Σάββατο, 21 Οκτωβρίου 2017

ADJUVANT B-BLOCKER USE FOR MELANOMA

An Italian single-center prospective cohort study suggests that adjuvant treatment with the beta-blocker propranolol significantly reduces the risk of melanoma recurrence in patients with stage IB to IIIA cutaneous disease. The findings were reported in JAMA Oncology by De Giorgi et al. Preclinical and retrospective studies have indicated that beta-blockers inhibit angiogenesis and interfere with the migration of melanoma cells via inhibition of noradrenaline-dependent responses.
Study Details
In the study, 53 patients with stage IB to IIIA cutaneous melanoma and no evidence of metastasis in the Department of Dermatology, University of Florence, were asked at the time of diagnosis between January 2011 and April 2013 to take propranolol at 80 mg daily as off-label adjuvant treatment after surgery. Of them, 19 accepted propranolol treatment and 34 declined but agreed to participate as a control group. Baseline characteristics were similar in the two groups except for a higher proportion of patients with ulcerated melanoma in the propranolol group (63% vs 35%).
Disease-Free Survival
After a median follow-up of 3 years, disease progression had occurred in 3 patients (15.8%) in the propranolol group and 14 patients (41.2%) in the control group. Disease-free survival at 3 years was 89% vs 64%, respectively. In an analysis adjusting for age, Breslow thickness, and ulceration, propranolol use was associated with a significantly reduced risk of recurrence (hazard ratio [HR] = 0.18, = .03).
Two patients in the propranolol group died (10.5%), one due to melanoma. Six patients in the control group died (17.7%), five due to melanoma. No significant difference in overall survival was observed (HR = 0.64, P = .63).
The investigators concluded: “In the absence of randomized, double-blind, placebo-controlled clinical trials, this study is the first off-label study of which we are aware of propranolol for melanoma treatment. These results confirm recent observation that β-blockers protect patients with thick cutaneous melanoma from disease recurrence. This study is in accordance with the present policy of ‘drug repurposing’ in oncology. Repurposing the vast arsenal of approved drugs with a non-oncology primary purpose may prove an attractive and inexpensive strategy for offering more effective treatment options to patients with cancer.”


Vincenzo De Giorgi, MD, of the Department of Dermatology, University of Florence, Italy, is the corresponding author of the JAMA Oncology article.

PI3K INHIBITORS FOR INDOLENT LYMPHOMA

As reported in the Journal of Clinical Oncology by Dreyling et al, the phase II CHRONOS-1 trial has shown a high response rate and durable responses with the phosphatidylinositol 3-kinase (PI3K) inhibitor copanlisib (Aliqopa) in adults with relapsed or refractory indolent lymphoma who had received at least two previous lines of therapy. Data in the subgroup of patients with follicular lymphoma in the trial supported the recent accelerated approval of copanlisib in relapsed follicular lymphoma after at least two prior therapies. Copanlisib is a pan-class I PI3K inhibitor that exhibits predominant activity against PI3K-α and -δ isoforms.
Study Details
In the study, 142 patients from 81 sites in Europe, Asia, the United States, Australia, and New Zealand were enrolled between November 2013 and February 2016 and received copanlisib at 60 mg intravenously on days 1, 8, and 15 of 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate on blinded independent review.
Patients had a median age of 63 years, 50% were female, 85% were white, and 11% were Asian. Tumor histology was follicular lymphoma in 104 (73%; grade 1, 2, and 3a in 21%, 50%, and 26%), marginal zone lymphoma in 23 (16%), small lymphocytic lymphoma in 8 (6%), and others in 7 (5%). Ann Arbor stage was I, II, III, and IV in 2%, 18%, 23%, and 58%, respectively.
Patients had received a median of three prior therapies (range = 2–9), with 100% receiving prior rituximab (Rituxan) and alkylating agents. The median time to most recent disease progression was 8 weeks. Overall, 61% of patients were refractory to their last regimen, including rituximab in 56%, alkylating agents in 42%, and both in 43%.
Response Rates
Among all patients, objective response was achieved in 84 patients (59%), with a complete response in 12%. The median time to response was 53 days. Stable disease was observed in 30% of patients. The median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached.
Objective response rates were 59% (14% complete response) in patients with follicular lymphoma, 70% (9% complete response) in those with marginal zone lymphoma, 75% among 8 patients with small lymphocytic lymphoma, 60% among those with disease refractory to the last treatment, and 57% among those with disease responsive to the last treatment. The median response duration was 12.2 months in patients with follicular lymphoma. A waterfall plot of best response in target lesions according to investigator assessment showed that 74 of 125 patients (59%) assessed had lesion reduction of ≥ 50%.
Among evaluated patients, high expression of PI3K/B-cell receptor pathway genes was found in 33 of 44 with an objective response (75%), including 6 of 8 with a complete response. High expression levels were found in 25 (76%) of 33 evaluable patients with follicular lymphoma with an objective response and in 5 of 6 patients with a complete response.
Adverse Events
The most common adverse events of any grade were hyperglycemia (50%), diarrhea (34%), fatigue (30%), hypertension (30%), and neutropenia (30%). Grade 3 or 4 adverse events occurred in 80%, with the most common being hyperglycemia (41%), hypertension (24%), neutropenia (24%), and lung infection (15%). Noninfectious pneumonitis occurred in 11 patients (8%, 1% grade 3). Abnormal laboratory tests of interest included increased alanine transaminase (23%, 19% grade 1) and aspartate transaminase levels (28%, 25% grade 1).
Serious grade ≥ 3 adverse events occurring in at least three patients consisted of lung infection (13%), hyperglycemia (5%), decreased neutrophil count (4%), fever (3%), and diarrhea (2%); grade 3 pneumonitis occurred in two patients and grade 4 colitis, in one. Adverse events led to treatment discontinuation in 25% of patients and were considered drug-related in 16%, including noninfectious pneumonitis in five patients (4%), lung infection in four patients (3%), and hyperglycemia in three patients (2%). Adverse events led to death in five patients (4%) during or within 35 days after treatment; death was considered treatment-related in three patients, due to lung infection in one patient, respiratory failure in one patient, and cerebral thromboembolic event in one patient.
The investigators concluded: “PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.”

