April 15, 2010 — Encouraging results with the investigational drug MDV3100 (Medivation) in patients with metastatic castration-resistant prostate cancer were published online April 15 in The Lancet.
These results show that the drug has "substantial antitumor activity" in men who have and who have not had previous exposure to chemotherapy, say the authors, headed by Howard Scher, MD, chief of genitourinary oncology at the Memorial Sloan-Kettering Cancer Center in New York City.
"MDV3100 could have the potential to significantly change the treatment options in metastatic disease," they conclude.
The results come from a phase 1/2 trial of 140 men, 65 of whom were chemotherapy-naïve. The drug was associated with tumor regression and stable disease in soft tissue, and stable disease in bone. Preliminary data from this trial were released last year. These results with MDV3100 are similar to those seen with another investigational agent, abiraterone.
Although the 2 drugs have different mechanisms of action — MDV3100 is an androgen-receptor antagonist and abiraterone is an androgen-synthesis inhibitor — both offer new options for hormonal manipulation.
"Both of these drugs look promising," said William Dahut, MD, clinical director of the National Cancer Institute in Bethesda, Maryland, who cowrote an accompanying editorial. In an interview with Medscape Oncology, he predicted that — if and when they reach the market — these drugs will be used in men who have progressed on hormonal therapy before they consider chemotherapy, pointing out that these new drugs are oral and are better tolerated.
"Most men would rather take a pill than move onto chemotherapy," he said.
Activity So Far Similar to Docetaxel
Until recently, prostate cancer that progressed despite hormonal treatment was considered to be "hormone refractory," Dr. Dahut explained. However, this term has been changed to "hormone resistant," or castration-resistant, because there are men who respond to further hormone manipulation. But for those who are not responding, often the only remaining option has been chemotherapy with docetaxel, which has been shown to improve survival.
So far, there are no survival data for the new drugs, but results seen so far related to prostate-specific antigen (PSA) levels and time to progression compare favorably with those seen in older trials with docetaxel, Dr. Dahut said.
Both new drugs are now in phase 3 trials with a survival end point, and the hope is that they will show an increase in survival. These trials are being conducted in men who have progressed on chemotherapy — the patient population with the greatest medical need, Dr. Dahut explained. This is also the population in which an impact on survival — needed for regulatory approval — can be shown most quickly.
However, these are not the patients in whom these drugs are likely to be used in clinical practice, or in whom "they will work the best," Dr. Dahut said.
The new agents are more likely to be used as an option in men who have progressed on hormonal therapy, before chemotherapy, he said. Dr. Scher agreed, and pointed out that a trial in this chemotherapy-naïve population is already underway with abiraterone, and one with MDV3100 is planned to start soon.
This is also where the greatest benefit is seen, Dr. Dahut said. In the MDV3100 trial, the PSA decline was similar in chemotherapy-naïve and chemotherapy-treated men, but the time to progression was greater in the chemotherapy-naïve group (41 vs 21 weeks).
The editorial makes the point, however, that even this 21-week time to progression after chemotherapy is "clinically meaningful, particularly for a class of agents believed, until recently, to have no rationale whatsoever in this patient population."
Validation of Hypothesis
The results with both MDV3100 and abiraterone "seem to validate the hypothesis that androgens and the androgen receptor are vital to progression of metastatic castration-resistant prostate cancer," the editorialists write.
This echoes the researchers' comment that the "encouraging antitumor activity" they saw with MDV3100 in castration-resistant prostate cancer validates preclinical studies that have implicated androgen-receptor signaling as a driver of this disease.
Because androgen-receptor signaling appears to drive this cancer, blocking this signaling should stop its growth, the researchers theorized, and they went on to develop a drug that would do just that. MDL3100 was coinvented by Charles Sawyers, MD, chair of human oncology and pathogenesis at Memorial Sloan-Kettering (and a coauthor on this study), and Michael Jung, PhD, professor of chemistry at the University of California, Los Angeles.
New Drug Is Potent Antagonist
MDV3100 is a very potent antagonist of androgen receptors, lead author Dr. Scher told Medscape Oncology. It binds to the receptor very tightly, and is a potent inhibitor of the process by which the receptor-hormone complex is transported to the nucleus to interact with genes, he explained.
MDV3100 is more potent and is also more specific than the older antiandrogens, such as flutamide (Drogenil) and bicalutamide (Casodex), which have been and still are used in prostate cancer, usually with gonadotrophin-releasing hormone agonists/antagonists, such as leuprolide (Lupron) and goserelin (Zoladex). However, these older antiandrogen compounds also have some agonist activity and have been found to stimulate prostate cancer growth in some men, Dr. Scher explained. This has not been seen with MDV3100, he noted.
The mechanism of action of MDV3100 is also very different from that of abiraterone, which is an inhibitor of androgen synthesis, but does not block androgen binding, Dr. Scher said. Although they act in different ways, overall, the 2 drugs "have produced similar effects," he said.
Because they act in different ways, there may be benefits from using the drugs together, he added. However, currently, there is no information on how one drug influences the response to the other, and there are also not enough data to suggest which drug should be used first. "These are questions that need to be studied," he added.
Dr. Scher and several coauthors report receiving research funding from Medivation (the manufacturer of MDV3100), and 3 coauthors are company employees. Coauthor Dr. Sawyer is a coinventor of MDV3100, and is entitled to royalties that could result from its commercial success. The editorialists have disclosed no relevant financial relationships.
Lancet. Published online April 15, 2010.
Κυριακή 18 Απριλίου 2010
SCREENING COLONOSCOPY DECREASES COLORECTAL CANCER RELATED DEATH
April 13, 2010 — Colonoscopy has been established as an effective method of screening for colorectal cancer, and now a study has found that it is associated with a reduction in disease-related mortality.
In the study, published online March 2 in the American Journal of Gastroenterology, researchers found that for every 1% increase in the complete colonoscopy rate, the hazard of colorectal-cancer-associated death decreased by 3%.
"We found that living in a region with higher colonoscopy rates was associated with a reduced risk of death from colorectal cancer," said lead author Linda Rabeneck, MD, MPH, professor of medicine at the University of Toronto in Ontario.
"The colonoscopies in our study were not only done for screening, but for other reasons, such as diagnosis," she told Medscape Oncology. "Overall, we can say at a population level that the increase in colonoscopy use has been associated with a benefit."
