Κυριακή, 18 Φεβρουαρίου 2018

NO BENEFIT OF OVARIAN CANCER SCREENING FOR GENERAL POPULATION

Women should not undergo screening for ovarian cancer if they do not have signs or symptoms of the disease, as it does not improve survival but may expose women unnecessarily to surgical complications. This is the final guidance from the US Preventive Services Task Force (USPSTF), published online February 13 in JAMA.
In a grade D recommendation against the use of ovarian screening, the USPSTF says that current tests do not accurately identify whether a woman does or does not have ovarian cancer.
A false positive result may lead to a woman's undergoing surgery to remove one or both ovaries without her having the disease.
The recommendation does not apply to women who are at high risk of developing ovarian cancer, such as those carrying BRCA gene mutations.
This final statement on ovarian cancer screening confirms a draft version of the guidelines released in July 2017, as reported by Medscape Medical News. The recommendation against routine screening also echoes recommendations of previous guidelines published in 2012 and 2004, all of which found that the potential harms of ovarian cancer screening outweighed the potential benefits.
The "evidence shows that current screening methods do not prevent women from dying of ovarian cancer, and that screening can lead to unnecessary surgery in women without cancer," USPSTF member Michael J. Barry, MD, Massachusetts General Hospital, Boston, commented in a statement.
USPSTF member Michael J. Barry, MD, Massachusetts General Hospital, said in a release that the "evidence shows that current screening methods do not prevent women from dying of ovarian cancer and that screening can lead to unnecessary surgery in women without cancer."
Coauthor Chien-Wen Tseng, MD, MPH, Hawaii Medical Service Association Endowed Chair in Health Services and Quality Research, who is also on the task force, called for research to find better screening methods to "help reduce the number of women who die from ovarian cancer."
"Ovarian cancer is a devastating disease, and we do not have a good way to identify women with ovarian cancer early enough to treat it effectively," she added.
Stephanie V. Blank, MD, professor of gynecologic oncology, Icahn School of Medicine at Mount Sinai, New York City, who was not involved in developing the recommendations, agreed that there is a lack of effective tests for the disease.
"In the general population, ovarian cancer is a relatively rare disease, and the specificity of our current tests is not acceptable," she said in a statement. "False positives in ovarian cancer screening can result in unindicated surgeries.
However, in a related editorial in JAMA Internal Medicine, Steven A. Narod, MD, Women's College Research Institute, Women's College Hospital, Toronto, Canada, argues that "we should not give up entirely on ovarian cancer screening."
He points to recent research showing that the majority of high-grade serous ovarian cancers originate in the fallopian tube and that striving to identify cancers in stages I and II is based on the false assumption that the cancer stage is the main predictor of survival.
Narod concludes: "Screening for ovarian cancer is not ready for prime time, but there are reasons why we should continue the quest."
In an JAMA  editorial, Karen H. Lu, MD, Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, echoes the call for more effective screening strategies, but also urges the development of complementary prevention programs.
She writes: "Broadening the strategy to include accurate risk models and genetic testing, novel prevention options, and effective early detection may help reduce the incidence and high mortality associated with ovarian cancer."
In an editorial in JAMA Oncology, Charles W. Drescher, MD, and Garnet L. Anderson, PhD, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, write that the incremental improvement of screening performance could result in meaningful benefits not yet seen in the trial data.
"Better risk-prediction tools could lead to more targeted screening and a higher likelihood of an overall benefit, even with current screening modalities," they write. "Additional biomarkers, particularly those that are not dependent on tumor burden, may provide better screening performance and potentially at an earlier, more treatable stage.
"Imaging technology that can reliably detect tumors as small as a few millimeters in size and localized to the fallopian tubes would also likely contribute," they add.

Recommendations Based on Systematic Review

To update the 2012 version of the UPSTF recommendations on ovarian cancer screening, the task force conducted a systematic review of the available evidence, searching the MEDLINE, PubMed, and Cochrane Collaborative Collaboration Registry of Controlled Trials databases for studies between 2003 and 2017.
They included four trials in the analysis. Three of the trials, which included a total of 293,038 women, examined ovarian cancer mortality; the remaining study, which involved 549 women, examined psychological outcomes.
Despite the inclusion of several screening interventions, including transvaginal ultrasound with or without cancer antigen 125 testing, no trial found that screening was associated with a significant difference in ovarian cancer mortality.
However, in two of the trials, 1% to 3% of women whose screening results led to surgery for suspected ovarian cancer were found not to have the disease. Major complications occurred in 3% to 15% of procedures.
There was little association between screening and psychological outcomes, although in one of the trials, repeated follow-up scans and tests appeared to increase the risk for psychological morbidity.
The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. The authors and editorialists have disclosed no relevant financial relationships.

INCREASE CANCER RISK IN ELDERLY DUE TO IMMUNE SYSTEM DECLINE?

Age-related declines in the immune system may better explain the increasing incidence of cancer with age than can simply the steady accumulation of genetic mutations. This new finding could affect cancer prevention and treatment, say the investigators.
The research, which was published online in the Proceedings of the National Academy of Sciences of the United States of America on February 5, used a mathematical model to compare age-related changes in the incidence of over 100 cancers with age-related declines in the immune system and found that the model fit very well for more than 50 types of cancer.
The model was a better fit than the traditional model of accumulating genetic mutations and was better able to explain sex differences in the age-related increase in cancer incidence for specific forms of the disease.
Senior author, Thea Newman, PhD, School of Life Sciences, University of Dundee, United Kingdom, said in a release, "This is still very early days but if we are proven right then you could be talking about a whole new way to treat and prevent cancer."
She continued: "Nearly all of the mainstream research into cancer is based on how we can understand genetic mutations, target them and thereby cure the disease.
"We're not debating the fact that mutations cause cancer, but are asking whether mutations alone can account for the rapid rise in cancer incidence with age when ageing causes other profound changes in the body."
Coauthor Clare C. Blackburn, PhD, Medical Research Council Centre for Regenerative Medicine University of Edinburgh, United Kingdom, added: "We believe that our findings are extremely relevant and show the need to take the immune system even more seriously in cancer research."
However, an expert in the field approached for comment questioned the researchers' conclusions, pointing out that they relied on an outdated model of tumorigenesis and that not all cancer incidence rates simply increase with age, as implied by their model.

