Taxane, Anthracycline Combo Most Effective in Reducing Breast Cancer Recurrence

 Combining anthracycline and taxane for early-stage operable breast cancer was more effective than either anthracycline or taxane chemotherapy alone in reducing breast cancer recurrence and death, according to a meta-analysis.

Moreover, regimens with higher cumulative doses of anthracycline plus taxane were associated with the greatest benefit, according to a report from Jeremy Braybrooke, BM, PhD, of University Hospitals Bristol in England, and colleagues of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG).

"The large number of available trials makes this the first study to reliably show that anthracycline and taxane significantly reduces breast cancer recurrence and mortality compared with taxane regimens without anthracycline," the authors observed in The Lancet

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"The finding that regimens with higher cumulative doses of anthracycline and taxane provide the greatest benefits ... challenges the current trend in clinical practice towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide," they added.

Specifically, the researchers found that among trials of taxane regimens with or without anthracycline involving about 18,000 women, recurrence rates were about 14% lower (RR 0.86, 95% CI 0.79-0.93) with taxane regimens including anthracycline than without anthracycline. This translated into an absolute reduction of 2.6% (95% CI 0.9-4.2) in 10-year recurrence risk, while 10-year breast cancer mortality was reduced by 1.6% (95% CI 0.1-3.1).

Furthermore, they found that the most definitive reductions in recurrence were seen when anthracycline was added concurrently to docetaxel plus cyclophosphamide, versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12.3% vs 21.0%, RR 0.58, 95% CI 0.47-0.73). Meanwhile, there was no significant reduction in recurrence risk with sequential anthracycline plus taxane versus docetaxel plus cyclophosphamide (RR 0.94, 95% CI 0.83-1.06, P=0.30), suggesting that higher cumulative anthracycline and taxane doses in concurrent regimens were more efficacious.

"For women with operable breast cancer at high enough risk of recurrence to be offered chemotherapy, our study shows that using both an anthracycline and a taxane, achieves the best results," Braybrooke said in a release. "This important finding should be considered in clinical practice as there has been a recent shift towards using shorter chemotherapy regimens that include a taxane but not an anthracycline; our research demonstrates that this is less effective than combination treatment."

Braybrooke and his colleagues noted that concerns about the short-term and long-term side effects of anthracyclines has led to increased use of taxane chemotherapy without an anthracycline.

"Long-term dose-dependent risks of acute myeloid leukemia (AML) and heart failure with anthracyclines are well established," they wrote, adding that the benefits of chemotherapy need to outweigh the short- and long-term risk associated with treatment.

Here, they found no significant difference between treatment groups for death without recurrence, including from cardiovascular disease or other primary cancers, as well as no difference in the overall incidence of new, non-breast primary cancers with and without anthracycline. There was an increase in the incidence of AML with anthracycline, with one additional case per 700 women treated. However, the authors wrote, this "is fewer than previous reports suggest."

The findings from this meta-analysis are "clinically important," wrote Song-Jie Shen, MD, of the Peking Union Medical College, and Chang-Mei Liu, PhD, of the University of Chinese Academy of Sciences, both in Beijing, in a commentary accompanying the study

opens in a new tab or window. "For patients at sufficient risk of recurrence, and fit enough to be offered chemotherapy, the combination of taxane and anthracycline can be suggested to achieve the best possible reductions in breast cancer recurrence and mortality."

Yet one chemotherapy regimen doesn't fit all breast cancer subtypes, they cautioned. "In particular, with the escalation of anti-HER2 therapy, prospective studies will be warranted to validate the more-the-better rule in chemotherapy within this setting."

For the present meta-analysis, the authors identified 28 trials comparing taxane-based regimens with and without anthracycline, 15 of which provided data on 18,103 women. In these 15 trials, the mean age of participants was 53 years, and 53% had cancers with lymph node involvement, 67% had estrogen receptor-positive tumors, 14% had HER2-positive tumors. Median follow-up was 5.4 years.

Separately, in an updated EBCTCG meta-analysis, 35 eligible trials assessing anthracycline-based regimens with and without taxanes provided patient-level data on 52,976 women.

These trials demonstrated a 13% average reduction in recurrence in anthracycline regimens with taxane compared with those without (RR 0.87, 95% CI 0.82-0.93), translating to an absolute reduction of 3.3% (95% CI 1.3-5.3) in 10-year risk of recurrence, and an absolute reduction in 10-year breast cancer mortality of 3.6% (95% CI 1.8-5.4).

Trials directly comparing anthracycline and taxane regimens "showed that a higher cumulative dose and more dose-intense schedules were more efficacious," the EBCTCG group reported.

Disclosures

The EBCTCG is supported by a Cancer Research UK grant paid to the University of Oxford.

Braybrooke had no disclosures. Multiple EBCTCG contributors reported relationships with industry.

The editorialists had no disclosures.

Primary Source

The Lancet

Source Reference: opens in a new tab or windowEarly Breast Cancer Trialists' Collaborative Group "Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials" Lancet 2023; DOI: 10.1016/S0140-6736(23)00285-4.

