Κυριακή, 15 Νοεμβρίου 2020

PPI USE INCREASE SEVERITY OF COVID DISEASE

NEW YORK (Reuters Health) - A new meta-analysis provides more evidence of an association between proton-pump inhibitors (PPIs) use and increased risk for poor outcomes in patients with coronavirus infection (COVID-19).

Dr. Syed Shahzad Hasan of the University of Huddersfield, in the U.K,, and Dr. Chia Siang Kow of the International Medical University, in Kuala Lumpur, Malaysia, analyzed five studies with a total of 37,372 patients.

A pooled analysis of three studies demonstrated a significantly increased likelihood for a severe or fatal course of COVID-19 with PPI use relative to nonuse (pooled odds ratio, 1.46; 95% confidence interval, 1.34 to 1.60), the researchers report in the Journal of Internal Medicine.

A pooled analysis of two studies also showed significantly increased odds for secondary infections with the use of PPIs in COVID-19 patients (pooled OR, 2.91; 95% CI, 1.58 to 5.36).

"The use of PPIs may lead to excessive suppression of gastric acid, and thus leading to impaired eradication of ingested pathogens, which results in the increased risk of secondary infection in patients with COVID-19," the authors said in a joint email to Reuters Health.

"The observed increased risk of severe or fatal course of illness with the use of PPIs may also be at least partially due to the development of secondary infections, leading to a more complicated course of illness," they noted.

Their advice: "Clinicians involved in the management of patients with COVID-19 receiving PPIs should routinely assess if PPI is appropriately indicated; if no appropriate indication, PPI should be discontinued. In patients with appropriate indications, the risk of continuing PPI should be balanced against the risk of discontinuation; otherwise, patients may also be switched to famotidine, a histamine-2 blocker, which has been associated with reduced risk of adverse outcomes in patients with COVID-19."

"Consistently, multinational studies are showing an association, not necessarily causation, but an association" between PPI use and COVID-19, Dr. Brennan Spiegel of David Geffen School of Medicine at UCLA and Cedars-Sinai, in Los Angeles, who wasn't involved in the study, noted in a phone interview with Reuters Health.

"This isn't necessarily surprising," he noted, as these medicines have been linked to increased risk of intestinal infections. "That's been shown many times and there's really no controversy about that anymore and COVID is an intestinal infection. It uses the GI tract to gain a foothold in the body and anything that we do to give it better access to the intestinal system, it makes sense that things could get worse and that's basically what we're seeing."

The results of this meta-analysis are consistent with a recent study (https://bit.ly/3iBIakm) by Dr. Spiegel and colleagues. In that study, people taking a PPI once a day had more than a two-fold higher risk of COVID-19, and people taking a PPI twice a day had more than a three-fold higher risk than those not taking a PPI.

"As a starting point, we might need to start thinking about reducing the high doses of PPIs that some people are on, particularly those who are at risk of a bad COVID outcome," Dr. Spiegel said.

SOURCE: https://bit.ly/35Zas2S Journal of Internal Medicine, online October 20, 2020.

RE-HOSPITALISATION FOR COVID DISEASE

November 11, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

About one in 11 patients discharged after COVID-19 treatment is readmitted to the same hospital, according to researchers from the Centers for Disease Control and Prevention (CDC).

Older age and chronic diseases are associated with increased risk, said senior author Adi V. Gundlapalli, MD, PhD, chief public health informatics officer of the CDC's Center for Surveillance, Epidemiology, and Laboratory Services.

Gundlapalli and colleagues published the finding November 9 in Morbidity and Mortality Weekly Report.

To get a picture of readmission after COVID-19 hospitalization, the researchers analyzed records of 126,137 patients hospitalized with COVID-19 between March and July and included in the Premier Healthcare Database, which covers discharge records from 865 nongovernmental, community, and teaching hospitals.

