ABIRATERONE EFFECTIVE ALSO IN HIGH GLEAN SCORE PROSTATE CANCER

In 1,048 prostate cancer patients previously treated with docetaxel, and 996 metastatic, castration-resistant patients, treatment with the androgen-lowering drug abiraterone acetate (Zytiga) led to longer overall disease control, even when a very high Gleason score indicated especially aggressive cancer.

Study Findings

Results recently published by Fizazi et al in the Annals of Oncology show that for patients with Gleason score greater than 8, postdocetaxel treatment with abiraterone extended progression-free survival from 5.5 months to 6.4 months, and prechemotherapy abiraterone treatment extended progression-free survival from 8.2 months to 16.5 months.

“We have the idea that with an unfavorable Gleason score, we have to immediately reach for the harshest chemicals, but this study shows that's not always the case. Abiraterone is easier to take, has fewer side effects, and shows prolonged survival,” said Thomas Flaig, MD, Associate Director for Clinical Research at the University of Colorado Cancer Center, and Associate Professor of Medicine at the University of Colorado School of Medicine.

Dr. Flaig was coinvestigator of clinical trials that led to U.S. Food and Drug Administration (FDA) approval of abiraterone acetate, and with collaborators, continues to explore the best use of the drug. Previous work showed that the drug is useful even in cases of prostate cancer that has metastasized to the liver, another poor prognostic sign. The current study extends this finding to include all aggressive prostate cancers marked by high Gleason score.

“The main thing this analysis does is help us better understand how to use this new agent. Certainly there are cases in which cytotoxic chemotherapies are appropriate. But this study points to a broad use of this oral hormonal agent,” Dr. Flaig said.

In addition to extending the duration of progression-free survival, this study showed greater overall survival and better control of prostate-specific antigen with abiraterone treatment. The treatment is used in combination with prednisone.

“Thus, the Gleason score at the time of diagnosis should not factor into the decision to prescribe or treat a patient with metastatic castration-resistant prostate cancer with abiraterone acetate plus prednisone,” the authors concluded.

FACTS FOR BREAST CANCER SCREENING

Findings of a systematic review of the benefits and harms of breast cancer screening commissioned by the American Cancer Society (ACS) to inform its updated guideline on screening in average-risk women were reported in JAMAby Myers et al of the Duke Evidence Synthesis Group. Their findings were published along with the updated ACS guideline.

The review included literature searches through March 2014, yielding 7 reviews, 10 randomized clinical trials, 72 observational studies, and 1 modeling study providing relevant data. Key findings of the systematic review are reproduced here.

Key Findings

• Across all ages of women at average risk, pooled estimates of the association between mammography screening and mortality reduction after 13 years of follow-up were similar for 3 meta-analyses of clinical trials: relative risk (RR) = 0.80, 95% confidence interval [CI] = 0.73–0.89, in a UK Independent Panel analysis; RR = 0.82, 95% CI = 0.74–0.94, in a Canadian Task Force analysis; and RR = 0.81, 95% CI = 0.74–0.87, in a Cochrane analysis.
• Risk reduction was greater in a meta-analysis of cohort studies (RR = 0.75, 95% CI = 0.69–0.81) and similar in a modeling study (Cancer Intervention and Surveillance Modeling Network; median RR equivalent among seven models = 0.85 (range = 0.77–0.93).
• There is uncertainty about the magnitude of screening-associated mortality reduction in the entire U.S. population, among women aged 40 to 49 years, and with annual vs biennial screening.
• There is uncertainty about the magnitude of overdiagnosis associated with different screening strategies, attributable in part to a lack of consensus on methods of estimation and the importance of ductal carcinoma in situ in overdiagnosis.
• For women with a first mammography screening at age 40 years, the estimated 10-year cumulative risk of a false-positive biopsy result was higher with annual (7.0%, 95% CI = 6.1%–7.8%) than biennial screening (4.8%, 95% CI = 4.4%–5.2%). Ten-year probabilities of false-positive biopsy results were similar among women first screened at age 50 years, but indirect estimates of lifetime probability of false-positive results were lower.
• Evidence for the relationship between screening and life expectancy and quality-adjusted life expectancy was of low quality.
• There was no direct evidence for any additional mortality benefit associated with the addition of clinical breast examination to mammography. Observational evidence from the United States and Canada suggested an increase in false-positive findings compared with mammography alone, with both studies finding an estimated 55 additional false-positive findings per extra breast cancer detected with the addition of clinical breast exam.

