Σάββατο, 9 Ιανουαρίου 2021

CAN STATINS PREVENT ANTHRACYCLINE CARDIOTOXICITY?

 Evidence supporting the use of statins to protect against cardiotoxic chemotherapy has been strengthened with new data from a propensity-matched analysis.

Among women with breast cancer treated with anthracycline chemotherapy, statins were associated with a 55% lower risk of hospitalizations or emergency room visits for heart failure (HF) at 5 years (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24 - 0.85).

The risk was 54% lower with statins among women whose cancer was treated with the monoclonal antibody trastuzumab (Herceptin, Genentech), although this did not achieve statistical significance (HR, 0.46; 95% CI, 0.20 - 1.07).

"I tend to be a skeptic in terms of how I design my research and my hypotheses, so I thought that if there was a protective effect it may be in the range of 20%, 30%, so I was surprised at how large the magnitude of protection was," Husam Abdel-Qadir, MD, PhD, Women's College Hospital, Toronto, Ontario, told theheart.org | Medscape Cardiology.

Dr Husam Abdel-Qadir

Exactly how cholesterol-lowering statins might reduce risk remains unknown, but they may ameliorate anthracycline- and trastuzumab-induced heart damage by decreasing production of reactive oxygen species and promoting cardiac muscle cell survival, the authors suggest in the study, published online January 6 in the Journal of the American Heart Association.

Abdel-Qadir noted that smaller, single-center observational studies have shown that women who undergo breast cancer chemotherapy and are taking a statin have less weakening of the heart muscle and a lower risk for incident HF

The present study extends these observations to a population-based sample that encompasses more patients than all previous studies combined and focuses on older women at high cardiovascular risk, he said.

The women had no prior HF and were at least 66 years old when newly diagnosed with early breast cancer in Ontario between 2007 and 2017. A total of 2545 were treated with anthracyclines and 1371 with trastuzumab, of whom 859 and 520, respectively, received at least two prescriptions for a statin in the year before starting chemotherapy.

More than 80% of cancers treated with anthracycline and more than 65% treated with trastuzumab were stage II or stage III. Similar to US practice, the most commonly used statins were rosuvastatin (46%) and atorvastatin (41%).

Women who received statins had more preexisting cardiovascular disease and associated risk factors, were older, and were more likely to live in lower-income neighborhoods.
After propensity score-matching, the median age was 69 in the anthracycline-treated cohort (666 pairs) and 71 in the trastuzumab-treated cohort (390 pairs).

At 5 years, the cumulative incidence of HF hospital presentations was 1.2% in statin-treated women and 2.9% in unexposed women in the anthracycline group, and 2.7% vs 3.7%, respectively, in the trastuzumab group."For women who already have an existing indication for a statin, this makes us feel even more strongly that these women should be treated with a statin before they start their cancer treatment," Abdel-Qadir said. "For women who are not on a statin and do not have another indication, I believe that the burden of proof to be able to add an extra medication to someone who is already going to be going through a lot needs to be high."

He noted that statins tend to be relatively well tolerated compared with other potential approaches to prevent cardiotoxicity such as angiotensin antagonists and beta-blockers, but there is the potential for muscle-related side effects and drug interactions.

The investigators also could not account for left ventricular ejection fraction, diastolic function, cardiac biomarkers, or biohumoral data and, thus, were unable to determine if the HF events occurred with preserved or reduced ejection fraction. Other limitations include a large proportion of missing low-density lipoprotein values and an inability to account for crossover attributable to starting or stopping statins after chemotherapy began.

Subgroup analyses were not performed based on breast cancer stage or statin lipophilicity. A recent observational study in 7.8 million adults without cancer reported that hydrophilic statins were associated with a slightly lower risk for incident HF compared with lipophilic statins.

Commenting on the study, Tochi M. Okwuosa, DO, vice chair of the American Heart Association Council on Clinical Cardiology, CLCD & GMP Cardio-Oncology Subcommittee, said, "the main thing this study brings to the forefront is that if people have their heart health taken care of prior to treatment — and it doesn't have to be anthracycline chemotherapy but any cardiotoxic problem — they tend to do better. And a good example of that is something like COVID."

She noted that oncologists may be hesitant to add another drug to tightly controlled chemotherapy regimens for fear of drug interactions, but that patients can experience a heart attack while going through treatment. In addition, a recent study reported that mice and patients with early-stage breast cancer who experienced a myocardial infarction had a higher risk for cancer recurrence and cancer-specific death.

"We know that statins reduce the risk of heart attack and stroke, so if you put all these things together, you start to see how statins can somehow modulate the risk of issues associated with breast cancer overall," said Okwuosa, who was not associated with the study and directs the Cardio-Oncology Program at Rush University Medical Center, Chicago, Illinois. "We just need good randomized studies to show this and we don't have that yet."

Abdel-Qadir pointed out that their team is currently conducting the phase II randomized Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline (SPARE-AF) study comparing 40-mg daily atorvastatin vs placebo in 112 patients. Another colleague is also using a mouse model to determine the mechanisms through which statins protect against cardiotoxicity.

The study funded by the Ted Rogers Centre for Heart Research and the Canadian Cardiovascular Society. Abdel-Qadir is supported by a national new investigator award from the Heart and Stroke Foundation of Canada; he has declared no relevant financial relationships.

J Am Heart Assoc. Published online January 6, 2021. Full text.

TOCLIZUMAB FOR SEVERE COVID

 Treating critically ill COVID-19 patients with Roche's Actemra or Sanofi's Kevzara arthritis drugs significantly improves survival rates and reduces the amount of time patients need intensive care, study results showed on Thursday.