Secondary Source

The Lancet

Source Reference: opens in a new tab or windowShen S, Liu C "Chemotherapy for early-stage breast cancer: the more the better?" Lancet 2023; DOI: 10.1016/S0140-6736(23)00094-6.

https://www.medpagetoday.com/hematologyoncology/breastcancer/104040

Long COVID-Fatigue Impacts 50M - Axcella Health Seeks Funding To Support Drug Development

 

• Axcella Health Inc 
  AXLA+0.77%+ Free Alerts
   is reportedly looking for funding to support its advanced trial of a drug initially found to improve fatigue in long Covid patients.
• An early-stage trial of the drug, dubbed AXA1125, with the University of Oxford, found that participants given the treatment significantly improved fatigue compared with those in the placebo arm, according to the results published Friday in the Lancet eClinical Medicine journal. 
• "There is still some way to go in treating all patients with long Covid – our results focus specifically on fatigue, rather than the breathlessness and cardiovascular issues that other long Covid patients have reported," Bloomberg reported citing a statement from Betty Raman, the trial's principal investigator.
• Axcella's Phase 2a trial results demonstrated statistically and clinically relevant improvement in fatigue in patients with Long COVID.
• The study, which did not meet an experimental biomarker primary endpoint, found that subjects who received AXA1125 experienced clinically and statistically significant improvement in mental (p=0.0097) and physical (p=0.0097) fatigue scores compared to placebo subjects. 
• Axcella discontinued its Phase 2b trial of AXA1125 in NASH.
• Axcella reported data from Phase 2b EMMPACT study of AXA1125 for nonalcoholic steatohepatitis (NASH). AXA1125 showed a statistically significant improvement in liver stiffness at a higher dose but did not reach statistical significance at a lower dose.
• Half of the 41 patients in the trial received the drug twice daily for four weeks. Participants generally suffered fatigue following Covid for 18 months before the study.
• Axcella has the U.S. and the U.K. regulatory authorization to proceed with advanced trials, and the company plans to enroll about 300 people once funding is secured.

https://www.benzinga.com/general/biotech/23/04/31805796/long-covid-fatigue-impacts-50m-people-axcella-health-seeks-funding-to-support-drug-development

FDA Advisors Endorse Rexulti for Agitation in Alzheimer's Dementia

 FDA advisors voted in favor of brexpiprazole (Rexulti) for treating agitation associated with Alzheimer's dementia (AAD), despite increased mortality risk.

By a vote of 9-1 on Friday, members of the agency's Psychopharmacologic Drugs Advisory Committee (PDAC) and the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) said the data presented by the drug's sponsors, Lundbeck and Otsuka Pharmaceutical, were sufficient to identify a population in whom the benefits of treating AAD with brexpiprazole outweighed its risks.

"I was very impressed with the sponsor's data and I also thought the agency and sponsor worked really well together to address a very, very difficult area with such a great need," said PDAC chairperson Rajesh Narendran, MD, of UPMC Western Psychiatric Hospital and the University of Pittsburgh School of Medicine. "Given that there are no good options, I feel like this data could be very helpful in informing providers and families and patients you know about the risks."

"The studies were well done. The analysis was quite convincing," said PDAC committee member Satish Iyengar, PhD, of the University of Pittsburgh. "Generally speaking, I'm always a little bit leery of secondary analyses looking at severity, but in this particular case, I think what people know already from their experience matches the data."

Kim Witczak, PDAC consumer representative and co-founder of Woodymatters, a drug safety advocacy group based in Minneapolis, provided the lone no vote.

"I don't think that the data demonstrated outweighs the dangers of an antipsychotic," Witczak said. "I do agree that it is an unmet need, and I hope I'm proven wrong in time. But with this limited amount [of data], I'm not willing to vote yes for this product."

Advisors highlighted a lack of options of evidence-based treatment for AAD and current reliance on off-label antipsychotics for these patients. They agreed brexpiprazole would not be appropriate for people with mild symptoms and emphasized the treatment also would not be appropriate for patients with severe symptoms of agitation. However, they stopped short of recommending a specific patient population because of the lack of available data.

Brexpiprazole currently is approved for treating major depressive disorder (MDD) and schizophrenia. In 2005, the FDA issued a boxed warning for all atypical antipsychotics after a systematic meta-analysis showed elderly patients with dementia who received antipsychotic treatment experienced a 70% increased risk of death.

During Friday's advisory committee meeting, the drug's sponsors presented data on the safety and efficacy profile of brexpiprazole based on phase III studies, a post-treatment observational study, and an open-label extension safety study.

Brexpiprazole's efficacy was supported by data from three phase III studies, two of which showed that over a 12-week treatment period, the drug had a statistically significant treatment effect in reducing agitation, based on the Cohen Mansfield Agitation Inventory (CMAI).

However, the third study found that flexible-dose brexpiprazole did not achieve statistical significant effect in the mean change from baseline CMAI agitation score at 12 weeks. Post-hoc exploratory analyses found numerical improvement in participants' response and tolerability with brexpiprazole compared with placebo in a subgroup of individuals who received a titrated dose from 0.25 mg to 2 mg/day over 4 weeks.