However, an expert contacted for independent comment cautioned that the findings need to be interpreted with care. There was an association between an increased colonoscopy rate and a decreased colorectal cancer mortality rate, but this does not necessarily mean that one was the result of the other, said Charles Kahi, MD, assistant professor of clinical medicine at Indiana University School of Medicine in Indianapolis.
Colonoscopy Is the Gold Standard
Colonoscopy has become the gold standard for detecting and removing adenomas, the authors note, and colonoscopic polypectomy is associated with a decrease in the incidence of colorectal cancer. The use of colonoscopy in the United States and Canada has increased during the past 2 decades, but it remains unclear whether increased use is associated with clinical benefits at the population level.
This was the question that Dr. Rabeneck and colleagues wanted to answer. They used population data from the Canadian Institute for Health Information discharge abstract and same-day surgery databases, the Ontario Health Insurance Plan database, the Registered Persons Database, and the Ontario Cancer Registry.
A cohort of 2,412,077 people between the ages of 50 and 90 years on January 1, 1993 was identified. Each person was assigned to 1 of 13 regions, based on his/her residence, and all participants were followed until December 31, 2006. Every year for each region, the rate of colonoscopies performed on people within this age group was calculated. The authors used the multivariable Cox proportional hazards models to evaluate the association between colonoscopy rate and colorectal-cancer-associated death, adjusting for confounders such as age, sex, comorbidity, income, and location of residence (urban vs rural).
The mean age of the participants was 64 years, and approximately half (53.7%) were female. During the 14-year follow-up, 62,819 study participants (2.6 %) were diagnosed with colorectal cancer, and 23,743 (0.98%) died from the disease. Of the entire cohort, 773,677 (32.1 %) participants died from all causes.
Rates Increased, Mortality Declined
From 1993 to 2006, rates of colonoscopy increased in all regions, and the researchers noted that this increased rate was inversely associated with colorectal-cancer-related deaths. The hazard ratio of 0.970 (95 % confidence interval, 0.949 - 0.991) indicated that for every increase in colonoscopy rate of 1% in the region the participant resided, the hazard of death decreased by 3%.
Colorectal-related mortality was lower among younger adults (50 to 69 years), and within each age group, the rates were lower for women than for men. The researchers also found that increased age, lower income, and a rural residence were associated with a higher risk for death from colorectal cancer; being female was associated with a lower risk. After adjustment for these confounders, an increased complete colonoscopy rate was still associated with a decreased risk for colorectal-cancer-associated mortality.
There are several interventions that have been shown to increase screening rates, Dr. Rabeneck pointed out. "One of the most important is the recommendation of the primary care provider or family physician. This is true not just for colorectal cancer screening, but for other cancer screenings as well," she said.
Removing barriers, such as lack of insurance, is important, as is having a social marketing or public awareness campaign, she added. "That is part of the reason breast cancer screening rates are higher than rates of colorectal cancer screening," she said. "For colorectal [cancer screening], we have not yet achieved such a high level of public awareness."
Findings Need Careful Interpretation
Although this is a very nicely done study by an expert group, the findings have to be interpreted within the context of the study, said Dr. Kahi, who was approached by Medscape Oncology for independent comment.
"This is a large-scale epidemiological study, and the authors found that increased colonoscopy use was associated with decreased colorectal mortality at the population level," he summarized.
However, there are some issues that preclude making additional valid conclusions, said Dr. Kahi. "First, this is a large-scale epidemiological study, and it is often hard to translate the findings of such studies into clinical decisions for individual patients, or even to compare the results with those of clinical smaller-scale studies," he noted.
Second, the finding of an "association" does not imply causality. "In other words, increased colonoscopy use is associated with decreased mortality, but these trends may be evolving in parallel, and it does not follow necessarily that increased colonoscopy use actually caused the drop in colorectal cancer mortality," Dr. Kahi added.
"Finally, given that the study is based on administrative claims, the authors could not distinguish screening from diagnostic colonoscopy, so it is not clear if the observed association is due to the benefit of screening itself," he said.
The study received no outside funding. The researchers have disclosed no relevant financial relationships.
Am J Gastroenterol. Published online March 2, 2010. Abstract
In the study, published online March 2 in the American Journal of Gastroenterology, researchers found that for every 1% increase in the complete colonoscopy rate, the hazard of colorectal-cancer-associated death decreased by 3%.
"We found that living in a region with higher colonoscopy rates was associated with a reduced risk of death from colorectal cancer," said lead author Linda Rabeneck, MD, MPH, professor of medicine at the University of Toronto in Ontario.
"The colonoscopies in our study were not only done for screening, but for other reasons, such as diagnosis," she told Medscape Oncology. "Overall, we can say at a population level that the increase in colonoscopy use has been associated with a benefit."
However, an expert contacted for independent comment cautioned that the findings need to be interpreted with care. There was an association between an increased colonoscopy rate and a decreased colorectal cancer mortality rate, but this does not necessarily mean that one was the result of the other, said Charles Kahi, MD, assistant professor of clinical medicine at Indiana University School of Medicine in Indianapolis.
Colonoscopy Is the Gold Standard
Colonoscopy has become the gold standard for detecting and removing adenomas, the authors note, and colonoscopic polypectomy is associated with a decrease in the incidence of colorectal cancer. The use of colonoscopy in the United States and Canada has increased during the past 2 decades, but it remains unclear whether increased use is associated with clinical benefits at the population level.
This was the question that Dr. Rabeneck and colleagues wanted to answer. They used population data from the Canadian Institute for Health Information discharge abstract and same-day surgery databases, the Ontario Health Insurance Plan database, the Registered Persons Database, and the Ontario Cancer Registry.
A cohort of 2,412,077 people between the ages of 50 and 90 years on January 1, 1993 was identified. Each person was assigned to 1 of 13 regions, based on his/her residence, and all participants were followed until December 31, 2006. Every year for each region, the rate of colonoscopies performed on people within this age group was calculated. The authors used the multivariable Cox proportional hazards models to evaluate the association between colonoscopy rate and colorectal-cancer-associated death, adjusting for confounders such as age, sex, comorbidity, income, and location of residence (urban vs rural).