The findings, which have not yet been peer-reviewed, showed that the immunosuppressive drugs - Actemra, also known as tocilizumab, and Kevzara, also known as sarilumab - reduced death rates by 8.5 percentage points among patients hospitalised and severely ill with the pandemic disease.

That would mean that for every 12 patients treated with one of the two drugs, an extra life would be saved, said Anthony Gordon, an Imperial College London professor of anaesthesia and critical care who co-led the study.

The data will boost confidence that some existing drugs could be repurposed to help with the pandemic that has killed more than 1.87 million people and crushed global economies.

It also comes as countries struggle to contain two variants of the virus found in South Africa and Britain that are more transmissible and have driven a surge in infections.

Drug companies have been scouring their existing portfolios for possible therapies. So far the generic steroid dexamethasone and Gilead's antiviral drug remdesivir have been approved for treating patients with severe symptoms.

The United States has also authorised emergency use of some antibody drugs for non-hospitalised COVID-19 patients.

The data, from around 800 severely ill COVID-19 patients involved in an international study known as the REMAP-CAP trial showed that the two drugs reduced mortality rates from 35.8% in a control group to 27.3% among patients receiving either tocilizumab or sarilumab.

"That's a big change in survival," said Gordon. "They are both lifesaving drugs."

The results also showed that on average, patients treated with Actemra or Kevzara recovered more swiftly and were able to be discharged from intensive care units around seven to 10 days earlier than those who did not get these drugs, Gordon said.

"This ... could have immediate implications for the sickest patients with COVID-19," he added. "We're seeing the actual benefit in terms of survival and quicker recovery."

Until now, results for Actemra and Kevzara - both a type of drug known as IL-6 receptor antagonists - in treatment trials in patients with COVID-19 have been mixed.

Sanofi said in September that Kevzara - which it produces with partner Regeneron - failed to meet the main goals of a U.S. study testing it in critically ill COVID-19 patients.

In November, Roche said research showed Actemra helped the sickest COVID-19 patients, but it was unclear if it kept people alive or shortened how long they needed intensive care support such as mechanical ventilation, or both.

Gordon noted on Thursday that previous studies had found no clear benefit, but said those trials had included less severely ill patients and started treatment at different stages in the disease course.

"A crucial difference may be that in our study, critically ill patients were enrolled within 24 hours of starting organ support," he said. "This highlights a potential early window for treatment where the sickest patients may gain the most benefit from immune modulation treatment."

Τετάρτη, 6 Ιανουαρίου 2021

COVID NEWS-FACE MASKS VACCINE DOSING

 

FDA Statement on Following the Authorized Dosing Schedules for COVID-19 Vaccines


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On January 4, U.S. Food and Drug Administration (FDA) Commissioner Stephen M. Hahn, MD, and Director of the FDA’s Center for Biologics Evaluation and Research Peter Marks, MD, PhD, issued the following statement on FDA-authorized dosing schedules for each COVID-19 vaccine.

Photo credit: Getty

Two different mRNA vaccines have now shown remarkable effectiveness of about 95% in preventing COVID-19 infection in adults. As the first round of vaccine recipients become eligible to receive their second dose, we want to remind the public about the importance of receiving COVID-19 vaccines according to how they’ve been authorized by the FDA in order to safely receive the level of protection observed in the large, randomized trials supporting their effectiveness.

We have been following the discussions and news reports about reducing the number of doses, extending the length of time between doses, changing the dose (half-dose), or mixing and matching vaccines in order to immunize more people against COVID-19. These are all reasonable questions to consider and evaluate in clinical trials. However, at this time, suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence. Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk, undermining the historic vaccination efforts to protect the population from COVID-19.

The available data continue to support the use of two specified doses of each authorized vaccine at specified intervals. For the Pfizer-BioNTech COVID-19 vaccine, the interval is 21 days between the first and second dose. For the Moderna COVID-19 vaccine, the interval is 28 days between the first and second dose.

What we have seen is that the data in the firms’ submissions regarding the first dose is commonly being misinterpreted. In the phase III trials, 98% of participants in the Pfizer-BioNTech trial and 92% of participants in the Moderna trial received two doses of the vaccine at either a 3- or 4-week interval, respectively. Those participants who did not receive two vaccine doses at either a 3-or 4-week interval were generally only followed for a short period of time, such that we cannot conclude anything definitive about the depth or duration of protection after a single dose of vaccine from the single-dose percentages reported by the companies.

Using a single-dose regimen and/or administering less than the dose studied in the clinical trials without understanding the nature of the depth and duration of protection that it provides is concerning, as there is some indication that the depth of the immune response is associated with the duration of protection provided. If people do not truly know how protective a vaccine is, there is the potential for harm because they may assume that they are fully protected when they are not, and accordingly, alter their behavior to take unnecessary risks.

We know that some of these discussions about changing the dosing schedule or dose are based on a belief that changing the dose or dosing schedule can help get more vaccine to the public faster. However, making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.