IMMUNOTHERAPY FOR LUNG CANCER

In a research letter to JAMA Oncology, Hwang et al detailed the outcomes of patients with metastatic lung cancer receiving an inhibitor of programmed cell death protein 1 (PD-1) or its ligand (PD-L1) with or without thoracic radiotherapy at Massachusetts General Hospital.
Study Details
The analysis included 164 patients treated between 2013 and 2016; 158 had non–small cell lung cancer and 6 (5%) had small cell lung cancer. Of them, 73 received thoracic radiotherapy and 91 did not; the 2 groups had similar baseline characteristics except for a lower proportion of patients in the radiotherapy cohort having adenocarcinoma (49% vs 75%) and targetable mutations (EGFR/ALK/ROS1; 4% vs 16%). Outcomes of interest were immune-related adverse events and survival.
Immune-Related Adverse Events
There were no significant differences between the radiotherapy group and the no-radiotherapy group with regard to the rates of grade ≥ 2 immune-related adverse events (13.7% vs 15.4%, = .83), any-grade pneumonitis (8.2% vs 5.5%, = .54), or grade ≥ 2 pneumonitis (4.1% vs 3.3%, > .99). In the radiotherapy group, the median radiotherapy dose was similar in those patients who did vs did not develop pneumonitis (52.8 vs 50.4 Gy, = .76). Of the 73 patients, 57 were treated with radiotherapy before checkpoint inhibitor initiation; pneumonitis did not occur in any of the 16 patients receiving radiotherapy between checkpoint inhibitor cycles or after treatment or receiving more than 1 course of radiotherapy.
Survival Findings
In the entire group, median overall survival was 12.1 months. On a multivariate analysis, all-cause mortality was lower in patients with grade ≥ 2 immune-related adverse events (hazard ratio [HR] = 0.45, = .03) and in those receiving fewer chemotherapy lines (HR as continuous variable = 1.21, = .01). Receipt of thoracic radiotherapy was associated with a nonsignificant reduction in all-cause mortality (HR = 0.66, = .06).
The investigators concluded: “[P]ending prospective validation, our results suggest that [thoracic radiotherapy] does not significantly increase the risk of symptomatic [immune-related adverse events], including pneumonitis, compared with [checkpoint inhibitors] alone.”
Florence K. Keane, MD, of the Department of Radiation Oncology, Massachusetts General Hospital, is the corresponding author of the JAMA Oncology article.


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®.

ADJUVANT CHEMORADIOTHERAPY IN GASTRIC CANCER

In the CALGB 80101/Alliance trial, no difference in overall survival was found for adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil (ECF) vs fluorouracil and leucovorin (5-FU/LV) after curative resection of gastric cancer. The findings were reported in the Journal of Clinical Oncology by Fuchs et al.
Study Details
In the trial, 546 patients who had undergone curative resection of stage IB through IV (M0) gastric or gastroesophageal junction adenocarcinoma were randomized between April 2002 and May 2009 to receive either postoperative 5-FU/LV before and after combined fluorouracil and radiotherapy (n = 280) or postoperative ECF before and after combined fluorouracil and radiotherapy (n = 266).
Overall Survival
Median follow-up was 6.5 years. Overall survival at 5 years was 44% in the ECF group vs 44% in the 5-FU/LV group (multivariate hazard ratio [HR] = 0.98, P = .69). Disease-free survival at 5 years was 37% vs 39% (multivariate HR = 0.96, P = .94). In post hoc subgroup analyses, treatment effects were similar across all examined subgroups.
The investigators concluded: “After a curative resection of gastric or gastroesophageal junction adenocarcinoma, postoperative chemoradiotherapy using a multiagent regimen of ECF before and after radiotherapy does not improve survival compared with standard [5-FU/LV] before and after radiotherapy.”
The study was supported by grants from the National Cancer Institute.
Charles S. Fuchs, MD, MPH, of Yale Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.


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®.

COMBINATION THERAPY FOR MELANOMA TREATMENT

A phase II study has shown that the addition of the oncolytic viral agent talimogene laherparepvec (Imlygic) to ipilimumab (Yervoy) significantly increased the response rate in patients with advanced unresectable melanoma. These findings were reported in the Journal of Clinical Oncology by Chesney et al.
Study Details
In the open-label trial, 198 patients with unresectable stage IIIB to IV melanoma and measurable/injectable disease from 45 sites in the United States, France, and Germany were randomized between August 2013 and February 2016 to receive talimogene laherparepvec plus ipilimumab (n = 98) or ipilimumab alone (n = 100). Patients had to have no more than one prior therapy if they had BRAF wild-type tumors or no more than two prior therapies if they had BRAF-mutant tumors. Talimogene laherparepvec was given at a first intralesional dose of ≤ 4 mL x 106 plaque-forming units/mL in week 1, followed by ≤ 4 mL x 108 plaque-forming units/mL at week 4 and every 2 weeks thereafter. Ipilimumab was given at 3 mg/kg every 3 weeks for up to four doses beginning at week 1 in the ipilimumab-alone group and week 6 in the combination group. The primary endpoint was investigator-assessed objective response rate on immune-related response criteria.
Response Rates
Objective response was observed in 38 patients (39%) in the combination group vs 18 patients (18%) in the ipilimumab group (odds ratio = 2.9, P = .002). Responses were not limited to injected lesions, with reductions in visceral lesions being observed in 52% vs 23% of patients. Response rates were 42% vs 10% among 122 patients with BRAF wild-type disease and 34% vs 32% among 69 patients with BRAF-mutant tumors. The median response duration was not reached in either group.
Adverse Events
Common adverse events of any grade in the combination group included fatigue (59% vs 42%), chills (53% vs 3%), and diarrhea (42% vs 35%). Grade ≥ 3 adverse events occurred in 45% vs 35%. Grade ≥ 3 ipilimumab-related adverse events occurred in 19% vs 18%, with the most common being gastrointestinal disorders including colitis (5% vs 4%), diarrhea (3% vs 3%), and autoimmune colitis (2% vs 3%). Grade ≥ 3 talimogene laherparepvec–related adverse events occurred in 15% of patients, with the most common being influenza-like illness (4%) and lymphopenia (4%). Fatal adverse events occurred in three patients in the combination group, with none considered related to treatment.
The investigators concluded: “The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.”

CANCER STATUS BEATS FAMILY HISTORY FOR BRCA TESTING

Using cancer status instead of family history to assess whether a person should undergo testing for breast cancer susceptibility genes is more effective and cheaper, new research shows.
In our study, if the decision to test had been made on the basis of family history, mutations in more than 5% of patients would have been missed, said Nazneen Rahman, MD, PhD, from the Institute of Cancer Research in London.
"We've been able to do BRCA testing for over 20 years, but studies have universally shown that we are not as effective at it as we would like," Dr Rahman said here at the American Society of Human Genetics 2017 Annual Meeting.
The health authorities in most countries recommend that people with a risk for BRCA mutations above 10% be offered genetic testing. In most systems, this involves complex, time-consuming, and costly counseling sessions and referrals, and access to testing can be limited by financial and staffing constraints, she explained.
"There have been many lost opportunities for optimizing the management of cancer patients, and for cancer prevention in well individuals," she said.
Dr Rahman and her colleagues wanted to develop a simpler and more effective way to test patients diagnosed with breast cancer for predisposition.
The team began by identifying five categories of high-risk breast cancer: onset before age 40; bilateral breast cancer before age 60; triple-negative breast cancer (estrogen-, progesterone-, and HER2-receptor-negative disease) at any age; breast and ovarian cancer at any age; and breast cancer in a male.
They then used the TruSight cancer gene panel, from Illumina, to test for BRCAmutations and to calculate mutation detection rates. They also looked at the rate of mutation detection for eight other breast cancer predisposition genes the panel tested for.
BRCA1 and/or BRCA2 mutations were detected in 110 (10.8%) of the 1020 breast cancer patients who met the criteria for a high-risk category and underwent testing. If the decision to test had been made on the basis of family history, mutations in 56 (5.5%) patients would have been missed.
And for each individual category, the mutation detection rate was above 10%.

