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Adding ixazomib (Ninlaro) to lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression or death by 26% compared with lenalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma, ac¬cording to findings from a phase III study published in the New England Journal of Medicine.
Findings from the trial, known as TOURMA¬LINE-MM1, were pivotal in the FDA approval of the oral proteasome inhibitor ixazomib in November 2015 for patients with relapsed multiple myelo¬ma. In the trial, median progression-free survival (PFS) with the ixazomib triplet was 20.6 months compared with 14.7 months with lenalidomide and dexamethasone alone.
In the study, 722 patients were randomized in a 1:1 ratio to receive lenalidomide and dexameth¬asone with placebo (n = 362) or ixazomib (n = 360). Ixazomib was given orally at 4 mg on days 1, 8, and 15 of a 28-day cycle. Patients received oral lenalidomide at 25 mg on days 1 to 21 and dexa¬methasone was administered orally at 40 mg on days 1, 8, 15, and 22.
The median age of patients was 66 years, and 12% had ISS stage III disease at baseline. The ECOG PS was primarily 1 or 2 (94%). The median creatinine clearance was 78.4 mL/min (range, 20- 233) and 19% of patients had high-risk cytogenet¬ics, including 10% with del17p.
A majority of patients had received 1 prior thera¬py (61%), with 10% having received 3. Overall, 57% of patients had received prior stem cell transplan¬tation, 77% had relapsed multiple myeloma, and 12% were both relapsed and refractory. Prior thera¬pies included bortezomib (69%), thalidomide (45%), and lenalidomide (12%). Twenty-three percent of patients had disease that was refractory to prior immunomodulatory agents.
The overall response rate was 78.3% with the ixazomib triplet versus 71.5% in the control arm. A very good partial response or better was achieved for 48% of those in the ixazomib arm versus 39% in the control arm. The complete response rate with the proteasome inhibitor was 12% versus 7% with placebo. The median duration of response was 20.5 months with ixazomib versus 15.0 months in the control arm. The median time to progression was 21.4 months with ixazomib versus 15.7 months in the control arm.
In those with high-risk cytogenetics, the median PFS with ixazomib was 21.4 months versus 9.7 months in the control arm. Specifically for those with del17p (n = 69), the median PFS was 21.4 versus 9.7 months, with and without ixazomib.
At the 23-month analysis, the most frequently reported all-grade adverse events (AEs) for the ixazomib arm versus the control group, respec¬tively, were diarrhea (45% vs 39%), rash (36% vs 23%), constipation (35% vs 26%), neutropenia (33% vs 31%), thrombocytopenia (31% vs 16%), anemia (29% vs 27%), nausea (29% vs 22%), and back pain (24% vs 17%), vomiting (23% vs 12%).
AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neurop¬athy occurred in 27% of patients treated with ixaz¬omib versus 22% with placebo; however, the rates of grade 3 AEs were similar in both arms, at 2%. Similar findings were seen for peripheral edema, with an all-grade rate of 28% and 20% and a grade 3 rate of 2% and 1%, with and without ixazomib, respectively.
Fewer cases of acute renal failure were seen with ixazomib (9% vs 11%). Cardiac events were similar between the arms, with heart failure experienced by 4% of patients in both arms. Thromboembolism was less common with ixazomib (8% vs 11%).
“The TOURMALINE-MM1 results demonstrated that ixazomib in combination with lenalidomide and dexamethasone is an effective and tolerable oral regimen with a manageable safety profile for patients with relapsed and/or refractory multiple myeloma,” said first author Philippe Moreau, MD, of University of Nantes, France.
In addition to the MM1 study, the TOURMALINE clinical trial program contains four other phase III studies that are exploring ixazomib. In the MM2 trial, the combination of ixazomib, lenalidomide, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. The MM3 and MM4 studies are investigating mainte¬nance therapy with ixazomib in patients who have or have not undergone an autologous stem cell transplant.
The primary completion date for the MM3 study is February 2018 (NCT02181413) and the primary completion date for MM2 is June 2018 (NCT01850524). The MM4 study is still recruit¬ing participants, with an enrollment goal of 761 (NCT02312258).
Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634.
Self-efficacy has been determined to be an accurate predictor for recovery after colorectal cancer surgery, independent from type of disease or treatment for it, according to findings of a new study (PLOS One. 2016 May 12;11(5):e0155434).
Patients with higher levels of self-efficacy—a personal confidence that they can manage illness-related problems—were found to have a better recovery, whereas those with depression and anxiety did not recover as well.
Findings of the study, led by Clare Foster of the University of Southampton in the United Kingdom, were based on questionnaire respons¬es from 857 patients aged ≥18 years, who were awaiting initial surgery for the purpose of curing their colorectal cancer and recruited between November 2010 and March 2012.
Questionnaires were administered before surgery, and at 3, 9, 15, and 24 months after surgery, assessing the patient’s (1) quality of life (QOL), (2) health status, and (3) well-being, and included measurements of the patient’s depression, anxiety, and self-efficacy.
After analyzing the responses, the researchers detected four distinct groups of patients depend¬ing on how well they recovered from colorectal cancer and its treatment. From this information, the authors identified how many patients fit into each of the 4 groups and what factors were associ¬ated with them.
Groups 1 and 2 recovered generally well, with results on each of the 3 indicators either above or within the normal range (QOL [70%]; health status [33.3%], and well-being [77.6%]). Group 3 had some problems (QOL [24.2%]; health status [59.3%], and well-being [18.2%]), whereas group 4 scored consistently poorly on QOL (5.3%), health status (7.4%), and well-being (4.2%).
Approximately 1 in 5 participants were found to be depressed at baseline. Of these 147 patients, 21% of those with depression were in the group having the worst health 2 years after treatment, compared with 2.9% of those without depression, and 18.4% were in the group with the worst qual¬ity of life 2 years after treatment, compared with 1.4% of patients who were not depressed.
Overall, the researchers found that higher levels of depression before surgery and lower feelings of self-efficacy were significantly linked to poorer outcomes in the areas of QOL, health, and well-being.
“Most people [treated with curative intent] have good quality of life and personal well-being in the first 2 years following colorectal cancer surgery in spite of reporting problems with their health,” explained Foster, a professor of psycho¬social oncology and director of the Macmillan Survivorship Research Group at the University of Southampton.
“However, around a third of patients report poorer quality of life and personal well-being over the first 2 years of treatment.”
Foster said that patients who reported depres¬sion and low confidence to manage illness-related problems before their treatment began were most likely to report poorer quality of life, poorer health status, and poorer personal well-being in the first 2 years following surgery compared with those who were not depressed or had high con-fidence in their ability to manage illness-related problems,” Foster said.
For clinicians, these findings suggest that they should assess each patient’s self-efficacy begin¬ning at the time of diagnosis to help determine which patients are more likely at risk of experi¬encing a poorer recovery. Those with depression and anxiety have the opportunity to receive the psychological and emotional support they need, hopefully helping them to achieve a more positive trajectory in recovery.
“This is significant, because gaining support to manage depression and increase confidence to manage may make a significant difference to these people’s recovery experiences,” Foster said. “We want this study to raise the profile of thesepsychosocial issues which are very important in how people manage during and following their treatment and may be improved by appropriate support.”
Foster and her research team are planning to continue their study, furthering their research with their group of patients with colorectal cancer as well as branching out to study more cancers.
Laura Metcalfe, MSN, RN, APN-C, AOCNS
Lauren M. Green
The combination of radium-223 dichlo¬ride (Xofigo) and abiraterone acetate (Zytiga) was associated with significant reductions in bone pain, as well as im¬provements in quality of life (QOL), in patients with metastatic castration-re¬sistant prostate cancer (mCRPC), accord¬ing to results of a phase II study present¬ed at the 2016 American Urological Association Annual Meeting held May 6-10, 2016 in San Diego. Abstract LB-S&T-12
Overall, pain severity decreased by 35.3% and more than half of patients had at least a 30% reduction of their worst pain. Additionally, half or more of the 31 evaluable patients in the open-label study had threshold-level improvement in multiple measures of QOL.
