2011 NOBEL PRIZE IN MEDICINE

October 3, 2011 — The Nobel prize for medicine was awarded today to 3 scientists whose discoveries about the immune system are expanding how clinicians prevent and treat infection, inflammatory diseases, and cancer, including a form that claimed the life of one of the new Nobel laureates 3 days ago.
Bruce Beutler, MD, and Jules Hoffmann, PhD, received a half-share in this year's prize for discovering receptor proteins that can spot bacteria and other microorganisms and then activate the body's innate immunity to defend itself. The other half of the $1.5 million prize went to the late Ralph Steinman, MD, who discovered the dendritic cells that turn on the T cells at the heart of active immunity, which creates an immunologic memory against invaders.
Dr. Steinman, age 68, a cell biologist at Rockefeller University in New York City, died on September 30 after a 4-year bout with pancreatic cancer. He extended his life with a form of immunotherapy that incorporated his research on dendritic cells, according to a Rockefeller University press release.
The Nobel committee at Sweden's Karolinksa Institute, responsible for awarding the prize in physiology or medicine, selected Dr. Steinman before learning of his death, according to the Nobel Foundation. Nobel prizes are not deliberately awarded on a posthumous basis, but the Nobel Foundation announced today that Dr. Steinman would remain a Nobel laureate because the decision to select him "was made in good faith, based on the assumption that [he] was still alive." The organization noted that Dr. Steinman's situation resembles an exception in the Nobel rules that allows a prize to be presented to someone who is named a laureate while alive, but dies before the prize ceremony.
"The Future Translation Is Obvious"
The work of Dr. Beutler and Dr. Hoffmann has "triggered an explosion of research in innate immunity" and the identification of dozen or so different receptor proteins called Toll-like receptors in humans and mice, according to the Nobel Foundation. Each Toll-like receptor recognizes certain types of molecules found in trespassing microorganisms. Genetic variations in these Toll-like receptors come with an increased risk for infection or chronic inflammatory disease.
Dr. Beutler is a professor of genetics and immunology at the Scripps Research Institute in La Jolla, California. Dr. Hoffmann is a senior researcher emeritus and professor at the National Center for Scientific Research in Strasbourg, France.
Dr. Steinman's research into dendritic cells figured into the development of sipuleucel-T (Provenge, Dendreon) for advanced prostate cancer, the first therapeutic vaccine for cancer.
All 3 scientists made "substantial contributions" to the field of immunology, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, said in an interview with Medscape Medical News.
For the most part, researchers are still in the early stages of turning the discoveries of the latest Nobel laureates into new vaccines and treatments for infectious disease, but "the future translation is obvious," said Dr. Fauci. "It's absolutely going to happen."

NEW RECOMMENDATION AGAINST ROUTINE PSA SCREENING IN USA

October 7, 2011 — Routine screening for prostate cancer using the prostate-specific antigen (PSA) test will no longer be recommended in the United States, where it is currently used more than in any other country in the world. As a result, prostate cancer is the most commonly diagnosed cancer in American men.
The recommendation against routine screening with the PSA test comes from the US Preventive Services Task Force (USPSTF), and was to have been published October 11 in the Annals of Internal Medicine, but the entire draft paper was leaked and posted October 6 on the Cancer Letter Web site, in "an egregious breach of our embargo and media policies," according to the journal. The news has since been widely disseminated on the Internet; as a result, the journal published the paper early.
The USPSTF already recommends against routine PSA screening in men older than 75 years. In the new draft recommendation, it extends this to all men. It now recommends against routine screening in men younger than 75 years, giving this a "D" rating, which means "there is moderate or high certainty that the service has no benefit or that the harms outweigh the benefits."
The news is likely to spark a furor in medical circles, not unlike the outcry that followed the USPSTF's recommendation in 2009 against routine mammography screening for breast cancer in women younger than 50 years. This provoked outrage from some breast cancer experts, patient advocates, and professional societies, with accusations that this was a move toward the "rationing" of healthcare.
Angry reactions to the latest news have already begun. The "decision of no confidence on the PSA test by the US government condemns tens of thousands of men to die," said Skip Lockwood, CEO of ZERO, the Project to End Prostate Cancer. ZERO is sponsored by many organizations with a stake in prostate cancer, such as Abbott, Beckman Coulter, Accuray, CyberKnife, Dendreon, and the American Urological Association (AUA).
Based on Reviews of Trials
The recommended change is based on a review of 5 randomized trials of screening and 3 trials and 23 cohort studies of treatments. Included in the review were the 2 largest trials of PSA screening, which reported conflicting results, the USPSTF notes. The European study found a reduction in mortality after 9 years of screening, but the American trial, which had high crossover and contamination rates, found no reduction in mortality after 10 years of screening, as previously reported by Medscape Medical News.
The review also noted that treatment for prostate cancer, such as prostatectomy and radiation, is associated with risks for problems such as erectile dysfunction, urinary incontinence, and bowel dysfunction.
The USPTSF concludes that "after about 10 years, PSA-based screening results in small or no reduction in prostate-cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary."
Delay in Announcement
This recommendation has been a long time coming, according to reports in the October 7 issue of the Cancer Letter and in the New York Times magazine. They assert that the timing of the release of this recommendation was influenced by political considerations. According to these reports, the task force first voted to recommend against routine PSA screening back in November 2009, but this "caused a violent political firestorm," and subsequent follow-up meetings were cancelled. The final vote was taken in March. After this, a paper summarizing the recommendation was submitted to the Annals of Internal Medicine, where is it expected to appear next week.
PSA Test is Not Specific
The main problems with the PSA test are that it is not specific for prostate cancer and it cannot differentiate between aggressive and indolent forms of the disease.
"It cannot distinguish cancer that will never make a difference in a man's lifetime from cancers that will make a difference," so might prompt men to undergo aggressive treatment unnecessarily, Virginia Moyer, MD, MPH, chair of the USPTSF panel that made the recommendation, stated in an interview yesterday with Bloomberg News. "So you go from being a guy who feels fine and who is potentially one of the majority who would never have known they had this disease, to being a guy who wears adult diapers," she said. Dr. Moyer is a professor of pediatrics at Baylor College of Medicine in Houston, Texas.
The PSA test is "hardly more effective than a coin toss," said Richard Ablin, PhD, research professor of pathology at the University of Arizona College of Medicine in Tucson. Dr. Ablin discovered PSA in 1970. Using this test to screen for prostate cancer in the general population has been a "hugely expensive public health disaster," he wrote in an opinion piece in the New York Times last year.
"Drug companies continue peddling the tests, and advocacy groups push 'prostate cancer awareness' by encouraging men to get screened," he wrote. "The medical community must confront reality and stop the inappropriate use of PSA screening," he stated. "Doing so would save billions of dollars and rescue millions of men from unnecessary, debilitating treatment."
Although PSA testing is recognized as being imperfect, it is the only test for prostate cancer that is widely available, and it does provide information that can be useful, proponents point out. One of the professional bodies that has long supported the use of the test, the AUA, emphasizes that it should not be used on its own, but needs to be combined with other information (such as family history).
The AUA issued a statement in reaction to the new USPSTF recommendations: "We are concerned that the Task Force's recommendation will ultimately do more harm than good to the many men at risk for prostate cancer, both here in the United States and around the world."
"The AUA's current clinical recommendations support use of the PSA test, and it is our feeling that, when interpreted appropriately, the PSA test provides important information in the diagnosis, pretreatment staging or risk assessment, and posttreatment monitoring of prostate cancer patients," according to the statement.
"Not all prostate cancers require active treatment and not all prostate cancers are life-threatening," the statement points out, and the decision of whether to proceed to active treatment or whether surveillance is an option needs to be discussed in detail with the patient.

ARE ANTHRACYCLINES NECESSARY IN HER2+ BREAST CANCER

October 6, 2011 — A large study addressing the critical question of whether adjuvant anthracyclines are necessary for the treatment of HER2-positive breast cancer has been published in the October 6 issue of the New England Journal of Medicine.