Table. Mutation Detection Rate in the High-risk Five Categories

Cancer StatusDetection Rate, %
Onset before age 4012.1
Bilateral breast cancer before age 6013.6
Triple-negative breast cancer at any age10.2
Breast and ovarian cancer at any age27.8
Breast cancer in a male11.5
To confirm these findings, Dr Rahman's team then conducted a retrospective study of 2036 patients recruited for the Breast and Ovarian Cancer Susceptibility study.
For every category but male breast cancer, the mutation detection rate ranged from 11.0% to 13.2%. The detection rate for men with breast cancer was just 3.2%, but the sample size too small — only 31 patients — to determine an accurate rate, Dr Rahman reported.
The researchers then used two BRCA mutation risk scores to assess the accuracy of family history as an indicator.
When a Manchester score of at least 15 was set as the threshold, only 53 of the 110 (48.2%) patients with mutations were identified. And when a Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk score of at least 10% was used, only 42 (38.2%) of the mutation carriers were identified.
With these risk models, "more than 50% of mutation carriers would not have been eligible for testing based on family history," Dr Rahman said.
When 368 patients with cancer who did not fall into any of the high-risk categories but who had a family history of cancer were assessed, the rate of mutations was 5.4% for patients with a moderate family history, and 7.0% for patients with a strong family history.
The take-home message from this study is that "once cancer-based testing has been done, current family history criteria are not good at predicting the likelihood of having a mutation," Dr Rahman explained.

Pound Wise

In addition, a financial analysis showed that use of the high-risk categories to identify candidates for genetic testing, rather than family history, would save a total of £3,063,681 (US$4,035,480) by preventing 1157 cancers and 222 deaths from breast or ovarian cancer each year.
This strategy appears to offer advantages over family history as a basis for test eligibility, said Ian Campbell, PhD, from the Peter MacCallum Cancer Centre in Melbourne, Australia.
"People's recollection of family history is notoriously bad," he told Medscape Medical News, noting that some people are not always aware of cancers in first-degree relatives. And others might overestimate risk because a more distant female relative died from breast cancer at an advanced age.
If implemented, such a system might reduce the use of pretesting genetic counseling, said Aisha Furqan, a genetic counselor at St. Agnes Medical Center in Fresno, California.
"You might be cutting some costs and time, but really, counseling is invaluable for individuals who don't have preconceived ideas about what genetic testing can or can't do," she said after the presentation.
Women have come to my office and declined genetic testing after counseling because, at that point in their treatment or in their family lives, they just weren't ready for it, she told Medscape Medical News. But they might be interested at another time, she added.
The study was supported by the Wellcome Trust and The National Institute for Health Research. Dr Rahman reports serving on the board of directors of AstraZenca. Dr Campbell and Ms Furqan have disclosed no relevant financial relationships.
American Society of Human Genetics (ASHG) 2017 Annual Meeting: Abstract 65. Presented October 18, 2017.
Follow Medscape on Twitter @Medscape and Neil Osterweil @NeilOsterweil

HIGH PREVALENCE OF HPV INFECTION IN MEN

High prevalence rates of oral human papillomavirus (HPV) of any type, as well as high-risk, oncogenic HPV types, are being reported among all ethnic groups of men in the United States, according to a comprehensive analysis of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014.
Among a sample of 4493 men and 4641 women, the prevalence of any type of oral HPV infection was 11.5% among men and 3.2% among women.
This means that 11 million men and 3.2 million women in the United States are infected with some type of oral HPV, the study authors point out.
Disturbingly, however, the prevalence of high-risk oral HPV infection was 7.3% among men and 1.4% among women.
This translates into 7 million men and 1.4 million women who have high-risk oral HPV infection. By far the most common type is HPV 16, which is commonly associated with oropharyngeal cancer.
Such risk factors as having more than 16 lifetime sexual partners, smoking, and marijuana use significantly increased the risk of men and women having any as well as high-risk oral HPV infection.
Just as dramatically, men with concurrent genital as well as any or high-risk oral HPV infection had among the highest prevalence rates of oral HPV infection of any subgroup analyzed.
The study was published online October 16 in Annals of Internal Medicine. 
"Overall prevalence of oral HPV infection was high among U.S. men," the authors comment.
"We previously used the latest NHANES data to study the prevalence of genital HPV among US men, and we found that one out of two US men have genital HPV and one out of three US men have high-risk genital HPV — findings which were shocking to us — so we wanted to look at the prevalence of oral HPV among these men because we thought they might be at high risk for having oral HPV infection as well," senior author, Ashish Deshmukh, PhD, MPH,  University of Florida, Gainesville, told Medscape Medical News.
"In this study, we found that the prevalence of overall oral HPV among men who have genital HPV was close to 20%, while the prevalence of high-risk HPV infection was close to 14%, whereas the prevalence of oral HPV infection was less than 5% in men without genital infection," he added.
"To me, this is important because this helps us understand HPV transmission dynamics and it also might help us stratify individuals with a higher prevalence of oral HPV and if we develop potential screening tools [for oral HPV] in the future, these are the men we need to target," Dr Deshmukh said.
NHANES involved US citizens aged 18 to 69 years who underwent a physical exam at a mobile examination center (MEC).
A dental hygienist collected oral rinse specimens, which were transferred to a MEC laboratory.
Each oral rinse sample was analyzed by polymerase chain reaction assay for the presence of any of 37 HPV types.
"Notably, the prevalence of HPV 16, the most common [high-risk] type, was sixfold higher among men (1.8%)…than women (0.3%) (P < 0.001)," the investigators report.
Indeed, men were consistently more likely than women to be infected with all high-risk as well as all low-risk HPV types, they add.
Non-Hispanic black men had the highest prevalence rates of overall oral HPV infection, at 15.8%, as well as high-risk oral HPV infection, at 8.8%.
Respective prevalence rates in white men were 11.7% for overall oral HPV infection and 7.8% for high-risk oral HPV infection.
Rates were lowest among Hispanic men, at a prevalence of 9.9% for overall oral HPV infection and 5.5% for high-risk oral HPV infection. 
However, the prevalence of overall and high-risk HPV oral infection was significantly influenced by behavioral factors, such as smoking and marijuana use.
Among men who smoked more than 20 cigarettes a day, the prevalence of overall oral HPV infection was 23.6% while the prevalence of high-risk oral HPV infection was 15% in the same group of men.
In comparison, among men who had never smoked or who had quit smoking, the prevalence of any oral HPV type infection was 8.3% while the prevalence of high-risk oral HPV infection was 5.4%.
Moreover, the prevalence of high-risk oral HPV infection was 4 to 10 times higher in men who reported having more than 16 lifetime sexual partners compared with men who reported only one or no lifetime sexual partners.
Prevalence rates of oral HPV infection were slightly lower but similar among women who reported the same number of lifetime sexual partners.
Men in particular, but women as well, who reported same-sex partners were also at fairly substantial risk for infection with high-risk oral HPV types: 12.7% and 3.6%, respectively.
"The prevalence of high-risk HPV infection was highest (22.2%)…among men who reported having 2 or more lifetime same-sex oral sex partners," the investigators note.
The overall prevalence of oral HPV infection in men who reported having sex with men was 18.2%.