We have committed time and time again to make decisions based on data and science. Until vaccine manufacturers have data and science supporting a change, we continue to strongly recommend that health-care providers follow the FDA-authorized dosing schedule for each COVID-19 vaccine. The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


(Reuters Health) - Two new literature reviews suggest face masks provide some protection to the wearer and when universally worn by the general public they substantially reduce the spread of the new coronavirus. The reviews, published in Annals of Internal Medicine, look specifically at the effect of masking on COVID-19 transmission. One report analyzed the impact of masking by the general public on the spread of the virus. Researchers reviewed over 100 research articles and concluded that masking could substantially reduce the spread of viruses, including SARS-CoV-2, without risks to the wearer. "Our review clearly shows that masks and face coverings worn by members of the public are highly effective in reducing the spread of SARS-CoV-2," said study leader Dr. Thomas Czypionka, head of the Health Economics and Health Policy Unit at the Institute for Advanced Studies in Vienna, Austria and visiting senior research fellow at the London School of Economics and Political Science. "A growing body of evidence suggests that the virus is transmitted through drops in close contact situations and through aerosols, small particles hovering in the air for extended periods of time that accumulate especially in closed and crowded spaces," Dr. Czypionka said in an email. "Such situations should be avoided of course, but if you can't - for example, on public transport, in shops etc. - masks and face coverings can substantially reduce the risk of infection, mainly by source control, that is, by trapping the particles exhaled. There is also laboratory evidence that they may protect the wearer as well. Therefore, masks can literally save lives, and in a situation like this, with community spread, they should be widely used." There are many misconceptions about masks, Dr. Czypionka said. "One is that they lead to physiological changes like elevated carbon dioxide levels or decreased oxygen levels in the blood," he added. "Masks and face coverings may cause discomfort for some people, but we found no empirical evidence for masks to cause harm." The second report -- an update to a "living review" of data on mask use by the general public and by health care workers -- focused mainly on three studies: one study of masking and the prevention of SARS-CoV-2 in a community setting (the DANMASK trial) and two studies of mask use in healthcare settings. The DANMASK open label trial, which included 6,024 community dwelling adults in Denmark, found that the incidence of SARSCoV-2 infection among participants was 2%. Surgical mask use as compared to no mask use was associated with a small reduction in risk for infection, but the finding was not statistically significant, the researchers noted. "The study suggests that masks may have small benefits in reducing the risk of infection in the wearer," said the report's lead author, Dr. Roger Chou, a professor in the School of Medicine at the Oregon Health and Sciences University. Unfortunately, Denmark is a place where it would be harder to show benefits because the infection rate there is low and people have been good about following guidelines, such as social distancing and handwashing, Dr. Chou said. "One important reason to wear masks is to prevent those who don't realize they are infected or have mild symptoms from infecting others," Dr. Chou said. "But this study wasn't designed to evaluate that." Of the two other studies, one, which included 16,397 health care workers and first responders, found that use of an N95 or surgical mask all of the time versus not all of the time was associated with a decreased risk for infection. The second study, which included 20,614 asymptomatic health care workers, found that the risk for infection was reduced with any mask use versus no mask use. The update of the living rapid review is important, said Juan Jesus Carrero, a professor of epidemiology in the department of medical epidemiology and statistics at the Karolinska Institute in Stockholm. "In interpreting the results of the DANMASK study, it is essential to remember that it was not a study of source control, and therefore doesn't tell us about the ability of community mask wearing to reduce overall transmission in the pandemic," Carrero said in an email. The new information included in Dr. Chou's study was welcomed by Dr. Catherine Clase, an associate professor in the department of medicine at McMaster University and a member of the Centre of Excellence in Protective Equipment and Materials. "The two additional observational studies on mask wearing are consistent with the expected degree of protection based on the authors' previous work and the meta-analysis on the effects of masks in the transmission of non-COVID coronaviruses," Dr. Clase said in an email. Face Masks Protect Wearers, Others From COVID: Studies 1/6/2021 https://www.medscape.com/viewarticle/943412_print https://www.medscape.com/viewarticle/943412_print 2/2 The Czypionka article highlighted the importance of masking to prevent the spread of COVID-19, Dr. Clase said. "I agree with their assessment that masks can play an important role in reducing the spread of particles of all sizes," she added. Calling the Czypionka article "outstanding," Carrero applauded the authors for pulling together "a network of evidence on the diverse questions which have surrounded mask use since the beginning of the pandemic. As they summarize, universal community masking has been associated with fewer new cases and lower mortality in every study to examine this question." SOURCE: https://bit.ly/2L8l6h3 and https://bit.ly/3n3olDD Annals of Internal Medicine, online December 29, 2020. Reuters Health Information © 2020 Cite this: Face Masks Protect Wearers, Others From COVID: Studies - Medscape - Dec 30, 2020


3 vs, 6 MONTHS OF ADJUVANT CHEMOTHERAPY FOR COLORECTAL CANCER

 Thierry André, MD, and colleagues reported the prospective pooled analysis of six phase III trials in the IDEA collaboration in The Lancet OncologyThe analysis showed that noninferiority in overall survival for 3 vs 6 months of adjuvant chemotherapy was not established in patients with stage III colon cancer, and the absolute difference in 5-year overall survival between approaches was 0.4%.

As noted by the investigators, the previous IDEA analysis did not show noninferiority for the primary endpoint of 3-year disease-free survival for 3 months vs 6 months of adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). However, 6 months of treatment did not provide additional benefit in patients receiving CAPOX, with noninferiority being shown, whereas 6 months of FOLFOX was associated with a moderate but significant improvement vs 3 months.

Thierry André, MD

Thierry André, MD

Study Details

The analysis included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients were recruited between June 2007 and December 2015 in 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials who started any treatment (modified intention-to-treat population).

Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant FOLFOX every 2 weeks or CAPOX every 3 weeks, as chosen by the treating physician. FOLFOX regimens consisted of infusional leucovorin at 200 mg/m² for FOLFOX4 (400 mg/m² for FOLFOX6), bolus fluorouracil at 400 mg/m² (400 mg/m²), infusional fluorouracil at 600 mg/m² (2,400 mg/m²), and infusional oxaliplatin at 85 mg/m² (85 mg/m²). The CAPOX regimen consisted of infusional oxaliplatin at 130 mg/m² and oral capecitabine at 1,000 mg/m² twice daily.

