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This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.
Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may articipate in this CE activity.
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Lauren M. Green
Although androgen deprivation therapy (ADT) has a survival benefit for patients with high-risk and locally advanced prostate cancer, it is associated with substantial safety concerns, and mixed data exist regarding whether ADT causes clinically significant depression. A new population-based study published online April 11, 2016, in the Journal of Clinical Oncology sought to explore this possible association.
Using the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database from 1992 to 2006, researchers identified a total of 78,552 men aged ≥65 years with stage I-III prostate cancer, of whom 33,882 (43%) received ADT within 6 months of diagnosis.
The association between pharmacologic ADT and a diagnosis of depression (primary endpoint) or receipt of psychiatric treatment (secondary endpoint) was analyzed using Cox proportional hazards regression.
The analysis demonstrated significantly increased risks for depression (23%) and inpatient psychiatric treatment (29%) among patients receiving ADT, and a nonsignificant 7% increased risk of outpatient psychiatric treatment. All three of these parameters demonstrated a significantly increased risk with duration of ADT: the risk of depressionrose from 12% with ≤6 months of treatment, to 26% with 7 to 11 months of treatment, to 37% with ≥12 months of treatment.
These findings add to accumulating evidence around the major adverse event profile associated with ADT, and the risk of psychiatric illness should be noted as a potential side effect when discussing ADT with patients. The possible adverse event should also be factored in when weighing the benefits and harms of ADT use in older men with intermediate-risk disease.
One study limitation noted by the researchers is that use of Medicare SEER data limited the scope to men aged ≥65 years at diagnosis, and thus, the results may not be applicable to younger men. Additionally, the relationship between depression and ADT treatment may be confounded by the fact that patients were older and had more comorbidity.
Lauren M. Green
An intervention specifically aimed at reducing the trauma and anxiety that often come with parenting a child undergoing hematopoietic stem cell transplant (HSCT) proved especially helpful for parents during the time of the actual transplant and subsequent hospitalization, according to findings of a randomized clinical trial published in the Journal of Consulting and Clinical Psychology.
The parent social-cognitive intervention program (P-SCIP) also proved more beneficial in subgroups of caregivers who came into the HSCT process with already elevated depression and anxiety, as well as among those whose children experienced graft-versus-host disease (GVHD).
Between 2008 and 2013, 218 biological or foster parents of transplant recipients under age 19 were randomized to receive P-SCIP (n = 110) or best practice psychosocial care ([BPC] n=108). P-SCIP involved five, 60-minute, in-person sessions over a 2-to-3-week period following the transplant in which parents viewed an interactive CD-ROM and were given guidance on relaxation techniques, such as deep breathing and guided imagery relaxation. Topics covered included:
• Worries about your child
• Coping with solvable concerns involving a stem cell transplant
• Coping with unchangeable problems
• Importance of expressing feelings and needs
The BPC control used for comparison had 4 components: a 1-hour video guide to a child’s stem cell transplant; a pamphlet covering common caregiver issues; an offer of 5 hours of respite care; and walkie-talkies to communicate with the child when the parent was not in the room.
A majority of caregivers in the P-SCIP group attended at least 3 of the 5 sessions where the intervention was offered. Participants were asked to complete an in-person survey within 1 month of their child receiving the transplant and to complete follow-up surveys at 1 month and phone or mail surveys at 6 months and 1 year. The surveys employed validated measures of depressive symptoms, anxiety, traumatic distress, and positive well-being.
Both P-SCIP and BPC were generally rated highly by participants. P-SCIP provided immediate relief of depression, anxiety, and traumatic distress compared with the BPC controls. “Such immediate relief as provided through this intervention is important, as it spares caregivers additional stress and trauma during a universally stressful life experience,” explained lead author Sharon L. Manne, PhD, associate director for Cancer Prevention, Control, and Population at the Rutgers Cancer Institute.
These psychological benefits seen during the time of the actual HSCT, when caregivers were experiencing the most distress, were not observed at the 6-month and 1-year assessments, however. This finding may reflect the fact that distress declines as the child recovers after the procedure, the researchers hypothesized.
Among the cognitive and social aspects which improved more in the intervention arm were acceptance, humor, and problem-solving; no effect was seen in the areas of positive reappraisal, seeking emotional support, or fear appraisals, compared with the usual care group.
Notably, longer-term benefits of the P-SCIP were seen in parents who reported more anxiety to begin with and in those whose children experienced more adverse medical effects from HSCT (eg, GVHD). Therefore, screening caregivers to target interventions at these specific subgroups may be beneficial.