Persistent Infection

Asked by Medscape Medical News whether most HPV infections aren't relatively rapidly cleared by the body, Dr Deshmukh acknowledged that most of the common HPV types are not harmful and are likely to be cleared after infection, but HPV16 in particular is much more likely to persist than even other high-risk HPV types.
In a study analyzing the persistence of HPV 16,  investigators found that most prevalent infections, though not newly acquired infections, persisted for at least 24 months.
"If a person has more than 16 lifetime sexual partners, then they have a high risk of acquiring HPV 16 but we also have some evidence that these individuals may not clear HPV 16 as fast, so that they are at risk for it to persist," Dr Deshmukh explained.
Dr Deshmukh also pointed out that HPV 16 was most prevalent in men aged 50 to 69 years, none of whom — and most likely, their sexual partners — would have been vaccinated against HPV infection.
This is again an important observation as a subanalysis of the current cohort indicated that men who reported being vaccinated against HPV had the lowest prevalence of oral HPV infection of any of the subgroups analyzed.
Interestingly, study authors also found that rates of oropharyngeal cancer appear to be declining among women, mirroring rates of decline in the incidence of cervical cancer among US women.
Between 2008 and 2012, an average of almost 40,000 HPV-related cancers were diagnosed in the United States each year, the most common being oropharyngeal squamous cell carcinoma: Over 12,000 cases occurred in men and 3100 cases were diagnosed in women.
The study was supported by the National Cancer Institute. Dr Deshmukh has disclosed no relevant financial relationships, but some co-investigators have disclosed relationships, stated in the published paper. 
Ann Intern Med. Published online October 16, 2017. Abstract
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ONCOLOGY MOST STRESSFUL OF SPECIALTIES

Oncology is one of the most stressful of all medical specialties, and among the healthcare professionals on the cancer care team, oncologists are at highest risk for burnout.
Highlighting these issues and outlining some strategies to protect against burnout here at the 18th World Conference on Lung Cancer (WCLC) was Dr Maria Flanou, clinical psychologist at the Peter MacCallum Cancer Center in Melbourne, Australia.
"My role is to provide psychological services to people with cancer across the whole cancer trajectory, from diagnosis to end-stage disease," she said. As part of a multidisciplinary team, the work is "very rewarding, but working in oncology is also very stressful."
The stress in oncology stems from the nature of the disease that is being treated. The work involves repeatedly breaking bad news to patients, witnessing patient deaths as well as severe reactions to and adverse events from treatments, watching patients deteriorate session by session and seeing their physical suffering. In addition, "we often have to manage very complicated situations," she added, which can include encounters with angry patients or angry families.
In addition, there are increasing demands that take up time, and there are often staff shortages, "so it can get to 3:00 pm before realizing that we haven't had lunch" she said.
Together these factors can lead to burnout, she warned. This is often described as complete emotional and physical exhaustion, but there are other elements, including depersonalization (feeling detached, cynical) and having a low sense of personal accomplishment (feeling unfulfilled and unsatisfied by work).
There are very few personal accounts of burnout in the literature, she noted. "None of us ever wants to admit that we are not coping and that we can't manage our workloads," she said. In addition, admitting to experiencing burnout can jeopardize future job chances.
However, she did find in the literature two cases in which oncologists had written about their experiences of burnout.
"Time is baffling. It seemed like just yesterday that I sat in a posh auditorium in Chicago, an enthusiastic young adult on my first day of medical school orientation.... Eighteen years later, I was a 43-year old burned out physician, searching Google for the most effective way to end my life. During my time of maximum burnout, I was the type of physician that I never wanted to be: impatient, sarcastic, and occasionally dismissive of my patients." (Murphy, 2015)
"I go through weeks where it's very difficult to come into work. I come in but I don't really want to be here at all. It's an effort to drag myself down to clinic.... because I know that I'm going to see patients who are going to do badly." (Granek et al, 2012)
This second quote comes from a study published in the Archives of Internal Medicines. That article has many other quotes from oncologists who talk specifically about the impact of seeing their patients die.
Sometimes I'll take a chart and I'll look at the imaging, and everything's worse and the numbers are worse, and I have to drag myself into the patient's room and figure out what can I offer them that's hopeful and positive. It's tough." 
"Let's face it, people who go into medicine have full-blown fantasies, I mean, I do. You think you're going to go in there to cure people...and it doesn't happen. It doesn't matter what you do really.... Sometimes I make an impact on what happens but sometimes I just get steamrolled." 
"There's always sadness with every loss."
"Sometimes I cry. I cry on the way home in the car." 
"I think you just get exposed to so much death that you just become somewhat accustomed to it.... It's part of our job. I mean death is normal, everybody dies, it's just that we experience a larger amount of it." 
"It keeps me awake at night." 
"It is a very bad thing to become emotionally attached to your patients, because you're going to suffer." 
"It's something bad, but I have to keep my personal feelings and personal life separate from my work feelings and work life. I have to keep reminding myself to have a little bit of dissociation like that, so I can sleep every night and not carry things home." 
"The issue with doing Oncology is that you walk a very fine line; if you get too involved with your patients you can't function because it's too much emotional load to bear, and if you get too distant from your patients then I don't think you're being a very good physician because people pick up on that." 
"I'm up to the point where I probably lose one or two patients a week minimum. And that's a lot of people.... It's a physical sensation of being ground away.... It takes me a long time to recover from that." 
The authors write that as far as they are aware, this study is the first qualitative exploration of the nature and impact of grief in oncologists. "We found that for oncologists, patient loss was a unique affective experience that had a smokelike quality. Like smoke, this grief was intangible and invisible. Nonetheless, it was pervasive, sticking to the physicians' clothes when they went home after work and slipping under the doors between patient rooms."

