Κυριακή, 20 Αυγούστου 2017

With all the recent advances in the drug treatment of lung cancer, most notably immunotherapy and targeted therapy, the American Society of Clinical Oncology (ASCO) has issued an update to its clinical practice guideline on advanced non–small cell lung cancer (NSCLC). 
"Treatment for lung cancer has become increasingly more complex over the last several years. This guideline update provides oncologists the tools to choose therapies that are most likely to benefit their patients," Nasser Hanna, MD, co-chair of the guideline expert panel, said in a news release.
The last update was in 2015.
The latest update, published online August 14 in the Journal of Clinical Oncology, reflects changes in evidence since then, including with regard to immune checkpoint therapy and targeted therapy for patients whose NSCLC has epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or proto-oncogene receptor tyrosine kinase (ROS1) targets.
"It is important to update the non-small cell lung cancer guidelines due to the rapid evolution of treatment options as our understanding of the molecular biology and genetics of lung cancer continues through basic research, translational research, and clinical trials," Gregory Masters, MD, co-chair of the guideline expert panel, told Medscape Medical News.
"We have new treatment options available with targeted therapies and immunotherapy as well as standard chemotherapy options, and we want to make sure clinicians throughout the country have the help and support they need in recommending the most appropriate care for their patients with this increasingly complex disease. Giving our patients the best, personalized approach to their individual cancer can improve their quality of life and survival and help us use our limited resources most efficiently," added Dr Masters.

First-L ine Therapy in Patients Without Mutations 

Regarding recommendations for first-line treatment for patients with non–squamous cell carcinoma or squamous cell carcinoma without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with a performance status (PS) of 0 or 1 (and appropriate PS of 2):
  • With high programmed cell death ligand 1 (PD-L1) expression (tumor proportion score [TPS] 50% or greater) and no contraindication, single-agent pembrolizumab (Keytruda, Merck) is recommended (evidence quality: high; strength of recommendation: strong).
  • With low PD-L1 expression (TPS < 50%), a variety of combination cytotoxic chemotherapies (with or without bevacizumab if patients are receiving carboplatin and paclitaxel) are recommended (platinum-based [evidence quality: high; strength of recommendation: strong]; non–platinum-based [evidence quality: intermediate; strength of recommendation: weak]).
  • All other clinical scenarios for first-line treatment follow 2015 recommendations.

Second-Line Therapy in Patients Without Mutations 

Regarding recommendations for second-line treatment in patients without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with a PS of 0 or 1 (and appropriate PS of 2):

Patients With Sensitizing EGFR Mutations

Patients With ROS1 Rearrangement 

Patients With BRAF Mutations 

Third-Line Therapy Recommendations  

For fourth-line treatment, ASCO advises patients and clinicians to consider and discuss experimental treatment, clinical trials, and continued best supportive (palliative) care.
"For all recommendations, benefits outweigh harms," the ASCO expert panel notes.
Disclosures provided by guideline writers are available online at www.jco.org 
J Clin Oncol. Published online August 14, 2017. Full tex

PERI-OPERATIVE B-BLOCKER AND COX2 INHIBITORS MAY DECREASE BREAST CANCER METASTASIS RISK

A combination of a cyclooxygenase-2 (COX-2) inhibitor and a β-blocker given perioperatively has been shown to inhibit a range of tumor and circulating biomarkers associated with disease progression and metastases in early-stage breast cancer in the first clinical trial of its kind. The researchers hope that this will translate clinically to fewer metastases and cancer recurrences.  
"The intervention is based on empirical findings," senior author, Shamgar Ben-Eliyahu, PhD, Tel Aviv University, Israel, explained to Medscape Medical News. The first is that "the perioperative period is really disproportionately significant in determining long-term cancer outcomes," and  second, "during this period, there are strong stress and inflammatory responses that suppress immunity and directly impact the malignant tissue and its microenvironment, making them more prometastatic and inviting disease progression."
 "So we treated patients with the combination of etodolac and propranolol beginning 5 days before surgery (and continued for 6 further days), and we found that treatment reduced the metastatic potential of the tissue and of the host," he said.
"Our hope is that, when we have a large enough sample, we will see more patients who don't develop metastatic disease down the line and who live without cancer recurrence," Dr Ben-Eliyahu added.
The research was published in the August issue of Clinical Cancer Research. 

Important Trial

Asked by Medscape Medical News to comment on the study, Jonathan Hiller, MD, a clinical and research anesthetist at the Peter MacCallum Cancer Centre in Victoria, Australia, said he felt that this study is an important trial and, excitingly, translates experimental findings in animals to measurable benefits in patients with breast cancer.
"In the trial, researchers used 2 commonly available and safe drugs together to achieve 2 important outcomes — reducing the metastatic potential of a breast cancer and reducing the inflammatory and immunosuppressive stress response of surgery," Dr Hiller said in an email.
"So this trial contributes to increasing research into the effects of inflammatory and immune changes occurring at the time of surgery and their effect on residual or dormant cancer cells," he added.
"And it suggests that a week of pre-operative dosing — 'a cancer pre-med' — may very well translate to a cancer benefit for patients," Dr Hiller concluded.