Overall, 15% of the patients died during hospitalization. Of those who survived to discharge, 9% were readmitted to the same hospital within 2 months of discharge; 1.6% of patients were readmitted more than once. The median interval from discharge to first readmission was 8 days (interquartile range, 3-20 days). This short interval suggests that patients are probably not suffering a relapse, Gundlapalli said in an interview. More likely they experienced some adverse event, such as difficulty breathing, that led their caretakers to send them back to the hospital.

Forty-five percent of the primary discharge diagnoses after readmission were infectious and parasitic diseases, primarily COVID-19. The next most common were circulatory system symptoms (11%) and digestive symptoms (7%).

After controlling for covariates, the researchers found that patients were more likely to be readmitted if they had chronic obstructive pulmonary disease (odds ratio [OR], 1.4), heart failure (OR, 1.6), diabetes (OR, 1.2), or chronic kidney disease (OR, 1.6).

They also found increased odds among patients discharged from the index hospitalization to a skilled nursing facility (OR, 1.4) or with home health organization support (OR, 1.3), compared with being discharged to home or self-care.

Looked at another way, the rate of readmission was 15% among those discharged to a skilled nursing facility, 12% among those needing home health care and 7% of those discharged to home or self-care.

The researchers also found that people who had been hospitalized within 3 months prior to the index hospitalization were 2.6 times more likely to be readmitted than those without prior inpatient care.

Further, the odds of readmission increased significantly among people over 65 years of age compared with people aged 18 to 39 years.

"The results are not surprising," Gundlapalli said. “We have known from before that elderly patients, especially with chronic conditions, certain clinical conditions, and those who have been hospitalized before, are at risk for readmission.”

But admitting COVID-19 patients requires special planning because they must be isolated and because more personal protective equipment (PPE) is required, he pointed out.

One unexpected finding from the report is that non-Hispanic White people were more likely to be readmitted than were people of other racial or ethnic groups. This contrasts with other research showing Hispanic and Black individuals are more severely affected by COVID-19 than White people. More research is needed to explain this result, Gundlapalli said.

The authors have disclosed no relevant financial relationships.

MMWR. Published online November 9, 2020. Full text

Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Visit him at lairdharrison.com or follow him on  Twitter: @LairdH .

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RISK OF METACHRONOUS TESTICULAR CANCER

In a Dutch study reported in the Journal of Clinical Oncology, Blok et al found a significant association between an increased number of cycles of platinum-based chemotherapy and a reduced risk of metachronous contralateral testicular cancer. As noted by the investigators, patients with testicular germ cell tumor are at increased risk of developing a contralateral testicular germ cell tumor.

Study Details

The study involved data from a nationwide cohort of 4,755 patients aged < 50 years who were diagnosed with and treated for primary testicular germ cell tumor in the Netherlands between 1989 and 2007. Metachronous contralateral testicular germ cell tumor was defined as any testicular germ cell tumor identified in the contralateral testicle ≥ 2 months after diagnosis of the first testicular germ cell tumor. The cohort included 2,612 patients with seminomatous germ cell tumor and 2,143 with nonseminomatous germ cell tumor.

Standardized incidence ratios were used to compare the incidence of contralateral testicular germ cell tumor incidence with expected incidence of testicular germ cell tumor in the general population. The effect of treatment with platinum-based chemotherapy on contralateral testicular germ cell tumor risk was assessed via multivariable Cox proportional hazards regression models.

“Approximately 1 in every 30 survivors of testicular germ cell tumor will develop a contralateral testicular germ cell tumor, with contralateral incidence increasing up to 20 years after a primary testicular germ cell tumor. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with contralateral testicular germ cell tumor risk.”
— Blok et al

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Key Findings

Metachronous contralateral testicular germ cell tumor was diagnosed in 136 patients (standardized incidence ratio = 14.6, 95% confidence interval [CI] =12.2–17.2). The cumulative incidence increased to 3.4% at 20 years of follow-up, including cumulative incidence of 4.0% after seminomatous germ cell tumor and 2.6% after nonseminomatous germ cell tumor.