Cancer Risk Increase With Age 

Previous studies have shown that the incidence of cancer increases with age, with a median pivot age (signifying the crossover between a very low to relatively high risk) of 49.9 years across all cancer types.
Moreover, it is known that genetic predisposition and exposure to lifestyle and environmental factors lead to cancer via the accumulation of DNA mutations, with the traditional belief that five to six rare "driver" mutations are required in one cell to initiate cancer, termed the power law model.
Because the incidence of many infectious diseases also increases with age, the researchers hypothesized that the age-related changes in cancer incidence may be better explained by the aging immune system than by solely the accumulation of mutations.
They therefore developed a mathematical model based on two assumptions:
1.    That potentially cancerous cells arise with equal probability at any age and
2.    That there is an immune escape threshold related to T cell production, above which immunogenic cells can overwhelm the immune system and lead to a clinically detectable disease.
"For our model, we imagined a war between T cells and cancer cells, which the cancer cells win if they grow beyond a certain threshold," said lead author, Sam Palmer, PhD, School of Mathematical and Computer Sciences, Heriot-Watt University Malaysia, Putrajaya.
"We then set this threshold to be declining with age, proportional to T cell production."
The team obtained cancer incidence data from the US Surveillance, Epidemiology, and End Results program on approximately 2 million cases of 101 types of cancer in adults aged 18 to 70 years, as well as data from the Centers for Disease Control and Prevention on bacterial and viral disease incidence.
They initially checked their mathematical model with incidence data for infectious disease, verifying that it fit.
They then showed that, by using a two-factor immune model, 57 cancer types fit very well (R> 0.95, or a median of 0.956) with their calculations, while only 47 cancers fit a power law model of accumulating genetic mutations (R> 0.95, or a median of 0.947).
Next, they focused on cancer incidence in males vs females because it has been shown that cancer is 1.33 times more common in men and that the incidence increases more rapidly in men in 70 of the 87 cancers that have sex separation.
The team found that T cell receptor excision circle (TREC) levels, which indicate T cell production, were 1.46 times higher in women than in men and that TREC rates declined faster in men than women.
"The increase of cancer incidence with age is slower in women, something which we would naively expect to be effectively gender-neutral," said study coauthor Luca Albergante, PhD, Institut Curie, Université de Recherche Paris Sciences et Lettres, Paris, France.
"However, the thymus gland shrinks more slowly in women, so we were able to make a prediction on the differential cancer incidence with gender that once again shows our model to be more accurate than the traditional model."
Dr Blackburn added: "In addition to mutations, this suggests we should also focus on how to boost thymus function in a controlled way, perhaps by transplantation or by controlled regeneration, so we can increase the number of T cells we are making."
"Of course, we also need to look at whether there may be unintended consequences of doing this, and how to minimize these if they occur."

Mutations as Key Cause of Cancer 

For comment, Medscape Medical News approached Cristian Tomasetti, PhD, from the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, who has coauthored several recent papers suggesting that random mutations are responsible for most cancers. Those findings were widely reported in the media as showing that most cancer is "due to bad luck."
Dr Tomasetti said that he does not "consider their study sound."
"The power law does not represent the correct model for tumorigenesis; it is a more than 50-year-old model that captures only some aspects of the tumorigenesis process," he said.
"Therefore, a comparison between their model and the power law does not represent the appropriate analysis to conclude that their model is better at explaining the observed data than the current theory based on the gradual accumulation of somatic mutations."
He added: "With their theory, it is very difficult to explain why for various cancer types the incidence decreases at very old ages."
Dr Tomasetti also noted that a large literature supports the gradual accumulation of cancer mutations as a key cause of cancer.
This work was supported by Scottish Universities Life Sciences Alliance and the National Institutes of Health through a Physical Sciences in Oncology Centres Grant, the Medical Research Council, the European Union Seventh Framework Programme collaborative project ThymiStem, and the Instituts Thé matiques Multi-Organismes Cancer, within the framework of the Plan Cancer 2014– 2019 and convention Biologie des Systè mes BIO2014. The authors have disclosed no relevant financial relationships.

APALUTAMIDE APPROVED FOR NON-METASTATIC CRPC

The US Food and Drug Administration (FDA) today approved apalutamide (Erleada, Janssen) for the treatment of patients with nonmetastatic prostate cancer who are at high risk for disease spread because treatment with hormone therapy is not effective and thus their disease is castration resistant.
This is the first FDA-approved treatment for nonmetastatic, castration-resistant prostate cancer. It is also the first time the FDA used metastasis-free survival (MFS) as the primary endpoint in its decision making.
"In the trial supporting approval, apalutamide had a robust effect on this endpoint. This demonstrates the agency's commitment to using novel endpoints to expedite important therapies to the American public," said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a press statement.
Apalutamide is an orally administered androgen-receptor inhibitor.
The FDA based its new approval on safety and efficacy data from the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting With ARN-509) trial. Investigators randomly assigned 806 men to receive treatment with apalutamide (240 mg per day) and 401 to receive placebo; all participants also received hormone therapy, either gonadotropin-releasing hormone analogue therapy or surgical castration.
All of the men had also undergone previous definitive treatment, either surgery or radiotherapy, for prostate cancer, but their PSA scores doubled within 10 months or less following treatment, despite hormone therapy.
Median MFS, which was the primary endpoint, was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (< .001). That translated into a 72% reduction in the relative risk for metastasis or death with the new drug (hazard ratio, 0.28; 95% confidence interval [CI], 0.23 - 0.35).
In addition, the results with apalutamide were superior for all secondary endpoints compared to placebo, including time to metastasis, progression-free survival, and time to symptomatic progression; all were significantly longer with apalutamide (< .001 for all comparisons).
Median follow-up in the study was 20.3 months.
The findings were published in the New England Journal of Medicine and were presented last week at the Genitourinary Cancers Symposium (GUCS) 2018, as reported by Medscape Medical News.

"New Standard of Care"

"These data suggest that apalutamide should be considered as a new standard of care for men with high-risk nonmetastatic castrate-resistant prostate cancer," said lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, last week during a GUCS presscast.
In the trial, the rate of discontinuation due to adverse events was 10.6% in the apalutamide group and 7.0% in the placebo group. Three adverse events occurred more commonly with apalutamide than with placebo: rash (23.8% vs 5.5%), hypothyroidism (8.1% vs 2.0%), and fracture (11.7% vs. 6.5%).

MELANOMA SCREENING-ABCD vs. UD SIGN

Malignant melanoma (MM) incidence has been rising for the past six decades, with 87,100 cases diagnosed in the United States in 2017.[1] Over half of melanomas are first detected by patients or their families,[2] with diagnosis of early-stage, thin MM dramatically improving 10-year survival rates.[3] These two facts taken together underscore the importance of patient education to encourage early MM detection.
Since its development in 1985, the ABCD rule (A=asymmetry, B=border irregularity, C=color variegation, D=diameter larger than 6 mm) has been taught as a simple pattern recognition tool to distinguish normal melanocytic nevi from melanomas. This simple rule has been a boon to early MM detection but may fail to pick up small or amelanotic MM, even when adding the "E" for "evolving lesion."[4] In contrast, a newer screening tool instructs patients to compare their cutaneous lesions in search of any outliers—the so-called "ugly duckling" (UD) sign.[5]
The UD rule stems from the notion of the "signature nevus"—that each person forms a characteristic pattern of melanocytic nevi based on genetic determinants such as skin phototype. Hence, by encouraging patients to look for cutaneous lesions that break their typical nevus pattern, the UD sign may show superior sensitivity and/or specificity for MM detection when compared with the more static ABCD rule.