Brexpiprazole's safety profile was similar to the treatment's use in adults with schizophrenia and MDD.

Concerns about increased mortality were based on nine deaths that occurred during the phase III studies. Of those deaths, eight occurred among participants who received brexpiprazole (1.2%; n=655) and one occurred in a patient who received placebo (0.26%; n=388). The overall incident rate ratio was 4.16 (95% CI 0.51-33.83).

The FDA advisory committees expressed concern over the increased mortality risk, and questioned the lack of a proven target treatment group beyond a broad group of patients between the ages of 55-90 who have Alzheimer's dementia and may experience agitation.

"Right now, there is no standard of care," noted PCNS panelist David Weisman, MD, of the Abington Neurologic Associates Clinical Research Center in Pennsylvania. "So there's this witch's brew of every medication, every intervention that you could imagine being used ... It's a mess."

"This is an unmet need," he added. "Whom would this benefit? It would benefit agitated people because the alternatives are so bad."

The FDA is not required to follow the recommendations of its advisory committees, but it often does. If approved, brexpiprazole would be the first drug indicated for AAD.

https://www.medpagetoday.com/psychiatry/dementia/104041

Starboard buys Parler, to shut down social media app temporarily

 Digital media conglomerate Starboard said on Friday it has bought Parler for an undisclosed sum and will temporarily shut down the social media app popular with U.S. conservatives to give itself time to roll out a revamped version of the platform.

The move comes months after the collapse of a deal that would have seen American rapper Kanye West, who now goes by Ye, buy the platform's parent company Parlement Technologies.

Starboard, formerly Olympic Media, founded in 2018 houses conservative-leaning platforms American Wire and BizPac Review. It plans to service "unsupported online communities" and build a home for them "away from the ad-hoc regulatory hand of platforms that hate them."

The Arlington, Virginia-based conglomerate did not immediately respond to a Reuters request for details on terms of the deal. However, it said the acquisition will be accretive by the end of second quarter 2023.

In September, Parler announced that it has restructured into Parlement Technologies Inc and bought Irvine, California-based private cloud services company Dynascale Inc.

Parler, which was founded five years ago, was reinstated on Google and Apple Inc's app stores after being removed following the U.S. Capitol riots in January 2021.

Parler is one of several social media platforms, from among Gettr, Gab and Truth Social, that have positioned themselves as free-speech alternatives to Twitter Inc prior to its $44 billion acquisition by billionaire and Tesla CEO Elon Musk.

"No reasonable person believes that a Twitter clone just for conservatives is a viable business any more," Starboard added.

https://www.marketscreener.com/quote/stock/ALPHABET-INC-24203373/news/Conglomerate-Starboard-buys-Parler-to-shut-down-social-media-app-temporarily-43494971/

Carlson Exposes How Establishment Media Is Desperate To Help Cover Up Info From Intel Leaks

 by Steve Watson via Summit News,

Fox News host Tucker Carlson noted Thursday that instead of asking questions about the substance of the information contained in the leaked intelligence material from the Pentagon, the corporate media simply wanted to know how they can help cover it up.

The documents, allegedly leaked by a 21-year-old National Guardsman, reveal information showing that the U.S. is deeply involved in the Ukrain/Russia war.

“If you want to get really sick to your stomach, go pull a transcript from the Pentagon briefing today where news reporters asked flacks from the Pentagon, what are we gonna do to keep information like this secret in the future?” Carlson urged.

The host added that the press failed to ask “one question about the substance of the information,” adding “We are fighting a war against Russia directly, really? Don’t they have the biggest arsenal in the world? Not one question,” instead the reporters asked “How can we help you keep it secret?”

“Those are the questions and not only are the media covering up the substance of the story, which is not who leaked it, but what he leaked, they are covering up the crimes committed to get you this information,” Carlson continued.

“The administration apparently used illegal surveillance techniques to identify this kid apparently with the help of The Washington Post and The New York Times,” Carlson emphasised, further charging that the media is working in lockstep with the intelligence community.

“If it’s illegal to see these documents if you don’t have a security clearance, how is the Washington Post doing this legally?” Carlson asked, further noting “They don’t have a security clearance. Well, obviously, they were given them by the U.S. Intel agencies and are working alongside them.”

Carlson asserted “this is information that is relevant to the public in a so-called democracy. You cannot lie about things that jeopardize our collective future and get away with it and you certainly shouldn’t be doing that with the assistance of the news media.”

“The news media whose job it is to inform you of what your government is doing, but instead they are working actively late into the night to lie to you on behalf of their masters in permanent Washington. By the way, just last week, the plan was to lie in an even more grotesque way and blame Russia for this,” the host also noted.

Watch:

Journalist Glenn Greenwald, who was the go between in the Edward Snowden revelations a decade ago, also noted that the media helped hunt down the whistleblower:

 

https://www.zerohedge.com/political/watch-carlson-exposes-how-establishment-media-desperate-help-cover-info-intel-leaks