Both radium-223 and abiraterone have FDA-approved indications for mCRPC. Preclinical stud¬ies have suggested potential therapeutic synergy with the combination of the two agents, providing a rationale for the trial reported by Neal Shore, MD, medical director of the Carolina Urologic Research Institute.
Investigators enrolled men with symptomatic mCRPC and metastases limited to bone. Treat¬ment consisted of radium-223 administered every 4 weeks for a total of 6 doses, concurrent abiraterone, and prednisone. Eligible patients had initiated a stable dose of daily abiraterone plus prednisone within 90 days of enrollment, or start¬ed a stable dose of abiraterone plus prednisone within 30 days of the first radium-223 infusion. Follow-up assessments occurred on day 1 of every treatment cycle.
The data analysis included 36 patients who received at least 1 radium-223 infusion. Effica¬cy analysis was based on the 31 patients who completed all 6 cycles of combined therapy. The primary endpoint was change in bone pain, as assessed by the Bone Pain Inventory-Short Form, and QOL as determined by the FACT-P question¬naire.
Secondary endpoints included findings from computed tomography and bone scans, changes in PSA and ALP, need for additional antineo-plastic therapy, occurrence of skeletal-related events (SREs), change in ECOG performance status, and safety.
The men were a median age of 75, two-thirds had Gleason grade 7-8 disease, and 44.4% were receiving narcotic pain medication at enrollment.
The primary analysis showed that 18 of 31 (58%) evaluable patients had at least a 30% reduc¬tion of worst pain without an increase in the use of analgesic medications. In the subgroup of pa¬tients with clinically significant pain at baseline, 84% had a 30% improvement or more in worst pain. The results also showed that 12 of 31 (39%) patients had clinically meaningful palliation of pain that interfered with daily activities. The fig¬ure increased to 50% of patients for the subgroup with clinically significant pain interference at the start of treatment.
An analysis of QOL data showed that a majority of patients met criteria for minimally important improvement in prostate cancer (80.6%), FACT-P total (64.5%), functional well-being (61.3%), trial outcome index (59.9%), physical well-being (58.9%), FACT-G (58.9%), and emotional well-being (54.8%).
Data on bone scans and ALP suggested addi¬tional benefits of the treatment. Investigators found that 19 of 31 (61%) of patients had improve¬ment in bone lesions, and 35% had stable bone lesions, leaving 1 patient with worsening bone scans. ALP response data showed 21 patients had reductions in serum ALP, 8 had increased ALP that was still within normal limits, and two pa-tients had increased ALP levels that exceeded normal limits.
Sixteen of 36 patients reduced their pain medi¬cation use. No patient required additional antican¬cer therapy, and no SREs occurred in any patient. Performance status remained stable throughout.
The safety analysis showed that 30 of 36 pa¬tients reported 186 adverse events (AEs), which were grade 1/2 severity in all but 7 cases. The most frequent treatment-related AEs were diar¬rhea (19.4%), nausea (19.4%), and fatigue (16.7%). Six serious AEs occurred, 1 of which (abdomi¬nal pain) led to withdrawal from the study. One patient died, but the death was not considered treatment related.
Andrew J. Roth
Research suggests that 25% to 40% of individuals receiving chemotherapy experience persistent mild to moder¬ate cognitive changes, and a study of breast cancer survivors suggests that a new type of psychotherapy delivered by videoconference may help reduce these effects, often referred to as “chemobrain” (Cancer. 2016;122(11):1782-1791).
The objective of the 4-part novel therapy explored in this study, Memory and Attention Adaptation Training (MAAT), is to “optimize be¬havioral, cognitive and emotional adaptation” to living with chemobrain, according to the authors.
The study involved 35 Caucasian female breast cancer survivors who met the following in¬clusion criteria: a diagnosis of stage I-IIIa breast cancer; treatment involving adjuvant chemotherapy; were 6 months out from treatment and cur¬rently disease free. Participants also had to have reported cognitive problems attributed to chemotherapy. Twenty-two women were randomized to MAAT and 13 to supportive talk therapy, which also was delivered via videoconference. Survivors on both arms of the study received therapy for 8 weekly visits of 30 to 45 minutes each.