Study Details 

The randomized, placebo-controlled biomarker trial involved 38 patients with stage I to III breast cancer. Patients received the two-drug combination or placebo for 11 consecutive days, starting 5 days before their primary tumor was resected.
Etodolac was given at a dose of 400 mg twice a day, while extended-release propranolol was given at a dose of 20 mg twice a day during the 5 days preceding surgery and at a dose of 80 mg on the morning and the evening of the surgery itself, as well as the morning after surgery. Thereafter, propranolol was given at a dose of 20 mg twice a day for 5 days after the operation.
Blood samples were taken at multiple time points, and both blood samples and the primary tumor were tested and profiled for a range of biological markers predictive of metastases, Dr Ben-Eliyahu noted.
Given the physiologic and psychologic stresses leading up to surgery, the placebo group showed an increase in certain cytokines: Serum levels of interleukin (IL)-6 increased by 24% and C-reactive protein (CRP) increased by 41.5% in the 5 days before surgery (measured from the morning of the fifth day before surgery [when participants started taking drug or placebo] to the morning before surgery).
 "This pattern was significantly reversed in the drug-treated group," investigators report, declining by 11.3% for IL-6 (P = .0009) and by 10% for CRP (P = .034).
The morning after surgery, both IL-6 and CRP increased dramatically in both groups relative to presurgical levels, they note.
But there was still a significant reduction in IL-6 levels between pretreatment and study endpoint (P = .011) among patients who received the perioperative regimen compared with placebo controls.
Changes in CRP were minimal in the perioperative regimen group.
As the researchers explain, IL-6 and CRP are both associated with tumor progression and poor prognosis in many solid tumors, including those of the breast, prostate, and lung.
Investigators also observed that the two-drug regimen reversed epithelial-to-mesenchymal transition — the process by which tumor cells escape from the primary tumor and metastasize to other organs.
Favorable influences from the same perioperative treatment strategy were also noted in the gene expression profiles of the primary tumor; circulating immune parameters (including increased levels of natural killer-cell activation markers), and reduced monocyte influx. All of these have been linked to a reduced risk for tumor progression in both animal models and human clinical studies, the researchers point out.
In a related study involving roughly the same numbers of patients with colorectal cancer, Dr Ben-Eliyahu and colleagues observed very similar changes in blood and tumor biomarkers when patients were treated with the same perioperative regimen.
"[C]ombined perioperative β-blockade and COX-2 inhibition may inhibit stress-induced inflammatory and metastatic processes through multiple cellular and molecular pathways," the researchers conclude.
In addition, they suggest that "the favorable safety profile and favorable impacts on tumor transcriptome profiles and immune parameters provide a rationale for future clinical trials."
The work was supported by the National Cancer Institute Network on Biobehavioral Pathways in Cancer, the Israel Science Foundation, and the National Institutes of Health/National Institute on Aging. The authors and Dr Hiller have disclosed no relevant financial relationships.
Clin Cancer Res. 2017;23:4651-4661. Abstract

FDA TOO QUICK IN APPROVALS

The quality of data used by the US Food and Drug Administration (FDA) for accelerated drug approvals and approvals of high-risk medical device modifications is relatively weak and raises questions about the rigor of the regulatory process, according to two studies published online August 15 in JAMA.
In one of the studies, Sarah Y. Zheng, MD, from the department of psychiatry at the University of California at San Francisco, and colleagues analyzed 83 studies that supported approvals for 78 modifications of high-risk devices between 2006 and 2015. High-risk devices are defined as those that support or sustain human life, such as coronary stents and hip prostheses.
"[F]ewer than half were randomized, blinded, or controlled, and most primary outcomes were based on surrogate end points," they write. Specifically, just 45% of the studies were randomized and only 30% were blinded.
Moreover, 71 (91%) approvals were supported by a single study.
Researchers found that the median number of patients per study was 185 and median follow-up was 6 months.
Of the primary end points, 121 of 150 (81%) were surrogates, defined as "a laboratory measurement or a physical sign used as a substitute for a clinically meaningful end point that measures directly how a patient feels, functions or survives."
While such end points allow for smaller and less costly trials, "surrogate measures can lead to uncertainty about clinical outcomes," the researchers note.
Remarkably, the device modifications the researchers studied were the ones expected to significantly change design or performance or indication for the device, and require the most rigorous approval process. Thus, even though the data uncovered in the current study are less than ideal, other levels of approval for device modifications would require even less rigorous evidence.
The researchers explain that modifying high-risk devices can have a direct effect on millions of people.
They use the example of the gastric Lap-Band, whose indications were expanded when the FDA approved the modification based on a single-group study of 160 people without controls.
Lap-Band's expanded indication meant that 19 million more people were able to have the band placed.
However, the authors report, "18.5% of Medicare beneficiaries who have received this device have undergone reoperation by 4.5 years, with an average of 3.8 procedures per patient."

Data for Accelerated Approvals

In the second study, Huseyin Naci, PhD, MHS, from LSE Health, department of health policy, London School of Economics and Political Science in London, United Kingdom, and colleagues find similar problems in the data used to support accelerated drug approvals.
Drugs to treat serious or life-threatening conditions can get fast-tracked based on surrogate end points that "are only reasonably likely to predict clinical benefit." The results then need to be confirmed in trials to see if they really lead to improvements.
The researchers found that between 2009 and 2014, 22 drugs received 24 indications via accelerated approval based on 30 studies. Among the studies, just 12 (40%) were randomized and 6 (20%) were double-blind. Moreover, 14 indications were initially approved after single-arm trials that lacked comparator groups, and the mean number of patients in all of the preapproval trials was just 132.
In addition, postmarketing studies were slow to come. "Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval," the authors write.
The researchers also found that in many cases design of the pre- and postmarketing studies was similar and many of the postmarketing trials also used surrogate end points instead of clinical end points.

"Sweeping Overhaul Needed"

Robert Califf, MD, former FDA commissioner and currently a cardiologist with Duke Health and Duke University School of Medicine in Durham,
North Carolina, writes in an accompanying editorial, that he agrees there are systemic problems that need to be addressed.
"A sweeping overhaul of the overall system is needed," he writes. "Fortunately, such a transformation is under way. Regardless of the type of medical product, substantial progress in balancing safety with access to effective therapies will come from systemic changes in the ecosystem rather than incremental modifications made by imposing more severe demands on individual products."
However, there are reasons behind the lack of blinding and control groups, Dr Califf explained.
When patients have life-threatening diseases without effective therapies, patients and their physicians are understandably hesitant to use a control group or placebo, he says. Similarly, blinding in trials for medical devices might be either impractical or expose patients to risk with no possible benefit.
In a related podcast, Dr Califf says that when there is a life-threatening disease with no effective treatment, "patient groups have been very clear that they are willing to take a high degree of risk to have earlier access."
He adds, "The goal is to keep the degree of regulation in sync with some benefits that might be anticipated."
As far as the small number of randomized, controlled clinical trials, he says that harnessing the power of electronic medical records to conduct such trials in a nontraditional, inexpensive way will help enable more randomized trials and help with continual surveillance of efficacy.
He said that despite the issues raised by the new studies, "[I]t is important to remember that decisions about postmarket requirements and monitoring of these studies are overseen by full-time FDA employees with no financial conflicts. These civil servants are charged with considering the complex issues involved when a presumably effective therapy is on the market but additional evidence is needed."