The primary endpoint was disease-free survival, with overall survival being the prespecified secondary endpoint. The noninferiority margin for overall survival was set as a hazard ratio (HR) of 1.11. Preplanned subgroup analyses included analysis by regimen and by risk group. Noninferiority was demonstrated if the one-sided false discovery rate adjusted (FDRadj) P value was < .025. The cutoff date for the final overall survival analysis was in January 2020.

Overall Survival

The analysis included 12,835 patients in the modified intention-to-treat population, with 5,064 (39.5%) receiving CAPOX, 7,771 (60.5%) receiving FOLFOX, and 6,425 receiving 3-month and 6,410 receiving 6-month regimens. Overall median follow-up was 72.3 months (interquartile range = 72.2–72.5 months). A total of 2,584 patients died (20.1%).

Among all patients, 5-year overall survival was 82.4% (95% confidence interval [CI] = 81.4%–83.3%) with 3 months of therapy vs 82.8% (95% CI = 81.8%–83.8%) with 6 months of therapy (HR = 1.02, 95% CI = 0.95–1.11; noninferiority FDRadj = .058; superiority for 6 months FDRadj P = .64). The absolute difference in 5-year overall survival was −0.4%.

Among patients receiving CAPOX, 5-year overall survival was 82.1% (95% CI = 80.5%–83.6%) in the 3-month group vs 81.2% (95% CI = 79.2%–82.9%) in the 6-month group (HR = 0.96, 95% CI = 0.85–1.08; noninferiority FDRadj = .033; superiority for 6 months FDRadj P = .62). The absolute difference in 5-year overall survival was +0.9%.

Among patients receiving FOLFOX, 5-year overall survival was 82.6% (95% CI = 81.3%–83.8%) in the 3-month group vs 83.8% (95% CI = 82.6%–85.0%) in the 6-month group (HR = 1.07, 95% CI = 0.97–1.18; noninferiority FDRadj =.34; superiority for 6 months FDRadj P = .38). The absolute difference in 5-year overall survival was −1.2%.

Among 7,507 patients with low-risk disease (T1, T2, or T3 and N1), 5-year overall survival was 89.6% vs 88.9% (HR = 0.95, 95% CI = 0.84–1.08; noninferiority FDRadj P =.033; superiority of 6 months FDRadj P = .58). Among 5,273 patients with high-risk disease (T4, N2, or both), 5-year overall survival was 72.0% vs 74.1% (HR = 1.08, 95% CI = 0.98–1.19; noninferiority FDRadj P = .39; superiority of 6 months FDRadj P = .29). In total, 5-year overall survival was 89.3% in the low-risk group and 73.1% in the high-risk group.

KEY POINTS

  • Noninferiority of overall survival was not established for 3 months vs 6 months of adjuvant chemotherapy, but 5-year overall survival differed by only −0.4%.
  • Among patients receiving CAPOX, 5-year overall survival differed by +0.9%.

Updated Disease-Free Survival

The hazard ratio for 5-year disease free survival for the 3-month vs 6-month groups among all patients was 1.08 (95% CI = 1.02–1.15; noninferiority FDRadj P= .25; superiority for 6 months FDRadj = .044). Among patients receiving CAPOX, the hazard ratio was 0.98 (95% CI = 0.88–1.08; noninferiority FDRadj = .027; superiority FDRadj P = .67). Among those receiving FOLFOX, the hazard ratio was 1.16 (95% CI = 1.07–1.26; noninferiority FDRadj P = .80; superiority for 6 months FDRadj = .0061). The P value for interaction between regimen and duration was .011. For low-risk vs high-risk patients, 5-year disease-free survival was 78.5% vs 57.7%.

Data on adverse events were not recorded beyond the initial primary analysis. As noted by the investigators, analysis at that time showed that grade ≥ 2 neurotoxicity during active therapy and in the first month after stopping study treatment occurred in 16.0% of patients in the 3-month group vs 44.5% of those in the 6-month group.

The investigators concluded, “Noninferiority of 3 months vs 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0.4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.”

Qian Shi, PhD, of the Department of Health Science Research, Mayo Clinic, Rochester, is the corresponding author for The Lancet Oncology article.  

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

SURGERY FOR METASTATIC BREAST CANCER?

 Surgery, in addition to treatments like chemotherapy and radiation therapy, may improve survival for certain patients with metastatic breast cancer. A research team studied nearly 13,000 patients with stage IV disease and found that those who had surgery in addition to other treatments had a survival advantage over those who had other treatments alone. These findings were published by Stahl et al in Annals of Surgical Oncology.

Stage IV breast cancer accounts for 6% of newly diagnosed breast cancer cases. Systemic therapy, which may include treatments like chemotherapy, hormone therapies, and immunotherapies, is routinely part of treatment plans for those patients. The benefits of surgery to remove the primary breast cancer are currently only recommended for relieving symptoms of advanced breast cancer such as pain and bleeding.

Surgery is the standard of care for some other types of metastatic cancers. Lead study author Kelly Stahl, MD, a surgical resident at Penn State Milton S. Hershey Medical Center, said that previous studies evaluating surgical interventions for metastatic breast cancer produced conflicting results, which has led to a lack of consensus among clinicians and researchers.

“Results from previous trials evaluating surgical benefit in [patients with] metastatic breast cancer have been questioned because of the small number of participants or the fact that patients weren't also receiving chemotherapy or other systemic therapies,” said Dr. Stahl in a press release. “We felt another key factor missing from those studies was whether the biologic subtype of breast cancer affected the survival rates in relation to surgical intervention.”