Which Detection Rule Is Best?

To test this hypothesis, Ilyas and colleagues[6] randomly assigned 101 adult volunteers into two groups: those to be taught the ABCD rule (n=51) versus those to be taught the UD sign (n=50). Volunteers were recruited from an outpatient multidisciplinary clinic (Mayo Clinic, Arizona), given a tutorial on their respective screening rule, and then asked to categorize nine skin lesions as MM or not MM. For the UD sign, images included a background of Photoshop-generated nevi.
Both volunteer groups were comparable with respect to age, history of melanoma (8.9%), education level (85% college level or higher), prior knowledge of melanoma recognition techniques, and prior dermatologic care.
The study findings included the following:
  • Both rules showed high sensitivity: 99% (ABCD group) vs 100% (UD group).
  • The UD sign group demonstrated better specificity than the ABCD group (88.3% vs 57.4%).
  • The UD sign group also demonstrated superior accuracy of MM recognition (90.9% vs 66.7%).
  • These differences in group specificity and accuracy persisted even when adjusted for volunteer age, education, and dermatologic history.

Discussion

In 2014 (the most recent year with available data), 76,665 new primary cutaneous MMs were diagnosed in the United States, and 9324 people died from MM, making this by far the most lethal form of skin cancer.[7]
Physicians and the media have done a good job of educating the public about the dangers of MM, primarily through teaching the ABCDE criteria, which emphasize evaluation of each individual lesion for asymmetry, border irregularity, color variegation, large diameter, and evolution.[8] In contrast, the UD rule relies more on intuitive pattern recognition, with patients using their own background nevi as controls to detect any outlying lesions of concern.
As Ilyas and colleagues have demonstrated, the UD sign yielded more accurate MM detection among laypeople than the ABCD rule—albeit in a simulated scenario. It would have been even more compelling if volunteers (or their partners) trained to look for ugly duckling lesions proved better at detecting melanomas in a real-life cohort study.
Nevertheless, teaching patients to add the UD sign to their screening criteria for MM seems like a no-brainer. As Daniel Jensen and Elewski[9] recently suggested, it may be time to add yet another letter to the ABCDE rule, adding "F" for "funny looking."

CABOZANTINIB ACTIVE IN RAI REFRACTORY THYROID CANCER

Cabozantinib (Cabometyx, Exelixis) has shown efficacy in the first-line treatment of radioactive iodine (RAI)–refractory differentiated thyroid carcinoma (DTC) and could offer an option in addition to the drugs approved for this indication, such as sorafenib (Nexavar, Bayer) and lenvatinib (Lenvima, Eisai).
New data from a phase 2 study showed that patients with thyroid cancer that progressed after surgery and RAI achieved an objective response rate of 54% with cabozantinib, and tumor shrinkage was seen in 34 of the 35 enrolled patients.
These data were highlighted at a press conference before their presentation at the 2018 Multidisciplinary Head and Neck Cancers Symposium, to be held in Scottsdale, Arizona, on February 15 to 17.
Presenter Marcia S. Brose, MD, PhD, an associate professor at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, noted that while RAI is curative for most patients, in about 5% to 15% of patients with thyroid cancer, the disease becomes refractory to treatment.
Patients whose disease is refractory to RAI have the option to be treated with sorafenib or lenvatinib — both vascular endothelial growth factor receptor (VEGFR) inhibitors. She noted, however, that responses to these drugs are not durable and patients need additional therapies. 
"Our positive results indicate that cabozantinib offers an additional option to shrink patients' tumors and provide an additional progression-free period," Brose said.
Cabozantinib is a multikinase tyrosine kinase inhibitors targeting VEGFRRETMET, and AXL and is already approved for use in patients with advanced thyroid cancer and renal cell carcinoma.
The manufacturer is exploring other indications. "Based on these promising results and data from other studies of cabozantinib in previously treated DTC, Exelixis plans to initiate a pivotal phase 3 study with cabozantinib in patients with advanced DTC later this year," Gisela Schwab, MD, company president and chief medical officer, said in a statement.

Shows "Good Activity" 

Brose presented data from the UPCC 28313 (NCT 02041260)  study, which enrolled 35 patients with metastatic, RAI-refractory thyroid cancer who had not received prior treatment with VEGFR inhibitors. Median age at enrollment was 65 years, and three fourths of the patients had papillary thyroid cancer.
Patients received cabozantinib, 60 mg daily.
The study was powered to detect an overall response rate of 15%, which translates to responses in at least 5 of the 35 patients.
Although no patient showed a complete response, partial responses were seen in 19 of 35 (54%) patients and stable disease was reported for 15 of 35 (43%) patients. Duration of partial response ranged from 11 weeks to more than 174 weeks.
Stable disease lasting for greater than 6 months was seen in 9 of 35 (26%) patients and ranged from 8 weeks to more than 142 weeks.
The clinical benefit rate (complete response + partial response + stable disease for >6 months) was reported for 80% of patients.
Brose reported that only 6 patients had disease progression so far and that median progression-free survival was not reached. Median time on drug was 35 weeks, and as of last week 16 patients were still receiving study treatment. Although the treatment was well tolerated, 23 patients required dose interruptions.  
Most common adverse events were hyperglycemia (80%), diarrhea (77%), malaise/fatigue (74%), and weight loss (71%). Grade 3/4 adverse events occurring in more than one patient were hypertension (14%), increased lipase (9%), pulmonary embolism (6%), and hyponatremia (6%).
Brose noted that the two approved drugs in the setting of RAI-refractory thyroid cancer are used sequentially. "But patients ultimately progress and need more treatment options," she said. "Cabozantinib will provide relief for these patients," she added.
Danielle Margalit, MD, a radiation oncologist at the Dana-Farber Cancer Center, Boston, Massachusetts, who moderated the presscast, remarked that these results are highly significant. "Cabozantinib has good activity in these patients and its activity is comparable to recently approved agents," she said.
However, she said that cabozantinib will need to be further evaluated in phase 3 studies and that the design of such a study is underway. When questioned about whether the drug is available to patients, Brose responded that once these data are published, there is hope that reimbursement will not be an issue. However, the best way to access the drug now is through a phase 3 trial, she indicated.
When the drug becomes available, Brose said that three good drugs will be available to patients in the first-line setting. "There is an art to sequence these drugs," Brose told Medscape Medical News. For example, with the current options, patients aged 65 years and older are prescribed lenvatinib because of favorable survival data in this population. Lenvatinib may also be prescribed for patients who need a quick response. For patients with indolent disease, sorafenib and lenvatinib are both viable options.
"With the availability of all these options, it does not matter which drug is used first," Brose said. "What is important is that patients have options. Over 90% of patients have good performance status even after two therapies, and a third one will fill a high unmet need," she said.   
The study was funded by Elixir Pharmaceuticals, the maker of cabozantinib. The trial was initiated and led by the Abramson Cancer Center at the University of Pennsylvania.  Brose receives grant funding from Loxo, Elixis, Bayer, Eisai, Genzyme/Sanofi, and AstraZeneca. She has also received honoraria or consulting fees from Loxo, Bayer, Eisai, Genzyme/Sanofi, and Blueprint pharmaceuticals 
2018 Multidisciplinary Head and Neck Cancers Symposium. Abstract 8. To be presented February 16, 2018.