Physician Finds Editorial Disconcerting

It's that assertion in the editorial that most troubles Vinay K. Prasad, MD,  MPH, a hematologist-oncologist and assistant professor of medicine at Oregon Health and Sciences University in Portland.
"Both of these studies continue to highlight deficiencies in the US Food and Drug administration's permissive approval and poor postmarketing enforcement," he told Medscape Medical News. 
"Dr Califf tries to reassure us that the FDA's employees have no financial conflicts, and, thus, the implication seems they are already doing the best job in balancing speed and safety. However, the fact remains these articles suggest we can and should be doing a better job in that balance," he continues.
Dr Prasad points to a study he coauthored that showed that 60% of FDA reviewers later go to work for pharma. [S]o there may be a bias for reviewers to act in a way that is favorable to industry in order to secure future employment if they were ever to leave."
Dr Prasad said that in walking the line between making products available quickly and ensuring safety and efficacy, the FDA has tipped toward making things available.
"Dr Califf points out that this move is acclaimed by patients and their families, but this is wrong," Dr Prasad says. "First, the patient voice in the drug approval space is dominated by patient advocacy groups that are funded by the industry. Whether these groups speak for all patients is uncertain and unlikely. Second, the role of a federal agency like the FDA is to protect people from choices that don't offer net benefit. If it were just about choices, why have the FDA at all? It is about having good choices, and these articles highlight ways in which that falls short."
Dr Naci is supported by the Higher Education Funding Council of England. A coauthor reports receiving unrelated grants from the FDA Office of Generic Drugs and Division of Health Communication and support from the Engelberg

REDUCE NEPHROTOXICITY IN CANCER PATIENTS UNDERGOING CT

In frail patients with cancer who are to undergo contrast-enhanced CT, the choice of iodated contrast medium can be key to reducing risk for impaired renal function and the development of contrast-induced nephropathy (CIN).
In a head-to-head comparison of two contrast media, iodixanol (Visipaque, GE Healthcare) appeared to have a better safety profile than iopromide (Ultravist, Bayer Healthcare).
The results come from the blinded, randomized COMEDIANS trial, which was conducted in 504 cancer patients at low risk for CIN who underwent chest-abdomen-pelvic CT. The trial was conducted by Maddalena Barba, MD, of the Regina Elena National Cancer Institute in Rome, Italy, and colleagues.
The study was published online August 4 in the Journal of Cellular Physiology.
Currently, there is no evidence to support the use of a specific contrast medium in cancer patients, the study authors note. They point out that CT is one of the imaging techniques most frequently used in cancer management, from diagnosis and disease staging to evaluation of treatment response and follow-up.
Although CIN can be minor ― defined by the study investigators as a 25% increase in serum creatinine level ― more severe cases can lead to renal failure, the need for dialysis, or death. Patients with cancer who are weakened by disease or treatment may be particularly vulnerable.
It is our responsibility to focus on the safety of fragile patients, such as those affected by cancer. Dr Irene Terrenato
"It is our responsibility to focus on the safety of fragile patients, such as those affected by cancer," coauthor Irene Terrenato, PhD, of the Regina Elena National Cancer Institute in Rome, said in a statement. "Iodated contrast media is essential, and, unfortunately, we often observe adverse events on renal function due to contrast media use, such as CIN."
"To understand which one [contrast medium] minimizes the incidence of CIN is fundamental, and this study arises from the need to protect our patients as much as possible," added Stefano Canitano, MD, who is also at the Regina Elena National Cancer Institute.

Cancer Patients Develop CIN

The cancer patients taking part in this study were at low risk of developing neuropathy. At baseline, the patients' estimated glomerular filtration rate (eGFR) was >60 mL/min.
The researchers report that CIN developed at 24 hours in seven patients in the iopromide group compared to two patients in the iodixanol group (= 0.34).
The same trend was seen with late-occurrence events, with eight patients in the iopromide group developing CIN at 72 hours compared to two in the iodixanol group (= .11).
Overall, 17 patients developed CIN. Among those patients, the event rate was higher in the iopromide arm (= .045), although no cases of permanent CIN or significant differences in adverse events or GFR were observed.
"The distribution of CIN events across the study arms seemed to provide a suggestion in support of the use of iodixanol in light of the more favourable toxicity profile," the study authors say. "However," they add, "none of these results reached the predefined cut off for statistical significance." These findings need to be confirmed and the underlying biological mechanisms clarified in larger trials with a similar design, they emphasize.
Our results can represent a first indication for radiologists who are responsible for performing CT scans on very compromised patients daily," commented coauthor Antonio Giordano, MD, PhD, from the University of Siena and Istituto Toscano Tumori, in Siena, Italy, who is also the president of the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, in Philadelphia, Pennsylvania.
He emphasized that "further studies are strongly recommended to confirm these results."
Specifically, biomarkers associated with increased risk for CIN need to be identified, Dr Giordano told Medscape Medical News. He noted that "sera from the participants in the COMEDIANS trial are stored at our biorepository."
Importantly, these results are consistent with those from previously published randomized controlled trials demonstrating less patient discomfort, lower frequency of adverse events, and equivalent or higher CT image quality with iodixanol compared with low-osmolar contrast media, Dr Giordano said.

Study Details

The study enrolled patients from four cancer enters who were to undergo a chest-abdomen-pelvis CT with iodated contrast media. A total of 247 patients were centrally randomly allocated to receive iodixanol; 250 patients received iopromide. Although patients and nurses were blinded to group assignment, the pharmacologist, radiologists, technicians, and statisticians were not.
CIN was defined as a decrease of baseline eGFR of >25%. Serum creatinine was used to assess CIN development in addition to eGFR.
The study design, with its focus on cancer patients at very low risk of developing CIN, "renders our findings worthy of attention," the study authors say. Previous studies have been largely observational and have varied in size, design, and patient characteristics, they note.
Limitations of the study include its low power and failure to reach the recruitment target of 2868 patients, the study authors acknowledge.
This study was funded by the Italian Agency of Drugs. GE Healthcare provided educational support to the biostatistical and methodologic core of the research group.