Study Methods

Researchers worked to identify 12,838 patients with stage IV breast cancer added to the National Cancer Database from 2010 to 2015 and whether these patients’ cancer cells had the growth-promoting protein HER2 and hormone receptors for estrogen and progesterone, which can fuel cancer growth. The researchers said knowing these characteristics of a cancer's biologic subtype can help determine which treatment plans may be effective.

Dr. Stahl studied patients who either had systemic therapy alone; had systemic therapy and surgery; or had systemic therapy, surgery, and radiation. She and her coauthors then evaluated whether certain biologic subtypes of breast cancer and timing of chemotherapy were associated with survival advantages.

“We evaluated whether the hormone status had an influence on surgical benefit in these treatment-responsive [patients with] breast cancer,” said study coauthor Daleela Dodge, MD, Associate Professor of Surgery and Humanities at Penn State Cancer Institute. “Some types of breast cancer, especially like triple-negative, where the cancer is hormone receptor– and HER2-negative, are not very responsive to treatment…. [O]ur goal was to see if surgery made a difference in metastatic breast cancers that were responsive to treatment.”

The researchers excluded patients who died within 6 months of their diagnoses in order to ensure that treatment-responsive cancers were being studied.

Effect of a Surgical Intervention

KEY POINTS

  • Patients with a surgical intervention tended to have a longer survival compared to patients with other treatment plans.
  • Patients whose cancers were HER2-positive especially saw prolonged survival when their treatment plan included surgery.
  • Regardless of hormone receptor or HER2 status, patients who received systemic therapy before surgery tended to live longer than those who had surgery before systemic treatment.

The research team found that patients with a surgical intervention tended to have a longer length of survival compared to patients with other treatment plans. Patients whose cancers were HER2-positive especially saw prolonged survival when their treatment plan included surgery.

Dr. Stahl and her coauthors further analyzed the patients who had undergone surgery to see whether receiving chemotherapy before or after surgery had an impact on survival. They found that regardless of hormone receptor or HER2 status, patients who received systemic therapy—including chemotherapy and targeted treatments—before surgery tended to live longer than those who had surgery before systemic treatment.

“Not only did we find that surgery may be beneficial for [patients with] treatment-responsive metastatic breast cancer, we also uncovered that getting chemotherapy before that surgery had the greatest survival advantage in patients with positive HER2 and estrogen and progesterone receptor status,” said study coauthor Chan Shen, PhD, Associate Professor of Surgery at Penn State Cancer Institute.

The researchers said that randomized, controlled trials evaluating the role of surgery after systemic therapy in a younger demographic with minimally metastatic cancers could be used to confirm their results, but added that patient resistance to random assignment in trials like this have resulted in poor study recruitment. Therefore, they encourage clinicians to evaluate real-world evidence, including their study, to choose the optimal treatment for their patients with metastatic breast cancer.

“[Patients with stage IV breast cancer] who are responsive to systemic therapy may be able to benefit from the addition of surgery regardless of their biologic subtype,” concluded Dr. Stahl.

Disclosure: For full disclosures of the study authors, visit link.springer.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

Δευτέρα, 4 Ιανουαρίου 2021

RESIDUAL BREAST CANCER BURDEN INDEX

 Residual cancer burden after neoadjuvant chemotherapy can accurately predict disease recurrence and survival across all breast cancer subtypes, according to the findings from a meta-analysis presented at the 2019 San Antonio Breast Cancer Symposium by W. Fraser Symmans, MD, Professor and Director of Research Operations in Pathology at The University of Texas MD Anderson Cancer Center, Houston.1


This is really about organizing the workflow in pathology to standardize how we evaluate response after neoadjuvant treatment.
— W. Fraser Symmans, MD

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This is not the first study to show residual cancer burden to be an independent factor for prognosis after neoadjuvant chemotherapy. This study, however, goes a step further in estimating the long-term prognosis for each class of residual cancer burden across breast cancer subtypes.

“The most important conclusion is that there is a strong potential to calibrate an individual’s [residual cancer burden] index score to her residual prognostic risk,” Dr. Symmans said. “There is a generally linear relationship between [residual cancer burden] index value and the log of risk.”

Calculating Residual Cancer Burden

“This is really about organizing the workflow in pathology to standardize how we evaluate response after neoadjuvant treatment,” Dr. Symmans said. He explained that pathologists calculate residual cancer burden from multiple factors: primary tumor area, percentage of the tumor area that is invasive cancer, and extent of lymph node involvement. Investigators at The University of Texas MD Anderson Cancer Center put these factors together to develop a residual cancer burden calculator, which computes an index and allocates a classification of pathologic complete response (www.mdanderson.org/breastcancer_RCB). A value of 0 equates to a pathologic complete response. This is then categorized into one of the following three classes: RCB-I (minimal burden), RCB-II (moderate burden), and RCB-III (extensive burden).

KEY POINTS

  • The residual cancer burden index categorizes patients with breast cancer into four groups (RCB 0–IV) based on level of residual disease after neoadjuvant therapy and several other factors as assessed by pathologists.
  • The index has a log-linear relationship with event-free survival at 5 and 10 years.
  • For all subtypes, residual cancer burden tracked consistently with long-term outcome.
  • The residual cancer burden calculator is available to all pathologists through an online calculator (www.mdanderson.org/breastcancer_RCB).

“The basic principle is that we estimate the area that still contains residual disease, map that area to the slides that we’ll be looking at under the microscope, and create an image so that we can reconstruct it and be able to determine what area still contains actual cancer,” Dr. Symmans explained. “Then, we combine that with the fraction of that area that still contains invasive cancer cells, as well as the number of positive lymph nodes and the size of the largest metastasis. This is just organizing what we would otherwise report in pathology, but we’re doing it in a quantitative and standardized manner.”