The results show that anthracyclines aren't necessary to treat early-stage breast cancer effectively, and that the cardiac and other associated toxicities can and should be avoided, according to the principal investigator Dennis Slamon, MD, PhD, director of clinical/translational research at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.
However, an accompanying editorial puts a slightly different slant on the same findings.
The Breast Cancer International Research Group (BCIRG) 006 study established the benefit of trastuzumab (Herceptin) in patients with HER2-positive early-stage breast cancer, and compared how the targeted agent performed in combination with an anthracycline-containing regimen (doxorubicin [Adriamycin], cyclophosphamide, and docetaxel) and with a nonanthracycline regimen (docetaxel and carboplatin).
In the editorial, Daniel Hayes, MD, from the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center in Ann Arbor, says that the study results "do not show the hoped-for superiority" of the nonanthracycline regimen.
"Taken together, these data do not clearly favor one regimen over the other," Dr. Hayes writes. Hence, this trial establishes the nonanthracycline regimen as "another (but not 'the') standard of care for adjuvant treatment of HER2-positive early-stage breast cancer," the editorial concludes.
This is at odds with the take-home message long espoused by Dr. Slamon, who is well known for his stance against the use of anthracyclines.
"This trial should impact the way these breast cancers are treated, with a nonanthracycline regimen being our preferred option," he said in a statement. "I think this is a change that is going to be slow in coming, unfortunately, as many of our adjuvant treatments for breast cancer are built on the backbone of anthracyclines. While they're effective, whatever gain patients may receive is more than made up for in the serious and chronic long-term side effects."
Not everyone agrees with that assessment, however. When Dr. Slamon first reported these results at the 2009 San Antonio Breast Cancer Symposium and concluded that anthracyclines are unnecessary, another breast cancer expert said his conclusions "were going beyond the data."
"Many oncologists will differ with his opinion," Gary Lyman, MD, from the Duke Comprehensive Cancer Center in Durham, North Carolina, told Medscape Medical News at the time. He emphasized the slight difference in efficacy favoring the anthracycline regimen, which is now pointed out in the editorial. "Bottom line, there can be, among intelligent people, very different conclusions about the same data, "Dr. Lyman said.
When approached for outside comment, Gabriel Hortobagyi, MD, FACP, professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News that "BCIRG 006 is the only clinical trial of adjuvant chemotherapy in HER2-positive primary breast cancer that contains a nonanthracycline-containing chemotherapy backbone. While this work was presented around the same time as the other pivotal trials of trastuzumab-containing adjuvant therapy, it has taken 6 years to go through peer review and be published. This, in and of itself, is highly unusual and somewhat puzzling."
"The strength of the work is its design, the large number of patients recruited, and the inclusion of the nonanthracycline arm. The weakness is the overinterpretation of the results. I think this work supports the use of a nonanthracycline-containing trastuzumab regimen for some patients with HER2-positive breast cancer. My group uses TCH [Taxotere (docetaxel), carboplatin, Herceptin] for patients with contraindications to anthracyclines or for patients with HER2-positive breast cancer but with a low enough risk to make the relative cardiac safety of TCH a worthwhile choice (e.g., the very small — less than 1 cm — HER2-positive node-negative tumors). Otherwise, we prefer the standard anthracycline-containing chemotherapy regimens," Dr. Hortobagyi explained.
No Difference in Efficacy
The BCIRG 006 study was conducted in 3222 women with HER2-positive early-stage breast cancer, and had 3 treatment groups, all containing some chemotherapy. One group did not contain trastuzumab, the agent targeted directly at HER2-positive disease; the patients in that group fared less well than those in the other 2 groups, which both contained trastuzumab.
Much of the interest in this trial, however, is directed at the other 2 groups, because they pitched an anthracycline regimen directly against a new nonanthracycline regimen.
The paper by Dr. Slamon and colleagues reports results at a median follow-up at 65 months.
The estimated disease-free survival rates at 5 years were 75% with the anthracycline regimen with no trastuzumab; 84% with the anthracycline regimen plus trastuzumab, and 81% with the nonanthracycline regimen plus trastuzumab. The estimated overall survival rates were 87%, 92%, and 91%, respectively.
No significant differences in efficacy were found between the 2 trastuzumab groups, but both were superior to the group without trastuzumab, the authors note.
There was a slight numerical benefit for the anthracycline regimen over the nonanthracycline regimen, but it was not statistically significant, Dr. Hayes writes.
Dr. Hortobagyi also focused on this point. The Kaplan–Meier curves show no statistically significant difference, but he noted that in all of them, the curves are numerically inferior for the nonanthracycline combination.
"There are more than 10,000 patients treated with the anthracycline-containing regimens in clinical trials, but only about 1000 are treated with TCH. I would like to see a confirmatory trial to ensure that we are not changing practice based on this limited experience. Furthermore, our group has some information, based on a retrospective analysis of our institutional experience, that suggests that TCH is significantly less effective than the anthracycline-containing regimens (manuscript in press)," Dr. Hortobagyi explained.
Significant Differences in Toxicity
However, there were major differences in adverse effects, with "significant increases in both acute and chronic toxic effects" seen with anthracycline plus trastuzumab, the researchers report.
Patients in the anthracycline groups had a significantly higher rate of congestive heart failure than those in the nonanthracycline group (21 vs 4 cases), and a significantly higher rate of acute leukemia (7 vs 1 case). However, the authors note that the leukemia in the nonanthracycline group developed outside of the study, after that patient had received an anthracycline for a B cell lymphoma that occurred after her breast cancer. At the time the paper was written, 5 of the 8 patients with leukemia had died.
There was also a significant difference favoring the nonanthracycline group for arthralgias, myalgias, hand-foot syndrome, nail changes, stomatitis, vomiting, and sensory and motor neuropathies, the authors report.
Dr. Slamon emphasized this toxicity difference between the anthracycline and nonanthracycline regimens.
"Given the data in this study, it makes one really question what role [the anthracycline doxorubicin] should play in the treatment of HER-2 positive early breast cancer, or in the treatment of early breast cancer at all," he said.
The editorial also notes this difference in toxicity. However, it points out that "overall, the absolute numbers of women who had some sort of life-threatening adverse events (either toxicity or cancer recurrence) were almost identical" in the anthracycline and nonanthracycline groups.
In addition, the editorial suggests that the risk for secondary leukemia or irreversible congestive heart failure from the anthracycline is arguably similar to the small but insignificant benefit of the anthracycline regimen over the nonanthracycline regimen (about 1 to 2 additional lives saved per 100 patients).
The BCRIG 006 results suggest that the nonanthracycline regimen of docetaxel plus carboplatin is "an acceptable standard of care," the editorial concludes.
The study was supported by Sanofi-Aventis and Genentech. Dr. Slamon reports receiving honoraria from Genentech and Sanofi-Aventis. Two of the coauthors are employees of Sanofi-Aventis. Dr. Lyman has disclosed no relevant financial relationships. Dr. Hayes reports serving as a board member for OncImmune; receiving grants from Veridex, Pfizer, and Novartis; and acting as a consultant to Compedia Biosciences, Chugai, and Biomarker Strategies.
N Engl J Med. 2011:365:1273-1283, 1336-1337. Abstract, Editorial