COMBINATION TREATMENT OF RENAL CANCER

The combination of an immunotherapy and a vascular endothelial growth factor (VEGF) inhibitor resulted in a groundbreaking response rate in metastatic renal cell carcinoma (RCC), according to results of an ongoing phase 1b study.
In a cohort of treatment-naive patients, 38 of 52 (73%) achieved an objective response, including 4 complete responses, with the combination of axitinib (Inlyta, Pfizer) plus pembrolizumab (Keytruda, Merck).
The study details were presented here at the Genitourinary Cancers Symposium (GUCS) 2018 and simultaneously published online February 10 in the Lancet Oncology.
The response rate was called "unprecedented" by the study authors, led by Michael Atkins, MD, from Georgetown-Lombardi Comprehensive Cancer Center in Washington, DC.
Median progression-free survival (PFS) was 20.9 months. Among responders, median duration of response was 18.6 months. Overall survival data were not mature.
This is uncharted territory, said Sumanta Pal, MD, a urologic oncologist at City of Hope Cancer Center in Duarte, California, who acted as meeting discussant: "An 18.6-month median duration of response and a median PFS of 21 months, this is unprecedented."
Median follow-up in the trial was 17.6 months.
"The regimen was highly active," Atkins told the meeting audience.
"The antitumor activity of the combination is superior to that expected from axitinib or PD-1/PD-L1 [programmed cell death-1/programmed cell death ligand-1] pathway inhibitor monotherapy," he said. The combination roughly doubled the efficacy of the drugs when used alone.
"We think this combination could present a major advance in the treatment of this disease as well as help define effective combinations of similar drugs for other cancers," Atkins said in a press statement.

Previous Combos Were Toxic 

In advanced RCC, treatment with various VEGF pathway inhibitors has "rarely" resulted in durable and complete responses, note the authors. "The standard first-line drugs sunitinib and pazopanib lead to a median progression free survival of around 8–12 months," they write.
The idea of combining anti-VEGF agents with immunotherapy is not new; previous research also showed efficacy. However, excessive toxicity caused investigators and developers to abandon the approach.
Axitinib is a newer, "more selective" VEGF receptor inhibitor than sunitinib and pazopanib, which are multitargeted tyrosine kinase inhibitors (TKIs) that have been tested in this setting. "Many of these toxicities were related to off-target effects of these multitargeted TKIs," Atkins said about the older drugs.
Axitinib is already approved for second-line treatment of advanced RCC. Pembrolizumab is approved for use in many cancer types, but not RCC
(nivolumab is the only immunotherapy approved for RCC).
The team reports that the new combination of axitinib and pembrolizumab  was "tolerable."
This outcome "contrasts with the toxicities reported in other clinical trials" combining checkpoint inhibitors with other TKIs of the VEGF pathway, the authors add.
For the combination of axitinib with pembrolizumab, the team reports that  grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients. The most common were hypertension (12 patients [23%]), diarrhea (5 patients [10%]), fatigue (5 patients [10%]), and increased alanine aminotransferase concentration (4 patients [8%]).
The most common possibly-immune-related adverse events included diarrhea
(15 patients [29%]), increased alanine aminotransferase (9 patients [17%]) or aspartate aminotransferase (7 patients [13%]) concentration, hypothyroidism (7 patients [13%]), and fatigue (6 patients [12%]).
A total of 28 (54%) patients had treatment-related serious adverse events. The most common serious adverse events included diarrhea (6 patients [12%]), dyspnea (4 patients [8%]), and colitis (3 patients [6%]).
Overall, the adverse events reported "seem to be largely related to axitinib" say the investigators. Notably, 27 patients (about half) discontinued both treatments. The most common reasons for discontinuing both study treatments were adverse events (10 patients) and disease progression (9 patients).
The patients in this study had more favorable prognoses than in typical RCC trials, the authors commented. They note that "very few" patients had poor-risk disease per the Metastatic Database Consortium criteria; 46% of patients had favorable-risk disease and 44% had intermediate-risk disease. All participants also had previously undergone nephrectomy.
The investigators enrolled 11 patients to the dose-finding phase and later enrolled another 41 patients to the dose-expansion phase.
All participants received the same dose and schedule. Axitinib 5 mg was administered orally twice daily, with pembrolizumab 2 mg/kg administered intravenously every 3 weeks. Tumors were assessed (according to RECIST version 1.1) at baseline, at week 12, and then every 6 weeks.
On the basis of the results of this phase 1b trial, the US Food and Drug Administration granted the axitinib–pembrolizumab combination a breakthrough status.
A randomized phase 3 trial (NCT0285331) comparing the new combination to sunitinib monotherapy in the first-line setting is underway.
That trial, known as KEYNOTE-426, is evaluating whether axitinib and pembrolizumab will work better as a sequential treatment. This is an important difference because it would cost less. Both drugs are administered for shorter dosing periods when given as monotherapies than when given in combination. The patient population is also "less heavily selected" than that of the current study.
The study was funded by Pfizer. Atkins has financial relationship with Pfizer and multiple other pharmaceutical companies. Pal has financial ties to Eisai, Ipsen, Astellas, Medivation, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Aveo, Novartis, and Pfizer.
Genitourinary Cancers Symposium (GUCS) 2018. Abstract 579. Presented February 10, 2018.