The median interval between primary testicular germ cell tumor and metachronous contralateral testicular germ cell tumor was 6.1 years, with no difference between patents with seminomatous germ cell tumor vs nonseminomatous germ cell tumor (P = .090).

The 20-year cumulative incidence was 1.7% in patients who had been treated with platinum-based chemotherapy and 4.4% in patients without platinum exposure (median intervals of 4.9 vs 7.5 years, P = .23).

On multivariate analysis, risk of a contralateral testicular germ cell tumor decreased with every additional cycle of platinum-based chemotherapy (hazard ratio [HR] per cycle = 0.74, 95% CI = 0.64–0.85). The hazard ratio for patients receiving four cycles of platinum-based chemotherapy vs those not receiving platinum-based chemotherapy was 0.18 (95% CI = 0.08–0.43).

Additional significant factors on meta-analysis consisted of reduced risk with increasing age (HR = 0.93, 95% CI = 0.90–0.96) and reduced risk after primary nonseminomatous germ cell tumor vs seminomatous germ cell tumor (HR = 0.58, 95% CI = 0.35–0.96).  

The investigators concluded, “Approximately 1 in every 30 survivors of testicular germ cell tumor will develop a contralateral testicular germ cell tumor, with contralateral incidence increasing up to 20 years after a primary testicular germ cell tumor. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with contralateral testicular germ cell tumor risk.”

Michael Schaapveld, PhD, of the Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by KWF Kankerbestrijding and Dutch Uro-Oncology Studygroup. For full disclosures of the study authors, visit ascopubs.org.

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®.

TEST ALL CANCER PATIENTS FOR DRIVER MUTATIONS

About 1 in 8 patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

"This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn't have a genetic mutation that is predisposing them to cancer," commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Arizona, Phoenix, Arizona.

Finding a genetic mutation can alter clinical management of the cancer.

"This really does open up treatment and management options that might not have been accessible to these patients," Samadder emphasized.

The results were published online on October 30 in JAMA Oncology and were presented simultaneously at the Society of Human Genetics. Samadder discusses details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

"For cancer patients, I think the debate is over. We should test everybody," Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, told Medscape Medical News.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

"Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family," Samadder said.

Study Details

The study included 2984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach to targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2984 patients).

"Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families' health," coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to "all cancer patients, not just breast cancer patients," Beitsch told Medscape Medical News.

Long-Running Debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, says Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

"The Invitae cash price for an 80-plus gene panel is $250. That's [the cost of] a mani-pedi in Dallas. I don't discount that it's a lot of money for a lot of people. Yes, it's expensive, but it's a lot less expensive than it used to be," Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors note that these results are consistent with past studies.

Beitsch says VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

"We all have VUSs. They're just minor variations in a gene. The vast majority of them have no consequence and don't alter the function of the gene," he said. "I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don't get stressed about it."

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Beitsch emphasized.

"Patients who have a VUS and don't have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history," Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

"This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing," Samadder said. "There are probably a number of other barriers ― socioecomic or emotional ― that we have to deal with."

Genetic testing was provided by the Invitae Corporation. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic's Center for Individualized Medicine. Two coauthors are employees of Invitae. Beitsch reports participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

JAMA Oncol. Published online October 30, 2020. Abstract

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BREAST CANCER SURVIVAL AFTER IM RT

As reported in The Lancet Oncology by Philip M. Poortmans, PhD, and colleagues, 15-year outcomes of the phase III EORTC 22922/10925 trial show continued reductions in both breast cancer mortality and recurrence with postsurgery internal mammary and medial supraclavicular (IM-MS) lymph node chain irradiation in patients with stage I to III breast cancer, with no significant difference in overall survival.

Study Details

The open-label trial included 4,004 women aged ≤ 75 years with unilateral stage I to III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumor from sites in 13 countries. Patients were randomly assigned between August 1996 and January 2004 to receive IM-MS irradiation at 50 Gy in 25 fractions (n = 2,002) or no IM-MS irradiation (control group; n = 2,002).

Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. The primary endpoint was overall survival on intention-to-treat analysis. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after random assignment.

Philip M. Poortmans, PhD

Philip M. Poortmans, PhD

Efficacy Endpoints

Median follow-up was 15.7 years (interquartile range = 14.0–17.6 years). Overall, death from any cause occurred in 27.7% of patients in the IM-MS irradiation group and 28.4% of patients in the control group.

Overall survival at 15 years was 73.1% vs 70.9% (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.84–1.06, P = .36). Median overall survival was not reached in either group; overall survival duration associated with the 75% survival probability (third quartile overall survival) was 14.2 years vs 13.0 years. In analysis excluding 25 patients without data on final pathologic T and N stage, the difference in overall survival remained nonsignificant (HR = 0.92, 95% CI = 0.82–1.04, P = .18).

Overall, 37.5% vs 39.1% of patients had breast cancer recurrence, a second breast cancer, or died. Disease-free survival at 15 years was 60.8% vs 59.9% (HR = 0.93, 95% CI = 0.84–1.03, P = .18). Overall, 29.2% vs 30.7% of patients developed distant metastases or died, with 15-year distant metastasis–free survival rates being 70.0% vs 68.2% (HR = 0.93, 95% CI = 0.83–1.04, P = .18). The cumulative incidence of any type of breast cancer recurrence at 15 years was 24.5% vs 27.1% (HR = 0.87, 95% CI = 0.77–0.98, P = .024).

Among patients who died, the cause of death was breast cancer in 56.7% of the IM-MS irradiation group vs 66.4% of the control group. Non–breast cancer death accounted for 30.9% vs 26.4% of deaths and cause of death was unknown for 12.5% vs 7.2% of deaths.

The cumulative incidence of breast cancer mortality at 15 years was 16.0% vs 19.8% (HR = 0.81, 95% CI = 0.70­–0.94, P = .0055). At 15 years, the cumulative incidence of death not due to breast cancer was 7.8% vs 7.0% (HR = 1.13, 95% CI = 0.91–1.40, P = .29) and the cumulative incidence of death from an unknown cause was 3.1% vs 2.3% (HR = 1.66, 95% CI = 1.13–2.44, P = .010).

Second Cancers

Second cancers occurred in 14.1% vs 14.8% of patients, including ipsilateral breast cancer in 0.6% vs 0.5% and contralateral breast cancer in 6.2% vs 6.9%. Second nonbreast cancers occurred in 8.3% vs 8.5% of patients. The distribution of nonbreast cancers indicated no obvious increase in lung, thyroid, esophageal, and mediastinal malignancies in the IM-MS group, with the exception of in-field tumors in four patients (three with angiosarcoma and one with pleural fibrosarcoma).

KEY POINTS

  • At 15 years, patients in the IM-MS irradiation group had reduced risks of breast cancer mortality and any breast cancer recurrence.
  • No difference in overall survival was observed.

Late Adverse Effects

Late adverse effects were evaluated in 1,922 patients in the IM-MS irradiation group and 1,944 in the control group who received study treatment at every follow-up visit until progression or development of new primary cancer. Any-grade pulmonary fibrosis occurred in 5.1% vs 2.3% of patients, cardiac fibrosis in 2.0% vs 1.1%, and any cardiac disease in 8.6% vs 7.2%.

Among the 935 vs 952 patients with right breast cancer, 2.0% vs 0.9% had clinical evidence of cardiac fibrosis and 8.3% vs 6.3% had any evidence of cardiac disease. Among the 987 vs 992 patients with left breast cancer, 1.9% vs 1.3% had clinical evidence of cardiac fibrosis and 8.8% vs 8.0% had any evidence of cardiac disease. Among the total study population, death due to cardiovascular disease occurred in 1.2% of patients in each group.