HPV+ OROPHARYNGEAL CANCER ON THE RISE

October 5, 2011 — The sharp rise in oropharyngeal cancer associated with human papillomavirus (HPV) and its association with oral sex have been highlighted again, and this time has gained widespread media attention.
This new epidemic of HPV-positive oropharyngeal cancer has been brewing for a while now, as previously reported by Medscape Medical News.
The growing disease burden has reignited interest in whether HPV vaccination, currently directed at preventing cervical cancer, will be useful here, and reopened the debate about vaccinating boys as well as girls.
The latest findings were published online October 3 in the Journal of Clinical Oncology, and were highlighted in a press release issued by the American Society of Clinical Oncology (ASCO).
The researchers, headed by Maura Gillison MD, PhD, professor of medicine and Jeg Coughlin Chair of Cancer Research at The Ohio State University Comprehensive Cancer Center in Columbus, report that there has been a dramatic increase in the incidence of oropharyngeal cancer since 1984.
A growing majority of new cases (70%) are associated with HPV, and the vast majority of patients are male.
If the current trends continue, HPV-related oropharyngeal cancer will become the major form of head and neck cancer by 2020, and will become the leading HPV-associated cancer in the United States, surpassing cervical cancer, Dr. Gillison said in a statement.
"The increase may reflect increases in sexual behavior, including increases in oral sex," she added.
Legacy of Sexual Revolution?
Dr. Gillison previously told Medscape Medical News that the dramatic increase in HPV-related oropharyngeal cancer seen in recent years is a legacy of the sexual revolution in the 1960s.
"Our own work, using the SEER [Surveillance, Epidemiology, and End Results] database, shows a strong cohort effect, which means the greatest determinant of risk in any age group is the year in which you were born," Dr. Gillison pointed out.
"These cohort effects are largely driven by societal changes, and they tend to affect people first who are younger, because they are the people leading the behavioral changes," she explained.
During the 1960s, teenagers and young adults were more active sexually than previous generations, and having multiple sexual partners became more acceptable. "The more sexual partners you have, the greater the risk of contracting any sexually transmitted disease, including HPV," Dr. Gillison noted.
The time lag between an oral HPV infection and the development of HPV-related oropharyngeal cancer is between 15 and 30 years, and the age at which this cancer is usually diagnosed is 50 years or older.
The increase in this cancer that was seen in the 1990s and the 2000s is likely the result of young people participating in increased sexual activity in the 1960s and 1970s, Dr. Gillison reported.
Opportunity for HPV Vaccines?
The majority (90% to 95%) of the HPV-oropharyngeal cancer samples examined in this study were associated with one subtype of the virus, HPV-16.
This is one of the HPV subtypes that is targeted by both of the currently available HPV vaccines used for cervical cancer prevention (Gardasil from Merck & Co, which protects against HPV subtypes 6, 11, 16, and 18; and Ceravix,from GlaxoSmithKline, which protects against HPV subtypes 16 and 18).
"With HPV vaccines, we have a great opportunity to potentially prevent oropharynx cancers in future generations — including in boys and men," Dr. Gillison said. However, she pointed out that studies to assess the efficacy of these vaccines in preventing oral HPV infections will be needed, and so far these have not been carried out. Such a trial was planned, but the pharmaceutical manufacturers pulled out, she said.
The potential for a role for HPV vaccines is highlighted in the press release from ASCO, and in an editorial accompanying the study.
"The findings could have particular relevance for the HPV vaccine administration policy," said Gregory Masters MD, FACP, a head and neck specialist in Newark, New Jersey, and a member of the ASCO Cancer Communications Committee. "We are encouraged by what the availability of HPV vaccines may be able to do to prevent these cancers now that we have a clearer understanding of causation".
The editorial, by James Rocco, MD, PhD, and Edmund Mroz, PhD, from the Massachusetts General Hospital in Boston, and Arlene Forastiere, MD, from the Johns Hopkins Medical Institutions in Baltimore, Maryland, notes that it is "expected" that HPV vaccination will reduce the incidence of HPV infections and oropharyngeal cancer, but this is "not yet documented."
"Direct tests of this efficacy are needed, given that prevention through vaccination will almost certainly be the ultimate solution to HPV-positive oropharyngeal cancer," they declare.
Current HPV vaccines are approved for use in girls for cervical cancer prevention, although the quadrivalent vaccine Gardasil is also approved for use in males and females to offer protection against genital warts and anal cancer (associated with HPV subtypes 6 and 11). However, there has not been any wholesale recommendation for the use of HPV vaccines in boys, even though some experts have argued that such a use would improve the overall efficacy of protecting against HPV genital infections.
Now that HPV-associated oral cancers have been added to the mix, the argument for using HPV vaccines in boys becomes more forceful. Current recommendations for vaccinating males "must be reconsidered in light of the growing incidence of male HPV-positive oropharyngeal cancer demonstrated in the current report," the editorialists write.
Because HPV cancers are now known to affect both men and women, and because current HPV vaccines are only effective before infection is established, the editorialists recommend that primary care providers inform parents of both boys and girls "about the risks of HPV-associated tumors and the likely reduction in risk provided by the vaccination."
Implications for Clinical Practice
In addition to the potential of HPV vaccination, the editorialists highlight 2 important implications for clinical practice from the latest study.
Now that significant risk factors for both HPV-positive and HPV-negative oropharyngeal cancer are well known, clinicians should encourage patients to "minimize behaviors that put them at risk from either form," they write.
"Third, oncologists should routinely test all patients with oropharyngeal cancer for HPV status, if for no other reason than to refine prognosis," the editorialists recommend. Such testing is already part of clinical trial design, and there is hope that the distinction between HPV-positive and HPV-negative cancers "may soon assist in selecting treatments," they add.
The 2 forms of this cancer have major differences in outcomes, they point out. HPV-positive oropharyngeal cancer is diagnosed at a younger age and has a good prognosis, with "substantial long-term survival," they note. This presents an urgent need for a lower-intensity therapy that maintains control of the disease while avoiding the significant short- and long-term morbidity of current therapy.
Small Sample Size
The study that provoked all of this commentary, and that reconstructs the recent history of oropharyngeal cancer in the United States, is based on only 271 cancer samples, the editorialist point out. But they add that "we are unlikely to get a better picture," because this study used all the samples that were available.
The samples came from 3 states — California (Los Angeles), Hawaii, and Iowa — from SEER registries that participate in the Residual Tissue Repositories program. Samples were only available for less than 5% of patients in these registries, the editorialists point out, and they estimate that during the 2-decade study (1984 to 2004), there were around 200,000 patients with oropharyngeal cancer in the United States.
In their analysis, the researchers used 69 samples of cervical cancer as positive controls and samples of 27 gastric cancers as negative controls.
The prevalence of HPV-associated oropharyngeal cancer increased significantly over the course of the study. HPV prevalence increased from 16.3% during the period from 1984 to 1989, to 71.1% during the period from 2000 to 2004.
First author Anil Chatrurvedi, PhD, from the National Cancer Institutes, and colleagues used these findings to estimate that the population-level incidence of HPV-positive oropharyngeal cancers increased by 22% from 1998 to 2004 (from 0.8 to 2.6 per 100,000 individuals), whereas the incidence of HPV-negative cancer declined by 50% (from 2.0 to 1.0 per 100,000 individuals).
The decline in HPV-negative oropharyngeal cancer parallels a decline in smoking in the United States; the increasing incidence of HPV-positive cancer "perhaps arises from increased oral sex and oral HPV exposure over time," the researchers note. In support of this theory, they cite data showing an increase in the prevalence of genital herpes simplex virus (HSV), both type 1 and type 2, and genital warts among recent birth cohorts in the United States, and note that all 3 are "accepted surrogates" for oral sex (HSV1), risky sexual behavior (HSV2), and HPV exposure (genital warts). The predominant rise in oropharyngeal cancer among the young is consistent with this scenario, they add.
However, the reason the increase in HPV-positive oropharyngeal cancer is so pronounced among males and whites "remains unexplained," they add.
Burden of Disease
On the basis of their findings, the researchers estimate that by the year 2020, the annual number of HPV-positive oropharyngeal cancers (approximately 8700 patients, with the majority of these — around 7400 — occurring in men) will surpass the annual number of cervical cancers (approximately 7700 patients).
This is based on a conservative assumption of 70% of oropharyngeal cancer being HPV-positive (which was the case in 2004, but because the trend is increasing, it might be even higher now).
So far, cervical cancer has been the focus of prophylactic HPV vaccination; this is justified, the researchers note, because of the substantially higher burden of cervical precancers, compared with invasive cervical cancers or oropharyngeal cancers, in the United States.
However, the rising burden of HPV-positive oropharyngeal cancer requires that attention focus on vaccination to prevent oral HPV infection, especially because there is no screening currently available for oropharyngeal cancer. "The high efficacy of HPV vaccines in preventing extracervical infections among women (e.g., vagina and vulva) and penile and anal infections among men implies that efficacy may be comparable against oral HPV infections," they write.
Dr. Gillison reports serving as a consultant for Merck & Co, GlaxoSmithKline, Amgen, and Bristol-Myers Squibb. The editorialists disclosed no relevant financial relationships.
J Clin Oncol. Published online October 3, 2011. Abstract, Editorial

LUNG CANCER WITH SOLITARY METASTASIS MAY BE CURABLE FOR INTRATHORACIC STAGE I-II DISEASE

NEW YORK (Reuters Health) Sep 30 - In the rare patient with non-small cell lung cancer with solitary metastasis not involving the brain or adrenal glands, resection can have an encouraging outcome, researchers report August 23 online in Lung Cancer.
"The findings of this study," senior author Dr. Salah Abbasi told Reuters Health by email, "give great hope to lung cancer patients with solitary metastasis; they can be treated now with curative intent instead of palliative intent."
Dr. Abbasi of the King Hussein Cancer Center in Amman, Jordan, and colleagues note that patients with solitary brain or adrenal metastasis have more favorable outcomes following surgical resection. Nevertheless, they add, "the outcome and predictive factors for survival following metastasectomy for patients with other metastatic sites are not well defined."
To gain more information, the team examined the literature and identified 51 articles involving 75 patients. After exclusions, 62 cases remained eligible for review and analysis.
Overall, the 5-year survival rate was 50%. Patients with non-visceral metastasis had a 5-year survival of 63%, compared to 39% for patients with visceral metastasis.
Smaller or larger primary tumors had no significant influence on survival, nor did sex, histology or the use of perioperative chemotherapy. However, patients with mediastinal lymph node involvement had a mean survival of 23 months compared to 75 months for the other patients. In fact, no patients with such involvement survived for 5 years, while 64% of other patients did.
Similarly, there were no 5-year survivals in patients with intra-thoracic stage III disease, compared to 77% for stage II and 63% for stage I. Their mean survival time was 23 months.
Overall, these patients, "especially if they have stage I or II intrathoracic tumor," say the investigators, "should be offered metastasectomy after complete and meticulous staging of the mediastinum and other distant sites."
Thus concluded Dr. Abbasi, "Oncologists treating lung cancer patients with solitary metastasis should look aggressively for the possibility of curative resection of the metastatic site and definitive treatment of the lung primary; these patients have a survival chance similar to patients who present as stage II disease."
SOURCE: http://bit.ly/pSaIzv
Lung Cancer 2011.

INTERMITTENT SUNITINIB DOSAGE SLIGHTLY BETTER THAN CONTINUOUS IN RENAL CANCER

NEW YORK (Reuters Health) Oct 04 - Continuous once-daily sunitinib is a feasible regimen for first-line treatment of advanced/metastatic renal cell carcinoma, when necessary, and might benefit selected patients, researchers say.
When the drug received FDA approval in 2007 the dosing schedule was 50 mg per day, 4 weeks on and 2 weeks off, as Dr. Carlos H. Barrios of PUCRS School of Medicine, Porto Alegre, Brazil and colleagues note in their report.
The continuous dosing regimen wasn't superior to the approved protocol in their study. However, it might prove useful in patients who develop symptoms in the off-treatment period, the investigators say.
They treated 119 treatment-naive patients with 37.5 mg daily for a median of 24.3 weeks, according to a September 6th online paper in Cancer.
The objective response rate was 35.3% and the median response duration was 10.4 months. Overall, 36% of patients had stable disease for at least 12 weeks. The one-year survival probability was 67.8%.
The median progression-free survival was nine months, shorter than the 11 months seen in the phase III trial with the intermittent 50 mg dosing.
Dosing delays were less frequent in the current study (18% vs 38%) but a similar proportion of patients required a dose reduction (33% vs 32%). A comparable proportion of patients discontinued treatment because of an adverse event.
Overall, the researchers favor the approved intermittent schedule, which showed trends toward a longer time to tumor progression and a longer progression-free survival, and a statistically superior time to deterioration.
Still, they say continuous dosing might be preferable in select circumstances, for example, when patients have tumor regrowth or symptom flare during the two-week off-treatment period.
"The regimen," Dr. Barrios told Reuters Health by email, "proved to be active with manageable toxicity. However, even though this was not a comparative trial we did not encounter any signal that the toxicity observed was significantly different from what we would have expected with the approved 4/2 regimen. Nevertheless the regimen could represent an alternative for individual patients that could potentially adapt better to this schedule."
In an editorial, Dr. Brian I. Rini of The Cleveland Clinic Taussig Cancer Institute, Ohio and Dr. Cristina Suarez of Hospital General Vall d'Hebron, Barcelona, Spain note that the most recently published study, a randomized trial comparing the two regimens, "supports clear advantages for the 50-mg dose using the 4/2 schedule."
Nevertheless, investigation is ongoing, and Dr. Rini told Reuters Health by email that the current data "extend the experience of alternative dosing of sunitinib. It is clear that dose and schedule impact outcome, and there is still more work to do to understand how to optimize giving targeted agents like sunitinib."
SOURCE: http://bit.ly/nbSQgd