The mean age of the participants was 64 years, and approximately half (53.7%) were female. During the 14-year follow-up, 62,819 study participants (2.6 %) were diagnosed with colorectal cancer, and 23,743 (0.98%) died from the disease. Of the entire cohort, 773,677 (32.1 %) participants died from all causes.
Rates Increased, Mortality Declined
From 1993 to 2006, rates of colonoscopy increased in all regions, and the researchers noted that this increased rate was inversely associated with colorectal-cancer-related deaths. The hazard ratio of 0.970 (95 % confidence interval, 0.949 - 0.991) indicated that for every increase in colonoscopy rate of 1% in the region the participant resided, the hazard of death decreased by 3%.
Colorectal-related mortality was lower among younger adults (50 to 69 years), and within each age group, the rates were lower for women than for men. The researchers also found that increased age, lower income, and a rural residence were associated with a higher risk for death from colorectal cancer; being female was associated with a lower risk. After adjustment for these confounders, an increased complete colonoscopy rate was still associated with a decreased risk for colorectal-cancer-associated mortality.
There are several interventions that have been shown to increase screening rates, Dr. Rabeneck pointed out. "One of the most important is the recommendation of the primary care provider or family physician. This is true not just for colorectal cancer screening, but for other cancer screenings as well," she said.
Removing barriers, such as lack of insurance, is important, as is having a social marketing or public awareness campaign, she added. "That is part of the reason breast cancer screening rates are higher than rates of colorectal cancer screening," she said. "For colorectal [cancer screening], we have not yet achieved such a high level of public awareness."
Findings Need Careful Interpretation
Although this is a very nicely done study by an expert group, the findings have to be interpreted within the context of the study, said Dr. Kahi, who was approached by Medscape Oncology for independent comment.
"This is a large-scale epidemiological study, and the authors found that increased colonoscopy use was associated with decreased colorectal mortality at the population level," he summarized.
However, there are some issues that preclude making additional valid conclusions, said Dr. Kahi. "First, this is a large-scale epidemiological study, and it is often hard to translate the findings of such studies into clinical decisions for individual patients, or even to compare the results with those of clinical smaller-scale studies," he noted.
Second, the finding of an "association" does not imply causality. "In other words, increased colonoscopy use is associated with decreased mortality, but these trends may be evolving in parallel, and it does not follow necessarily that increased colonoscopy use actually caused the drop in colorectal cancer mortality," Dr. Kahi added.
"Finally, given that the study is based on administrative claims, the authors could not distinguish screening from diagnostic colonoscopy, so it is not clear if the observed association is due to the benefit of screening itself," he said.
The study received no outside funding. The researchers have disclosed no relevant financial relationships.
Am J Gastroenterol. Published online March 2, 2010. Abstract
IXABEPILONE FOR TRIPLE NEGATIVE BREAST CANCER
Breast Cancer Res Treat. 2010 Mar 13. [Epub ahead of print]
Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer.
Perez EA, Patel T, Moreno-Aspitia A.
Division of Hematology and Oncology, College of Medicien, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, perez.edith@mayo.edu.
Abstract
Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23% in triple-negative patients. A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. Ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors.
Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer.
Perez EA, Patel T, Moreno-Aspitia A.
Division of Hematology and Oncology, College of Medicien, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, perez.edith@mayo.edu.
Abstract
Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23% in triple-negative patients. A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. Ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors.
CHEMORADIOTHERAPY IMPROVES OUTCOME FOR D1 RESECTION IN GASTRIC CANCER
J Clin Oncol. 2010 Apr 5. [Epub ahead of print]
Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer.
Dikken JL, Jansen EP, Cats A, Bakker B, Hartgrink HH, Meershoek-Klein Kranenbarg E, Boot H, Putter H, Peeters KC, van de Velde CJ, Verheij M.
Leiden University Medical Center, Leiden; and the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Abstract
PURPOSE: The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. PATIENTS AND METHODS: Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. RESULTS: With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. CONCLUSION: After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.
Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer.
Dikken JL, Jansen EP, Cats A, Bakker B, Hartgrink HH, Meershoek-Klein Kranenbarg E, Boot H, Putter H, Peeters KC, van de Velde CJ, Verheij M.
Leiden University Medical Center, Leiden; and the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Abstract
PURPOSE: The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. PATIENTS AND METHODS: Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. RESULTS: With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. CONCLUSION: After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.
PROSTATE CANCER INCREASES THROMBOEMBOLIC RISK
April 15, 2010 — All men with prostate cancer have a higher risk for thromboembolic disease, compared with the general population, and the risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) is "especially high" in those undergoing hormonal therapy.
These results come from a new analysis of data from the Swedish National Prostate Cancer Register, published online in The Lancet Oncology.
Lead author Miekle van Hemelrijck, MSc, at the Cancer Epidemiology Group at King's College Hospital, London, United Kingdom, who is a doctoral candidate, said she has just been asked to present these data at a late-breaking session at the European Association for Urology meeting taking place this weekend.
This same team has recently reported, from the same database, that the risk for cardiovascular disease is increased by hormonal therapies used in prostate cancer. Similar findings have been reported from several other studies, and earlier this year the increased risk for cardiovascular disease in men with prostate cancer treated with hormonal therapies was highlighted in an advisory in February 2010 issued jointly by the American Heart Association, the American Cancer Society, and the American Urological Association.
Suppression of Testosterone Detrimental?
This new study focused on thromboembolic disease, but some of the findings are similar to the group's previous study on cardiovascular disease, Ms. Van Hemelrijck commented in an interview with Medscape Oncology.
For instance, the highest risk for both was seen in men undergoing gonadotrophin-releasing hormone (GnRH) agonist therapy or those who had undergone orchidectomy, whereas men who were treated with antiandrogens were at the lowest risk among those who were treated with hormonal therapies. This ties in with research suggesting that testosterone is important both in the functioning of the heart and in thromboembolism and that suppressing it completely is detrimental to both, Ms van Hemelrijck explained. With antiandrogens, there is still testosterone circulating, but it is prevented from acting on the prostate by androgen receptor blockade, she added.
However, an accompanying editorial points out that several factors limit the observation that antiandrogens were associated with a more modest increase in the risk of thromboembolism compared with GnRH agonist or orchidectomy.