The online calculator page receives about 16,000 visits per month, “so it’s being used out there,” he noted. The website offers instructional videos, protocols, illustrations, and diagrams as resources for the pathologists who use it.

Pooled Data

The pooled analysis came from the I-SPY Clinical Trials Consortium, involving 12 institutions or clinical trials and encompassing 5,160 patients. The study examined the relationship between the continuous residual cancer burden index and event-free survival, as well as distant relapse–free survival for four breast cancer phenotypes: hormone receptor–negative/HER2-negative (triple-negative), hormone receptor–negative/HER2-positive, hormone receptor–positive/HER2-positive, and hormone receptor–positive/HER2-negative. For each subtype, a multivariate analysis adjusted for patient age, tumor size, nodal status, and grade.

Relationship Between Residual Cancer Burden and Prognosis

The residual cancer burden index was tightly associated with both event-free and distant disease–free survival. This finding was consistent across 12 clinical sites and all cancer subtypes.

“The most interesting result, in my opinion, is that you see a log-linear relationship for the [residual cancer burden] index score and survival,” Dr. Symmans said. “The implication is that you can take an individual patient’s score representing how much residual cancer she has and calibrate that to an accurate estimate of her risk over time.”

A pathologic complete response (RCB-0) was most likely to be achieved by hormone receptor–negative/HER2-positive patients (69%) and least likely by the hormone receptor–positive/HER2-negative group (11%); the triple-negative group (43%) and hormone receptor–positive/HER2-positive group (38%) fell in between.

The residual cancer burden index values were associated with 5-year and 10-year event-free survival, as shown in Table 1.

Elaborating on what emerged from the four subgroups, Dr. Symmans said that in the hormone receptor–negative/HER2-positive group, the 69% rate of pathologic complete response was “striking” and “illustrates how effective these current [HER2-targeted] treatments are.” The 20% of patients who were classified as RCB-II and RCB-III had significantly worse survival than the others. “It’s a small quintile of patients that’s still at fairly substantial risk.”

He added, “In the hormone receptor–positive/HER2-negative breast cancer group, where there is still a bit of confusion about whether or not chemotherapy can help patients, we see that the extent of residual disease is strongly prognostic.”

In the subgroup with hormone receptor–positive/HER2-negative disease, he continued, “you can see that there’s clearly an effect on prognosis from the chemotherapy. However, the most prognostic aspect of the distribution of response is where there is the most residual disease—the RCB-III and RCB-II groups. Their long-term risk is still continuing beyond 10 years.”

The residual cancer burden index remained independently prognostic in multivariate models adjusting for patient age, grade, and clinical T and N stage at diagnosis. Its value was 1.93 in the triple-negative group, 2.04 in the hormone receptor–negative/HER2-positive group, 1.67 in the hormone receptor–positive/HER2-positive group, and 1.52 in the hormone receptor–positive/HER2-negative group. T4 tumors (and in the triple-negative group, also T3) remained independent predictors of prognosis as well.

Message to the Pathology Community

“Looking ahead, if we can standardize the reporting of residual cancer burden, that will only improve its usefulness in determining long-term prognosis,” Dr. Symmans emphasized. “This study is important in showing the generalizability of residual cancer burden, and it’s of sufficient size to generate the evidence to convince the pathology community to change the way we do things.”

Looking ahead, if we can standardize the reporting of residual cancer burden, that will only improve its usefulness in determining long-term prognosis.
— W. Fraser Symmans, MD

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Dr. Symmans noted that synoptic reporting is a requirement in oncology, but there is only one synoptic report for invasive cancer—one that is designed for a surgery-first examination. What’s lacking is a neoadjuvant synoptic report that specifically addresses the needs in interpreting a post-neoadjuvant response, he said. “The neoadjuvant model is increasingly related to precision medicine. We are standing at that transition point.” 

DISCLOSURE: Dr. Symmans holds a patent for the method of calculating residual cancer burden. The residual cancer burden calculator and educational materials are freely and publicly available online. He is also cofounder, owns shares in, and is an unpaid scientific advisor for Delphi Diagnostics.

REFERENCE

COVID NEWS


An international team of clinicians and researchers have described the pathology of the novel coronavirus, or COVID-19, for the first time. Their findings were published by Tian et al in the Journal of Thoracic Oncology.

The article’s senior author, Shu-Yuan Xiao, MD, from the University of Chicago Medicine in Chicago, teamed up with a small group of clinicians from the Zhongnan Hospital of Wuhan University, in Wuhan, China.

Photo credit: Getty

The article describes two patients who recently underwent lung lobectomies for adenocarcinoma and were retrospectively found to have had COVID-19 at the time of surgery. Pathologic examinations revealed that, apart from the tumors, the lungs of both patients exhibited edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and multinucleated giant cells. Fibroblastic plugs were noted in airspaces.

“This is the first study to describe the pathology of disease caused by...COVID-19 pneumonia, since no autopsy or biopsies had been performed thus far. This would be the only description of early-phase pathology of the disease due to this rare coincidence...Since both patients did not exhibit symptoms of pneumonia at the time of surgery, these changes likely represent an early-phase of the lung pathology of COVID-19 pneumonia," Dr. Xiao said.

Two Cases

The first case was an 84-year-old female patient who was admitted for treatment evaluation of a tumor measuring 1.5 cm in the right middle lobe of the lung. The tumor was discovered on chest computed tomography scan at an outside hospital. She had a past medical history of hypertension for 30 years, as well as type 2 diabetes. Despite comprehensive treatment, assisted oxygenation, and other supportive care, the patient’s condition deteriorated, and she died. Subsequent clinical information confirmed that she was exposed to another patient in the same room who was subsequently found to be infected with the 2019 novel coronavirus.