The first component of MAAT, education, is a common characteristic of any cognitive behavior¬al therapy, intended to help make survivors aware of the possibility that other factors, eg, stress, age or inattention, can contribute to memory issues.
“We want people to not get into a habit of attributing all memory failures to chemotherapy,” explained study author Robert J. Ferguson, MD, a clinical psychologist who led the research effort at Eastern Maine Medical Center and Lafayette Family Cancer Center in Bangor, Maine. He is now an assistant professor of medicine at the University of Pittsburgh Cancer Institute. He also emphasized that his intention is not to dismiss any experiences of a cancer survivor.
While education is a discussion between patient and clinician, the second component of MAAT, self-awareness, moves the patient toward taking action. As part of this, individuals are asked to self-monitor and record memory failures that bother them.
“We want individuals to identify and be more aware of—through this self-monitoring or recording process—of the situations where they’re at risk for memory failure in daily life,” Ferguson elaborated.
The third component, stress management and self-regulation, will typically include relax-ation training, “cognitive restructuring” and sleep quality improvement.
Finally, cognitive compensatory strategies training includes “self-instructional training, verbal rehearsal, visualization strategies, keeping an organized schedule and active listening to enhance verbal-auditory encoding,” according to the study’s authors.
Survivors on the other arm of the trial who re-ceived supportive therapy worked on building an alliance with their physician through empathy, support, and warmth, without any behavioral training.
Following MAAT or supportive therapy, individuals were assessed using the Perceived Cog¬nitive Impairments (PCI) questionnaire which asked individuals to rate perceived memory issues over the previous week, on a scale of 0 (never) to 4 (several times a day).
Survivors were also asked to rate their memory and cognitive abilities with the Perceived Cogni¬tive Abilities questionnaire. Individuals were as¬sessed before therapy, immediately after therapy, and 2 months after completion of therapy.
A trend towards benefit in perceived cognitive impairment for individuals in the MAAT group was seen in the posttreatment analysis. That benefit became significant at 2-month follow up, according to the authors. A benefit for MAAT was also observed for survivors in processing speed in the posttreatment analysis, though the 2-month follow-up data were not statistically significant.
Participants in either group did not differ in posttreatment results with regard to anxiety about cognitive problems (quality of life). At the 2-month follow up, though, MAAT individuals had decreased anxiety, suggesting they “continued to build coping skills beyond the cessation of clinician interaction,” study authors noted. Ferguson said that future research is warranted to improve methods of preventing and treating cognitive failure. These studies must be expanded to include men, survivors of other types of cancer, survivors of different ethnic backgrounds and at other sites.
Virginia Powers, PhD
Efficacy and safety remained strong at 2 years following treatment with nivolum¬ab in previously treated patients with ad¬vanced, refractory, squamous non–small-cell lung cancer (NSCLC), according to updated results from the CheckMate 063 and CheckMate 017 trials presented at the 2016 European Lung Cancer Confer¬ence. An exploratory analysis also sig¬naled an association between baseline serum cytokine levels and the immuno¬therapy’s efficacy.
With nivolumab, the 2-year overall survival (OS) rate in CheckMate 063 was 22%, and medi¬an OS was 8.1 months.
“Findings were consistent across the phase II CheckMate 063 trial of nivolumab and phase III CheckMate 017 trial of nivolumab versus docetaxel in patients with advanced platinum-refractory squamous NSCLC,” reported Suresh Ramalingam, MD, of the Winship Cancer Insti¬tute at Emory University in Atlanta, Georgia.
Ramalingam also presented findings from a multivariate analysis of baseline levels of serum cytokines in patients participating in both trials. A SQ-cytoscore was generated, defined as “high” or “low” based on the median cutoff, and the association of the score to OS was assessed by Kaplan-Meyer analysis.