The investigators concluded, “The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I–III breast cancer. However, this is not converted to improved overall survival.”

They noted, “Although overall disease-free survival was not significantly longer with IM-MS irradiation, breast cancer recurrence at 15 years was significantly lower. The fact that this does not translate into longer overall survival might be explained by non–breast cancer–related deaths or those from an unknown cause, which together constituted 38% of all deaths, an imbalance in missing data on the cause of death between treatment groups, and salvage treatment after recurrence.”

Dr. Poortmans, of the Faculty of Medicine and Health Sciences, University of Antwerp, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the U.S. National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding. 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®.

SIPULEUCEL-T FOR PROSTATE CANCER

he first and only immunotherapy product for advanced cancer, sipuleucel-T (Provenge), has not been widely used clinically since its launch 10 years ago, and has been largely eclipsed by two drugs launched since then — the androgen-receptor signaling pathway inhibitors (ASPIs) abiraterone acetate (Zytiga) and enzalutamide (Xtandi).

But new data from a retrospective observational study involving more than 6000 participants show that men with advanced prostate cancer who received sipuleucel-T had a significantly prolonged overall survival.

The median overall survival was 34.9 months with sipuleucel-T vs 21.0 months in men who were treated with ASPIs in the first-line setting.

The study was published October 7 in Advances in Therapy.

"These data highlight that Provenge is a viable option for patients with metastatic castration-resistant prostate cancer and should be considered and used as a treatment for a subset of patients eligible to receive this medication," said lead author Rana McKay, MD, an associate professor of medicine at the University of California-San Diego School of Medicine.

However, an expert approached for comment cautioned that these new data should be viewed as hypothesis-generating only.

Daniel Geynisman, MD, assistant professor, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, pointed out that sipuleucel-T is the only immunotherapy FDA- approved specifically for castration-resistant prostate cancer.

Often referred to as a vaccine, the product is an autologous active cellular immunotherapy, made from the patient's own white blood cells, which are collected and then reprogrammed to attack cancer cells.

"It is infrequently used in clinical practice compared to androgen pathway inhibitors such as abiraterone acetate or enzalutamide, due to perceived marginal survival benefit, lack of a PSA response, and inability to gauge a patient's response, and also cost," Geynisman commented.

Although this new analysis suggests a survival benefit with use of sipuleucel-T, it should be considered "as hypothesis-generating only, given its severe limitations in controlling for key clinical variables — such as PSA, Gleason score, performance status and other key laboratory values — that may severely differentiate the group of men who did vs did not receive sipuleucel-T," said Geynisman.

"Sipuleucel-T remains an option for men, but guidelines and clinical practice cannot be altered based on this analysis alone," he added.

He emphasized that these results do not suggest that sipuleucel-T is superior to abiraterone acetate or enzalutamide in improving overall survival. "They suggest that men who at some point in their treatment trajectory received sipuleucel-T have superior overall survival," he explained. "These results are once again intriguing and supportive of the use of sipuleucel-T, but as any claims-based research remain only hypothesis-generating given the multiple possible confounders."

Study Details

For their study, McKay and colleagues developed multivariable models to analyze data obtained from the longitudinal Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index.

The authors hypothesized that patients receiving sipuleucel-T would have improved survival compared with users of other treatments, potentially because of its distinct mechanism of action compared with other mCRPC-directed therapies.

The model included 6044 men with mCRPC who were treatment naive and had continuous Medicare eligibility (Parts A, B, and D) over a 3-year observation starting in 2014.

Analyses were conducted in two cohorts. The first included men who received first-line sipuleucel-T vs those who received first-line ASPIs, and these patients were permitted to receive any other type of therapy in subsequent lines. The second analysis was the "any-line cohort" of patients who were treated with sipuleucel-T vs those treated with any-line ASPIs, but who did not receive sipuleucel-T.