PET RESPONSE NOT PROGNOSTIC IN GASTRIC ADENOCARCINOMA

Post-treatment/preoperative tumor response, as measured on positron emission tomography (PET), does not predict outcomes in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma, according to a database review.
PET is commonly used to evaluate tumor responses to therapy, and some have suggested that repeat PET/CT imaging is prognostic in patients with GEJ cancer and gastric cancer.
To investigate, Dr. Daniel G. Coit and colleagues from Memorial Sloan Kettering Cancer Center, New York City, analyzed the relationship between changes in standardized uptake value (SUV) on PET imaging and histopathologic response and survival after neoadjuvant therapy.
Maximum SUV responses showed small but statistically significant correlations with histologic tumor responses for patients with GEJ cancers (rho=0.19) and those with gastric cancers (rho=0.44).
None of the SUV variables, however, was significantly associated with disease-specific survival (DSS) in patients with GEJ or gastric cancers, the researchers report in Annals of Surgery, online August 1.
In bivariate models, histologic tumor response, but not maximum SUV response, significantly predicted outcomes for patients with GEJ and gastric cancers.
In multivariable analyses, only N stage and lymphovascular invasion were significant predictors of DSS in patients with GEJ cancers, whereas only T stage and N stage were significant predictors of DSS in patients with gastric cancers.
SUV responses did not show any significant relationship with DSS for patients with either cancer.
“We therefore conclude that the routine use of repeat preoperative PET imaging following neoadjuvant therapy for locoregionally advanced adenocarcinoma of the stomach and GEJ is of limited prognostic value, and should be abandoned, unless being performed in the context of a research setting to assess its value in redirecting neoadjuvant therapy for nonresponders,” the researchers write.
Dr. Coit did not respond to a request for comment.
SOURCE: http://bit.ly/2wau6JJ
Ann Surg 2017.

IMMUNE RICH TRIPLE NEGATIVE BREAST CANCER

In a study reported in JAMA Oncology, Karn et al found that triple-negative breast cancers with high immune gene expression levels were characterized by lower clonal heterogeneity, reduced copy number alterations, and lower somatic mutation and neoantigen loads.
Study Details
In the study, DNA and RNA sequencing and messenger RNA expression data from The Cancer Genome Atlas breast cancer data set were used to calculate immune metagene expression values and histologic lymphocyte counts to measure immune infiltration and determine prognostic categories of triple-negative breast cancers. Among 193 triple-negative breast cancer samples with survival information, 25 were classified as good prognosis, defined as high immune infiltration (ie, major histocompatibility complex class II metagene expression in the top quartile) and low inflammation markers (ie, interleukin 8–vascular endothelial growth factor metagene expression below the median). Disease-free survival was significantly better in the good-prognosis group (P = .02). Immune-rich good prognosis and immune-poor poor prognosis cohorts were compared for clonal heterogeneity, somatic total mutational load, neoantigen load, and somatic copy number alteration levels.
Immune Infiltration and Tumor Characteristics
The immune-rich good prognosis samples had significantly lower mutant-allele tumor heterogeneity (MATH) scores, indicating lower clonal genomic heterogeneity (= .001). Among all tumors, there were inverse associations between clonal heterogeneity and immune metagene expression (ρ = −0.395, = 2 × 10−8), particularly marked in good-prognosis triple-negative breast cancers, and between somatic copy number alteration levels and immune metagene expression (ρ = −0.484, = 2 × 10−10). Levels of somatic copy number alterations were significantly lower in good-prognosis triple-negative breast cancers (< .001), as were somatic mutational load (= .02) and neoantigen load (= .04), compared with poor-prognosis triple-negative breast cancers. Findings were confirmed in an independent data set (METABRIC).
The investigators concluded: “This study suggests that immune-rich [triple-negative breast cancers] may be under an immune surveillance that continuously eliminates many immunogenic clones, resulting in lower clonal heterogeneity. These cancers may also represent the subset of [triple-negative breast cancers] that could derive benefit from immune checkpoint inhibitor therapy to tilt the balance in favor of the immune system.”
The study was supported by H.W. & J. Hector-Stiftung, the Breast Cancer Research Foundation, the Susan Komen Foundation, the National Cancer Institute, and Associazione Italiana per la Ricerca sul Cancro.

COMBINATION IMMUNOTHERAPY FOR FIRST LINE TREATMENT OF RENAL CANCER

On August 15, Bristol-Myers Squibb Company announced topline results from the CheckMate-214 trial investigating nivolumab (Opdivo) in combination with ipilimumab (Yervoy) vs sunitinib (Sutent) in intermediate- and poor-risk patients with previously untreated advanced or metastatic renal cell carcinoma.
The study met the coprimary endpoint of objective response rate, which was 41.6% for the combination vs 26.5% for sunitinib. Median duration of response was not reached for the combination of nivolumab and ipilimumab, and was 18.17 months for sunitinib. While there was an improvement in progression-free survival (hazard ratio = 0.82; 95% confidence interval [CI] = 0.64–1.05; stratified 2-sided P = .03), it did not reach statistical significance. The median progression-free survival was 11.56 months (95% CI = 8.71–15.51) for the nivolumab and ipilimumab combination vs 8.38 months (95% CI = 7.03–10.81) for sunitinib.
The study will continue as planned to allow the third coprimary endpoint of overall survival to mature. 
The tolerability profile observed in CheckMate-214 was consistent with that observed in previously reported studies of this dosing schedule.
“We are encouraged by the totality of the CheckMate-214 data. The overall response rate and durability of response favored the combination of [nivolumab and ipilimumab]and the trend for progression-free survival supports the potential of the combination in intermediate- and poor-risk advanced renal cell carcinoma, the most common type of kidney cancer. This is an important study in first-line renal cancer as these patients need new options,” said Vicki Goodman, MD, Development Lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. “We look forward to presenting the full results from this study at an upcoming medical meeting.”
About CheckMate-214
CheckMate-214 is a phase III, randomized, open-label study evaluating the combination of nivolumab and ipilimumab vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma.
Patients in the combination group received nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks. Patients in the comparator group received sunitinib at 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Patients were treated until disease progression or unacceptable toxic effects.
The primary endpoints of the trial are progression-free survival, overall survival, and objective response rate in an intermediate to poor-risk patient population (approximately 75% of patients). Safety is a secondary endpoint.