Editorialists Philip Saylor, MD, and Annmarie Fogerty, MD, from the Massachusetts General Hospital Cancer Center in Boston, note that the antiandrogen subset was small. These patients were also less likely to have metastatic disease than patients in the other treatment groups. In addition, antiandrogen monotherapy "is not currently the standard of care in any setting," they point out.
Main Message: Monitor Patients
The most important point from these studies, Ms. van Hemelrijck says, is that men with prostate cancer who are being treated with hormonal therapies should be monitored for cardiovascular disease (as suggested by the first study) and also for thromboembolic disease (as suggested by this present study), because they are at increased risk of both.
"But we are not saying that these hormonal therapies should not be used," she emphasized, pointing out that hormonal therapy is often the only option in locally advanced and metastatic prostate cancer.
The accompany editorial concurs. These new data "should increase clinical suspicion for venous thromboembolism in men with prostate cancer," the editorialists write, but the data "do not support withholding GnRH agonists or orchidectomy in clinical situations where they are known to be beneficial."
Highest Risk Is for DVT
The new study analyzed data collected in Sweden from 1997 to 2007 on 76,600 men with prostate cancer. Of these, 30,642 were treated with hormonal therapies, specifically, 9066 with a GNRH agonist, 5340 with orchidectomy, 3391 with antiandrogens, and 1199 with a combination of other drugs. The remaining men received either curative treatment, such as prostatectomy (n = 26,432) or active surveillance (n = 19,526).
Thromboembolic disease developed in 1881 of these men: 767 had a DVT, 873 had a PE, and 241 had an arterial embolism (AE).
This incidence of thromboembolic disease is higher than is seen among men in the general population, and this is "not surprising," commented Ms. van Hemelrijck, "as cancer is known to increase the risk of thromboembolism."
The risk was increased (nearly doubled) for DVT and PE but not for AE (although the AE numbers were small, the researchers point out).
The results are expressed as a standardized incidence ratio (SIR), defined as the ratio of the observed number of a particular thromboembolic disease to the expected number of that disease.
The SIRs for all men with prostate cancer were 1.9 for DVT, 1.85 for PE, and 1.02 for AE.
The increase in risk was seen regardless of the treatment received, but the magnitude of this increased risk varied. The largest absolute risk (more than doubled) was seen for DVT for men receiving endocrine treatment.
The SIRs for men with prostate cancer undergoing endocrine therapy were 2.48 for DVT, 1.95 for PE, and 1.0 for AE.
For men who had undergone curative treatment, the SIRs were 1.73 for DVT, 2.03 for PE, and 0.95 for AE, whereas for men undergoing surveillance the SIRs were 1.27 for DVT, 1.57 for PE, and 1.08 for AE.
However, this study "cannot directly quantify how much the observed differences in thromboembolic disease risk between treatments groups are due to the treatments themselves," the researchers write.
Cancer itself, increased age, and hormonal treatments all increase the risk of thromboembolic disease, but "we cannot tease out the contribution made by each of these factors," Ms. Hemelrijck added.
Causation Cannot Be Inferred
Although an increase risk in both DVT and PE was seen with endocrine therapy, "causation cannot be inferred from these observations," the editorialists emphasize.
They point out that men treated with endocrine therapy had a greater proportion of metastatic or otherwise poor-risk disease, and advanced cancer is a known risk factor for venous thromboembolism. This group of patients also included the highest proportion of men older than 75 years, and advanced age is also a known risk factor for venous thromboembolism in patients with cancer, they add.
Nevertheless, these latest data raise the question of whether endocrine therapy increases the risk of venous thromboembolism, they concede. They hope that the new findings will "stimulate further study of potential interactions between androgen deprivation and blood coagulability."
Ms. Hemelrijck has disclosed no relevant financial relationships, but 2 coauthors do: one has served on the data monitoring committee for AstraZeneca, and another has received consultancy fees from Ferring Pharmaceuticals (which markets a GnRH agonist). The editorialists have disclosed no relevant financial relationships.
Lancet Oncol. Published online April 14.
These results come from a new analysis of data from the Swedish National Prostate Cancer Register, published online in The Lancet Oncology.
Lead author Miekle van Hemelrijck, MSc, at the Cancer Epidemiology Group at King's College Hospital, London, United Kingdom, who is a doctoral candidate, said she has just been asked to present these data at a late-breaking session at the European Association for Urology meeting taking place this weekend.
This same team has recently reported, from the same database, that the risk for cardiovascular disease is increased by hormonal therapies used in prostate cancer. Similar findings have been reported from several other studies, and earlier this year the increased risk for cardiovascular disease in men with prostate cancer treated with hormonal therapies was highlighted in an advisory in February 2010 issued jointly by the American Heart Association, the American Cancer Society, and the American Urological Association.
Suppression of Testosterone Detrimental?
This new study focused on thromboembolic disease, but some of the findings are similar to the group's previous study on cardiovascular disease, Ms. Van Hemelrijck commented in an interview with Medscape Oncology.
For instance, the highest risk for both was seen in men undergoing gonadotrophin-releasing hormone (GnRH) agonist therapy or those who had undergone orchidectomy, whereas men who were treated with antiandrogens were at the lowest risk among those who were treated with hormonal therapies. This ties in with research suggesting that testosterone is important both in the functioning of the heart and in thromboembolism and that suppressing it completely is detrimental to both, Ms van Hemelrijck explained. With antiandrogens, there is still testosterone circulating, but it is prevented from acting on the prostate by androgen receptor blockade, she added.
However, an accompanying editorial points out that several factors limit the observation that antiandrogens were associated with a more modest increase in the risk of thromboembolism compared with GnRH agonist or orchidectomy.
Editorialists Philip Saylor, MD, and Annmarie Fogerty, MD, from the Massachusetts General Hospital Cancer Center in Boston, note that the antiandrogen subset was small. These patients were also less likely to have metastatic disease than patients in the other treatment groups. In addition, antiandrogen monotherapy "is not currently the standard of care in any setting," they point out.
Main Message: Monitor Patients
The most important point from these studies, Ms. van Hemelrijck says, is that men with prostate cancer who are being treated with hormonal therapies should be monitored for cardiovascular disease (as suggested by the first study) and also for thromboembolic disease (as suggested by this present study), because they are at increased risk of both.
"But we are not saying that these hormonal therapies should not be used," she emphasized, pointing out that hormonal therapy is often the only option in locally advanced and metastatic prostate cancer.