During the 36-month observation period, 75% of patients receiving ASPIs in any line without sipuleucel-T had one or two lines of therapy, while 75% of those treated with sipuleucel-T at any time received two to three lines of therapy. Among men who received sipuleucel-T, 71% received it as first-line therapy.

In the overall analysis, median survival was 22.9 months. For the first line cohort, patients who received sipuleucel-T as a first-line treatment had 44% reduction in the risk of death at 36 months vs those receiving ASPIs (adjusted hazard ratio [HR], 0.56; P < .0001).

A similar pattern was observed in the any-line cohort. Those in the sipuleucel-T group had a 41% decrease in the risk of death at 36 months vs patients receiving an oral ASPI (without sipuleucel-T) (adjusted HR, 0.59; P < .0001). This extrapolated to a 14.5-month difference in median overall survival between the any-line groups, with duration of survival 35.2 months (sipuleucel-T) vs. 20.7 months (ASPI, without sipuleucel-T).

In an exploratory analysis, no survival differences were seen when the sequence of first-line sipuleucel-T followed by ASPIs was compared with first-line ASPIs followed by sipuleucel-T (HR, 1.17; P = .521). The authors did note that survival outcomes were significantly improved when sipuleucel-T was used with an ASPI when compared with either an ASPI used alone or if two ASPIs were used in sequence (HR, 0.48; P < .0001).

"Even given the potential limitations associated with claims analyses, such as selection bias and confounding by indication, this research provides important insights into real-world treatment outcomes and is complementary with other recently published real-world evidence analyses from other data sources," the authors conclude.

The study was funded by Dendreon Pharmaceuticals, LLC. McKay reports research funding from Pfizer, Bayer, and Tempus, as well as advisory board/consulting roles for Bayer, Bristol-Myers Squibb, Dendreon, Exelixis, Johnson and Johnson, Novartis, Pfizer Sanofi, and Vividion. Several coauthors also report relationships with industryThe full list can be found with the original article.

Adv Ther. Published online October 7, 2020. Full text

PLATINUM THERAPY FOR ADVANCED PROSTATE CANCER

NEW YORK (Reuters Health) - Platinum-based treatment is associated with antitumor activity in patients with advanced prostate cancer with DNA-repair-gene aberrations, according to a multinational group of researchers.

Genomic aberrations that impair DNA-repair genes occur at a frequency of up to 30% in advanced prostate cancer, Dr. Sabine Schmid of Princess Margaret Cancer Centre, in Toronto, Canada, and colleagues note in JAMA Network Open. Some have been associated with sensitivity to platinum compounds and/or PARP inhibitors.

To find out if platinum-based therapy might be beneficial in patients with castration-resistant prostate cancer (CRPC), as it is known to be in certain patients with triple-negative breast cancer, the team examined data on 508 patients from 25 academic centers in 12 countries. The men's median age was 61 years.

For most patients (65%), there were no data on DNA-repair-gene aberrations, but such aberrations were found to be present in 80 patients (14.7%) and absent in 19.3%. The most common aberration consisted of alterations in BRCA2 seen in 44 patients.

Eighty percent of patients received a platinum-combination treatment with drugs including docetaxel, etoposide and paclitaxel. Only 100 patients were given platinum-based monotherapy with carboplatin.

A prostate-specific antigen (PSA) decrease of at least 50% was seen in 47.1% of patients with DNA-repair aberrations and 36.1% of those with negative testing. Corresponding proportions for soft-tissue responses in evaluable patients were 48.3% and 31.3%.

In the subgroup of patients with BRCA2 gene alterations, PSA level decreases of at least 50% were seen in 23 patients (63.9%). Soft tissue responses were seen in 17 of the 34 patients (50.0%) with evaluable disease.

In the 284 patients without DNA profiling, 28.5% showed a PSA decrease of at least 50%, and soft-tissue response was reported in 38 of 185 (20.5%) with evaluable disease.

"Based on our analysis," the researchers conclude, "platinum-containing therapy should be considered in patients with DNA repair gene aberrations especially if access to a PARP inhibitor is not available."