The second case was a 73-year-old male patient who presented for elective surgery for lung cancer, which presented as a small mass in the right lower lobe of the lung. He had a past medical history of hypertension for 20 years, which had been adequately managed. Nine days after lung surgery, he developed a fever with dry cough, chest tightness, and muscle pain. A nucleic acid test for COVID-19 came back as positive. He gradually recovered and was discharged after 20 days of treatment in the infectious disease unit.

Common Scenario

According to the study, these two incidences also typify a common scenario during the earlier phase of the COVID-19 outbreak, during which a significant number of health-care providers became infected in hospitals in Wuhan, and patients in the same hospital room were cross-infected as they were exposed to unknown infectious sources. The presence of early lung lesions days before the patients developed symptoms corresponds to the long incubation period (usually 3 to 14 days) of COVID-19.

The long incubation period made it difficult to prevent transmission during the early days of this outbreak, as many health-care workers in Wuhan became infected when they were seeing patients without sufficient protection, according to Dr. Xiao. As of today, more than 15 doctors in Wuhan have died of COVID-19.

“We believe it is imperative to report the findings of routine histopathology for better understanding of the mechanism by which [COVID-19] causes lung injury in the unfortunate tens and thousands of patients in Wuhan and worldwide,” said Dr. Xiao.

Further studies by Dr. Xiao’s team and collaborators on COVID-19 pathology through postmortem biopsies are ongoing, which should provide data on the late changes of this disease.


 Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center. The CDC has issued updated guidance for people with underlying medical conditions who are considering getting the coronavirus vaccine. "Adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes COVID-19," the CDC said in the guidance posted on Saturday. "mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine." Both the Pfizer and Moderna vaccines use mRNA, or messenger RNA. The CDC guidance had specific information for people with HIV, weakened immune systems, and autoimmune conditions such as Guillain-Barre syndrome and Bell's palsy who are thinking of getting the vaccine. People with HIV and weakened immune systems "may receive a COVID-19 vaccine. However, they should be aware of the limited safety data," the CDC said. There's no information available yet about the safety of the vaccines for people with weakened immune systems, the CDC said. People with HIV were included in clinical trials, but "safety data specific to this group are not yet available at this time," the CDC said. Cases of Bell's palsy, a temporary facial paralysis, were reported in people receiving the Pfizer and Moderna vaccines in clinical trials, the FDA said Dec. 17. But the new CDC guidance says the FDA "does not consider these to be above the rate expected in the general population. They have not concluded these cases were caused by vaccination. Therefore, persons who have previously had Bell's palsy may receive an mRNA COVID-19 vaccine." Researchers have determined the vaccines are safe for people with GBS, a rare autoimmune disorder in which the body's immune system attacks nerves just as they leave the spinal cord, the CDC said. "To date, no cases of Guillain-Barre syndrome (GBS) have been reported following vaccination among participants in the mRNA COVID-19 vaccine clinical trials," the CDC guidance says. "With few exceptions, the independent Advisory Committee on Immunization Practices (ACIP) general best practice guidelines for immunization do not include a history of GBS as a precaution to vaccination with other vaccines." For months, the CDC and other health authorities have said that people with certain medical conditions are at an increased risk of developing severe cases of COVID-19. Sources: CDC: "COVID-19 Vaccination Considerations for Persons with Underlying Medical Conditions"