OCCULT LYMPH NODE DISEASE NOT PROGNOSTIC IN EARLY BREAST CANCER

NEW YORK (Reuters Health) Sep 28 - Occult axillary lymph node metastases don't influence outcome in early breast cancer, researchers reported online August 25th in Cancer.
The subject "has been controversial, because some studies have demonstrated reduced survival when occult metastases were identified, and others have demonstrated no survival difference" - and when significant differences did show up, they were often too small to be clinically meaningful, said lead author Dr. Yun Wu and colleagues at The University of Texas MD Anderson Cancer Center, Houston.
Furthermore, because of different methodologies, studies can be hard to compare, the authors said.
For the current study they reviewed data on 267 patients who had axillary lymph node dissection between 1987 and 1995, with negative pathologic evaluations.
More recently, all of the dissected lymph nodes from these patients were re-evaluated by intensified pathologic methods and 39 patients (15%) were found to have occult metastases.
According to standard practice at the time, none of the patients received systemic chemotherapy or hormone therapy - which today makes it possible for Dr. Wu's group to analyze the natural history of occult lymph node disease.
Twenty percent of patients with occult lymph node disease had macrometastases (>2 mm), 40% had micrometastases (>0.2 mm to 2 mm) and 40% had isolated tumor cells (< 0. 2 mm).
Median follow-up for all patients was 15.7 years. Thirty patients (11%) died of the disease and 77 (29%) died of other causes. The median follow-up for patients who remained alive at the time of analysis was 17.8 years.
There was no difference in recurrence-free or overall survival between lymph node-negative patients and patients with occult metastases. There was also no relationship between survival and metastasis size.
The researchers note that this is in contrast to a recent report from Memorial Sloan-Kettering Hospital in New York that used similar methods. However, they point out that the Memorial study included patients with larger tumors, more metastases, and more patients with multiple involved lymph nodes.
The results from the current study, according to Dr. Wu and colleagues, "contribute further to the growing body of literature indicating that occult lymph node metastasis identified by intensified pathologic methods in patients with early stage breast cancer may not be biologically or clinically significant."
SOURCE: http://bit.ly/rkn1Nj

ASCO UPDATES RECOMMENDATIONS FOR ANTIEMETICS USE

NEW YORK (Reuters Health) Oct 03 - The American Society of Clinical Oncology (ASCO) has updated its recommendations for the use of antiemetics during cancer treatment, and one key change is the classification of the combination of an anthracycline and cyclophosphamide as very likely to cause nausea and vomiting, even though the separate components are only moderately emetogenic.
The clinical guideline update on antiemetics, based on a systematic review of the literature published since the last update in 2006, appeared online September 26 in the Journal of Clinical Oncology.
"There have been improvements in stratifying the risk of side effect risks according to the type of drug treatment used," said update panel co-chair Dr. Ethan Basch, with Memorial Sloan-Kettering Cancer Center in New York, in a prepared statement. "This guideline update reflects further progress refining antiemetic approaches and minimizing these side effects."
For highly emetogenic chemotherapy, the guideline recommendations are unchanged from the last update and call for the three-drug combination of a neurokinin-1 (NK1) receptor antagonist, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, and dexamethasone.
Palonosetron is the preferred 5-HT receptor antagonist, but if it is not available a first-generation 5-HT3 blocker (granisetron or ondansetron) can be substituted, the authors say. (In a warning on its website, however, ASCO points out that the U.S. Food and Drug Administration recently informed the public that ondansetron may increase the risk of developing a potentially fatal arrhythmia; for more information see http://1.usa.gov/qfe9yv.)
The NK1 receptor antagonist aprepitant and its relatively new intravenous formulation fosaprepitant are equivalent, the panel notes. However, the fact that fosaprepitant is given for one day rather than the three days for aprepitant may make it preferable for patients.
For moderately emetogenic chemotherapy regimens, palonosetron plus dexamethasone is sufficient, the report continues. However, moderate evidence suggests that aprepitant may add benefit.
For low-risk regimens, a single dose of dexamethasone is recommended.
When it comes to preventing radiation-induced nausea and vomiting, the panel again stratifies antiemetic treatment based on risk.
For example, with high-risk radiotherapy such as total body irradiation, patients should receive a 5-HT3 receptor antagonist before each fraction and for 24 hours after treatment, and may receive a five-day course of dexamethasone with each fraction.
By comparison, radiotherapy to the breast and extremities carries minimal emetic risk but when it does occur, rescue therapy with a 5-HT3 antagonist or dopamine receptor antagonist (e.g., metoclopramide) is indicated.
"In general, we have more effective and better tolerated antiemetic agents today, and we have also learned how to use the available agents in more effective ways," commented panel co-chair Dr. Gary Lyman, with Duke University in Durham, North Carolina, in the statement.
SOURCE: http://bit.ly/ppIDak.

ECCO 2011-MUTATION IN SF3B1 LINKED TO IMPROVED PROGNOSIS IN MDS

September 29, 2011 (Stockholm, Sweden) — Mutations in the SF3B1 gene might indicate a more favorable prognosis in myelodysplastic syndromes (MDS).
The SF3B1 gene is involved in the modification of RNA. In a recent study, it was observed in 20% of MDS patients; there was a particularly high frequency in patients whose disease was characterized by ring sideroblasts (65%).
Importantly, patients with SF3B1 mutations had fewer episodes of cytopenia and enjoyed longer event-free survival than patients without these mutations.
The study results were published online September 26 in the New England Journal of Medicine to coincide with their presentation here at the 2011 European Multidisciplinary Cancer Congress.
"Genomic studies give new insight into the causes of MDS, and can complement standard analyses," said lead author Elli Papaemmanuil, PhD, a postdoctoral research fellow working at the Cancer Genome Project, the Wellcome Trust Genome Centre, Cambridge, United Kingdom. "Using SF3B1 could improve and accelerate diagnosis and can identify high-risk patients, and understanding the molecular mechanisms will help stratify therapy and search for drug targets.
Genetic Mutations Unclear
MDS are a heterogeneous group of hematologic cancers that are characterized by low blood counts, most commonly anemia, explained Dr. Papaemmanuil. Patients face a risk for progression to acute myeloid leukemia (AML).
More than a quarter of all patients with MDS present with large numbers of ring sideroblasts in the bone marrow. These are abnormal precursors of mature red blood cells, and have a distinctive partial or complete ring of iron-laden mitochondria that surrounds the cell nucleus. Several genetic lesions related to inherited sideroblastic anemias have been identified, but the pathogenesis of ring sideroblasts in MDS remains unclear.
Improved Diagnostics Needed
Patients often present with symptoms of unexplained anemia, bleeding, bruising, and frequent infections. "But the diagnostic course in the clinic is not always very straightforward," she said. "It will take multiple blood tests, most of which will be abnormal, and the exclusion of other common infections before the hematologist will decide to subject the patient to a bone marrow examination."
Bone marrow exams are invasive, painful, expensive, and time consuming, but are often needed to confirm a diagnosis of MDS, Dr. Papaemmanuil explained. "This process can take anywhere from a few months to 2 years; during that time, the patient is living with MDS."
"What is most important about this is that for every patient who is diagnosed with MDS, it is estimated that there is another patient with MDS who never gets diagnosed," she emphasized. "The key point is that there is a large proportion of MDS patients."
Receiving an MDS diagnosis is not the end point, she continued. About 20% will progress to AML and require different treatment.
Quite often, a patient cannot be assigned to any of the disease subtypes. This makes it difficult to decide on an appropriate treatment regimen, Dr. Papaemmanuil explained.
Although there are a number of mutations in MDS, none of them really explain the different subtypes or the different responses seen in patients. "We believe that there are mutations that can not only explain every MDS subtype, but can directly inform us of the likely response of the patient and clinical course," she said.
Mutation in SF3B1 Identified
Dr. Papaemmanuil and colleagues sought to identify recurrently mutated cancer genes in patients with low-grade MDS, which could prove useful in diagnosing these disorders and provide insight into the molecular pathogenesis.
Using massively parallel sequencing technology of all protein-coding exons, the researchers identified mutations in the genome of 9 patients with low-grade MDS. In 6 of these patients, recurrent somatic mutations in the SF3B1 gene, which encodes a core component of the RNA splicing machinery, were identified. Overall, 64 point mutations were identified in the 9 patients.
The gene was then resequenced in 2087 specimens from patients with MDS, primary cancers, and core cancer cell lines. The researchers detected somatic mutations of SF3B1 in 28.1% of patients with MDS, 19.3% of patients with MDS or myeloproliferative neoplasm, and 5.3% of patients with AML.
Mutations of the gene were also observed in 1% to 5% of other common tumor types, including breast cancer, multiple myeloma, and renal cancer. In patients with myeloid neoplasms, there was also a close relation between mutant SF3B1 and the presence of ring sideroblasts (P < .001). In multivariable analysis, SF3B1 mutations were independently associated with better overall survival (hazard ratio [HR], 0.18; P = .028) and a lower risk for leukemic evolution (HR, 0.32; P = .048).
A "Seminal Discovery"
Acting as a discussant of the study, Carlos Caldas, MD, from the Cambridge Research Institute, United Kingdom, asserted that "we now have to look at all of these genes as candidate cancer genes in all tumor types."
"Not just point mutations but amplifications also," he emphasized." I think we are in the face of a seminal discovery, and we have to broaden our understanding of cancer."
"There is a lot of positive potential here for prognostication and for therapeutic strategies," he concluded.
The study was funded by the Wellcome Trust, the Kay Kendall Leukaemia Fund, Leukemia Lymphoma Research, the Adenoid Cystic Carcinoma Research Foundation, the Medical Research Council, the Oxford National Institutes for Health Research Biomedical Research Centre, the Swedish Cancer Society, the International Human Frontier Science Program Organization, the Department of Veterans Affairs, the National Institutes of Health, the Association for International Cancer Research, the Leukemia Lymphoma Society, Associazione Italiana per la Ricerca sul Cancro, and Fondazione Cariplo. Dr. Papaemmanuil has disclosed no relevant financial relationships. Several coauthors disclosed financial relationships with pharmaceutical and biotechnology companies.
N Engl J Med. Published online September 26, 2011. Abstract
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract LBA 11. Presented September 27, 2011.