Oncologists Most Vulnerable

In the literature, estimates of the prevalence of burnout among oncology professionals are from 35% to 60%, Dr Flanou noted in her talk. A random sample of 1000 US oncologists found that 56% had experienced burnout at some point in their career ( J Clin Oncol . 1991;9:1916-20).
Even higher rates have been reported ― a survey conducted by the European Society of Medical Oncology in 2014 found that 70% of young oncologists reported feeling burned out. Three of these oncologsts discuss their experiences in a Medscape report; they conclude that "there is no such thing as work/life balance."
Among the cancer care team, oncologists are at highest risk, Dr Flanou noted. She cited a study from 2014 that found that 38.9% of oncologists reported burnout, compared to 20.8% of nurses, 22.2% of specialist nurses, 20.9% of social workers, and 13.8% of psychologists.
"It is the physicians who are the most vulnerable to burnout, and I think this is because they have to be everything to everyone and perform a number of different roles in their workplace," she commented.
There can be serious consequences from burnout ― both for the healthcare professional who experiences burnout and for the patients under their care, she warned.
Among individuals who are experiencing burnout, it is likely that 20% to 33% experience mental health problems; 34%, poor quality of life; 30%, impaired intimate and social relationships; 15%, suicidal ideation; and 15%, drug and/or alcohol abuse problems.
Physicians who are experiencing burnout have less empathy for their patients, may offer reduced quality of care, and may make medical errors, particularly in drug dosing.
On the organizational level, burnout leads to increased absenteeism, high staff turnover, poor service delivery, and increased legal costs.

Importance of Self-care

The first step in addressing burnout is to measure it, Dr Flanou told the audience here.
The most frequently used tool to determine rates of burnout is the Maslach Burnout Inventory. This is a 22-item self-report questionnaire that measures the three distinct dimensions of burnout: emotional exhaustion, depersonalization, and personal accomplishment.
There are steps that can be taken to reduce burnout, both at the individual and organizational levels.
"Developing personal resilience is essential for combating stress and burnout," she said.
"Resilience is not something that we are born with, it's something that we need to develop," she continued. It involves "adapting well in the face of significant stress."
Four components help build resilience:
"Often these are the things that we neglect when we are most stressed," Dr Flanou commented, but these are the things that we need to make time for, because they help with coping with that stress.
Within the workplace, ways to build resilience including the following:
"Debriefing is vitally important," she said. "We have had patients who have gotten under our skin or who have died in traumatic ways, and making sure that we reflect on this with even a couple of people helps to deal with the stress."
Mindfulness ― being in the present moment, rather than worrying about what could happen or what has happened ― is very useful for coping with stress and for dealing with patients, she said. Mindfulness programs, which are usually run in group sessions, change one's awareness of how one feels emotionally. They can include breathing and stretching exercises and understanding stress. Several studies have shown very positive benefits from such programs for clinicians. These studies have found that participants in mindfulness training programs sleep better, cope better, and have increased empathy for their patients, she noted.
Communication training has also been shown to be beneficial, especially in helping physicians to break bad news to patients, which is one of the most stressful aspects of the job. These programs, which often involve role playing, are facilitated by mental health professionals. They have been shown to increase oncologists' confidence in delivering difficult information, she noted.
Dr Flanou has disclosed no relevant financial relationships.
18th World Conference on Lung Cancer (WCLC). Abstract MA 21, presented October 19, 2017.
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DURVALUMAB WELL TOLERATED

New data from the PACIFIC study of durvalumab (Imfinzi, AstraZeneca) in patients with unresected stage III non-small cell lung cancer (NSCLC) show that the drug is well tolerated and does not affect quality of life.
In fact, some symptoms, such as dysphagia and alopecia, improved, most likely because of resolution of toxicities related to the prior chemoradiotherapy that all patients received.
These new patient-reported outcomes, a secondary endpoint of the trial, add to the recently reported efficacy results showing that durvalumab significantly improved progression-free survival (PFS) compared with placebo. The median PFS was 16.8 months with durvalumab vs 5.6 months with placebo (hazard ratio, 0.52; P < .0001).
"This is an important advance," commented Michael Boyer, MD, clinical professor of medicine at the University of Sydney, Australia.
Numerous previous trials have attempted to improve outcomes in this patient population, and all have failed. Researchers contemplating new trials must have felt as if they were banging their heads against a brick wall, Dr Boyer said. Now, a few bricks have fallen away and blue skies are visible beyond.
Dr Boyer was speaking at a plenary session here at the 18th World Conference on Lung Cancer (WCLC), acting as a discussant for the new data on patient outcomes from the PACIFIC trial, which had just been presented.
The efficacy data, which were the primary endpoint, had been presented a month ago at the European Society for Medical Oncology annual meeting and were simultaneously published online in the New England Journal of Medicine.
At that time, lung cancer experts welcomed the new results enthusiastically, as reported by Medscape Medical News. While overall survival results are now eagerly awaited, the magnitude of PFS benefit supports durvalumab as a new standard of care for patients with unresectable stage III NSCLC who had no progression after standard care with platinum-based chemotherapy and concomitant radiotherapy, commented Pilar Garrido, MD, PhD, head of the Thoracic Tumour Section of the Medical Oncology Department at Ramón y Cajal University Hospital, Madrid, Spain.
Since then, several lung cancer experts have commented that this trial changes the treatment paradigm because it shows — for the first time — that an immunotherapy is beneficial at an earlier stage of lung cancer. These patients had locally advanced unresectable stage III NSCLC. All the previous trials with immunotherapy in lung cancer (pembrolizumab, nivolumab, atezolizumab) have been in later-stage disease: advanced and metastatic NSCLC.
Dr Boyer provided the human context for this in his discussion — these patients with locally advanced stage III NSCLC are potentially curable, he said.
At present, about 15% of this patient population is still alive 5 years after treatment.
Numerous attempts have been made to improve upon the results achieved with standard-care chemoradiotherapy, he said. Clinical trials have compared sequential and concurrent chemotherapy and radiation but found no difference between the two. The RTOG 0617 trial in 2014 looked at increased radiotherapy dose but found only increased toxicity. Other trials looked at adding more chemotherapy before or after chemoradiotherapy (Cancer and Leukemia Group B in 2007, and Hoosier Oncology Group  in 2008), adding another chemotherapy to cisplatin (pemetrexed in the PROCLAIM study in 2016 and docetaxel in 2010), or adding targeted agents (cetuximab in RTOG 0617 in 2008 and gefitinib in the Southwestern Oncology Group S0023 trial in 2008). Another approach was the use of tecemotide vaccination after chemoradiotherapy (in the START trial in 2014).
But all of these trials failed to improve the outcomes for these patients.
That's why Dr Boyer considers the durvalumab results as "an important advance in the management of unresectable stage III NSCLC."
"For the first time in a long time, there was a significant improvement in outcomes," Dr Boyer commented.
Median PFS with durvalumab was 11 months longer than with placebo, about a 20% improvement, he said. Overall survival results are now anticipated — they should be reported in the coming months, he said.
The new data showing no impact on quality of life are important, he said, because "we want to ensure that the gains achieved in survival are not countered by adverse events."  
The quality-of-life data were presented at the WCLC meeting by Rina Hui, MD, from the Westmead Hospital and the University of Sydney in Australia.
In the PACIFIC trial, symptoms, physical function, and global health status/quality of life were evaluated on the European Organisation for Research and Treatment of Cancer QLQ-C30v3 questionnaire and its lung cancer module, QLQ-LC13, she explained. These were completed at baseline and weeks 4 and 8, and then every 12 weeks until disease progression.
The results show no change from baseline in most symptoms. A clinically relevant improvement in dysphagia and alopecia was reported at 48 weeks in both the durvalumab and the placebo groups. This is likely to reflect resolution of the toxicity from the chemoradiotherapy that all patients received (they were enrolled in the trial with 6 weeks of undergoing chemoradiotherapy), Dr Hui commented. In addition, reports of improvement in appetite loss and other pain favored durvalumab.
Dr Hui concluded that adding durvalumab to chemoradiotherapy "did not compromise quality of life." 
Durvalumab, a checkpoint programmed cell death ligand 1 inhibitor, is not yet approved for use in lung cancer, although the manufacturer has said it will be submitting the PACIFIC data to regulatory authorities. At present, the drug is approved for use in urothelial carcinoma.
The PACIFIC trial was sponsored by AstraZeneca. Dr Hui reports receiving advisory board fees from AstraZeneca, Merck Sharp & Dohme, and Novartis; speaker honorarium from Merck Sharp & Dohme; and accommodation expenses from Roche. Dr Boyer reports research funding and/or honoraria paid to his institution from Bristol-Myers Squibb, Merck, AstraZeneca, Amgen, Pfizer, Genentech/Roche, and Peregrine Pharmaceuticals.
18th World Conference on Lung Cancer (WCLC). Abstracts PL 02.02 (Dr Hui) and PL02.03 (Dr Boyer). Presented October 17, 2017.
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ELDERLY WITH BREAST CANCER STILL OVERTREATED WITH RADIOTHERAPY