The accompany editorial concurs. These new data "should increase clinical suspicion for venous thromboembolism in men with prostate cancer," the editorialists write, but the data "do not support withholding GnRH agonists or orchidectomy in clinical situations where they are known to be beneficial."
Highest Risk Is for DVT
The new study analyzed data collected in Sweden from 1997 to 2007 on 76,600 men with prostate cancer. Of these, 30,642 were treated with hormonal therapies, specifically, 9066 with a GNRH agonist, 5340 with orchidectomy, 3391 with antiandrogens, and 1199 with a combination of other drugs. The remaining men received either curative treatment, such as prostatectomy (n = 26,432) or active surveillance (n = 19,526).
Thromboembolic disease developed in 1881 of these men: 767 had a DVT, 873 had a PE, and 241 had an arterial embolism (AE).
This incidence of thromboembolic disease is higher than is seen among men in the general population, and this is "not surprising," commented Ms. van Hemelrijck, "as cancer is known to increase the risk of thromboembolism."
The risk was increased (nearly doubled) for DVT and PE but not for AE (although the AE numbers were small, the researchers point out).
The results are expressed as a standardized incidence ratio (SIR), defined as the ratio of the observed number of a particular thromboembolic disease to the expected number of that disease.
The SIRs for all men with prostate cancer were 1.9 for DVT, 1.85 for PE, and 1.02 for AE.
The increase in risk was seen regardless of the treatment received, but the magnitude of this increased risk varied. The largest absolute risk (more than doubled) was seen for DVT for men receiving endocrine treatment.
The SIRs for men with prostate cancer undergoing endocrine therapy were 2.48 for DVT, 1.95 for PE, and 1.0 for AE.
For men who had undergone curative treatment, the SIRs were 1.73 for DVT, 2.03 for PE, and 0.95 for AE, whereas for men undergoing surveillance the SIRs were 1.27 for DVT, 1.57 for PE, and 1.08 for AE.
However, this study "cannot directly quantify how much the observed differences in thromboembolic disease risk between treatments groups are due to the treatments themselves," the researchers write.
Cancer itself, increased age, and hormonal treatments all increase the risk of thromboembolic disease, but "we cannot tease out the contribution made by each of these factors," Ms. Hemelrijck added.
Causation Cannot Be Inferred
Although an increase risk in both DVT and PE was seen with endocrine therapy, "causation cannot be inferred from these observations," the editorialists emphasize.
They point out that men treated with endocrine therapy had a greater proportion of metastatic or otherwise poor-risk disease, and advanced cancer is a known risk factor for venous thromboembolism. This group of patients also included the highest proportion of men older than 75 years, and advanced age is also a known risk factor for venous thromboembolism in patients with cancer, they add.
Nevertheless, these latest data raise the question of whether endocrine therapy increases the risk of venous thromboembolism, they concede. They hope that the new findings will "stimulate further study of potential interactions between androgen deprivation and blood coagulability."
Ms. Hemelrijck has disclosed no relevant financial relationships, but 2 coauthors do: one has served on the data monitoring committee for AstraZeneca, and another has received consultancy fees from Ferring Pharmaceuticals (which markets a GnRH agonist). The editorialists have disclosed no relevant financial relationships.
Lancet Oncol. Published online April 14.
AN INTERESTING STUDY
Anticancer Drugs. 2010 Apr 8. [Epub ahead of print]
Triplet combination of carboplatin, irinotecan, and etoposide in the first-line treatment of extensive small-cell lung cancer: a single-institution phase II study.
Charpidou A, Tsagouli S, Tsimpoukis S, Vassias A, Makrilia N, Stratakos G, Gkiozos I, Syrigos K.
Oncology Unit, Third Department of Medicine, Sotiria General Hospital, Athens University School of Medicine, Greece.
Abstract
Small-cell lung cancer is a rapidly progressive tumor and median survival is less than 10 months in patients with extensive stage of the disease. This study aims to evaluate the efficacy and tolerability of the carboplatin, etoposide, and irinotecan triplet as a first-line treatment in extensive small-cell lung cancer. Chemonaive patients with documented diagnosis of extensive small-cell lung cancer, performance status 0-2, and adequate organ function were eligible. Patients received triweekly carboplatin area under the curve 5 on day 1, irinotecan 150 mg/m on day 2, and etoposide 75 mg/m on days 1, 2, and 3 for up to six cycles. A total of 54 patients were enrolled. Forty-seven of 54 patients (87%) had a performance status of 0-1. The response rate was 75% and complete response was achieved in 10 of 54 patients (18%). The median time to progression was estimated at 8 months (95% confidence interval: 6.6-8.9) and median overall survival at 12 months (95% confidence interval: 10.3-13.9). Patients with one site of metastases had prolonged survival as compared with those with two or more sites. Normalization of lactate dehydrogenase values after treatment was not correlated to survival. Grade 3-4 neutropenia occurred in nine patients (16.7%) and grade 3 fetal thrombocytopenia in one patient (1.9%). Two toxic deaths (3.7%) were reported. The carboplatin, irinotecan, and etoposide triplet is a very effective and well-tolerated combination for the poor prognosis group of extensive-stage small-cell lung cancer patients.
Triplet combination of carboplatin, irinotecan, and etoposide in the first-line treatment of extensive small-cell lung cancer: a single-institution phase II study.
Charpidou A, Tsagouli S, Tsimpoukis S, Vassias A, Makrilia N, Stratakos G, Gkiozos I, Syrigos K.
Oncology Unit, Third Department of Medicine, Sotiria General Hospital, Athens University School of Medicine, Greece.