ANOTHER URBAN LEGEND-OFF PUMB CABG MAY BE WORSE THAN CONVENTIONAL CABG

October 3, 2011 (Lisbon, Portugal) — New data from a large UK observational study have somewhat controversially shown that off-pump coronary artery bypass surgery (CABG) is associated with significantly higher in-hospital and mid-term mortality than conventional on-pump CABG. Dr Domenico Pagano (University Hospital and University of Birmingham, UK) reported the findings in a last-minute addition to the program at the European Association for Cardio-Thoracic Surgery 2011 Annual Meeting here yesterday.
Off-pump CABG "was associated with a 34% increased risk of in-hospital mortality overall and a 28% reduced risk of mid-term survival, out to almost three years, compared with on-pump," Pagano noted. These new data are in line with findings from smaller, randomized studies, says Pagano, adding, "It's a good snapshot of contemporaneous practice in the UK."
But others criticized the study. Dr David Taggart (University of Oxford, UK), said, "The fundamental flaw in what is potentially a dangerous interpretation is that this was done at an institutional level, and that covers many sins, including surgeons who had attempted off-pump surgery--it didn't work out for them, and they abandoned it. I would want to see these data reanalyzed looking at what happened in the outcomes of surgeons who are high-volume users of off-pump surgery. We need propensity-matching of the operators. That's my concern in the interpretation of these data."
Other attendees pointed out further drawbacks, including the fact that off-pump CABG (also known as OP-CAB) is a whole family of approaches, and the way it was performed in this study was not properly defined. In addition, some of the findings could have been driven by graft failure, and there was no allowance for this in the study design.
Asked to comment on the results, Dr John Pepper (Imperial College London, UK) explained to heartwire there have been "many subtle improvements in heart-lung machines" since off-pump CABG first emerged, and now "the pump is pretty safe. Plus you have to remember that many CABG operations are done in conjunction with valve procedures, which are done on a heart-lung bypass machine."
With this background, "My opinion is that off-pump and on-pump are similar," says Pepper. "Off-pump is not significantly better than on-pump, but in experienced hands, in experienced units, they can achieve extremely good results with off-pump. I think the message is that off-pump is only for a group of people who are very keen on doing it, who have trained themselves obsessively, and then they can get results that are comparable to, but probably not much better than, on-pump."
Pepper added that the results of an ongoing large Canadian randomized clinical trial of off-pump vs on-pump surgery in around 4000 patients are eagerly awaited to try to discern whether there truly is a difference between these two approaches in terms of outcomes.
Compared With on-Pump Surgery, 108 Extra Deaths on off-Pump Group
When off-pump CABG first emerged as a surgical technique, it was thought it would reduce or eliminate the neuropsychological risks of putting a patient on a heart-lung bypass machine, avoiding or reducing so-called "pump head." Pagano explained that off-pump CABG may improve outcomes of selected groups of patients, and "there are a number of small randomized trials that show superiority in some subgroups." But "landmark randomized trials to address short-term and long-term mortality are still not available," he noted.
In the new analysis, he and his colleagues examined data on patients undergoing isolated, first-time CABG between March 2004 and April 2009, obtained from the national database for cardiothoracic surgery of Great Britain and Ireland. Mortality data were extracted from the UK Office for National Statistics. While observational data are no substitute for randomized controlled trials, "they still have a role to provide the best available evidence for practice to date," Pagano observed.
The overall patient population consisted of 58 072 patients, of whom 14% (n=9590) underwent off-pump CABG and 86% (n=48 482) had on-pump surgery. Of these, 6374 off-pump patients were propensity-matched with 6374 on-pump patients for the primary analysis. To further reinforce the main analysis, the propensity score was also used as a covariant to give results on the overall group of 58 072 patients in a weighted analysis.
For the primary analysis, in-hospital mortality was significantly higher among those who had off-pump CABG, at 2.4% vs 1.8% for those who underwent on-pump surgery (odds ratio 1.34; p=0.02). Mid-term survival, with a median follow-up of 2.9 years, was also significantly worse among those who had off-pump surgery (HR 1.28 for mid-term mortality; p=0.002) compared with on-pump.
"In simple terms, it accounts for 108 extra deaths for the off-pump group," Pagano noted.
In the weighted analysis, results were similar, with a 35% increased risk of in-hospital death among those in the off-pump CABG group (p=0.001) and 27% greater mid-term mortality (p<0.0001) compared with on-pump.
But Volume of off-Pump by Institution Modifies the Results
The researchers did find, however, that analyzing the mortality according to volume of off-pump procedures performed per institution modified the results somewhat, at least for short-term, in-hospital deaths.
The median rate of off-pump procedures for institutions in the study was 3.8%, and they divided hospitals into high-performing off-pump CABG centers (>3.8%) and low-performing ones.
For in-hospital deaths, there was no difference in mortality between off-pump and on-pump CABG when the analysis was confined to high-volume centers.
But for mid-term survival, there was still an advantage of on-pump even when it was compared only with off-pump performed at higher-volume institutions, Pagano noted. The hazard ratio was 1.25 for mortality among off-pump patients operated on at such institutions compared with on-pump (p=0.007), "and there was no interaction throughout the data set between the volume of off-pump and the mid-term survival," he said.
But Taggart reiterated his concerns about how the analysis was done. "They propensity-matched their patients very well, but the one thing it doesn't tell you is about the relative experience of the people who were doing these operations," he commented to heartwire . "If it includes surgeons who had a go at doing off-pump surgery and got bad results, they are still included, so this is an institutional analysis as opposed to a per-surgeon analysis, and there is a real danger to that."
But Pagano said it wasn't possible with this database to perform this analysis, and in any case it would suffer from confounding by indication. And while he acknowledged that there is a learning curve for off-pump CABG, he said that in the UK, generally, "in the high-volume units, you mostly have surgeons who do most of their work off-pump."
Taggart told heartwire if the researchers could not perform the analysis in the way he suggested "they shouldn't be making those conclusions."
No Benefits of off-Pump CABG Seen in Any Other Subgroups
Pagano and colleagues also performed a number of subgroup analyses. For those with renal dysfunction, there were too few events to determine whether there was any advantage of one operative procedure over the other. But for those with a previous neurological disorder, who tended to have worse outcomes whichever form of surgery they underwent, "the disadvantage of off-pump did not disappear," he pointed out.
The researchers also went on to pool the results of all other known randomized trial data on this subject in which patients were followed up for at least one year, including the ROOBY trial. These pooled data were remarkably similar to the new UK findings, said Pagano, with a 34% increased risk of in-hospital mortality and a 28% higher risk of mid-term death with off-pump surgery compared with on-pump CABG. "This is where we sit. We are in line with these randomized trials," he observed.
Let's Agree to Disagree
Further discussion after the presentation centered on the fact that off-pump CABG "is a whole family of approaches," according to one attendee, who added to Pagano, "You have not defined your primary variable correctly, and therefore the whole study carries a major flaw."
Pagano said they would have to agree to disagree. "There are no data about the type of off-pump surgeries on survival. While I accept there are many ways of doing OP-CAB, we still don't know the long-term safety, and the purpose of this trial was to generate some reflection."
Meanwhile Dr Teresa Kieser (University of Calgary, AB) said she wondered whether some of the findings could have be driven by graft failure and therefore whether an assessment by the use or lack of use of certain graft assessment techniques would have provided further information.
"We cannot answer this question, since we don't have the data available," said Pagano. "There may be centers and techniques and ways to make sure [off-pump CABG] is safe, but what we are saying here is that actually that's not been tested yet and there are no answers. I wouldn't like to speculate on data I haven't got."
Off-Pump CABG the Norm in Some Asian Centers
As an interesting aside, Pepper told heartwire that in some countries, particularly in Asia, there is an economic advantage to using off-pump CABG.
"There, it is significantly cheaper to use off-pump, and so you will find in, for example, Delhi, Chennai, or Mumbai--the big Indian centers--very large numbers of patients being done off-pump because it's economically sensible. They are very talented surgeons, and they can get comparable results. It's a different economic climate from Europe," he explained.
Asked whether he thought Asian centers would reconsider their high use of off-pump CABG if it is ultimately shown to have no advantage over on-pump CABG or even to have worse outcomes, he commented, "I don't know! Probably not; we'll have to wait and see."
Pagano reports no conflicts of interest. Pagano reports no conflicts of interest.

