior to chemotherapy would be of benefit to muscle-invasive bladder cancer patients, particularly in a setting of low mi-R-34a expression," the authors write.
Since their discovery in 1993, microRNAs have been found to be involved in a number of types of cancer, heart disease and diseases of the nervous system. In 2007, deVere White was part of a team that identified miR-125b, a gene that encodes for a microRNA that jump starts prostate cancer cell growth midway through the disease process, eventually causing it to become fatal.
The microRNA studied here was also recently found to play a role in medulloblastoma, an aggressive type of brain cancer. MicroRNAs, which are usually 22 to 33 nucleotides in length, are known as post-transcriptional regulators. That means they work by turning genes on or off during the part of the protein synthesis process that involves making a strand of RNA from a DNA template. The human genome encodes for an estimated 1,000 microRNAs.
According to the authors, future studies involving miR-34a will focus on testing its ability to increase sensitivity to chemotherapy and analysis of miR-34a expression in patients with muscle-invasive bladder cancer. With the currently low chemotherapy success rate and poor five-year survival rate for patients with this disease, "such studies are clearly warranted," the authors write.
"If we can prove what is causing chemotherapy resistance in patients with muscle-invasive bladder cancer, American ingenuity will come up with ways to overcome it," predicted deVere White.
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