The investigators concluded: “For women of all ages at average risk, screening was associated with a reduction in breast cancer mortality of approximately 20%, although there was uncertainty about quantitative estimates of outcomes for different breast cancer screening strategies in the United States. These findings and the related uncertainty should be considered when making recommendations based on judgments about the balance of benefits and harms of breast cancer screening.”

The study was funded by the American Cancer Society.

SURGERY FOR METASTATIC BREAST CANCER ?

The overall survival of patients who are initially diagnosed with metastatic breast cancer has improved by 6 months over the past 2 decades, according to a population-based study conducted in the United States.

And the improvement is associated with breast surgery after the initial diagnosis, which is a debated practice in these patients, according to the authors, led by Mary Schroeder, PhD, a health services researcher at the University of Iowa in Iowa City.

The investigators reviewed data on 21,372 metastatic patients from the Surveillance, Epidemiology, and End Results (SEER) program for two periods — 1988 to 1991 and 2007 to 2011. They found that median survival increased from 20 months in the earlier period to 26 months in the later period.

None of the patients received radiation therapy as part of their first course of treatment, and only 39% underwent surgery.

Nevertheless, surgery was found to be associated with better survival on multivariate analysis that controlled for patient characteristics, clinical characteristics, and time period (hazard ratio, 0.60; 95% confidence interval [CI], 0.57 - 0.63).

The study, which was published online today in JAMA Surgery, provides a "contemporary" look at these patients, the investigators say.

"This updates earlier reports, which described outcomes for women diagnosed as having stage IV breast cancer more than a decade ago," they explain.

So does the study suggest that patients diagnosed with metastatic breast cancer should undergo surgery?

Not necessarily, according to the investigators.

Surgery might provide "critical disease control" for some patients and "could be" a component of prolonged survival, they conclude.

But they acknowledge that surgery might be a "surrogate" for other factors that extend life but are not reviewable in the SEER data, such as systemic therapies, social support, and access to care.

Randomized clinical trials and prospective patient registries are needed to truly define the observed survival benefit seen in this study, Dr Schroeder and her colleagues note.

In fact, a randomized trial being conducted in Canada and the United States (ECOG E2108) has recently completed accrual, and a Japanese trial is nearing completion, Dr Schroeder told Medscape Medical News.

In the meantime, what should clinicians and patients do?

"I offer breast surgery selectively to patients with stage IV disease," said Lisa A. Newman, MD, MPH, director of the breast oncology program at the Henry Ford Health System in Detroit.

The goals of surgery include the reduction of the "total body burden of disease," Dr Newman, who also wrote an accompanying editorial, told Medscape Medical News.

Patients who are "more likely" to benefit in this way are "medically fit with limited distant organ involvement and with disease that is amenable to targeted endocrine and/or anti-HER2/neu therapy," she said.

But other patients might also benefit. "Evidence of metastatic focus downstaging in response to primary systemic therapy would be another feature indicating possible benefit," Dr Newman added.

And patients with "bulky, ulcerated, or fungating breast tumors represent a distinctly different scenario, where surgery might be considered purely for palliation," she added.

Metastatic patients "often" want surgery, Dr Schroeder explained. However, "most commonly," surgery is not recommended by their multidisciplinary teams.

Two recent phase 3 trials comparing surgery with no surgery in metastatic breast cancer have shown no survival benefit with surgery, Dr Newman reports in her editorial.

However, both of these studies were international, and might not be relevant in a "more affluent country such as the United States, where patients have improved access to advanced diagnostic and treatment options," she said. For example, the trial conducted in India did not include anti-HER2/neu therapy, as reported by Medscape Medical News in 2013.

If surgery does indeed improve survival, it is probably a modest benefit, Dr Schroeder and her colleagues contend.

"A large benefit for many women with stage IV breast cancer with surgery to the intact primary tumor is unlikely, especially as an ever-increasing array of more potent and targeted drugs may be able to provide better control or even eradication of systemic disease," they write.

However, their results suggest that the benefit could be long term, which is the hoped-for outcome for all metastatic cancers.