INCREASED BLEEDING RISK WITH SSRIs ANTIPLATELETS COMBINATION

September 27, 2011 (Montreal, Quebes City) — Selective serotonin-reuptake inhibitor (SSRI) antidepressants appear to increase the risk of bleeding in patients taking antiplatelet agents following an MI, a new study suggests [1].
The study, published online in CMAJ on September 26, 2011, was conducted by a team led by Dr Elham Rahme (McGill University, Montreal, QC).
Rahme explained to heartwire that data on whether SSRI antidepressants increase bleeding risk have been mixed. "It is a controversial area, but several studies have suggested that these agents may be associated with a higher bleeding risk," she said. While the mechanism is not completely clear, it is thought that blockade of serotonin reuptake into platelets somehow causes the platelets to become less reactive.
"We showed a definite increase in bleeding risk in patients taking both antiplatelet agents and SSRIs, which physicians need to be aware of, especially as depression is a common condition in patients who have recently had an MI," Rahme commented. "Obviously, patients who have major depression after an MI will still need to be treated with an antidepressant, but when making treatment decisions doctors need to bear in mind that an increased risk of bleeding may be a possibility with the SSRIs for patients taking aspirin and/or clopidogrel."
Balance Risk of Bleeding With Risk of Depression
She said she could not recommend using a different class of antidepressant, as their study did not investigate this option. "All we are saying is that doctors prescribing either antiplatelet agents or antidepressants need to be aware of this interaction with SSRIs and try to balance the increased bleeding risk with the risk of depression."
For the study, the researchers linked together databases on hospitalizations, physician billing, medication-reimbursement claims, and demographic data from Quebec province to identify patients over the age of 50 who were discharged from the hospital on antiplatelet therapy following an MI between 1998 and 2007 and those who were also taking SSRIs.
Bleeding was defined as a hospitalization for bleeding or bleeding in-hospital during follow-up and was identified using hospital-discharge diagnosis codes.
Of the 27 058 patients included, 14 426 were taking aspirin alone; 2467 were on clopidogrel alone; 9475 were on both aspirin and clopidogrel; 406 were taking aspirin and an SSRI; 239 were taking aspirin, clopidogrel, and an SSRI; and 45 were taking clopidogrel and an SSRI.
Results showed that after adjustment for baseline demographics, adding an SSRI to aspirin increased bleeding risk by 42% and adding an SSRI to dual antiplatelet therapy increased bleeding risk by 57%; both these increases reached statistical significance.
There were not enough patients taking the combination of clopidogrel plus an SSRI for a meaningful result, but the bleeding risk was still numerically higher in those taking both drugs compared with clopidogrel alone.
The researchers did not find any difference in bleeding risk with individual SSRIs. Rahme told heartwire that some previous studies have suggested that the SSRIs with higher affinity to serotonin may increase bleeding more, but they could not corroborate this.
She added that because of the retrospective nature of this study, the results should be confirmed in further trials.

IT HAPPENS EVERYWHERE-STOCK FRAUD WITH NEW DRUGS

September 30, 2011 — Has there been insider trading based on embargoed clinical trial results with experimental anticancer therapies? That's the suggestion in a paper published online September 26 in the Journal of the National Cancer Institute.
The stock prices of companies that eventually report positive results tend to increase before those results are publicly announced, whereas the stock prices of companies that end up reporting negative results decline before the results see the light of day, the authors report.
Allan S. Detsky, MD, PhD, and his colleagues from the University of Toronto, Ontario, Canada, explain that phase 3 clinical trials and US Food and Drug Administration (FDA) regulatory decisions "are critical for the success of new drugs and can influence a company's market valuation.
"Knowledge of trial results before they are made public (i.e., insider information) can affect the price of a drug company's stock," they add.
Dr. Detsky and his team were curious about the stock prices of companies before and after public announcements about experimental anticancer drugs.
In this study, they identified drugs that were undergoing evaluation in phase 3 trials or awaiting regulatory approval from the FDA from January 2000 to January 2009.
They analyzed the stock prices for the 120 trading days before and after the results of clinical trial outcomes or FDA regulatory decisions were publicly announced.
Stock prices were obtained from the Center for Research in Security Prices and from Bloomberg Professional, and most companies were listed on the NASDAQ or the New York Stock Exchange.
They found that the mean stock price in the 120 days before a positive result was announced increased by 13.7% (95% confidence interval [CI], –2.2% to 29.6%); before a negative result, the price decreased by 0.7% (95% CI, –13.8% to 12.3%).
In a post hoc analysis, Dr. Detsky and colleagues compared average stock prices in the 120 to 60 days before clinical trial announcements with the average price in the subsequent 60 days.
In that analysis, they found that companies reporting positive trial results showed a mean increase in their stock price of 9.4%, whereas those reporting negative results showed a decrease of 4.5% (P = .03).
However, stock prices were not affected by positive or negative FDA decisions.
One Explanation? Insider Trading
Dr. Detsky and colleagues write that one possible explanation for their findings is insider trading.
"Before clinical trial results are made public, many people involved in the trial process are likely to have information regarding the outcomes," they write.
"The changes in postannouncement share price that we have demonstrated highlight the potential use of this information by individuals for profit once it becomes public."
They add that FDA decisions would not influence stock prices because the information on which these decisions are based is already public.
Finally, Dr. Detsky and his team write: "The results of this study call for increased awareness by investigators regarding the legal and ethical aspects of divulging nonpublic information regarding clinical trials."
They're Wrong
"We're very concerned about what the authors suggest, but they're wrong," Mark J. Ratain, MD, professor at the University of Chicago, Illinois, told Medscape Medical News.
Dr. Ratain and Adam Feuerstein, a senior columnist at TheStreet.com, wrote an editorial that accompanies the paper.
The editorialists undertook their own analysis of the companies that were studied by Dr. Detsky and his team, and calculated the market capitalization of the companies 120 days before public announcements. They found that market capitalization was 80-fold greater for companies with positive trials than for those with negative trials, indicating that the subsequent negative trials were not a surprise.
"The difference in the market capitalization at day –120 most likely reflects publicly available information regarding the phase 1 and 2 clinical trials (as well as other factors, including competition and management), which has been incorporated into the market value of a stock," the editorialists write.
They add: "The stock market is known to anticipate future events, as opposed to reacting to the past. Thus, it is not surprising that sophisticated investors are able to judge the probability of success, which is reflected in the share price."
100% Wrong
"As we point out in our editorial, the data were misanalyzed," Dr. Ratain told Medscape Medical News. "There is no basis for their conclusion. They just didn't analyze the data properly. They are completely wrong."
By the time phase 3 trial results are announced, they are usually no surprise, he added.
"Many of the references in our editorial are to Mr. Feuerstein's writings as the biotech columnist for TheStreet.com. He commented on many of these companies before their phase 3 results were announced, basically saying that these drugs suck," Dr. Ratain said.
If there is any wrong doing, it is on the part of companies that continue to do phase 3 trials inappropriately, he said.
Medscape Medical News tried to reach Dr. Detsky for his comments, but he had not responded by press time.
Dr. Detsky and Dr. Ratain have disclosed no relevant financial relationships.
J Natl Cancer Inst. Published online September 26, 2011. Abstract, Editorial

ECCO 2011-VORINOSTAT FAILURE FOR MESOTHELIOMA

September 29, 2011 (Stockholm, Sweden) — The largest randomized phase 3 study ever conducted in patients with advanced malignant pleural mesothelioma has failed; no survival benefit was seen with vorinostat (Zolinza, Merck & Co).
"Despite the negative data, we want to pledge our best efforts to continue to find new therapies for this dreadful disease," said principal investigator Lee Krug, MD, from the Memorial Sloan-Kettering Cancer Center in New York City. He was addressing a presidential session here at the 2011 European Multidisciplinary Cancer Congress. The study was chosen as a best abstract.
Vorinostat, a histone deacetylase inhibitor, is marketed for use in the treatment of cutaneous T-cell lymphoma. Dr. Krug explained that the manufacturer agreed to fund the large study of mesothelioma after a small phase 1 study suggested a benefit from this drug. In that small trial, 5 of 13 patients experienced stable disease lasting 4 to 13 months.
The phase 3 study was conducted in 660 patients with malignant pleural mesothelioma who had progressed after 1 or 2 systemic therapies, including pemetrexed (Alimta) and cisplatin.
All patients received best supportive care, and were randomized to receive placebo or vorinostat 300 mg orally twice daily for 3 days, each week of a 21-day cycle.
There was no significant difference in median overall survival between the vorinostat and placebo groups (30.7 vs 27.1 weeks; hazard ratio [HR], 0.98; P = .858). Median progression-free survival was slightly better with vorinostat (6.3 vs 6.1 weeks); this reached statistical significance but is not considered to be clinically significant, Dr. Krug noted.
Further analysis found no significant differences between the 2 groups in overall response rate, forced vital capacity, dyspnea, or in the proportion of patients reporting serious adverse events.
"This is the biggest study so far," said Rolf Stahel, MD, from the University Hospital in Zurich, Switzerland, "but the overall results are negative, and they are also negative in each subgroup."
Dr. Stahel said that another approach to the treatment of mesothelioma — adding bevacizumab (Avastin) to chemotherapy — has also recently failed.
"What is on the horizon" he asked. Noting that his group recently reported finding a mutation in the BAP1 gene in mesothelioma, he explained that "we may have to break down into subgroups of mutations, even in very rare diseases such as mesothelioma."
Mesothelioma, a rare but fatal cancer resulting from exposure to asbestos, is diagnosed in about 2000 to 3000 individuals each year in the United States. The number of cases is expected to peak from 2015 to 2020, according to Dr. Krug. The use of asbestos has decreased since the 1970s, and the latency period between exposure and mesothelioma is 20 to 50 years.
The trial was funded by Merck & Co, the manufacturer of vorinostat.
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 1LBA. Presented September 24, 2011.