In an accompanying editorial, Drs. Frederick J. Meyers and Mili Arora of the University of California, Davis, in Sacramento, note that comprehensive sequencing of human cancers is "revealing that seemingly disparate malignant neoplasms may be more similar than not."

Dr. Meyers told Reuters Health by email, "The similarity in genomic alterations and responsiveness to targeted therapy between triple-negative breast cancer (TNBC) and hormone refractory prostate cancer has not been previously emphasized. Prospective trials that include deeper sequencing and detailed phenotyping of both groups of patients is likely to refine this observation."

Dr. Schmid did not respond to requests for comments.

MRI HELPFUL FOR MESOTHELIOMA

NEW YORK (Reuters Health) - MRI offers advantages over CT for assessing primary-tumor volume in patients with mesothelioma, researchers from U.K. report.

"MRI measurements of tumor volume appeared more discriminatory in predicting subsequent survival than CT measurements of the same factor," Dr. Kevin G. Blyth of Queen Elizabeth University Hospital and the University of Glasgow, U.K., told Reuters Health by email. "We also observed that the volume of tumor seen using MRI was higher, which may explain this, as mesothelioma is known to be difficult to identify on CT."

Primary-tumor volume is a critical determinant of survival in malignant pleural mesothelioma (MPM). Tumor volume as assessed by CT is associated with overall survival, but CT volumetry is uncommonly used because of the laborious nature of the manual segmentation required.

Dr. Blyth and colleagues compared CT volumetry with a novel MRI volumetry protocol they developed for their study of 31 patients with a final diagnosis of MPM.

Using their MRI method, the mean analysis time was 14 minutes, the intraobserver agreement was 87.5%, and the interobserver agreement was 96.2%.

Mean CT analysis time was significantly longer (151 minutes), and interobserver agreement was only moderate (72%).

The mean primary-tumor volume was significantly higher by MRI (370 cc) than by CT (302 cc), and MRI tumor volumes were consistently larger than CT tumor volumes, the researchers report in Lung Cancer.

There was no correlation between either MRI tumor volume or CT tumor volume and clinical T-stage.

When dichotomized at 300 cc, higher MRI tumor volume was associated with a 4.03-fold greater risk of death, but there was no significant relationship between CT tumor volume at this cutpoint and overall survival.

"We need to look beyond traditional measures of tumor stage in mesothelioma and also look beyond CT imaging, which is the workhorse of chest radiology but has its limits," Dr. Blyth said.

"We need larger, multicenter validation studies to prove that the findings we report are reproducible," he said. "We are launching these now as part of the CRUK-funded PREDICT-Meso International Accelerator Network, of which I am chief investigator."

Dr. Blyth added, "We also need to complete large-scale studies to demonstrate that tumor volume (however you measure it) outperforms the currently used descriptors for T-stage (which don't account for volume or size - only the extent of invasion into adjacent structures)."

SOURCE: https://bit.ly/34EOfqf Lung Cancer, online October 1, 2020.

PEMBROLIZUMAB FOR TNBC APPROVED BY FDA

On November 13, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda) in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score [CPS] ≥ 10) as determined by an FDA-approved test.

The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic for selecting patients with triple-negative breast cancer for pembrolizumab.

KEYNOTE-355 Results

Approval was based on the phase III KEYNOTE-355 study, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally recurrent unresectable or metastatic triple-negative breast cancer, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomly assigned (2:1) to receive pembrolizumab 200 mg on day 1 every 3 weeks or placebo in combination with different chemotherapy treatments (paclitaxel protein-bound, paclitaxel, or gemcitabine plus carboplatin) via intravenous infusion.