ADJUVANT TREATMENT OF UPPER TRACT UROTHELIAL CANCER

"Congratulations for doing the undoable," said Surena Matin, MD, a urologic oncologist at the University of Texas MD Anderson Cancer Center, Houston, standing at a microphone station on the meeting floor here at Genitourinary Cancers Symposium (GUCS) 2018.
Matin was addressing Alison Birtle, MD, a consultant clinical oncologist at the Rosemere Cancer Center, Royal Preston Hospital, Fulwood, United Kingdom, who was at the speakers' podium in front of the gathering.
She had just finished reporting on the design and conduct of a phase 3 randomized clinical trial in upper tract bladder cancer, a "rare" malignancy in which only about 1400 new cases occur per year in the United Kingdom.
Birtle and her UK colleagues not only managed to successfully perform a trial in upper tract bladder cancer in 261 patients, they also claimed to have established "a new standard of care."
The trial, known as POUT, demonstrated for the first time that chemotherapy after surgery improved disease-free survival (DFS) in upper tract urothelial cancer, compared to observation after surgery. Most of the study patients had locally advanced disease.
The 2-year DFS was 71% for the chemotherapy group vs 54% for the surveillance group (HR = 0.49; P = .001).
POUT is the best-run trial to date in these patients, agreed Sumanta Pal, MD, urologic oncologist at City of Hope Cancer Center in Duarte, California, who was asked for comment. "Every other trial we had in this space has suffered from methodological issues, such as poor accrual or attrition due to not sticking to the treatment algorithms," he said.
"I think this is going to change management," said Pal.
I think this is going to change management. Dr Sumanta Pal
Meeting attendees apparently agreed. In a #GU18 Twitter poll, 62% of 73 respondents cited POUT as the "main practice change" presented at the meeting (the SPARTAN trial was a distant second, at 19%).
After her presentation, Birtle told reporters that upper tract urothelial cancer is "a very neglected tumor" for which there is "no real interest" from researchers worldwide, owing to its low incidence.
"It's a real genuine Cinderella cancer," she said, explaining that, in the universe of genitourinary cancer research, prostate and lower tract bladder cancer dominate. Upper tract bladder cancer, or upper tract urothelial cancer, consists of malignancy in the ureter, kidney, and related tissue.
Birtle knows a bit about hardworking underdogs. Earlier in her career, she was at the famed research-intensive Royal Marsden Hospital in London before relocating to take care of her parents. She joined the relatively less glamorous Royal Preston Hospital in Preston, where she is a full-time clinician. Birtle, who is an award-winning investigator, served as lead investigator for POUT, "with no time allowance in my clinical schedule." In short, she ran the trial in her spare time.
The trial, which is the largest randomized trial ever conducted in these patients, was stopped early because of outstanding efficacy of chemotherapy, which was mostly gemcitabine-cisplatin. For patients whose kidney function score was low, gemcitabine-carboplatin was used.
"Based on these results, adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients," Birtle told the GUCS audience.
Not everyone in the audience agreed.
For example, Matthew Campbell, MD, urologic oncologist from MD Anderson, flatly disagreed, saying adjuvant therapy "should not be standard of care." If these patients are to be treated with chemotherapy, it should be administered before surgery or as neoadjuvant therapy, which is the preferred choice at MD Anderson, he said.
Academics from Dana Farber Cancer Institute in Boston and the University of Chicago also challenged Birtle with objections, and they too touted neoadjuvant use.
In a conversation with Medscape Medical News, Birtle said the main objection from the neoadjuvant chemotherapy camp concerned safety.
She explained that for upper tract urothelial cancer, nephro-ureterectomy is performed. That procedure involves removing one kidney, ureter, and other tissue. If chemotherapy is given before surgery, the patient still has two kidneys with which to process the toxicity associated with chemotherapy, which is obviously preferable to one.
But there are competing safety concerns, in light of which chemotherapy after surgery is advantageous — a factor that tips the scales toward adjuvant use, Birtle emphasized.
She explained that approximately 10% of suspected upper tract urothelial cancers will prove not to be cancerous upon excision and subsequent examination. "There is a lack of definitive histological diagnosis in some patients," she said. She explained that it is not possible to perform a biopsy in some upper tract bladder cancers, owing to the thinness of the tissue wall.
In addition, 10% to 15% of cases are found at surgery not to be invasive of muscle and therefore are "superficial" tumors. In such cases, chemotherapy is not needed, Birtle explained. "There is a concern about overtreatment," she summarized.
The main reason for patients not being able to enroll in the POUT study was "ineligible pathology," said Birtle. This raises the question of whether or not you can tell that a patient has locally advanced disease prior to nephro-ureterectomy, she said. Approximately 60% of patients who were thought to have muscle-invasive disease were found not to have such disease after surgery. "That was the biggest exclusion" in the trial, she said.
Currently, there is no international consensus on systemic therapy for these patients because of a "paucity" of data, said Birtle.
Katrin Schlack, MD, a urologist at the University Hospital of Meunster, attended GUCS and said that "everyone talked about" the POUT study. She offered a German perspective on the controversy.
We usually give chemotherapy after surgery. Dr Katrin Schlack
"We usually give chemotherapy after surgery," Schlack told Medscape Medical News. European guidelines state that neoadjuvant chemo can be offered to these patients, but "it is not required," she said. The guidance also recommends use of adjuvant chemotherapy.
The bigger question is whether or not to give chemotherapy to patients with upper tract endothelial cancers, she said. The patient's tumor stage, kidney function, ECOG performance status, and other factors are considered.
Schlack echoed Birtle's comment about not knowing histology in some upper tract bladder cancers because of the difficulty of conducting a biopsy on tissue there. "Diagnostics in the upper tract are not as good as the lower tract," she said. Evaluating surgically removed tissue can be very helpful in assessing the need for adjuvant chemotherapy, she added.
Birtle had some final thoughts about the neoadjuvant vs adjuvant argument. With POUT, she said, there is finally a well-executed phase 3 trial in the adjuvant setting, she said.
The various champions of neoadjuvant chemotherapy have been advocating it for years — but they still don't have phase 3 clinical trial data in hand, Birtle observed.
But that's understandable, she suggested: It's hard to conduct a clinical trial in a cancer with so few patients.
Extraordinary teamwork produced POUT, she said. "It is a triumph of everybody [in the UK urology community] getting behind the trial in a low-incidence tumor." Of 71 eligible centers in the United Kingdom, 57 enrolled patients in the trial, she observed.
"This is a study that should never have really been done," she added, "because it wasn't with sexy new drugs. It was standard chemotherapy." POUT also had strong input from patients regarding its design, which was extremely helpful but time intensive, she explained.

More Study Details

In POUT, patients were randomly assigned in a 1:1 ratio within 90 days after undergoing surgery either to receive four cycles of chemotherapy or to undergo surveillance. Patients underwent cross-sectional imaging and cystoscopy at 6-month intervals for the first 2 years, then annually for 5 years.
Chemotherapy consisted of gemcitabine-cisplatin or gemcitabine-carboplatin if the glomerular filtration rate (GFR) was "poor" (30-49 mL/min).
Patients were excluded if their GFR was especially low (<30 comorbidities="" distant="" factors.="" had="" if="" metastases="" min="" ml="" or="" other="" p="" significant="" they="">
The primary endpoint was DSF.
The study was "ambitiously powered" to detect 15% improvement in 3-year DFS. In the surveillance control arm, the 3-year DFS was assumed to be 40%. DFS was defined as time from randomization to death (any cause), metastases, or ureteric or renal bed recurrence.
The independent data and monitoring committee (IDMC) recommended early closure of the trial in November 2017, because the stopping rule had been met.
In the trial, between May 2012 and September 2017, 260 patients were recruited and enrolled. (The planned sample size of the study was 338 patients.) In October 2017, the IDMC recommended that POUT be closed to recruitment, because by that point, the data that had been collected met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months.
The median age of the patients was 69 years. Baseline characteristics included pathologic stage. Most cases were stage pT2 (23.3%) or pT3 (68.2%); the latter is locally advanced disease.
Compliance was "very good," the researchers reported. In terms of adverse events, the trialists saw "the standard side effects you see with chemo," said Birtle. Specifically, 53.2% of the chemotherapy group experienced toxicities of grade 3 or higher, vs 13.5% of the surveillance group.
For the secondary endpoint of metastasis-free survival (MFS), the 2-year rate was 60% for surveillance and 74% for chemotherapy. MFS favored chemotherapy (HR = 0.49; P = .002).
There was also early indication that chemotherapy improved overall survival, said Birtle, but the data need maturation.
Having already accomplished much, Birtle said she would like to obtain international research partners and perform a larger confirmatory trial. She also said that future research should combine chemotherapy with immunotherapies.
The study was funded by Cancer Research UK and sponsored by the Institute of Cancer Research. Dr Birtle has financial ties with Janssen, Roche, Astellas Medivation, AstraZeneca, Bayer, and Sanofi. Other investigators also have ties to industry.
Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 407. Presented February 9, 2018.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