ECCO 2011-VISMODEGIB FOR BASAL CELL CARCINOMA

September 29, 2011 (Stockholm, Sweden) — The investigational drug vismodegib, which has a novel mechanism of action (inhibiting the hedgehog signaling pathway), has shown "substantial clinical benefit" in advanced basal cell carcinoma, in both metastatic and locally advanced settings.
This finding comes from a pivotal trial of the product in 104 patients, presented here at the 2011 European Multidisciplinary Cancer Congress. The results were presented by Luc Dirix, MD, from the Iridium Kankernetwerk, Antwerp, Belgium, from a paper selected as a best abstract for the presidential session.
Vismodegib is "a potential new therapy" for advanced basal cell carcinoma, he told the meeting attendees. It is under development by Genentech/Roche, which has recently filed an approval application with the US Food and Drug Administration for its use in the treatment of inoperable advanced basal cell carcinoma.
The results from the pivotal trial were "totally convincing" and there were some "very spectacular responses" said Caroline Robert, MD, PhD, from the Institut Gustave Roussy in Paris, France, who acted as discussant for the paper.
"Vismodegib is a breakthrough for the treatment of advanced basal cell carcinoma," she said, but cautioned that "long-term tolerance is an issue."
This novel drug is the first in the class of hedgehog pathway inhibitors. This pathway is disrupted in about 90% of basal cell carcinomas; it is also affected in several other cancers, including medulloblastoma.
Advanced Cases Not Operable
Basal cell carcinoma is the most commonly diagnosed human cancer, with more than 2 million cases each year in the United States, Dr. Dirix noted.
Most cases are treated with surgery, he explained. However, a small proportion of patients (less than 5%) progress to locally advanced or even metastatic disease, for which there is currently no standard of care.
In a phase 1 study of 33 patients with advanced basal cell carcinoma, vismodegib showed a 55% response rate and was generally well tolerated (N Engl J Med. 2009;361:1164-1172). The results generated considerable excitement among scientists, and were heralded as a new era in the treatment of basal cell carcinoma.
Those results led to the pivotal phase 2 study conducted by Dr. Dirix's team. Patients recruited to this study had histologically confirmed basal cell carcinoma that was inoperable, or were patients for whom surgery would be significantly disfiguring, he explained. All patients had either locally advanced (n = 63) or metastatic (n = 63) disease, and all received treatment with vismodegib 150 mg orally until progression or until withdrawal from the study.
"Nearly all patients had some tumor shrinkage," Dr. Dirix reported.
Of the patients with locally advanced disease, 43% responded, and "many had huge responses with massive decreases in tumor size," he said. One patient had no evaluable basal cell carcinoma after treatment, he noted.
Patients with locally advanced disease, assessed by independent review, had an overall response rate of 43% (95% confidence interval [CI], 31% to 56%; P < .0001), and patients with metastatic disease had an overall response rate of 30% (95% CI, 16% to 48%; P = .0011).
Median time to progression was 9.5 months for both groups of patients, Dr. Dirix noted.
Adverse events that were reported in more than 30% of patients included muscle spasms, alopecia, taste disturbance, weight loss, and fatigue. Serious adverse events were reported in 26 patients (25%); in 4 patients the serious adverse event was considered to be related to the vismodegib. Fatal adverse events were reported in 7 patients (7%), but none were considered to be related to the drug.
In her discussion of the study, Dr. Robert drew attention to these tolerability findings. She noted that in a another study of vismodegib, conducted in 41 patients with Gorlin syndrome, about 30% stopped taking the drug because of adverse events, and most patients could not tolerate the drug for more than 18 months.
Dr. Robert speculated that there might be a use for vismodegib in the neoadjuvant treatment of advanced basal cell cancer, for example with patients taking it for 3 months or so to shrink their tumors and then undergoing surgery. "We need to explore other modalities," she said, and "surgery must always remain in the algorithm."
Dr. Robert also provided interesting insight into how the drug was developed. Cyclopamine, a chemical extracted from the corn lily, was found to be an inhibitor of the hedgehog pathway. Attention was drawn to this plant after it was noticed that sheep that fed on the flowers while they were pregnant gave birth to deformed offspring, with only 1 eye and brain malformations.
The trial was funded by Genentech/Roche, the companies that are developing vismodegib.
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 1BA. Presented September 24, 2011.

HIGHER DOSE RADIOTHERAPY NOT SUPERIOR FOR NSCLC

October 4, 2011 (Miami Beach, Florida) — A landmark trial in nonsmall-cell lung cancer (NSCLC) has found that high-dose conformal radiotherapy (74 Gy) did not improve survival, compared with the standard dose (60 Gy), in patients with unresectable stage III disease.
In fact, median overall survival was better with the standard dose than with the high dose (21.7 vs 20.7 months; P = .02).
"I think it changes practice," said study chair Jeffrey Bradley, MD, from the Washington University School of Medicine in St. Louis, Missouri.
Dr. Bradley spoke at a press conference here at the American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting; he presented the results of a study of 423 patients with grade 3 NSCLC at the plenary session.
Dr. Bradley explained that high-dose radiation — not standard-dose radiation — is typically used in this setting in the United States.
These NSCLC stage III patients are "technically curable" and receive "aggressive" treatment because their cancer, although not operable, is limited to the lungs and lymph nodes and has not yet spread elsewhere, he explained.
A community-based clinician concurred that the high-dose radiation has been a community standard for an extended period of time. "We have been using 74 Gy at Boca Raton Hospital for the past 5 years," said Tim Williams, MD, a radiation oncologist at the Florida hospital and a past chair of ASTRO. He moderated the press conference.
However, another community-based radiation oncologist refuted the idea that a high dose is frequently used in stage III patients.
"A minority of our patients receive 74 Gy," said Christopher Koprowski, MD, from the Helen Graham Cancer Center of the Christiana Care Health System in Newark, Delaware. "We individualize treatment, and patients receive somewhere between 60 and 74 Gy," he told Medscape Medical News at the meeting. The determinant of the dose is the "hazards to the organs at risk," said Dr. Koprowski, referring to the lungs, esophagus, heart, and spinal cord. The patients who receive the high dose are "usually those with lower tumor bulk," he said. "Therefore, we are not violating normal tissue constraints."
Unexpected Finding
The trial, known as Radiation Therapy Oncology Group (RTOG) 0617, is the first randomized trial in 30 years to assess optimal radiation dose in lung cancer, said Dr. Bradley. Earlier smaller trials had found a survival advantage with high-dose radiotherapy.

We were surprised by the results.

The finding that high-dose radiation does not improve survival was unexpected. "We were surprised by the results," he told the ASTRO audience. Most clinicians have believed that higher doses of radiation cured more patients with lung cancer, Dr. Bradley said in a press statement.
But that is not what the study found.
At the initial planned interim analysis for overall survival, the investigators found that, after 90 deaths, the high-dose radiation groups had "crossed the futility boundary." The study was designed to detect a median overall survival improvement of 7 months in the high-dose radiation groups.
"High-dose radiation, as delivered in this trial, does not improve overall survival," Dr. Bradley and colleagues conclude.

An emphatic no to dose escalation.