Abstract
Small-cell lung cancer is a rapidly progressive tumor and median survival is less than 10 months in patients with extensive stage of the disease. This study aims to evaluate the efficacy and tolerability of the carboplatin, etoposide, and irinotecan triplet as a first-line treatment in extensive small-cell lung cancer. Chemonaive patients with documented diagnosis of extensive small-cell lung cancer, performance status 0-2, and adequate organ function were eligible. Patients received triweekly carboplatin area under the curve 5 on day 1, irinotecan 150 mg/m on day 2, and etoposide 75 mg/m on days 1, 2, and 3 for up to six cycles. A total of 54 patients were enrolled. Forty-seven of 54 patients (87%) had a performance status of 0-1. The response rate was 75% and complete response was achieved in 10 of 54 patients (18%). The median time to progression was estimated at 8 months (95% confidence interval: 6.6-8.9) and median overall survival at 12 months (95% confidence interval: 10.3-13.9). Patients with one site of metastases had prolonged survival as compared with those with two or more sites. Normalization of lactate dehydrogenase values after treatment was not correlated to survival. Grade 3-4 neutropenia occurred in nine patients (16.7%) and grade 3 fetal thrombocytopenia in one patient (1.9%). Two toxic deaths (3.7%) were reported. The carboplatin, irinotecan, and etoposide triplet is a very effective and well-tolerated combination for the poor prognosis group of extensive-stage small-cell lung cancer patients.
ADVANTAGES LAPAROSCOPIC SURGERY FOR RIGHT COLON CANCER
April 15, 2010 (Landover, Maryland) — New research suggests there is a difference in the proliferation and migration of colon cancer cells based on the use of open or laparoscopic surgery. This question has been a concern for surgeons intent on reducing tumor burden through appropriate surgical intervention.
In research presented here at the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 12th World Congress of Endoscopic Surgery, hosted by SAGES and the Canadian Association of General Surgeons, Heidi Bahna, MD, of M.D. Anderson Cancer Center, Orlando, Florida, and colleagues report on the growth of murine colon cancer CT26 cells injected into animals before an open or laparoscopic surgery.
It is known that individuals undergoing open surgery have higher levels of circulating cytokines than those who undergo laparoscopic surgery. The increase in cytokines produces an environment rich in inflammatory mediators that can affect tumor growth and metastasis. The researchers hoped that laparoscopic procedures would decrease cytokine levels, specifically interleukin 6 (IL-6), and that the preservation of normal immune function would create an antitumor environment where cancer cells were unable to thrive.
The results presented during the poster session at the SAGES congress provide evidence that the IL-6 peak is significantly higher in open vs laparoscopic surgery and that cancer cells were able to grow more effectively in animals that had undergone open surgery vs laparoscopic surgery.
Tumors harvested from animals who had open surgery averaged 1.46 g (range, 0.51 – 1.95 g) vs 0.67 g (range, 0.04 – 1.49 g) for laparoscopic cases. Tumors volumes were 22.08 mm3 and 7.41 mm3, respectively.
"These data suggest that surgery-induced levels of cytokines may play a crucial role in the in vivo growth of colon cancer," Dr. Bahna noted. "The different effects of open vs laparoscopic surgery on the growth of colon cancer may be important in prognosis for colon cancer patients."
Makoto Hashizume, MD, from the Department of Surgery at Kyusu University, Fukuoka, Japan, commented, "This research suggests the movement towards laparoscopic surgery for an increasing number of colon surgeries, particularly the right colon, will be helpful from more than one angle. We can reduce tumor burden mechanically and through a reduction in the inflammation that occurs simply due to the act of surgery."
Dr. Bahna and Dr Hashizume have disclosed no relevant financial relationships.
Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 12th World Congress of Endoscopic Surgery: Abstract P014. Presented April 15, 2010.
In research presented here at the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 12th World Congress of Endoscopic Surgery, hosted by SAGES and the Canadian Association of General Surgeons, Heidi Bahna, MD, of M.D. Anderson Cancer Center, Orlando, Florida, and colleagues report on the growth of murine colon cancer CT26 cells injected into animals before an open or laparoscopic surgery.
It is known that individuals undergoing open surgery have higher levels of circulating cytokines than those who undergo laparoscopic surgery. The increase in cytokines produces an environment rich in inflammatory mediators that can affect tumor growth and metastasis. The researchers hoped that laparoscopic procedures would decrease cytokine levels, specifically interleukin 6 (IL-6), and that the preservation of normal immune function would create an antitumor environment where cancer cells were unable to thrive.
The results presented during the poster session at the SAGES congress provide evidence that the IL-6 peak is significantly higher in open vs laparoscopic surgery and that cancer cells were able to grow more effectively in animals that had undergone open surgery vs laparoscopic surgery.
Tumors harvested from animals who had open surgery averaged 1.46 g (range, 0.51 – 1.95 g) vs 0.67 g (range, 0.04 – 1.49 g) for laparoscopic cases. Tumors volumes were 22.08 mm3 and 7.41 mm3, respectively.
"These data suggest that surgery-induced levels of cytokines may play a crucial role in the in vivo growth of colon cancer," Dr. Bahna noted. "The different effects of open vs laparoscopic surgery on the growth of colon cancer may be important in prognosis for colon cancer patients."
Makoto Hashizume, MD, from the Department of Surgery at Kyusu University, Fukuoka, Japan, commented, "This research suggests the movement towards laparoscopic surgery for an increasing number of colon surgeries, particularly the right colon, will be helpful from more than one angle. We can reduce tumor burden mechanically and through a reduction in the inflammation that occurs simply due to the act of surgery."
Dr. Bahna and Dr Hashizume have disclosed no relevant financial relationships.
Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 12th World Congress of Endoscopic Surgery: Abstract P014. Presented April 15, 2010.
MOLECULAR PROFILING AND TREATMENT SELECTION IN COLORECTAL CANCER
J Clin Oncol. 2010 Apr 12. [Epub ahead of print]
Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.
Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M, Malka D, Trégouët DA, Bouché O, Le Corre D, Miran I, Mulot C, Ducreux M, Beaune P, Laurent-Puig P.
Departments of Medicine, Biostatistics and Epidemiology, and Oncogenetics and Institut National de la Santé et de la Recherche Médicale (INSERM) U981, Institut Gustave-Roussy, Villejuif; Université Paris Descartes, INSERM UMR-S775; INSERM UMR-S 937, Pierre et Marie Curie University and Medical School, Paris; and Department of Hepatogastroenterology, Centre Hospitalier Universitaire de Reims, Reims, France.
Abstract
PURPOSE: The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. RESULTS: The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5'UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5'UTR genotypes, respectively. Conversely, patients with the TS-5'UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). CONCLUSION: A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.
Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.
Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M, Malka D, Trégouët DA, Bouché O, Le Corre D, Miran I, Mulot C, Ducreux M, Beaune P, Laurent-Puig P.