IMMUNOTHERAPY ADVERSE EVENT TREATMENT

The introduction of immune checkpoint inhibitors has dramatically changed the treatment of a number of cancer types, but these drugs are quite different from those that have been used before, and clinicians are having to manage with a whole new spectrum of adverse effects.
To help with this, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have jointly developed new guidelines for assessing and managing these side effects. The guidelines were published February 14 in the Journal of Clinical Oncology and online at NCCN.org.
"With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles," said Clifford A. Hudis, MD, FASCO, FACP, who is also the chief executive officer of ASCO, in a statement.
"Some people will brush their symptoms aside, but any unusual symptom should be reported to the doctor," said Julie Brahmer, MD, chair of the expert panel that developed the guidelines, in a statement.
"These guidelines will help all providers who care for patients treated with immune checkpoint inhibitors — not just oncologists but also emergency room and primary care doctors — assess and manage these side effects," she added.

Many Drugs, Many Indications

A growing number of immune checkpoint inhibitors have received approval by the US Food and Drug Administration for an ever increasing number of indications. The drugs include ipilimumab (Yervoy, Bristol-Myers Squibb), nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck Sharp Dohme), atezolizumab (Tecentriq, Genentech), durvalumab (Imfinzi, AstraZeneca), and avelumab (Bavencio, EMD Serono)
Approved indications include melanoma, metastatic non–small cell lung cancer, head and neck squamous cancers, urothelial carcinoma, mismatch repair–deficient solid tumors, Hodgkin's lymphoma, renal cell carcinoma, urothelial cancers, and Merkel cell carcinoma.
Adverse effects with these agents can affect a wide range of organs. The most common ones affect the skin, the gastrointestinal tract, the lungs, endocrine organs (thyroid, adrenal gland, pituitary gland), and musculoskeletal, renal, nervous, hematologic, cardiovascular, and ocular systems.
The growing use of these agents, along with increasing recognition of the wide range of adverse events — which have been fatal in severe cases — highlighted the need for guidance, the authors write.
To develop the guidelines, ASCO and the NCCN convened multidisciplinary panels that included experts from a wide range of medical disciplines, along with participants from nursing and patient advocacy organizations.
The panel based the recommendations on a systematic review of literature and an informal consensus process. ASCO and the NCCN emphasize that these guidelines pertain only to immune checkpoint inhibitors, not other types of immunotherapy.
The NCCN plans to update its guidelines continuously as data evolve. It notes that it plans to include the toxicities associated with CAR T-cell therapies later this year.

Key General Recommendations

The guidelines note that these general recommendations should be followed irrespective of affected organs. It is recommended that clinicians manage toxicities as follows:
  • Patients and their families should receive timely and up-to-date education about immunotherapies, the mechanism of action, and information about related adverse effects prior to initiating treatment and throughout therapy and survivorship.
  • When new symptoms develop, there should be a high level of suspicion that they are treatment related.
  • Therapy can generally be continued with close monitoring for grade 1 toxicities, with the exception of neurologic and some hematologic toxicities.
  • Treatment should be halted for most grade 2 toxicities and held until symptoms and/or laboratory values revert to effects of grade 1 or less. Corticosteroids (initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent) may be administered.
  • The drugs should be stopped for grade 3 toxicities, and high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d) should be initiated. Corticosteroids should be tapered over a period of at least 4 to 6 weeks; if symptoms do not improve after 48 to 72 hours of treatment with high-dose corticosteroids, infliximab may be offered for some toxicities.
  • When symptoms and/or laboratory values revert to effects of grade 1 or less, a treatment rechallenge may be offered, although caution is advised, especially for patients who experience adverse events early in therapy. Dose adjustments are not recommended.
  • Grade 4 toxicities will generally warrant permanent discontinuation of the drug, except for endocrinopathies that have been controlled by hormone replacement.
The guidelines also provide detailed recommendations for managing the specific toxicities that have been observed in each system of the body.
These include skin reactions, such as inflammatory dermatitis and bullous dermatosis; gastrointestinal toxicities, such as colitis and hepatitis; lung toxicities, such as pneumonitis; endocrine toxicities, such as primary hypothyroidism, hyperthyroidism, primary adrenal insufficiency, hypophysitis, and diabetes; musculoskeletal toxicities, such as inflammatory arthritis, myositis, and polymyalgia-like syndrome; renal toxicities, such as nephritis; nervous system toxicities, such as myasthenia gravis, Guillain-Barré syndrome, autonomic neuropathy, peripheral neuropathy, aseptic meningitis, encephalitis, and transverse myelitis; hematologic toxicities, such as autoimmune hemolytic anemia, acquired thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, aplastic anemia, lymphopenia, immune thrombocytopenia and acquired hemophilia; cardiovascular toxicities, such as myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis, and venous thromboembolism; and ocular toxicities, such as uveitis/iritris, episcleritis, and blepharitis.
The guidelines also emphasize that patients should be educated about immune checkpoint inhibitors. They stress the importance of patients' reporting changes in how they feel to the physician, because such changes may be early signs of an adverse reaction.
The Oncology Nursing Society has produced immunotherapy wallet cards for patients to carry. The cards detail symptoms to watch for and how to notify their healthcare provider. They may also be useful for healthcare providers (eg, emergency department staff) who care for patients with a history of immunotherapy, the authors note.
Copies of the immunotherapy wallet card and more information can be obtained by e-mailing clinical@ons.org.
The authors' relevant financial relationships are listed in the published guidelines.
J Clin Oncol. Published online February 14, 2018.