Of the 7504 patients diagnosed with metastatic disease before 2002, survival of at least 10 years was seen in 353 patients who underwent surgery and in 107 who did not (9.6% vs 2.9%; odds ratio [OR], 3.61; 95% CI, 2.89 - 4.50).

On multivariate analysis, survival of at least 10 years was associated with receipt of surgery (OR, 2.80; 95% CI, 2.08 - 3.77). Surgery was a more powerful predictor of this long-term survival than age, tumor size, year of diagnosis, marital status, race/ethnicity, or tumor receptor status, the investigators report.

This study was supported in part by the University of Iowa Holden Comprehensive Cancer Center Population Research Core, which is supported in part by a National Cancer Institute grant. The study authors and Dr Newman have disclosed no relevant financial relationships.

ANTHRACYCLINE USE LINKED TO LONG TERM MEMORY PROBLEMS?

Anthracyclines might increase the risk for certain long-term memory problems and brain injury in patients with breast cancer, according to a small study published online December 3 in JAMA Oncology.

The study is the first to directly assess the neurotoxic effects of anthracyclines and nonanthracyclines in long-term survivors of breast cancer.

Cognitive problems related to cancer and its treatment are sometimes referred to as "cancer brain." These problems can persist over the long term and greatly decrease quality of life. Studies have linked chemotherapy to faster brain aging and to neurodegenerative disorders like Alzheimer's disease.

So far, the neurotoxic effects of various types of chemotherapy regimens are unclear, say researchers Shelli Kesler, PhD, from the University of Texas M.D. Anderson Cancer Center in Houston, and Douglas W. Blayney, MD, from the Stanford University School of Medicine in Palo Alto, California.

But their study indicates that regimen matters.

"Using standardized neuropsychological tests and resting state fMRI, we demonstrated significantly lower verbal memory performance and left precuneus connectivity in participants who received anthracycline regimens compared with those who received nonanthracycline regimens and to participants who did not receive chemotherapy," the pair write.

The left precuneus region is involved in memory, visuospacial processing, and consciousness. It is part of the brain's default mode network, which refers to cognitive activities carried out while the brain is at rest. Changes in connectivity in this region could lower the efficiency of information processing. Past studies have suggested that the default mode network is particularly vulnerable to the chemotherapy used to treat breast cancer. Studies have also linked changes in the default mode network to neurodegenerative disorders, Drs Kesler and Blayney report.

In their study, the researchers evaluated results from standardized cognitive tests and resting state functional MRI data for 62 survivors of primary breast cancer (mean age, 54.7 years). Patients had been off therapy for an average of 2 years. Twenty patients had received four to eight cycles of anthracycline-based chemotherapy, 19 had received four to eight cycles of nonanthracycline chemotherapy, and 23 had no history of chemotherapy. Patients were treated at Stanford University from 2008 to 2014.

There was a significant decrease in verbal memory performance in the anthracycline group, compared with the other two groups. This included a decrease in immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001).

There was also less left precuneus connectivity in the anthracycline group than in the other two groups (F = 7.48; P = .001). And patients treated with anthracyclines had significantly less default mode network connectivity (effect size, 0.6 - 1.3; P = .001).

Patient-reported outcomes for cognitive dysfunction and psychologic distress were worse in patients treated with anthracyclines (F = 7.27; P = .002) and nonanthracyclines (F = 5.64; P = .006) than in those not treated with chemotherapy. Executive functioning and fatigue were also worse in both chemotherapy groups than in the no-chemotherapy group.

There was no association between the number of chemotherapy cycles and cognitive status (P > .50), or between the number of cycles and treatment with endocrine therapy (P > .63). Adjustment for disease stage did not significantly change the results.

The small sample size and the retrospective cross-sectional design limited the study, the researchers acknowledge.

"Larger, prospective studies are needed that include pretreatment and post-treatment assessments so that patients' individual cognitive and neurobiologic trajectories can be evaluated with respect to potential anthracycline-related neurotoxic effects," the researchers conclude. "Continued research regarding the mechanisms by which anthracyclines disrupt neurocircuitry could help identify interventions that will protect against anthracycline-associated neurotoxic effects without reducing the anticancer efficacy of these regimens."

The complexity of research in this area was highlighted in an accompanying editorial by Kelly Nudelman, PhD, Brenna McDonald, PsyD, and Andrew Saykin, PsyD, all from the Indiana University School of Medicine in Indianapolis.