Departments of Medicine, Biostatistics and Epidemiology, and Oncogenetics and Institut National de la Santé et de la Recherche Médicale (INSERM) U981, Institut Gustave-Roussy, Villejuif; Université Paris Descartes, INSERM UMR-S775; INSERM UMR-S 937, Pierre et Marie Curie University and Medical School, Paris; and Department of Hepatogastroenterology, Centre Hospitalier Universitaire de Reims, Reims, France.
Abstract
PURPOSE: The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. RESULTS: The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5'UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5'UTR genotypes, respectively. Conversely, patients with the TS-5'UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). CONCLUSION: A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.
WOMEN WITH NSCLC LIVE LONGER
NEW YORK (Reuters Health) Apr 08 - Pooled data on more than 1300 patients with nonoperable small-cell lung cancer indicate that gender is the most significant factor influencing survival, researchers report.
Dr. Benjamin Movsas of the Henry Ford Health System, Detroit, and colleagues analyzed 2-year overall survival data on 1365 patients treated in 9 prospective trials in the 1990s. All received radiotherapy alone or in combination with chemotherapy. None had surgery.
In Cox proportional hazard regression models, men had significantly higher mortality than women (hazard ratio, 1.22).
Comparing subgroups for overall survival, the authors found adjusted hazard ratios of 0.72 for single males vs single females, 0.85 for single males vs married females, and 0.86 for married males vs married females.
"Both married and single males had inferior outcomes when compared with married females, underscoring the fact that gender was the primary determinant of outcome," the researchers write in a March 20th online report in the Journal of Thoracic Oncology.
Dr. Movsas commented to Reuters Health by mail, "Although race and marital status contribute to the overall prognostic picture, this study demonstrated that gender is by far the most important predictor of survival among patients with nonoperative non-small cell lung cancer."
Race and marital status did not significantly affect the results in this study, but the number of nonwhite patients might have been too small to show an impact of race, the authors said.
Dr. Movsas concluded, "Further studies are needed to better understand why women in this setting have a better prognosis than men in order to improve the outcomes for all patients with this devastating disease."
J Thorac Oncol 2010.
Dr. Benjamin Movsas of the Henry Ford Health System, Detroit, and colleagues analyzed 2-year overall survival data on 1365 patients treated in 9 prospective trials in the 1990s. All received radiotherapy alone or in combination with chemotherapy. None had surgery.
In Cox proportional hazard regression models, men had significantly higher mortality than women (hazard ratio, 1.22).
Comparing subgroups for overall survival, the authors found adjusted hazard ratios of 0.72 for single males vs single females, 0.85 for single males vs married females, and 0.86 for married males vs married females.
"Both married and single males had inferior outcomes when compared with married females, underscoring the fact that gender was the primary determinant of outcome," the researchers write in a March 20th online report in the Journal of Thoracic Oncology.
Dr. Movsas commented to Reuters Health by mail, "Although race and marital status contribute to the overall prognostic picture, this study demonstrated that gender is by far the most important predictor of survival among patients with nonoperative non-small cell lung cancer."
Race and marital status did not significantly affect the results in this study, but the number of nonwhite patients might have been too small to show an impact of race, the authors said.
Dr. Movsas concluded, "Further studies are needed to better understand why women in this setting have a better prognosis than men in order to improve the outcomes for all patients with this devastating disease."
J Thorac Oncol 2010.
VELCADE BOOSTS SURVIVAL IN MM
NEW YORK (Reuters Health) Apr 13 - The survival benefit of adding bortezomib (Velcade) to melphalan and prednisone for first-line treatment of multiple myeloma persists even after long-term follow-up and salvage therapy, researchers reported online April 5th in the Journal of Clinical Oncology.
"This confirmed survival advantage represents an important finding, as an overall survival benefit has not been consistently reported" in any other trials of newer agents versus the melphalan/prednisone combination, the researchers said.
Their results, from the phase III VISTA trial, confirm a 2008 report from the same study, in which the triple-drug regimen was more effective than melphalan plus prednisone alone. Patients who required salvage therapy received bortezomib, thalidomide or lenalidomide.
In their more recent paper, senior author Dr. Jesus F. San Miguel of Hospital Universitario de Salamanca in Spain and colleagues reported that the efficacy of salvage was similarly effective whether patients had received all three drugs or just two, "demonstrating that the use of bortezomib upfront does not preclude the successful use of novel agents at relapse."
In addition, survival was no worse, "and may even be longer," in patients who received first-line therapy that included bortezomib, "indicating that first-line bortezomib use does not induce more resistant relapse."
At the outset of the study, the researchers treated 682 multiple myeloma patients (median age 71) with up to nine 6-week cycles of melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1 to 4, all cycles) and, in those randomized to receive it, bortezomib 1.3 mg/m2 for eight days in cycles 1-4 and four days in cycles 5-9). In all cases, patients were receiving first-line treatment and were ineligible for high-dose therapy.
At a median follow-up of 36.7 months, 3-year overall survival was 68.5% in patients who received bortezomib versus 54.0% in those who did not.
Overall, 411 patients required subsequent therapy. Patients who had received bortezomib had a significantly longer median time to salvage therapy (28.1 vs 19.2 months) and a longer median treatment-free interval (17.6 vs 8.4 months).
Rates of mortality and treatment discontinuation for adverse events were similar in the two groups.
The researchers conclude that "using bortezomib-based treatment in the first-line setting provides greater survival benefit to patients compared with the approach of administering first-line treatment with conventional agents and saving bortezomib- and other novel agent-based treatment for salvage."
J Clin Oncol 2010.
"This confirmed survival advantage represents an important finding, as an overall survival benefit has not been consistently reported" in any other trials of newer agents versus the melphalan/prednisone combination, the researchers said.
Their results, from the phase III VISTA trial, confirm a 2008 report from the same study, in which the triple-drug regimen was more effective than melphalan plus prednisone alone. Patients who required salvage therapy received bortezomib, thalidomide or lenalidomide.
In their more recent paper, senior author Dr. Jesus F. San Miguel of Hospital Universitario de Salamanca in Spain and colleagues reported that the efficacy of salvage was similarly effective whether patients had received all three drugs or just two, "demonstrating that the use of bortezomib upfront does not preclude the successful use of novel agents at relapse."