A large proportion of surgeons in the United States and even a good percentage of radiation oncologists still insist on treating women aged 70 years and older with adjuvant radiotherapy after they undergo lumpectomy for early-stage breast cancer. This is despite overwhelming evidence that adjuvant radiotherapy provides no survival benefit and very little protection against recurrence compared with no radiation.
The finding comes from a nationwide survey of surgeons and radiation oncologists published online in the Annals of Surgical Oncology.
"In the last 30 to 40 years, we've learned the value of doing less," Dean Shumway, MD, University of Michigan, Ann Arbor, said in a statement.
"[But] 60 percent of patients older than age 80 still receive radiation, so the [aim] of this study was to investigate how physicians view the option of omitting radiotherapy, with the goal of understanding more about why practice patterns haven't changed," he added. 
"The finding we didn't expect was that surgeons are generally more uncomfortable with the idea of omitting radiation than radiation oncologists are — it's viewed as a departure from the standard of care — and since the population is aging, this is going to be an issue that affects more women," Dr Shumway indicated.

No Benefit From Radiation  

Two large studies have shown that the addition of radiotherapy has no benefit for most older women who undergo lumpectomy and then endocrine therapy.  
In 2004, the Cancer and Leukemia Group B (CALGB) 9343 trial showed that adjuvant radiotherapy can be safely omitted in women age 70 years and older who have small, estrogen receptor–positive breast cancer treated with lumpectomy and tamoxifen.
Again in 2015, investigators involved in the PRIME II trial reported similar findings in women 65 years of age and older with early breast cancer followed out to 5 years.
In other words, 90% of patients such as those involved in these two trials do not benefit from radiation and do well with lumpectomy alone, provided they take endocrine therapy for 5 years.
"These studies have widely been interpreted as establishing breast-conserving surgery with omission of radiotherapy as a reasonable option for similar women who receive endocrine therapy," Dr Shumway and colleagues write.
And indeed, 96% of radiation oncologists included in the current survey indicated that they were familiar with findings from at least the CALGB 9343 study.

Why No Change in Practice? 

To find out why practice has changed so little despite the publication of these two pivotal trials — and despite radiation oncologists seeming to be familiar with them — Dr Shumway and colleagues mailed an eight-page questionnaire to 879 surgeons and 713 radiation oncologists who routinely treat breast cancer in the United States.
We evaluated physicians' attitudes and general knowledge by asking respondents to rate their agreement with statements such as 'Adjuvant radiation improves survival for elderly patients with early-stage breast cancer treated with lumpectomy'," the investigators note.
They also explored physicians' knowledge and recommendations regarding omission of radiotherapy in older patients with favorable-prognosis breast cancer by using various clinical vignettes.
Results showed that 40% of surgeons and 20% of radiation oncologists felt that omitting radiotherapy after lumpectomy was "unreasonable" (P < .001).
"Nearly a third of surgeons (29%) and 11% of radiation oncologists erroneously associated radiotherapy in older women with improvement in survival," the researchers add.
A "nontrivial minority" of both groups overestimated remaining life expectancy in such patients, while almost a third of surgeons and 19% of radiation oncologists overestimated the risk for locoregional recurrence as being at least 15% after 10 years if radiation therapy were omitted.
Importantly, those who wrongly attributed a survival benefit from radiotherapy and who overestimated remaining life expectancy were more than 6 times more likely to find the omission of adjuvant radiotherapy in this patient population as unreasonable.
Moreover, "one-third of surgeons and radiation oncologists would continue to recommend adjuvant radiotherapy even for an unhealthy 81-year-old," the  investigators write.