Σάββατο, 10 Φεβρουαρίου 2018

HUMAN EGGS FULLY GROWN IL LAB FOR FIRST TIME

Human oocytes have been fully matured in a laboratory setting for the first time, in a move that could lead to improved fertility treatments and new options for young women with cancer who may be facing chemotherapy that could destroy their ovaries.
The scientists, led by Marie McLaughlin, PhD, of the Institute of Cell Biology, University of Edinburgh, UK, took biopsies from the ovarian cortex of 10 women undergoing cesarean sections and attempted to grow follicles into mature eggs. Their findings were published online January 30 in Molecular Human Reproduction.
The research has given new understanding into how human eggs develop at various stages. In previous studies, scientists have developed mouse eggs to produce live offspring and matured human eggs from a relatively late stage of development.
But this latest study is the first time a human egg has been developed in the lab from its earliest stage to full maturity.
However, outside experts point out that the treatment is inefficient, with only around 10% of the eggs developing to full maturity. Out of 87 immature eggs, only nine developed fully. Also, egg quality has not been tested as none had been fertilized.
Dr McLaughlin and colleagues, who include scientists from the Center for Human Reproduction in New York, acknowledge their work is at a very early stage: "We describe here the successful development of a small number of human oocytes capable of acquiring and expressing a level of development approaching that of an ovulated ovum."
Senior author Evelyn Telfer, PhD, of the University of Edinburgh, says: "Being able to fully develop human eggs in the lab could widen the scope of available fertility treatments."
"We are now working on optimizing the conditions that support egg development in this way and studying how healthy they are. We also hope to find out, subject to regulatory approval, whether they can be fertilized," she noted in a statement from her institution.

How Did They Do it? If Replicated, This Could Be a Seminal Advance

Researchers cultured the follicular tissue from the ovarian biopsies in serum-free media for 8 days and then selected 87 intact follicles of 100–150 µg in diameter (mean 120 µg) for further culture. After a further 8 days, 54 of the 87 follicles had reached the next stage of development (antral). They further selected and matured follicles deemed to be developing properly, and ended up with nine mature oocytes.
They note that although this is a small number of samples, it is "proof-of-concept that complete development of human oocytes can occur in vitro."
More work is needed, however, to see if these eggs are morphologically normal and whether they could potentially be fertilized, they recognize.
Commenting on the research in a statement, Daniel Brison, PhD, scientific director of the Department of Reproductive Medicine at the University of Manchester, says: "This is an exciting breakthrough which shows for the first time that complete development of human eggs in the laboratory is possible, more than 20 years after this was achieved in mice.
"As the authors acknowledge, there is much more important research still to do, but this could pave the way for fertility preservation in women and girls with a wider variety of cancers than is possible using existing methods."
Darren Griffin, PhD, professor of genetics at the University of Kent, Canterbury, says, "The main 'selling point' of this paper is that, in the past, the authors have been successful in developing two stages of the process through which ovary material can be taken and an egg ready for fertilization can be produced."
"Here, they have, through meticulous experimentation, worked out how to complete the third and final stage. This is all proof of principle and small numbers at this stage, but the signs are good."
He adds, "It will be a while until this is implemented in the clinic, but if and when it is, this will be seen as one of the seminal advances."

Hope for Cancer Patients and Those Struggling With Infertility

The advance could one day safeguard the fertility of girls with cancer ahead of potentially harmful medical treatment, such as chemotherapy, the authors say.
Immature eggs recovered from patients' ovarian tissue could be matured in the lab and stored for later fertilization. Conventionally, cancer patients can have a piece of ovary removed before treatment, but reimplanting this tissue can risk reintroducing cancer.
As the study has also improved understanding of how human eggs develop at various stages, it could aid research into other infertility treatments and regenerative medicine.
Aileen Feeney, chief executive of the charity Fertility Network UK, commented: "This research is very much in its infancy, but its potential significance for women and girls hoping to protect their future fertility is huge."
The work was funded by the UK Medical Research Council. The authors have reported no relevant financial relationships.
Mol Hum Reprod. Published online January 30, 2018. Full article

NO CARDIOVASCULAR BENEFIT OF OMEGA-3 FATTY ACIDS

Another meta-analysis has suggested that daily supplementation with marine-derived omega-3 fatty acids (FAs) does not significantly reduce the rate of fatal or nonfatal CHD or any major vascular events in high-risk individuals.[1]
After examining data from 10 randomized trials following 77,917 participants with prior CHD or stroke or at high-risk for CVD, British researchers found that at least 12 months of supplementation had no significant effect on rates of any CHD events (rate ratio [RR], 0.96; P =0.12), including nonfatal MI (RR, 0.97; P=0.40) or CHD death (RR, 0.93; =0.05).
Omega-3 FAs also were not significantly associated with rates of major vascular events (RR, 0.97; P =0.10), stroke (RR, 1.03; P =0.56), or revascularizations (RR, 0.99; P =0.61).
"The results of these 10 trials involving 78,000 participants treated for 4 years provide no support for the current AHA guidelines that patients with prior CHD should take omega-3 FA for prevention of CVD," senior author, Dr Robert Clarke (University of Oxford, UK), told theheart.org | Medscape Cardiology in an email.
In an updated scientific statement last year, the AHA said omega-3 FA supplementation is reasonable in patients with prior CHD or HF with reduced ejection fraction but made no recommendation for use in primary prevention because of a lack of randomized data. In contrast, European guidelines say it is debatable whether omega-3 FAs exert a protective effect and that more evidence is needed to justify their use, note the authors.
The study, led by Dr Theingi Aung (University of Oxford) for the Omega-3 Treatment Trialists' Collaboration, was published January 31 in JAMA Cardiology.
Commenting for theheart.org |Medscape Cardiology, Dr Carl 'Chip' Lavie (Ochsner Heart and Vascular Institute, New Orleans, LA) said it is still very reasonable for physicians to recommend omega-3 FAs for CV protection and that he would to do so after MI and in patients with systolic HF or high LDL cholesterol or triglycerides.
"This paper will hardly be a death sentence as omega-3 is very safe and relative inexpensive, and several studies have shown at least modest or even quite profound benefits," he said.
Lavie noted that many of the trials in the meta-analysis were "either too small, too underpowered, too low dose, or too short to show any effects. Even still, almost all of the endpoints leaned toward a trend for benefit and the 7% reduction in CHD death was of borderline significance, with a P value of 0.05."
Given the safety and low cost of omega-3 FAs, Lavie argues the evidence doesn't have to be at nearly the same level of that for expensive and risky medications and devices.
"The fact is that a lot of our patients who oppose many therapies are very happy to use things like omega-3 supplements, and this should not be ignored," he said.
Clarke pointed out that the present meta-analysis is different from previous meta-analyses in that it assessed the effects of omega-3 FAs on prespecified CVD subtypes and CVD in a range of patient populations.
"The results demonstrated no beneficial effects of treatment with omega-3 FA on any CVD, or on any subtype of CVD, or on any CVD in any subgroup of the population," he said.
Nevertheless, the authors write that the 95% CIs in the analysis "cannot exclude a 7% lower risk of major vascular events and a 10% lower risk of CHD associated with omega-3 FA supplements."
The meta-analysis included several high-profile trials, such as ORIGIN, JELIS, GISSI-HF, and GISSI-P—all with at least 500 participants and an average duration of 1 to 6.2 years. All but one trial tested a daily dose of omega-3 FA of 226 to 1800 mg of eicosapentaenoic acid (EPA) and 0 to 1700 mg of docosahexanoic acid (DHA), with one using 1800 mg/d EPA alone.
About 23% of participants had prior CHD, prior diabetes, total cholesterol of 193.1 mg/dL or greater, or triglycerides greater than 150.4 mg/dL, and about 15% reported prior statin use.
Clarke observed that two large ongoing trials—VITAL in the United States and ASCEND in the United Kingdom—will provide additional evidence later this year on the effects of 1 g of omega 3 FA per day in a further 40,000 patients.
"Most experts would await the results of these trials before revising the guidelines. However, in the light of the consistent null findings from the 10 previous trials, there is little expectation that the results of the ongoing trials will differ from the results of the present meta-analysis," he said. "Patients are still advised to eat fish at least two per week, but taking fish oil supplements has no beneficial effects."
VITAL principal investigator, Dr JoAnn Manson (Brigham and Women's Hospital, Harvard Medical School, Boston) said in an email, "When effects of an intervention remain inconsistent and inconclusive despite extensive study, it is often because effects are modest in the populations tested."
In the case of omega-3 FAs, the agents have been tested predominantly in secondary prevention and high-risk populations, often in the setting of concomitant use of other medications, such as aspirin, statins, ACE inhibitors, and β-blockers. Also, many of the trials were of short duration and tested low doses, she said.
A key unanswered question is whether marine omega-3 FAs reduce the risk for MI, stroke, CV mortality, and other CVD events in a primary prevention setting, among those at "usual" risk of CVD.
VITAL, the first such large-scale randomized trial, is being conducted in 25,874 participants who were selected only on age (men aged 50 years or older and women aged 55 years or older), were free of CVD at baseline, and did not have high use of aspirin or statins (less than 50% for each). The mean trial duration is 5 years; results are expected this fall.  
Other trials, such as ASCENDDO-HEALTHSTRENGTH, and REDUCE-IT, will also add importantly to the evidence base, Manson said.
"While awaiting additional data, it remains important to meet guidelines for dietary fish intake (or plant-based sources of omega-3s, if vegetarian), which will not only provide these nutrients but also replace less healthful foods in the diet," she added.
Lavie expressed concern that patients in VITAL may be too healthy, controls may have decent omega-3 levels, and event rates may be low and called for further research with 2 to 4 g/d omega-3 FA in CHD and HF. REDUCE-IT and STRENGTH are assessing 4 g/d in addition to statins in hypertriglyceridemia, but these are with prescription products.
Clarke reports no relevant conflicts of interest. Coauthor disclosures are listed in the paper. Lavie reports having served as a speaker and consultant for DSM, the Global Organization for EPA and DHA Omega-3S (GOED), and Amarin.
Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