The main efficacy outcome measure was progression-free survival as assessed by blinded independent review according to RECIST 1.1, tested in the subgroup of patients with CPS ≥10. Median progression-free survival was 9.7 months (95% confidence interval [CI] = 7.6–11.3) in the pembrolizumab plus chemotherapy arm and 5.6 months (95% CI = 5.3–7.5) in the placebo arm (hazard ratio [HR] = 0.65; 95% CI = 0.49–0.86; one-sided = .0012).

Adverse Events

The most common adverse reactions (incidence ≥ 20%) in patients receiving pembrolizumab plus chemotherapy in KEYNOTE-355 were fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache. The most common laboratory abnormalities (incidence ≥ 20%) in patients receiving pembrolizumab plus chemotherapy were anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated ALT and AST, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.

The recommended pembrolizumab dose for adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months. When given with pembrolizumab, either paclitaxel protein-bound 100 mg/m2 on days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28 days; or gemcitabine 1,000 mg/m2 plus carboplatin AUC 2 mg/mL/min on days 1 and 8 every 21 days is administered via intravenous infusion.

NO BENEFIT OF ADJUVANT IRINOTECAN FOR SCLC

In a Japanese phase III trial reported in the Journal of Clinical Oncology, Kenmotsu et al found that adjuvant irinotecan/cisplatin did not improve relapse-free survival vs etoposide/cisplatin in patients with completely resected, pathologic stage I–IIIA, high-grade neuroendocrine carcinoma of the lung.

Study Details

In the multicenter trial, 221 patients were randomly assigned between April 2013 and October 2018 to receive etoposide at 100 mg/mon days 1 to 3 plus cisplatin at 80 mg/m2 on day 1 every 3 weeks for up to four cycles (n = 111) or irinotecan at 60 mg/m2 on days 1, 8, and 15 plus cisplatin at 60 mg/m2 on day 1 every 4 weeks for up to four cycles (n = 110). The primary endpoint was relapse-free survival in the intention-to-treat population.

Relapse-Free Survival

At the second interim analysis, early termination of the trial was recommended due to futility. At median follow-up of 24.1 months, 3-year relapse-free survival was 65.4% in the etoposide/cisplatin group vs 69.0% in the irinotecan/cisplatin group (hazard ratio [HR] = 1.076, 95% confidence interval [CI] =0.666–1.738, P = .619).

KEY POINTS

  • Adjuvant irinotecan/cisplatin did not improve relapse-free survival vs etoposide/cisplatin.
  • The trial was ended early due to futility.

No significant difference in 3-year recurrence-free survival was observed between 59 vs 58 patients with histology of small cell lung cancer (SCLC) or combined SCLC (65.2% vs 66.5%, HR = 1.029, 95% CI = 0544–1.944) or between 52 vs 52 patient with large-cell neuroendocrine carcinoma or combined large-cell neuroendocrine carcinoma (66.5% vs 72.0%, HR = 1.072, 95% CI = 0.517–2.222). No significant differences were observed according to pathologic disease stage.

No significant difference in overall survival was observed. Overall, 13 patients in the etoposide/cisplatin group vs 19 in the irinotecan/cisplatin group had died at time of analysis; at 3 years, overall survival was 84.1% vs 79.0%.

Adverse Events

Grade 3 or 4 adverse events were more common in the etoposide/cisplatin group vs the irinotecan/cisplatin group, including neutropenia (97% vs 36%), leukopenia (60% vs 14%), and febrile neutropenia (20% vs 4%). Grade 3 or 4 nonhematologic adverse events occurred in 40.4% vs 31.2% of patients. Grade 3 or 4 anorexia (6% vs 11%) and diarrhea (1% vs 8%) were more common in the irinotecan/cisplatin group.

The investigators concluded, “Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving relapse-free survival in patients with completely resected high-grade neuroendocrine carcinoma of the lung; thus, etoposide plus cisplatin remains the standard treatment.”

Hirotsugu Kenmotsu, MD, PhD, of the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Japan Agency for Medical Research and Development and National Cancer Center Research and Development Funds. For full disclosures of the study authors, visit ascopubs.org.

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®.