Concern Over Legal Liability

Almost half of the surgeons surveyed were concerned about legal liability issues if radiotherapy were omitted and patients subsequently developed a local recurrence, as were about one quarter of radiation oncologists.
Fifteen percent of radiation oncologists were also concerned about the financial repercussions that could occur if they did not offer radiotherapy to this patient population.
Approximately half of radiation oncologists pointed out that it's really a patient's decision to undergo radiotherapy and that patients often want to be treated more aggressively, even if the benefit is small.
Almost half of respondents indicated that it's more effort to convince patients they don't need radiotherapy than it is to recommend it, the investigators add.
As the authors point out, the surgeon is usually the first physician to discuss treatment options with patients with breast cancer and thus is the one most likely to set expectations, including the expectation that radiotherapy will be needed after lumpectomy.
This is why the investigators suggest that targeting surgeons may well be key to reducing aggressive care in older women with early-stage breast cancer.
"Our study provides a detailed view into the physician perspective on how the decision is made to omit radiotherapy and we hope this insight will be useful in improving delivery of individualized care for older women with early-stage breast cancer," Dr Shumway concluded.

FROZEN GLOVES TO PROTECT AGAINST PACLITAXEL NEUROPATHY

Getting patients with breast cancer to wear frozen gloves and socks for 90 minutes while receiving weekly paclitaxel chemotherapy significantly reduces objective and subjective assessments of chemotherapy-induced peripheral neuropathy (CIPN) across at least 12 treatment cycles, a self-controlled, prospective study indicates.
"CIPN is a substantial clinical problem, there is no good prevention of it except to not give the drug or to decrease the dose, and there's limited benefit for treating established neuropathy," Charles Loprinzi, MD, professor of breast cancer research, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. He was not involved in this research and was approached for comment.
"So this study is clearly interesting and the data do support the fact that cryotherapy seems to work, but it would be nice to have more data before we can really recommend it," he added.
The study was published online October 12 in the Journal of the National Cancer Institute.
Coauthor Hiroshi Ishiguro, MD, PhD, Kyoto University, Japan, and colleagues report that 44 patients were enrolled in the trial, 36 of whom were evaluable for the analysis at study endpoint.
"Each patient wore frozen flexible gloves and socks [Elasto-Gel, Akromed] on the dominant hand and foot from 15 minutes before paclitaxel administration to 15 minutes after the infusion was complete," the investigators write. "The nondominant side acted as the untreated control," they add.
Participants were given another pair of frozen gloves, though not socks, 45 minutes after the intervention had been initiated.  
Patients were assessed for symptoms of CIPN at multiple time points: at baseline and before they received each cycle of chemotherapy during outpatient care. Chemotherapy consisted of weekly paclitaxel at a dose of 80 mg/m2.
Symptoms of CIPN were also assessed when patients had reached a cumulative treatment dose of 960 mg/m— the dose recommended for both neoadjuvant and adjuvant weekly paclitaxel therapy.
Twenty-five of the 36 evaluable participants reached the cumulative dose of 960 mg/m2, while another 11 patients received even higher doses, the researchers point out. 
"The primary end point was the incidence of CIPN (any grade), defined as a decline in tactile sensation from the pretreatment baseline as assessed by the Semmes-Weinstein monofilament test," study authors note. This test is the most widely used test to diagnose the loss of protective sensation, one component of CIPN.  
On the dominant side, where patients had been treated with cryotherapy, 27.8% of hands had detectable tactile deterioration — the definition of CIPN for the study — compared with 80.6% of untreated hands (P < .001).
Similarly, 25% of feet that had been treated with cryotherapy had evidence of tactile deterioration at study endpoint compared with 63.9% of untreated feet (P < .001).
Large differences between treated and untreated hands and feet were also detected in several secondary endpoints.
For example, perception of warmth was reduced in only 8.8% of treated hands vs 32.4% of untreated hands (P = .02) and in 33.4% of treated feet vs 57.6% of untreated feet (P = .04).
Compared with baseline, delay in performance speed (also referred to as delay in manipulate dexterity) was greater on the untreated side at 8.6 seconds compared with a –2.5-second delay on the intervention side (P = .005).
At a cumulative dose of 960 mg/m2, sensory dysfunction was almost prevented, with only 2.8% of treated hands developing symptoms of severe CIPN as assessed by the Patient Neuropathy Questionnaire (PNQ) compared with 41.7% of untreated hands (P < .001).
For severe CIPN of the foot, percentages were nearly identical, with only 2.8% of treated feet developing severe CIPN compared with 36.1% of untreated feet, again based on PNQ assessment.
"CIPN also occurred faster on the control side than on the intervention side," the investigators observe (< .001). "Furthermore, no patients dropped out due to cold intolerance."
The few adverse events resulting from cryotherapy resolved almost immediately.
"Compression therapy [using surgical gloves] and cryotherapy share an analogous mechanism of reduced drug exposure due to vasoconstriction during paclitaxel infusion," the investigators explain.
"We conclude that cryotherapy is a simple, safe, and effective strategy for the prevention of CIPN in patients with cancer undergoing paclitaxel treatment," they suggest.

Accompanying Editorial

In an accompanying editorial, Dawn Hershman, MD, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, cautions that the pathophysiology of CIPN may vary depending on the chemotoxic agent used, and it is not clear whether cryotherapy can prevent CIPN induced by a drug such as oxaliplatin, which also causes a lot of CIPN. 
"If the results are confirmed, cryotherapy has the advantage of a limited side effect profile, it is low cost, and it appears to prevent components of CIPN other than neuropathic pain," Dr Hershman writes.

Further Study

Commenting further on cryotherapy for the prevention of CIPN, Dr Loprinzi said that there is in fact a larger study, with accrual completed, in which where  investigators, including Dr Loprinzi, will be evaluating topical cryotherapy for reducing pain in patients with CIPN or the paclitaxel-induced acute pain syndrome (the ACCRU trial).
He also pointed out that further support for the benefit of using surgical gloves to protect patients against paclitaxel-induced CIPN was published last year at the American Society of Clinical Oncology (ASCO) annual meeting, where investigators reported significant reductions in both sensory and motor neuropathy in hands protected by a surgical glove during chemotherapy compared with unprotected hands.
"Our trial should be reported at ASCO 2018, and hopefully we will see enough information about cryotherapy in CIPN by then that will allow us to proceed with it," Dr Loprinzi said.