PREDICTION OF RESPONSE TO REGORAFENIB

Administering a magnetic resonance imaging (MRI) scan and a blood test to patients with metastatic colorectal cancer may help to select those who would benefit from a targeted cancer treatment, a new study published by Khan et al in Gutreported.
Researchers found that after only 2 weeks on the drug regorafenib (Stivarga), a test based on an MRI scan could tell which patients would respond an average of 9.4 months longer than those whose treatment failed early.
Testing for cancer DNA in the bloodstream also tracked the benefit of treatment—with patients with low levels of cancer DNA after 2 months surviving an average of 9.7 months longer than those where there was no change or an increase.
Early findings suggest that combining the MRI scan with the blood test could give an even stronger prediction of which patients will respond to treatment. The tests could allow doctors to rapidly identify which patients are no longer benefiting from treatment and switch them to an alternative treatment plan.
Monitoring the Tumor Blood Supply
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust tested 27 patients with chemotherapy-resistant advanced colorectal cancer and mutations in the gene KRAS as part of a phase II clinical trial of regorafenib.
One of the ways regorafenib works is by restricting the blood supply to tumors, starving them of oxygen and the vital nutrients they need to grow. Researchers developed a new method using MRI to assess whether the drug is hitting its target by viewing reductions in blood vessels feeding the tumor.
Patients who showed a reduction in tumor blood supply by 70% as viewable by MRI all survived 6 months on the treatment, and 75% were still alive after a year. These patients survived for an average of 15.2 months, compared with only 5.8 months for those who didn’t respond to the drug in this way.
Monitoring ctDNA in the Bloodstream
Researchers also found that patients who responded well to the drug had a marked drop in cancer DNA in the bloodstream, which continued throughout treatment.
About 48% of the 27 patients in the trial sustained this drop in the level of circulating tumor DNA (ctDNA) for 2 months. These patients survived 15.2 months after beginning treatment, compared with only 5.5 months for patients who experienced no change or an increase in the levels of ctDNA.
Combining Testing Strategies
Early data on use of the two tests together has prompted optimism that they could be even more effective at picking out patients who are most likely to respond, guiding clinical decisions with greater confidence.
A trial will now be run in a larger group of patients that assesses using both tests in succession.


The study was funded by Bayer Pharmaceuticals, Cancer Research UK, the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the ICR, and The Royal Marsden Cancer Charity.

CRIZOTINIB IN PEDIATRIC PATIENTS

In a Children’s Oncology Group study, high response rates were achieved with crizotinib (Xalkori) treatment in pediatric ALK-positive anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors. These results were reported by Mossé et al in the Journal of Clinical OncologyALK gene fusions are the primary genetic lesion underlying these pediatric tumors.
Study Details
The current report involved 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive inflammatory myofibroblastic tumors from a phase I/II study who received oral crizotinib twice daily.
Response Rates
Response was observed among 5 of 6 patients (83%) with ALCL receiving crizotinib at 165 mg/m2 per dose and 18 of 20 patients (90%) receiving the recommended phase II dose of 280 mg/m2 per dose, with complete response observed in 5 (83%) and 16 (80%), respectively. Response was observed in 12 of 14 patients (86%) with inflammatory myofibroblastic tumors receiving 100, 165, or 280 mg/m2 per dose, with a complete response in 5 (36%). The remaining 1, 2, and 2 patients in the ALCL 165 mg/m2 and 280 mg/m2 groups and inflammatory myofibroblastic tumors group had stable disease as best response.
Initial evidence of response was observed by 4 weeks in 5 of the ALCL 165-mg/m 2 group, 13 of the ALCL 280-mg/m2 group, and 7 of the inflammatory myofibroblastic tumors group. The median duration of therapy was 2.79, 0.4, and 1.63 years in the 3 groups, respectively, with 12 patients stopping study therapy to undergo stem cell transplantation. Levels of NPM-ALK fusion transcripts decreased during treatment in most patients with ALCL.
Adverse Events
Grade 3 or 4 adverse events occurred in 83% and 100% of the ALCL dose groups and 71% of the inflammatory myofibroblastic tumors group. The most common grade 3 or 4 drug-related adverse event was decreased neutrophils, observed in 33% and 70% of the ALCL 165-mg/m2 and ALCL 280-mg/m2groups and in 43% of the inflammatory myofibroblastic tumors group. Treatment was discontinued due to adverse events in two of the ALCL patients (neutropenia) and four of the inflammatory myofibroblastic tumors patients (neutropenia and lower extremity edema).
The investigators concluded: “The robust and sustained clinical responses to crizotinib therapy in patients with relapsed ALCL and metastatic or unresectable [inflammatory myofibroblastic tumors] highlight the importance of the ALK pathway in these diseases.”
The study was supported by the National Cancer Institute, Cookies for Kids Cancer Foundation, and Pfizer Inc.

PARTIAL BREAST RADIOTHERAPY

The UK IMPORT LOW phase III trial has shown noninferiority in local relapse for partial-breast and reduced-dose vs standard whole-breast radiotherapy after breast-conserving surgery in early breast cancer. These study results were reported by Coles et al in The Lancet.
Study Details
In the noninferiority trial, 2,016 women aged ≥ 50 years who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1 to 3 and who had a tumor size of ≤ 3 cm (pT1–2), 0 to 3 positive axillary nodes (pN0–1), and minimum microscopic margins of noncancerous tissue of ≥ 2 mm from 30 sites were randomized 1:1:1 between May 2007 and October 2010 to receive 40 Gy of whole-breast radiotherapy (control, n = 674), 36 Gy of whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group, n = 673), or 40 Gy to the partial breast only (partial-breast group, n = 669) in 15 daily treatment fractions. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams, reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse at 5 years in the intent-to-treat population, with noninferiority shown in experimental groups if the upper limit of the two-sided 95% confidence interval for the local relapse hazard ratio [HR] was < 2.03.
Local Relapse
Median follow-up was 72.2 months. Estimated cumulative 5-year local relapse rates were 1.1% in the control group, 0.2% in the reduced-dose group (difference = –0.73% vs control), and 0.5% in the partial-breast group (difference = –0.38% vs control). Noninferiority (HR > 2.03) vs the control group was established for both the reduced-dose (P = .003) and partial-breast groups (P = .016).
Late Normal Tissue Effects
Photographic, patient, and clinical assessments showed similar adverse effects after reduced-dose and partial-breast radiotherapy; significantly reduced adverse effects vs the whole-breast group were observed for change in breast appearance (35% vs 48%, = .007) in the partial-breast group and breast harder or firmer in the reduced-dose group (21% vs 35%, = .002) and in the partial-breast group (15% vs 35%, < .0001).
The investigators concluded: “We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide.”
The study was funded by Cancer Research UK.