This analysis revealed a relationship between baseline serum cytokine levels and therapeutic efficacy. OS in 102 patients with high baseline cytoscores was nearly 3 times longer with nivo-lumab when compared with 120 patients who had low serum cytokine levels at baseline. Me¬dian OS was 15.6 versus 5.3 months in the high and low cytoscore groups, respectively.
Although an effect from baseline serum cyto¬kine levels was observed among docetaxel-treat¬ed patients in CheckMate 017, median OS was longer with nivolumab versus docetaxel in both cytoscore groups. With docetaxel, 70 patients having high and 48 patients with low cytoscores showed median OS of 9.1 versus 4.9 months, respectively. Difference in median OS in the high and low cytoscore groups (6.5 and 5.4 months, respectively) favored nivolumab over docetaxel.
Nivolumab had been administered in Check¬Mate 063 at 3 mg/kg every 2 weeks to 117 pa-tients until progressive disease (PD) or unaccept¬able toxicity occurred. CheckMate 017 random¬ized 135 patients to receive nivolumab at the same dose and 137 patients to docetaxel at 75 mg/m2 every 3 weeks until PD or discontinuation due to toxicity or other reasons.
The primary endpoints were overall response rate (ORR) by independent radiology committee (IRC; RECIST v1.1) in CheckMate 063 and OS in CheckMate 017. Treatment beyond PD was permitted in both studies.
In CheckMate 017, the 12- and 18-month OS was 42% and 28%, respectively, with nivolumab, compared with 24% and 13% with docetaxel. Me¬dian OS was 9.2 months with nivolumab versus 6.0 months (95% CI, 5.29-7.39) with docetaxel.
In CheckMate 063, the IRC-assessed ORR at 6 months was 12%, and median time to response (TTR) was 3.0 months (range, 1.7-4.0). The best overall response included 12 partial responses (PR), 29 patients achieved stable disease (SD), and 43 patients showed PD. Response was un-able to be determined in 16 patients. Median duration of response was not reached with 71% of patients showing an ongoing response. The 6-month PFS rate was 27%, and median PFS was 1.9 months.
“Patients with platinum-refractory, advanced squamous NSCLC had few treatment options until nivolumab was approved for treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy in both the United States and the European Union,” Ramalin¬gam noted. “Nivolumab continues to demonstrate clinically meaningful efficacy in CheckMate 063.”
The 24-month efficacy update showed IRC-assessed ORR of 15%, with 29% of patients show¬ing an ongoing response. Complete response was achieved by 2 patients, 13 showed PR, 30 had SD, and 45 patients experienced progression. The PFS rate was 9%, and median PFS was 2 months. Median TTR was 3.3 months and median dura¬tion of response was 19 months. Ten patients were unevaluable for response.
It was noted that 4 patients were on nivolumab at the 24-month data cutoff, and 5 of 26 patients treated beyond PD showed a nonconventional pattern of benefit.
The CheckMate 063 safety update after 2 years was similar to that seen at 1 year; treatment-re¬lated adverse events (TRAEs) of any grade were reported in 75% of patients, with 12% leading to study discontinuation. Grade 3/4 TRAEs occur-red in 18% of patients leading to study discontin¬uation in 10% of patients.
As of the December 2015 database lock, 82% of patients had died; of these deaths, 74% were due to disease progression, 2% from study drug tox¬icity and 7% of patients died due to other reasons.
“The safety profile of nivolumab is manageable and consistent with previous studies,” Ramalin¬gam said.
Importantly, no treatment-related deaths oc¬curred since the 6-month database lock, and no new grade 3/4 TRAEs have been reported since the database lock at 1 year.
“The results presented here today demonstrate that the SQ-cytoscore, derived from select serum cytokines at baseline, appears to be associated with better prognosis in advance squamous NSCLC,” concluded Ramalingam.
“These preliminary SQ-cytoscore findings re¬quire prospective validation in future studies.
Lena H, Rizvi NA, Wolf J, et al. Nivolumab in patients (pts) with advanced refractory squamous (SQ) non-small cell lung cancer (NSCLC): 2-year follow-up from CheckMate 063 and exploratory cytokine profiling analyses. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract 137O