"Level I evidence demonstrates no role for dose escalation" in stage III NSCLC, said Benjamin Mosvas, MD, from Henry Ford Hospital in Detroit, Michigan. Dr. Mosvas, who served as discussant of the paper at the plenary session. He also said the study results were "an emphatic no" to dose escalation.
More Study Details
The study was a 2 ₓ 2 design, with patients randomized to standard-dose or high-dose radiation with or without the targeted therapy cetuximab (Erbitux; Bristol-Myers Squibb). The high-dose regimen was 7 weeks and 37 fractions (2 Gy per day); the standard-dose regimen was 6 weeks and 30 fractions (2 Gy per day).
Concurrent chemotherapy for all patients included weekly paclitaxel (45 mg/m²) and carboplatin (area under the curve, 2). Patients were randomized to a 400 mg/m² loading dose of cetuximab on day 1, followed by weekly doses of 250 mg/m².
The high-dose radiation groups are now closed, but the study remains open to the standard-dose groups so that the addition of cetuximab can be examined.
Dr. Bradley said that he and his coinvestigators cannot explain the results and that the data are being carefully reviewed.
In the study, both 3-dimensional conformal radiation therapy (55% of patients) and intensity-modulated radiation therapy (IMRT; 45%) were used. However, there was no difference in outcome with the different technologies, said Dr. Bradley. RTOG is the first phase 3 lung cancer study to include IMRT, he noted.
There were no statistically significant differences in toxicities between the high-dose and standard-dose groups, Dr. Bradley pointed out.
On multivariate analysis, 3 factors were significantly associated with overall survival, noted Dr. Bradley: the 60 Gy dose; nonsquamous cell histology; and smaller gross tumor volume.
The trial, which has a goal of 500 patients, accrued 423 from November 2007 to April 2011.
Eligibility criteria included biopsy-proven stage IIIA/B NSCLC, a performance status of 0 or 1, and a forced expiratory volume in 1 second of at least 1.2 L/s. Exclusion criteria included supraclavicular or contralateral hilar disease, weight loss of at least 10%, and previous nonsurgical therapy for NSCLC.
This study was supported by the National Cancer Institute, Bristol-Myers Squibb, and ImClone. The authors have disclosed no relevant financial relationships.
American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting: Abstract LB2. October 3, 2011.

AN UNEXPECTED FAILURE

(Reuters) - Pfizer Inc said two of its anti-fungal drugs, when used together to treat a dangerous systemic fungal infection, failed to meet the main goal of a late-stage trial.
The company tested its treatment Vfend in combination with its other antifungal drug Eraxis in people suffering with invasive aspergillosis, a life-threatening fungal infection that can develop in patients with compromised immune systems.
Eraxis is an injectable drug used to treat Candida and other fungal infections. It was approved five years ago after positive data from a late-stage trial that compared it with the widely used antifungal fluconazole.
The drugs, when used in combination, did show a lower all-cause mortality rate at six weeks compared with treatment with Vfend alone, Pfizer said on Friday. But the difference was not deemed statistically significant.
The safety and tolerability of the combination of Vfend and Eraxis was similar to that of Vfend by itself.

A RARE CERVICAL CANCER

J Obstet Gynaecol Res. 2011 Sep 28. doi: 10.1111/j.1447-0756.2011.01643.x. [Epub ahead of print]

Adjuvant combined paclitaxel and carboplatin chemotherapy for glassy cell carcinoma of the uterine cervix: Report of three cases with clinicopathological analysis.

Takahashi Y, Sasaki H, Mogami H, Hamada S, Konishi I.

Source

Departments of Obstetrics and Gynecology Pathology, Otsu Municipal Hospital, Shiga Department of Obstetrics and Gynecology, National Hospital Organization Osaka National Hospital, Osaka Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Abstract

Glassy cell carcinoma of the uterine cervix (GCC) is a rare form of cervical carcinoma that is characterized by aggressiveness and poor prognosis. We reviewed a variety of clinicopathological features, treatment strategies, and outcomes in three women with GCC. The three patients were successfully treated by radical hysterectomy with pelvic/para-aortic lymphadenectomy. The patients had stage Ib1, stage IIa, and stage Ib2 tumors without lymph node metastases. A 44-year-old woman with stage Ib1 tumor did not undergo adjuvant chemotherapy or radiation therapy. She had recurrent pelvic tumors 12 months after surgery, and died 6 months after the recurrent disease. The histological findings of her cervix, which were different from the other two patients, did not show the marked infiltration of eosinophils. The other two patients with stage Ib2 and IIa tumors underwent adjuvant chemotherapy with paclitaxel and carboplatin, and had disease-free survival for 4.5 and 9 years. We think that all patients with GCC of stage Ib1 or more should undergo adjuvant chemotherapy of paclitaxel and carboplatin or other adjuvant therapies.

TRASTUZUMAB USE AS NEOADJUVANT THERAPY

Cancer. 2011 Sep 27. doi: 10.1002/cncr.26555. [Epub ahead of print]

Efficacy of neoadjuvant therapy with trastuzumab concurrent with anthracycline- and nonanthracycline-based regimens for HER2-positive breast cancer.

Bayraktar S, Gonzalez-Angulo AM, Lei X, Buzdar AU, Valero V, Melhem-Bertrandt A, Kuerer HM, Hortobagyi GN, Sahin AA, Meric-Bernstam F.

Source

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

BACKGROUND:

The aim of this study was to evaluate the pathologic complete response (pCR) rates and relapse-free survival (RFS) and overall survival (OS) of patients receiving neoadjuvant systemic therapy (NST) with trastuzumab in combination with an anthracycline- or nonanthracycline-based regimen.

METHODS:

In this retrospective nonrandomized study, the authors reviewed records of 300 patients with HER2-positive breast cancer treated with either sequential paclitaxel and trastuzumab and FEC75 in combination with trastuzumab (PH-FECH) or docetaxel, carboplatin, and trastuzumab (TCH). The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models and Cox proportional hazards models were fit to determine the associations between NST, pCR, and survival.

RESULTS:

There was no significant difference in the decline in cardiac ejection fraction; however, patients who received PH-FECH had fewer cardiac comorbidities at baseline (P = .002). pCR rates were 60.6% and 43.3% for patients who received PH-FECH (n = 235) and TCH (n = 65), respectively (P = .016). Patients who received PH-FECH were 1.45 times more likely to have a pCR (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06-1.98; P = .02). Three-year RFS rates were 93% and 71% (P < .001), and 3-year OS rates were 96% and 86% (P = .008) for patients who received PH-FECH and TCH, respectively. Patients who received PH-FECH had a lower risk of recurrence (hazard ratio [HR], 0.27; 95% CI, 0.12-0.60; P = .001) and death (HR, 0.37; 95% CI, 0.12-1.13; P = .08) than those treated with TCH.

CONCLUSIONS:

The type of NST in HER2-positive breast cancer is predictive of pCR rate independent of disease and patient characteristics. Although TCH is active,

IMATINIB FOR GRANULOSA CELL TUMOR

J Obstet Gynaecol Res. 2011 Sep 28. doi: 10.1111/j.1447-0756.2011.01649.x. [Epub ahead of print]

Third-line chemotherapy with tyrosine kinase inhibitor (imatinib mesylate) in recurrent ovarian granulosa cell tumor: Case report.

Raspagliesi F, Martinelli F, Grijuela B, Guadalupi V.

Source

Department of Gynecologic Oncology, IRCCS Istituto Nazionale Tumori, Milan, Italy.

Abstract

Granulosa cell tumors (GCT) of the ovary represent less than 5% of malignant ovarian tumors. Primary treatment of GCT is surgery. GCT present indolent growth and also tend to relapse many years after diagnosis. Radiotherapy, chemotherapy and hormonal therapy are of little benefit. We report a case of a 60-year-old woman with a heavily pretreated recurrent, c-kit positive, GCT of the ovary who underwent an experimental therapy with imatinib, a tyrosine kinase inhibitor. Imatinib (400 mg/day during the first 2 months; 800 mg/day after) was given, without notable side-effects. Monthly positron emission tomography-computed tomography scan evaluations were performed revealing a marked reduction of disease after 6 months of treatment. To our knowledge this is the first case of highly recurrent and unresponsive GCT of the ovary responding to imatinib. Further studies evaluating this drug in recurrent and/or aggressive GCT are warranted.

© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.

METRONOMIC CYCLOPHOSPHAMIDE FOR PROSTATE CANCER

Cancer Treat Rev. 2011 Oct;37(6):444-55. doi: 10.1016/j.ctrv.2010.12.006. Epub 2011 Jan 28.

Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature.

Nelius T, Rinard K, Filleur S.

Source

Department of Urology, Texas Tech University Health Sciences Center, Lubbock, USA. thomas.nelius@ttuhsc.edu

Abstract

PURPOSE:

Castration-refractory prostate cancer remains a therapeutic challenge even after introduction of docetaxel as first-line treatment. Castration-refractory prostate cancer cannot be cured by any available therapeutic option, and chemotherapy still needs to be considered palliative. The survival benefit is modest, and treating physicians are searching for alternative treatment options. Despite new drugs currently under investigation, some conventional and well known chemotherapeutic drugs are experiencing a renaissance. The development of anti-angiogenic approaches in cancer treatment has led to the development of metronomic dosing of conventional chemotherapeutic drugs including cyclophosphamide. The intention of this review is to evaluate the efficacy and toxicity of oral/metronomic cyclophosphamide in the treatment of patients with castration-refractory prostate cancer.

MATERIALS AND METHODS:

A comprehensive literature search was performed in different databases using various key words. Relevant articles and references between 1962 and 2010 were reviewed and analyzed for data regarding the association between oral cyclophosphamide treatment and prostate cancer.

RESULTS:

Oral cyclophosphamide is active in the treatment for castration-refractory prostate cancer even in patients treated with previous chemotherapy including docetaxel. It yields symptomatic and objective remissions. The side effects are usually grade 1-2 and easy to manage. Grade three to four side effects are less common.

CONCLUSIONS:

Oral cyclophosphamide treatment for patients with castration-refractory prostate cancer deserves more attention and validation, and warrants further testing of various treatment combinations. Given the fact that castration-refractory prostate cancer includes an extremely heterogeneous group of patients with variability of tumor growth rates, the combination of cyclophosphamide with other active agents such as angiogenesis inhibitors and immunomodulatory compounds need to be explored.