In addition, survival was no worse, "and may even be longer," in patients who received first-line therapy that included bortezomib, "indicating that first-line bortezomib use does not induce more resistant relapse."
At the outset of the study, the researchers treated 682 multiple myeloma patients (median age 71) with up to nine 6-week cycles of melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1 to 4, all cycles) and, in those randomized to receive it, bortezomib 1.3 mg/m2 for eight days in cycles 1-4 and four days in cycles 5-9). In all cases, patients were receiving first-line treatment and were ineligible for high-dose therapy.
At a median follow-up of 36.7 months, 3-year overall survival was 68.5% in patients who received bortezomib versus 54.0% in those who did not.
Overall, 411 patients required subsequent therapy. Patients who had received bortezomib had a significantly longer median time to salvage therapy (28.1 vs 19.2 months) and a longer median treatment-free interval (17.6 vs 8.4 months).
Rates of mortality and treatment discontinuation for adverse events were similar in the two groups.
The researchers conclude that "using bortezomib-based treatment in the first-line setting provides greater survival benefit to patients compared with the approach of administering first-line treatment with conventional agents and saving bortezomib- and other novel agent-based treatment for salvage."
J Clin Oncol 2010.
ARSENIC TRIOXIDE MECHANISM OF ACTION IN APL REVEALED
SINGAPORE (Reuters) Apr 09 - Scientists in China have demonstrated how arsenic can treat leukemia by targeting and killing specific proteins that keep the cancer alive.
"Our study showed how arsenic directly targets these proteins and kills them," lead researcher Dr. Zhang Xiaowei at the State Key Laboratory of Medical Genomics in Shanghai, China, told Reuters.
"Unlike chemotherapy, the side effects of arsenic (in treating acute promyelocytic leukemia) are very low. There is no hair loss or suppression of bone marrow (function). We are interested in finding out how arsenic can be used in other cancers," Dr. Zhang said by telephone.
Well known for its toxicity, arsenic was regarded in the past as the king among poisons because its symptoms are like those of cholera and can often go undetected.
In China, however, it has long served a dual purpose. Apart from intentional poisoning, it has been used for at least 2,000 years in traditional Chinese medicine.
In 1992, a group of Chinese doctors reported how they used arsenic to treat acute promyelocytic leukemia (APL), which has surprisingly high cure rates of over 90% in China.
However, the actual workings of arsenic and how it interacts with cancer has never been clear -- until Dr. Zhang and his colleagues used modern technology to find out.
In a paper published April 9th in Science, Dr. Zhang and his team, which includes Health Minister Chen Zhu, reported that arsenic attacked specific proteins that would otherwise be keeping the cancer alive and well.
"This shows how Western technology can be used to find out about the mysteries of Chinese medicine," Dr. Zhang said.
According to the researchers' article, arsenic promotes degradation of an oncogenic protein that drives the growth of APL cells. This protein, PML-RAR alpha, is a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha. The investigators discovered that arsenic binds directly to cysteine residues in the zinc fingers. Arsenic binding induces oligomerization of PML, "which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation," the researchers report.
They add, "The identification of PML as a direct target of (arsenic) provides new insights into the drug's mechanism of action and its specificity for APL."
"Although many countries are now using arsenic to treat APL, some countries are resistant to the idea. It depends a lot on whether doctors recommend it and whether patients accept it," Dr. Zhang said.
The clinical result of arsenic in treating APL is well-established, with 5-year disease-free survival of more than 90% of APL patients in China, he added..
In a separate commentary in Science, Dr. Scott Kogan at the University of California San Francisco Cancer Center wrote that proper case selection and combination therapy with arsenic may lead to improved outcomes for treating not only promyelocytic leukemia, but other diseases as well.
"If so, an ancient medicine, revived through careful clinical and biological studies in modern times, will have an even greater impact on human health," wrote Dr. Kogan.
Science 2010;328:240-243.
"Our study showed how arsenic directly targets these proteins and kills them," lead researcher Dr. Zhang Xiaowei at the State Key Laboratory of Medical Genomics in Shanghai, China, told Reuters.
"Unlike chemotherapy, the side effects of arsenic (in treating acute promyelocytic leukemia) are very low. There is no hair loss or suppression of bone marrow (function). We are interested in finding out how arsenic can be used in other cancers," Dr. Zhang said by telephone.
Well known for its toxicity, arsenic was regarded in the past as the king among poisons because its symptoms are like those of cholera and can often go undetected.
In China, however, it has long served a dual purpose. Apart from intentional poisoning, it has been used for at least 2,000 years in traditional Chinese medicine.
In 1992, a group of Chinese doctors reported how they used arsenic to treat acute promyelocytic leukemia (APL), which has surprisingly high cure rates of over 90% in China.
However, the actual workings of arsenic and how it interacts with cancer has never been clear -- until Dr. Zhang and his colleagues used modern technology to find out.
In a paper published April 9th in Science, Dr. Zhang and his team, which includes Health Minister Chen Zhu, reported that arsenic attacked specific proteins that would otherwise be keeping the cancer alive and well.
"This shows how Western technology can be used to find out about the mysteries of Chinese medicine," Dr. Zhang said.
According to the researchers' article, arsenic promotes degradation of an oncogenic protein that drives the growth of APL cells. This protein, PML-RAR alpha, is a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha. The investigators discovered that arsenic binds directly to cysteine residues in the zinc fingers. Arsenic binding induces oligomerization of PML, "which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation," the researchers report.
They add, "The identification of PML as a direct target of (arsenic) provides new insights into the drug's mechanism of action and its specificity for APL."
"Although many countries are now using arsenic to treat APL, some countries are resistant to the idea. It depends a lot on whether doctors recommend it and whether patients accept it," Dr. Zhang said.
The clinical result of arsenic in treating APL is well-established, with 5-year disease-free survival of more than 90% of APL patients in China, he added..
In a separate commentary in Science, Dr. Scott Kogan at the University of California San Francisco Cancer Center wrote that proper case selection and combination therapy with arsenic may lead to improved outcomes for treating not only promyelocytic leukemia, but other diseases as well.
"If so, an ancient medicine, revived through careful clinical and biological studies in modern times, will have an even greater impact on human health," wrote Dr. Kogan.
Science 2010;328:240-243.
Εγγραφή σε:
Αναρτήσεις (Atom)