ARTERIAL THROMBOEMBOLISM RISK AFTER CANCER DIAGNOSIS

Patients newly diagnosed with cancer may have a substantially increased short-term risk of arterial thromboembolism, according to a study published by Navi et al in the Journal of the American College of Cardiology.
Patients with cancer face an increased risk of medical complications. However, the risk of arterial thromboembolism in patients with cancer is not well understood.
Study Findings
Researchers found that patients who were newly diagnosed with cancer faced a considerably increased short-term risk of arterial thromboembolism. Within 6 months of diagnosis, more than twice as many patients with cancer had experienced arterial thromboembolism as compared with matched control patients without cancer.
The risk of arterial thromboembolism varied by cancer type, with lung, gastric, and pancreatic cancers conferring the highest risk. Additionally, advanced cancer stage was associated with increased risk, directly relating arterial thromboembolism to overall tumor burden and extent of disease.
The risks of both heart attack and ischemic stroke were also increased in patients with cancer.


According to the authors, these findings raise the question of whether patients with newly diagnosed malignant cancer, particularly those with advanced disease, should be considered for antithrombotic and statin medicines for primary prevention of cardiovascular disease. They stress that because patients with cancer are also prone to bleeding due to frequent coagulopathy and invasive procedures, carefully designed trials are needed to answer these questions.

CLONAL HEMATOPOIESIS IN CANCER PATIENTS

In a study of nearly 9,000 people treated for solid tumors, researchers found that radiation treatment and tobacco use were linked to higher rates of blood-based DNA mutations that could lead to a higher risk for blood cancers such as leukemia.
The study, published by Coombs et al in Cell Stem Cell, revealed new risk factors for “clonal hematopoiesis,” a medical phenomenon in which genetic mutations are found in the blood cells of patients who do not have an existing blood cancer. Twenty-five percent of the patients in the study had clonal hematopoiesis. Of the subset of patients they actively followed, those with clonal hematopoiesis had a small but increased (+1%) estimated incidence of developing blood cancer later on.
“The presence of clonal hematopoiesis can lead to an increased risk for subsequent blood cancers,” said UNC Lineberger's Catherine Coombs, MD. “We wouldn’t recommend forgoing treatment that is medically indicated, because the risk of a secondary cancer is relatively low, but it is important to closely watch those patients who are at high risk.”
Dr. Coombs was first author of the study at Memorial Sloan Kettering (MSK) Cancer Center, where she completed a fellowship in oncology before coming to UNC Lineberger. The study analyzed genetic changes from 8,810 MSK patients.
Study Findings
The researchers found clonal hematopoiesis in 25% of patients, with the highest incidence in patients with thyroid cancer and the lowest in patients with germ cell tumors. Mutations were more common in older people, with the odds of clonal hematopoiesis increasing 6% for each decade above age 30. Clonal hematopoiesis was also strongly associated with current or former tobacco use.
“A major risk factor for developing clonal hematopoiesis that can be modified or changed is tobacco use,” Dr. Coombs said. The researchers also found a higher frequency of patients with clonal hematopoiesis who had received radiation therapy. Forty-one percent of patients with clonal hematopoiesis received radiotherapy, compared to 35% of patients who did not have clonal hematopoiesis and had received radiotherapy.
Risk for developing a secondary blood cancer was very small in the patient population overall. Only 19 of the 5,394 patients the researchers actively followed developed a new blood cancer within 18 months. However, for patients who did get a blood cancer, the risk was higher for patients who had clonal hematopoiesis. About 1% of patients with clonal hematopoiesis were estimated to develop a secondary cancer, which was 3 times higher than the estimated 0.3% for patients who developed blood cancer and did not have clonal hematopoiesis.
“This has been borne out by other groups: if you have these clonal hematopoiesis mutations, you have a greater risk for developing hematologic cancer than do patients who don’t have them,” she said.
Dr. Coombs said more research is needed to determine the cause of these increases.

SCREENING FOR NASOPHARYNGEAL CARCINOMA

In a Hong Kong study reported in The New England Journal of Medicine, Chan et al found that screening for circulating cell-free Epstein-Barr virus (EBV) DNA is useful in detecting nasopharyngeal carcinoma in asymptomatic individuals.
Study Details
In the study, 20,174 participants underwent testing for EBV DNA in plasma specimens. Those with initially positive results were retested approximately 4 weeks later, and those with persistently positive results underwent nasal endoscopic examination and magnetic resonance imaging (MRI) for detection of nasopharyngeal cancer.
Screening Detection Rates
Overall, EBV DNA was detected in 1,112 participants (5.5%); 309, representing 1.5% of all participants and 27.8% of those with initially positive results, had persistently positive results.
Among the 309 persistently positive subjects, 300 underwent endoscopic examination, and 275 underwent both endoscopic examination and MRI; of them, 34 (11.0% of all with persistent positive findings, 11.3% of those undergoing endoscopy, and 12.4% of those undergoing endoscopy and MRI) had nasopharyngeal carcinoma. A significantly higher proportion of participants with nasopharyngeal carcinoma identified by EBV DNA screening had stage I or II disease compared with all patients diagnosed with nasopharyngeal carcinoma in Hong Kong in 2013 (71% vs 20%, < .001). Those with screen-detected disease in the current study had better 3-year progression-free survival vs a Hong Kong historical cohort of 1,278 age- and sex-matched patients (97% vs 70%; hazard ratio = 0.10; 95% confidence interval = 0.05–0.18).
Of nine participants with persistently positive screening results who declined further testing, one presented with advanced nasopharyngeal carcinoma 32 months after enrollment. Nasopharyngeal carcinoma was observed in one participant with negative EBV DNA screening within 1 year after testing. Overall, screening had a sensitivity and a specificity for nasopharyngeal carcinoma of 97.1% and 98.6% as well as positive and negative predictive values of 11.0% and > 99.9%, respectively.
The investigators concluded: “Analysis of EBV DNA in plasma samples was useful in screening for early asymptomatic nasopharyngeal carcinoma. Nasopharyngeal carcinoma was detected significantly earlier and outcomes were better in participants who were identified by screening than in those in a historical cohort.”
The study was funded by the Kadoorie Charitable Foundation and Research Grants Council of the Hong Kong government.