UPFRONT IMMUNOTHERAPY FOR RENA CANCER

In a phase 3 study of patients with previously untreated metastatic renal cell cancer (mRCC), use of the anti-PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq, Roche) in combination with bevacizumab (Avastin, Roche) delayed disease progression by about 3 months longer than standard treatment with sunitinib (Sutent, Pfizer), with fewer side effects.
The benefit of atezolizumab plus bevacizumab was greater for patients with programmed cell death ligand 1 (PD-L1)–positive tumors.
Results of the study "support the consideration of atezolizumab plus bevacizumab as a first-line treatment option" in patients with PD-L1–positive mRCC, said lead author, Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City.
He discussed the results at a presscast February 5 ahead of the Genitourinary Cancers Symposium (GUCS) 2018, which will be held later this week in San Francisco, California.
The study, known as IMmotion151, is the first randomized, phase 3 trial of a PD-L1/programmed cell death 1 pathway inhibitor (atezolizumab) combined with an anti–vascular endothelial growth factor agent (bevacizumab) as first-line therapy in patients with previously untreated mRCC.
A total of 915 patients were randomly assigned to receive atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) intravenously every 3 weeks or oral sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off treatment).  Patients were stratified by PD-L1 status (<1 362="" a="" cells="" expression="" immune="" of="" on="" p="" patients="" pd-l1="" positive.="" total="" tumor-infiltrating="" vs="" were="">
At a median follow-up of 15 months, PD-L1–positive patients treated with atezolizumab plus bevacizumab had a 26% lower chance of disease progression than those treated with sunitinib. The median time to progression was 3.5 months longer with the combined treatment than with sunitinib. The overall response rate (ORR) was also better with atezolizumab plus bevacizumab.
Table 1. Results in PD-L1–Positive Patients
OutcomeAtezolizumab + Bevacizumab (n = 178)Sunitinib (n = 184)Hazard Ratio
Median PFS11.2 mo (8.9 - 15.0 mo)7.7 mo (6.8 - 9.7 mo)0.74 (0.57 - 0.96)
ORR (%)43 (35 - 50)35 (28 - 42) 
Values in parentheses are 95% confidence intervals. ORR, objective response rate; PFS, progression-free survival. 
The benefits of atezolizumab plus bevacizumab were also observed, though more modest, in the entire study population (intention-to-treat [ITT] population), Dr Motzer reported. Patients who received atezolizumab and bevacizumab had a 17% lower chance of progression, with a median time of 2.4 months longer until the cancer worsened.
Table 2. Results in ITT Population 
OutcomeAtezolizumab + Bevacizumab (n = 454)Sunitinib (n = 461)Hazard Ratio
Median PFS11.2 mo (9.6 - 13.3 mo)8.4 mo (7.5 - 9.7 mo)0.83 (0.70 - 0.97)
ORR (%)37 (32 - 41)33 (29 - 38) 
Values in parentheses are 95% confidence intervals. ORR, objective response rate; PFS, progression-free survival.
"The results of the overall survival in the group of patients expressing PD-L1 and in the ITT group are immature. They await further follow-up but certainly the trend that we are seeing, or the path that is being taken here, is in favor of atezolizumab plus bevacizumab over sunitinib," said Dr Motzer.
"One of the main benefits of the atezolizumab plus bevacizumab is its safety profile," Dr Motzer said. "It is very well tolerated" and compared with sunitinib, was associated with fewer high-grade treatment-related adverse events (40% vs 54%), low steroid use, and delayed symptom interference with daily life, he noted.
[This study represents an] important breakthrough in kidney cancer therapy. Dr Sumanta Pal
Briefing moderator and American Society of Clinical Oncology expert Sumanta Pal, MD, said this study represents an "important breakthrough in kidney cancer therapy."
"For several years now, we've had debates on which treatment strategy is best for this disease — targeted therapy or immune therapy.  This study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth, and there is also an early trend toward improving survival. Another important piece of this data is the tolerability of combining targeted therapy with immune therapy," said Dr Pal, a medical oncologist at the City of Hope Cancer Center in Los Angeles, California.
Dr Pal also said he agrees with Dr Motzer that the data support consideration of bevacizumab and atezolizumab as a first-line option.
This study was funded by F. Hoffmann-La Roche Ltd. Dr Motzer and several study authors have financial ties to industry, including Pfizer, Bristol-Myers Squibb and Genentech/Roche. Dr Pal has financial ties to multiple pharmaceutical companies.
Genitourinary Cancers Symposium (GUCS) 2018. Abstract 578. To be presented February 8, 2018.