Now that COVID-19 vaccines are being distributed, the American Association for Cancer Research (AACR) has called for people with cancer to be considered as a high priority group. "The available evidence supports the conclusion that patients with cancer, in particular with hematological malignancies, should be considered among the high-risk groups for priority COVID-19 vaccination," says the AACR's COVID-19 and Cancer Task Force. A review of literature suggests that COVID-19 fatality rates for patients with cancer were double that of individuals without cancer, the team notes. The higher mortality rates still trended upward, even after adjusting for confounders including age, sex, and comorbidities, indicating that there is a greater risk for severe disease and COVID-19 related mortality. The new AACR position paper was published online December 19 in Cancer Discovery. "We conclude that patients with an active cancer should be considered for priority access to COVID-19 vaccination, along other particularly vulnerable populations with risk factors for adverse outcomes with COVID-19," the team writes. However, the authors note that "it is unclear whether this recommendation should be applicable to patients with a past diagnosis of cancer, as cancer survivors can be considered having the same risk as other persons with matched age and other risk factors. "Given that there are nearly 17 million people living with a history of cancer in the United States alone, it is critical to understand whether these individuals are at a higher risk to contract SARS-COV-2 and to experience severe outcomes from COVID-19," they add. Allocation of Initial Doses There has already been much discussion on the allocation of the initial doses of COVID-19 vaccines that have become available in the US. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommended that the first wave of vaccinations, described as Phase 1a, should be administered to US healthcare workers (about 21 million people) and residents of long-term care facilities (about 3 million). The next priority group, Phase 1b, should consist of front-line essential workers, a group of about 30 million, and adults aged 75 years or older, a group of about 21 million. When overlap between the groups is taken into account, Phase 1b covers about 49 million people, according to the CDC. Finally, Phase 1c, the third priority group, would include adults aged 65-74 years (a group of about 32 million), adults aged 16-64 years with high-risk medical conditions (a group of about 110 million), and essential workers who did not qualify for inclusion in Phase 1b (a group of about 57 million). With the overlap, Phase 1c would cover about 129 million people. "Cancer is one of the categories of individuals at high risk," said Antoni Ribas, MD, PhD, AACR president and chair of the AACR COVID-19 and Cancer Task Force. "At the ACIP vote on December 20, the priority access was assigned to Phase 1c, but this results in a potential significant delay in vaccination for the particularly vulnerable population of patients with cancer at this time of highest risk, with the winter worsening of the COVID-19 pandemic." "Any delay in vaccine access will result in loss of life that could be prevented with earlier access to vaccination," Ribas told Medscape Medical News. He noted that the task force agrees that people whose work is essential to run society should receive priority vaccination, but consideration should be given to first vaccinating patients with cancer who are at increased risk of dying if they get COVID-19. "This would include the 2 or 3 million people in the US who currently are receiving treatments for cancer, in particular if they have blood cancers or lung cancer, as they are at a particularly higher risk of dying based on the studies we reviewed," he said. Patients With Cancer a 'High Priority' for COVID-19 Vaccine 1/4/2021 https://www.medscape.com/viewarticle/943308_print https://www.medscape.com/viewarticle/943308_print 2/3 "Moreover, a subset of cancer patients appears to have prolonged viral shedding, placing their healthcare providers and caregivers at higher risk." The best scenario, Ribas emphasized, "would be that with two approved COVID-19 vaccines there is enough stock in the next few weeks to vaccinate all individuals assigned to Phase 1b and 1c." Questions Remain Approached for independent comment, Cardinale Smith, MD, PhD, chief quality officer for cancer services for the Mount Sinai Health System in New York City, agreed with the AACR task force. "I share that they should be high priority," she said, "But we don't know that the efficacy will the same." Smith noted that the impact of cancer therapy on patient immune systems is more related to the type of treatment they're receiving, and B and T cell responses. "But regardless, they should be getting the vaccine, and we just need to follow the guidelines," she said. The AACR task force notes that information thus far is quite limited as to the effects of COVID-19 vaccination in patients with cancer. In the Pfizer-BioNTech BNT162b2 COVID vaccine trial, of 43,540 participants, only 3.7% were reported to have cancer. "It is clear that we need more data and specific studies in patients with cancer, but this should not delay access to priority vaccination," said Ribas. "There is considerable experience with other vaccines, such as the yearly flu vaccine, in cancer patients with very good safety records." Other large COVID-19 vaccine trials will provide further follow-up information on the effectiveness of the vaccines in patients receiving different cancer treatments, they write, but for now, there is "currently not enough data to evaluate the interactions between active oncologic therapy with the ability to induce protective immunity" to COVID-19 with vaccination. Ribas pointed out that studies of natural immune response to COVID-19 have documented that patients with hematologic malignancies have a suboptimal ability to mount an immune response to the virus. This results in these patients having a "remarkably" high risk of fatality compared with other patient populations with COVID-19 infection. "The fact that the antibody and T-cell responses to the COVID-19 vaccines are higher than in many individuals with natural COVID-19 infection provides an even stronger rationale to offer vaccination to persons with lower immune responses to the virus," he said. "Although ongoing studies will provide more information about how to best protect cancer patients with vaccines, at present, there is no evidence that the vaccine should be delayed in cancer patients. "Of course, patients with cancer should consult with their healthcare providers about their potential risks and benefits to decide whether getting vaccinated is right for them," he added. In a recent interview with Medscape Medical News, Nora Disis, MD, a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, University of Washington, Seattle, also discussed vaccinating cancer patients. She pointed out that even though there are data suggesting that cancer patients are at higher risk, "they are a bit murky, in part because cancer patients are a heterogeneous group." "For example, there are data suggesting that lung and blood cancer patients fare worse," said Disis, who is also editor-in-chief of JAMA Oncology. "There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities." She also pointed out the likelihood that individualized risk factors including the type of cancer therapy, site of disease, and comorbidities "will shape individual choices about vaccination among cancer patients." It is also reasonable to expect that patients with cancer will respond to the vaccines, even though historically some believed that they would be unable to mount an immune response. "Data on other viral vaccines have shown otherwise," said Disis. "For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection." Several of the authors of the AACR position paper, including Ribas, report relationships with industry as detailed in the paper.


Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center. Anthony Fauci, MD, says the coronavirus pandemic may get worse in coming months, including a post-holiday surge in cases. In an interview on CNN, Fauci was asked if he thought "the worst was yet to come." He said, "I do." "We very well might see a post-seasonal ― in the sense of Christmas, New Year's ― surge, and, as I have described it, as a surge upon a surge," said Fauci, the director of the National Institute of Allergy and Infectious Diseases. Fauci said holiday travel could cause a spike in cases. Besides exposing themselves at airports, travelers usually mix households when they arrive at their destinations, he said. Even though health authorities urge people not to travel, "it’s going to happen," Fauci said. "We are really at a very critical point. ... So I share the concern of President-elect (Joe) Biden that as we get into the next few weeks, it might actually get worse," Fauci said. Biden recently said that the "darkest days" in the coronavirus pandemic are ahead and urged Americans to prepare themselves for a difficult struggle. Fauci has agreed to serve as Biden’s top health adviser. December has already been the hardest month for the COVID-19 pandemic in the United States. More than 65,000 people have died of coronavirus-related reasons so far this month, compared to only about 37,000 in November, according to the Covid Tracking Project. Hospitalizations are up, with more than 100,000 people in the hospital per day since Dec. 2. Overall, there have been more than 19 million confirmed cases in the United States and more than 333,000 COVID-related deaths ― the most of any nation in the world. COVID-19 vaccinations should bring the pandemic under control, but it will take many months for the United States to develop herd immunity, Fauci said. Health care workers and residents of long-term care facilities are the top priority groups receiving the vaccine. "I hope that by the time we get to the fall we will reach that critical percentage of people that we can really start thinking about a return to some form of normality," Fauci said. Fauci, who just turned 80, got a COVID-19 vaccination recently. He said he had no side effects besides arm soreness for about