GERMLINE MUTATIONS IN SPORADIC PANCREATIC CANCER

As reported by Shindo et al in the Journal of Clinical Oncology, deleterious germline mutations in known pancreatic cancer susceptibility genes were frequently found in patients with pancreatic cancer who do not have a reported family history of cancer.
Study Details
The study involved sequencing for 32 known or candidate pancreatic susceptibility genes or other cancer susceptibility genes in DNA from normal tissue from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at The Johns Hopkins Hospital between 2000 and 2015.
Identification of Known Susceptibility Mutations
Overall, 33 of 854 patients (3.9%) with pancreatic cancer had a deleterious germline mutation; 31 (3.5%) involved known familial pancreatic cancer susceptibility genes, including BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these mutations were younger than those without the mutations (mean age = 60.8 vs 65.1 years, P = .03). Deleterious germline mutations were also found in the candidate pancreatic cancer susceptibility genes BUB1B (one patient) and BUB3 (one patient).
A family history of pancreatic cancer was reported for only 3 of the 33 patients. Although most of the patients (82%) had a family history of other cancers, only 5 (15%) had histories suggestive of a familial cancer syndrome.
Of the 339 patients with diagnoses other than pancreatic ductal carcinoma, 5 (1.5%) had a deleterious germline mutation. Each of the 5 had another malignancy.
The investigators concluded: “Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.”
The study was supported by National Institutes of Health grants, Susan Wojcicki and Dennis Troper, and Rolfe Pancreatic Cancer Foundation.

Κυριακή, 13 Αυγούστου 2017

NIVOLUMAB FOR MSI-H METASTATIC COLORECTAL CANCER

The immune checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) may provide a new treatment option for patients with metastatic colorectal cancer with a certain genetic defect — DNA mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H).
Results from a phase 2 trial (CheckMate 142) showing benefit from nivolumab in this tumor subtype were published online July 19 in Lancet Oncology.
"Nivolumab provided promising and durable responses with prolonged survival relative to the anticipated median survival in patients with dMMR/MSI-H metastatic colorectal cancer," write first author, Michael J. Overman, MD, from the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
Nivolumab has just been approved by the US Food and Drug Administration (FDA) for this indication.
Another similar drug, pembrolizumab (Keytruda, Merck & Co), has also been approved for this indication. This approval was hailed at the time as a paradigm shift for cancer care because it was the first FDA approval of a cancer drug for treating tumors with a certain genetic defect regardless of where the tumor appears in the body, rather than for a specific tumor type.
"The results of the CheckMate 142 trial, which are broadly consistent with previous findings of studies of pembrolizumab, are notable in view of the generally poor prognosis of patients with dMMR/MSI-H metastatic colorectal cancer," commented Francesco Sclafani, MD, from the Royal Marsden NHC Foundation Trust (Sutton, Surrey, United Kingdom), writing in an accompanying
MMR/MSI testing…should now be routinely offered to all patients with metastatic colorectal cancer. Dr Francesco Sclafani 
"Therefore, despite the small numbers and non-randomised study design, the
results establish a new treatment option in this setting and confirm that MMR/MSI testing can no longer be considered as an ad-hoc screening procedure for genetic susceptibility or treatment selection in early-stage
tumours, but should now be routinely offered to all patients with metastatic colorectal cancer," he added.

Nivolumab Study Details 

CheckMate 142 was a multicenter, open-label phase 2 study and is the largest so far to evaluate an immune checkpoint inhibitor in patients with dMMR/MSI-H metastatic colorectal cancer, note the researchers.
dMMR/MSI-H tumors are found in about 15% of early-stage and 5% of metastatic colorectal cancer, and they carry a poor prognosis when treated with conventional chemotherapy, the authors comment.  However, this type of cancer has high levels of tumor neoantigens, tumor-infiltrating lymphocytes, and checkpoint regulators, all of which respond to immune checkpoint blockade. Immune checkpoint inhibitors such as nivolumab activate the immune system to help fight cancer and are already used in other types of tumors.
To see how well this type of cancer responds to nivolumab, researchers recruited 74 adults with histologically confirmed metastatic dMMR/MSI-H colorectal cancer. Patients either were intolerant to at least one past line of chemotherapy or had progressive cancer despite treatment. Fifty-four percent (n = 40) had received three or more past rounds of chemotherapy. Participants were recruited at 31 sites in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the United States) between March 2014 and March 2016.   
Participants received 3 mg/kg intravenous nivolumab monotherapy every 2 weeks until tumor progression, death, unacceptable toxicity, study withdrawal, or end of the study.
The primary endpoint was investigator-assessed objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Response was evaluated by local investigators and blinded independent central review.
During a median follow-up of 12 months, 31.1% of patients (n = 23 of 74; 95% confidence interval [CI], 20.8% to 42.9%) reached the primary endpoint, all of whom showed partial response. Disease control of 12 weeks or longer was achieved by 69% (n = 51; 95% CI, 57% to 79%).
By 1 year, no participants had reached median duration of response, and all responders remained alive. Eight participants had responses that lasted 12 months or more.
Participants had a median progression-free survival of 14.3 months (95% CI,
4.30 months to not estimable), with 12-month progression-free survival of 50% (95% CI,  38% to 61%). Twelve-month overall survival was 73% (95% CI, 62% to 82%).
Forty-one percent of patients (n = 31) experienced grade 3 adverse events, and 14% (n = 10) developed grade 4 adverse events, the most common of which included increased lipase (6 patients [8%]) and amylase (2 patients [3%]). Seven percent of patients discontinued nivolumab because of drug-related adverse events.
Twenty-three (31%) participants died during the study, but no deaths were thought to be related to nivolumab.
Further analyses showed that programmed cell death (PD) ligand 1 expression (linked to increased tumor aggressiveness) and biomarkers for colorectal cancer (BRAF and KRAS) did not predict response to nivolumab, nor did a history of Lynch syndrome (a genetic disease that greatly increases the risk for colorectal cancer).
"These findings strongly suggest dMMR/MSI-H is a marker for response
to PD-1 checkpoint inhibition in metastatic colorectal cancer. These findings are in line with the recent amendment to the National Comprehensive Cancer
Network guidelines, which recommend universal testing for dMMR/MSI-H in all patients with metastatic colorectal cancer," the authors write.
In the editorial, Dr Sclafani says that more work is needed, but he predicts that the treatment algorithm for dMMR/MSI-H colorectal will rapidly evolve. Continuing research on immune checkpoint inhibitors in dMMR/MSI-H metastatic colorectal cancer "will prompt the gastrointestinal oncology community to look at the potential of immunotherapy with renewed enthusiasm," he concludes.
Ongoing research is looking at combination therapy with nivolumab plus ipilimumab, which has shown preliminary efficacy in dMMR/MSI-H colorectal cancer. Studies are also looking at combinations of nivolumab with other immunotherapies, as well as the safety and efficacy of nivolumab with other anticancer therapies. Researchers are also evaluating other biomarkers for clinical outcome with nivolumab.