COST EFFECTIVENESS OF ZOLEDRONIC ACID

At a time when rising healthcare costs in the United States are coming under intense scrutiny, one of the first independent analyses to compare a proprietary drug with its generic counterpart shows that zoledronic acid given every 3 months is more cost-effective than monthly denosumab (ProliaXgeva, Amgen) in women with breast cancer and skeletal metastases, say researchers.
Analysis of data from the Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology trial 70604 shows that compared with the cost of zoledronic acid every 3 months, the mean cost of administering monthly denosumab to prevent skeletal-related events (SREs) was nine times higher over a 2-year period, according to Charles L. Shapiro, MD, professor of medicine, Icahn School of Medicine at Mt Sinai, New York City, and colleagues.
The study also compared monthly denosumab to monthly zoledronic acid.
The mean incremental costs per mean SRE avoided ranged from $162,918 to $347,655 for denosumab, the study authors say in a report published online October 12 in the Journal of Clinical Oncology. When compared with the cost of zoledronic acid given monthly, the mean incremental costs of denosumab per mean SRE avoided ranged from $137,905 to $283,109 over 24 months.
Importantly, the analysis was sponsored by the National Cancer Institute and not by Novartis, the manufacturer of zoledronic acid, or by Amgen, which makes denosumab, the investigators note. In the past, most analyses comparing cost-effectiveness between zoledronic acid and denosumab have been sponsored by the companies, they say.
"As we move toward a value-based health care model, every 3-month ZA [zoledronic acid] may be a viable alternative to monthly denosumab when costs are considered," write Dr Shapiro and colleagues.
Up to 75% of women with metastatic breast cancer develop bone metastases, a cause of significant morbidity, including pain, pathologic fracture, spinal cord compression, and hypercalcemia requiring surgery and/or radiation therapy.
Earlier this year, the CALGB/Alliance trial showed that zoledronic acid every 4 months was noninferior to monthly zoledronic acid in terms of 2-year cumulative incidence of SRE and selected toxicities in patients with breast cancer, prostate cancer, and multiple myeloma. Dr Shapiro and colleagues used these data to construct a hypothetical cohort of 10,000 women with breast cancer and bone metastases to analyze the value of monthly zoledronic acid and  zoledronic acid every 3 months and compare them to monthly denosumab.
We've got to start doing more trials like this. Dr Charles L. Shapiro
"We've got to start doing more trials like this," Dr Shapiro said in an interview with Medscape Medical News."It's about value — how much do you get for what it costs? In this age, we're moving towards a value assessment of costs and yet it's part of our culture that no matter how expensive a drug is, we keep going back to it. Is $100K to $200K a year for a 2-month survival advantage worth it?"
Even though denosumab is more efficacious in terms of delaying time to first SRE and time to subsequent events, "there is no survival difference," Dr Shapiro emphasized. "This is not strong enough [evidence] to make it a preference."
There is no survival difference. Dr Charles L. Shapiro 
A 2010 randomized, double-blind trial showed that monthly denosumab was 23% better than zoledronic acid in delaying time to first SRE and the time to first and subsequent SREs, the investigators point out. That study also showed that overall survival, disease progression, and rates of adverse and serious adverse events were similar between the treatment groups.
On October 16, the American Society of Clinical Oncology (ASCO), in collaboration with Cancer Care Ontario (CCO), published an online update on the role of bone-modifying agents in metastatic breast cancer.
After conducting a targeted literature review, the joint ASCO-CCO update committee concluded there was insufficient evidence to support the use of one bone-modifying agent over another in the treatment of patients with breast cancer with bone metastases. Their recommended treatment options include denosumab, 120 mg subcutaneously, every 4 weeks; pamidronate (Aredia, Novartis), 90 mg intravenously, every 3 to 4 weeks; or zoledronic acid, 4 mg intravenously every 12 weeks or every 3 to 4 weeks.
Given that the new ASCO guidelines don't endorse any single bone-modifying agent, Dr Shapiro said he found the price differential between zoledronic acid and the new denosumab somewhat surprising. "I think that's the point," he told Medscape Medical News. "This study is a way to alert the oncology community to the fact that if you use every-3-month zoledronic acid, you can save a whole bunch of costs. It's a lot cheaper."
Sensitivity analyses were performed from a US payer perspective. The average cost of a treatment strategy was calculated by using the average of the drug cost, the cost of drug administration, and the cost associated with having SREs.
The researchers used the assumption that the probability of SREs in patients treated with denosumab would be 50%, 75%, and 90% lower than the probability of SREs with zoledronic acid. Factors taken from data in the CALGB/Alliance trial as well as the 2012 study by Xie et al were used to determine SRE probabilities.

Other Considerations Come Into Play

When asked to comment, Hatem Soliman, MD, associate member of the breast, tumor biology, and immunology departments at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, pointed out that it would be "difficult to demonstrate cost-effectiveness between a branded drug given monthly and a generic drug given once every 3 months unless the difference in the primary outcome was very large."
Depending on which cost-effectiveness model is used, "less expensive pamidronate may be even more cost-effective than zoledronic acid," said Dr Soliman, who is associate professor in the Division of Oncologic Sciences at the University of South Florida.
Definitions of cost-effectiveness can vary, he said, depending on what healthcare policy experts consider "acceptable" in any particular healthcare setting. However, monthly pamidronate is about 20% less effective than zoledronic acid in patients with breast cancer, he noted. "The ultimate question becomes, is the difference in efficacy observed worth the extra cost to us? The answer to this question can vary depending on who you ask."
The costs associated with SRE-related events, such as the costs of monitoring and treating renal events with bisphosphonates, providing additional rehabilitation care, and lost productivity, aren't included in the study, noted Dr Soliman. He acknowledged that estimating and incorporating these costs would be difficult to model.
The take-home message is that every-3-month zoledronic acid is likely to be a cost-effective method to reduce SREs in an increasingly resource-challenged medical care environment," he told Medscape Medical News. "However," he emphasized, "patient-specific characteristics should be taken into consideration to make sure the optimal treatment for their particular circumstance is selected, and costs/benefits should be discussed with patients as well."
The "trade-offs" for using less expensive zoledronic acid include a less convenient dosing route, Dr Soliman pointed out. Some patients may require port placement for intravenous administration, and others with poor peripheral circulation will need maintenance and a longer infusion time for each appointment.
There are also a higher risk for acute phase reactions with zoledronic acid compared with denosumab (27% vs 10%) and a greater likelihood of kidney dysfunction with zoledronic acid. In addition, "acceptance of a higher rate of skeletal events affecting patient functioning to achieve the desired cost savings" would be needed, he said.
Currently, two open-label phase 3 noninferiority trials are actively recruiting patients with metastatic breast or prostate cancer to receive different dosing schedules of bone-modifying agents. The SAKK 96/12: REDUSE trial is randomly assigning patients to monthly or every-3-months courses of denosumab, and the REaCT-BTA trial is randomly assigning patients to 4-week or 12-week denosumab, pamidronate, or zoledronic acid.
"The benchmark is that every-3-month denosumab is not going to be noninferior to zoledronic acid, but it's not a slam-dunk for me," said Dr Shapiro. "We will have to wait and see."
This study was supported by the National Cancer Institute of the National Institutes of Health. Dr Shapiro has disclosed no relevant financial relationships. Dr Soliman reports relationships with Amgen, Novartis, Celgene, Eli Lilly, and AstraZeneca.
J Clin Oncol.  Published online October 12, 2017. Abstract