Imaging studies have suggested that a wide array of brain regions are affected by cancer and chemotherapy, they write. "Connectomics," they suggest, could help create a larger picture of the way cancer and its treatment affect cognitive functioning and brain networking.

Larger studies need to include different types of cancer, evaluate genetic factors, and look at the differential role of various cancer agents in neurodegeneration and cognitive aging, they explain.

"Additional prospective studies are needed to address baseline differences and the impact of specific treatments on cognitive function, the underlying neural substrate, and specific biological pathways," the editorialists write. "Resolving the pathways leading to cognitive dysfunction will be important for development of targeted interventions."

Dr Kesler and her colleagues note that anthracyclines, such as doxorubicin, work by inducing double-stranded DNA breaks and free-radical damage in both healthy and cancerous cells. The use of these agents has been linked to neuroinflammation, oxidative stress, and cerebrovascular disease, such as microinfarcts, all of which could contribute to neurodegeneration.

NINTEDANIB FAILED IN OVARIAN CANCER

NEW YORK (Reuters Health) - In a phase III trial, women with advanced ovarian cancer had a small improvement in progression-free survival with nintedanib, but at the expense of gastrointestinal side effects, according to European investigators.

Nintedanib is an oral inhibitor of the VEGF receptors (VEGFRs) 1-3, fibroblast growth factor receptors (FGFRs) 1-3, and platelet-derived growth factor receptors (PDGFRs) alpha and beta, with anti-angiogenic activity.

"The trial supports the concept that angiogenesis is a valuable target in ovarian cancer," wrote Dr. Andreas du Bois, in an email to Reuters Health. At this point, however, it's not clear whether the company will try to register the drug for ovarian cancer, he said. It is approved for lung cancer treatment.

In a paper online November 15 in Lancet Oncology, Dr. du Bois of Oslo University Hospital in Norway and colleagues reported on 1,366 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-IV ovarian cancer and upfront debulking who were randomly assigned to receive standard carboplatin and paclitaxel chemotherapy protocols with or without nintedanib.

Nine study groups in 22 countries participated.

Median progression-free survival was about two weeks longer with nintedanib vs placebo (17.2 vs 16.6 months; p=0.024).

"There will be another analysis focusing on overall survival," Dr. du Bois told Reuters Health. "It is not mature yet."

Post hoc analyses revealed that women with low postoperative tumor burden saw the largest benefit in progression-free survival. In this non-high-risk subgroup, median progression-free survival was 27.1 months with nintedanib, compared to 20.8 months with placebo.

Gastrointestinal side effects occurred in 21% in the nintedanib group vs 2% in the placebo group.

Rates of grade 3 and grade 4 neutropenia were 20% and 22%, respectively, with nintedanib and 20% and 16% with placebo.

Serious adverse events occurred in 42% of the nintedanib group and 34% of the placebo group. The rate of adverse events leading to death were 3% with nintedanib and 4% with placebo.

The high rate of adverse GI events "demands more attention and needs further optimization," Dr. du Bois said. "However, the rate of patients stopping the drug completely was not so high, indicating that dose modifications and pauses may be an appropriate way to improve tolerability."

Dr. Charles Drescher of the Fred Hutchinson Cancer Research Center at the University of Washington in Seattle, who was not involved in the research, told Reuters Health, "Similar to prior trials, it is demonstrating some activity for anti-angiogenesis effect. However, the effectiveness is pretty modest and not a huge impact."

He added: "You have to balance that against the GI toxicity and the cost of the drug."

In a comment published with the paper, Dr. Sean Kehoe from the Institute of Cancer and Genomics at the University of Birmingham, UK, points to the "intriguing" finding that "women at lower risk of progression or lower postsurgical tumor burden who were in the nintedanib group had a longer median progression-free survival."

Dr. Kehoe contrasts this with findings from the ICON7 trial of bevacizumab added to upfront therapy, in which women with larger tumor burden or stage IV disease had improved overall survival.

"Besides the different drugs used, how can this difference be explained?" Dr. Kehoe asks. He suggests, as does Dr. du Bois, that patients with stage IV cancer in ICON7 might have been reclassified in this trial as low-risk after tumor clearance.

The study was funded by Boehringer Ingelheim.

SOURCE: http://bit.ly/1MRD51Q

Lancet Oncol 2015.