NO BENEFIT OS SIRT IN COMBINATION WITH FOLFOX FOR METASTATIC COLORECTAL CANCER

Selective internal radiotherapy (SIRT) plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) does not improve overall survival among patients with liver-only and liver-dominant metastatic colorectal cancer compared with FOLFOX alone, according to a study published in The Lancet Oncology.1
Evidence from previous studies suggested that SIRT could provide clinical benefit if given after chemotherapy. The efficacy of administering SIRT with first-line chemotherapy was investigated in the phase 3 FOXFIRE, SIRFLOX (ClinicalTrials.gov Identifier: NCT00724503), and FOXFIRE-Global (ClinicalTrials.gov Identifier: NCT01721954) studies.
Researchers assigned treatment-naive patients to receive FOLFOX or a single treatment of SIRT concurrently with cycle 1 or 2 of FOLFOX. Median follow-up was 43.3 months.
No difference was observed in overall survival between the 2 study groups; 411 (75%) patients receiving FOLFOX alone died, and 433 (78%) patients receiving FOLFOX plus SIRT died (hazard ratio [HR], 1.04; 95% CI, 0.90-1.19; P = .61).
The median survival was 23.3 months (95% CI, 21.8-24.7) in the FOLFOX alone arm vs 22.6 months (95% CI, 21.0-24.5) in the FOLFOX plus SIRT arm.
The most frequently reported grade 3 to 4 adverse event (AE) was neutropenia, occurring in 24% and 37% of patients receiving FOLFOX alone and FOLFOX plus SIRT, respectively. All-grade serious AEs occurred in 43% and 54% of patients receiving FOLFOX alone and FOLFOX plus SIRT, respectively.
There were 8 treatment-related deaths in the FOLFOX plus SIRT arm vs 3 in the FOLFOX alone group.


The authors concluded that “the routine early integration of SIRT in combination with oxaliplatin-based, first-line chemotherapy cannot be recommended as therapy for metastatic colorectal cancer.”

OVERUSE OF MAMMOGRAPHY FOR BREAST CANCER SURVIVORS

More than half of a nationally representative sample of older breast cancer survivors in the United States with a life expectancy of less than five years received annual surveillance mammography despite the unknown benefits of screening in this age group, a survey study showed.
Analysis of data from the National Health Interview Study (NHIS) (2000 to 2015) revealed that 57% of women with a short life expectancy underwent regular breast cancer screening. At the same time, only 14% of those with an estimated life expectancy of 10 years or more received the same testing, Rachel A. Freedman, MD, MPH, of Dana-Farber Cancer Institute, in Boston, MA, and colleagues reported online in the Journal of Clinical Oncology.
"Our findings highlight the urgent need for more data on the risks and benefits of mammography surveillance among older women with limited life expectancy so we can better inform patients," the study authors wrote. "Future studies should focus on developing strategies on how best to engage older women with a history of breast cancer in shared decision making and how to best tailor surveillance mammography."
Evidence-based guidelines on the use of surveillance mammography in older breast cancer patients will help sort out the benefits and potential harms, they added. This will make it possible for oncologists and primary care providers to initiate discussions with patients that focus on interventions "that may better promote longevity and well-being," they said.
NHIS data from 2000, 2005, 2008, 2010, 2013, and 2015 were analyzed for women 65 and older who reported a history of breast cancer. Among 1,040 women, 9% and 35% had an estimated life expectancy of ≤5 and ≤10 years, respectively, and 79% reported having routine surveillance mammography in the last 12 months. One-third were 80 or older and 89% were white.
Freedman and colleagues assessed the probability of mammography within the last 12 months by 5- and 10-year life expectancy using the validated Schonberg index. Estimates were adjusted for survey year, region, age, marital status, insurance, educational attainment, and indicators of access to care.
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In adjusted analyses, lower life expectancy was significantly associated with lower odds of mammography with an odds ratio of 0.4 for both ≤5-year and ≤10-year life expectancy.
Previous trials indicated that screening mammography has little value beyond age 70. Still, many women in this age group continue routine mammographic screening without discussing the risks and benefits with a clinician.
"Many clinically important breast cancers will present by physical examination alone," Freedman and colleagues wrote, "and it remains unclear whether the addition of mammography over physical examination alone among the oldest and frailest women meaningfully improves outcomes."
More research is needed to determine whether the use of mammography in older women with shorter life expectancies has an actual benefit, agreed Richard J. Bleicher, MD, of Fox Chase Cancer Center in Philadelphia, PA. "This pattern of use tells us who is getting it, and that we need to study it further, but [the study] doesn't tell us who is served best or least by mammography," he told MedPage Today.
Many clinicians don't discuss the use of mammography with patients, "because of the strong public and medical perceptions about their benefits," explained Bleicher, who was not affiliated with the study. A mammogram can be booked by patients without a prescription, he noted, but even when a clinician orders the mammogram, there's often no follow-up visit.
In addition, recent negative publicity about mammography, and how it may not serve women as well as previously thought, has resulted in "too many women" refusing to undergo the screening test at all, Bleicher pointed out. "We must be very cautious," he warned.
Clinicians must come to the table fully armed with the right information, argued Catherine M. Appleton, MD, of Washington University in St. Louis. "These conversations require time and a deep understanding of an individual patient's personal risk, balanced against the potential benefits," she said.
"Tailored and patient-specific decisions are going to be more appropriate than sweeping guidelines," she emphasized. "There is not a 'one size fits all' solution." Radiologists should "make themselves available as a resource to primary care providers who seek additional guidance on appropriate screening and imaging of patients," suggested Appleton, who also was not affiliated with the study.
The need for personalized and risk-specific screening extends beyond older women, she pointed out, adding that better access and affordability of breast cancer screening should also be a key priority. "Additional research to identify and correct gaps in care delivery is needed."
Study limitations include the self-report nature of the survey and the fact that investigators didn't have information on the timing of breast cancer diagnosis in relation to mammography, tumor characteristics, or the use of mammography in metastatic disease.


    This study was funded by the American Cancer Society, Susan G. Komen, the National Cancer Institute, and the National Institute on Aging. Freedman reported institutional relationships with Puma Biotechnology, Genentech, and Eisai. No other potential conflicts of interest were reported.