One limitation of the study cited by the authors is a “relatively high dropout rate,” with 19% of caregivers in the P-SCIP arm not attending any or only 1 of the 5 sessions, a finding they said may be attributable, in part, to caregivers not wanting to leave their child’s bedside.
“If this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone- or web-based contact that would allow the parent to remain in the room with the child during hospitalization might enable caregivers to more easily access the intervention.”
Manne S, Mee L, Bartell A, Sands S, Kashy DA. A randomized clinical trial of a parent-focused social-cognitive processing intervention for caregivers of children undergoing hematopoetic stem cell transplantation. J Consult Clin Psychol. 2016;84(5):389-401.
Melissa Baker, RN, MSN, OCN, APN-C
Combining ipilimumab and nivolumab showed a 42% improvement in overall survival (OS) compared with ipilimumab monotherapy for patients with advanced melanoma in a 2-year assessment of the phase II CheckMate-069 trial, announced Michael Postow, MD, at the 2016 AACR Annual Meeting. Abstract CT002
These results extend the enthusiasm for combination immunotherapy owing to complementary and non-redundant mechanisms of action between anti-CTLA-4 ipilimumab and anti-PD-1 therapy nivolumab, said Postow, of the Melanoma-Sarcoma Oncology Service at Memorial Sloan Kettering Cancer Center.
The 2-year OS rate with the combination was 69% compared with 53% for ipilimumab alone, for patients with BRAF wild-type melanoma. The median OS among patients was not reached with the combination regimen and was 24.8 months with ipilimumab monotherapy.
In the overall study population, the 2-year OS rate was 64% with the combination compared with54% for ipilimumab alone. The median OS at 2 years in patients randomized to either the combination or monotherapy has not been reached.
Findings from the CheckMate-069 study add to results from the phase III CheckMate-067 study, which showed improvements in progression-free survival (PFS) and objective response rates (ORR). The FDA granted an accelerated approval to the combination for BRAF wild-type tumors in October 2015 and for those with BRAF mutations in January 2016.
In the phase II study, treatment-naïve patients (n =142) with unresectable stage III or metastatic stage IV melanoma were randomized in a 2:1 ratio to either 3 mg/kg of ipilimumab in combination with 1 mg/kg of nivolumab (n = 95) or placebo (n = 47) once every 3 weeks for 4 doses. This was followed by nivolumab at the same dose or placebo every 2 weeks until disease progression
or unacceptable toxicity.
As reported previously, with 11 months of follow-up, the ORR in the BRAF wild-type group (the primary endpoint) was 61% in the combination arm compared with 11% in the ipilimumab monotherapy arm (N Engl J Med; 2015; 372(21):2006-2017). The results were similar among all randomized patients, which included patients with BRAF-mutant melanoma.
With 2-year follow-up, among all patients randomized to combination treatment, the median tumor burden by RECIST v1.1 decreased by 70%, whereas the median tumor burden among all patients randomized to ipilimumab increased by a median of 5%. The median duration of response was not reached in either arm. Eighty percent of responses to the combination (45 of 56) and ipilimumab monotherapy (4 of 5) were ongoing at the 2-year follow-up.
“The majority of these responses happened early, at the time of the first scan,” said Postow. “The median time to response was 2.8 months in the combination arm and 2.7 months for ipilimumab alone.” Twenty-nine of 45 patients (64%) who discontinued combination treatment remain in response.
Median PFS at 2 years in the BRAF wild-type population was not reached in the combination arm and was 4.4 months in patients randomized to ipilimumab alone, for a hazard ratio of 0.35 in favor of the combination.
“This reflects a statistically significant difference in the reduction of progression or death in favor of the combination over ipilimumab monotherapy,” he said.
The 2-year PFS rate with combination treatment in BRAF wild-type tumors was 54% compared with 11% with ipilimumab alone. Similar PFS rates were observed in the all-randomized population. The combination of ipilimumab and nivolumab resulted in a median PFS that still has not been reached at the 2-year follow-up. With ipilimumab monotherapy, the median PFS was 3 months. “This reflects a 64% reduction in the hazard of progression or death in this all-randomized patient population, whichis very impressive and statistically significant,” Postow said.
Overall, 35% of patients in the combination arm and 70% in the monotherapy arm received any subsequent therapy. Altogether, 64% of patients randomized to ipilimumab crossed over to receiveany systemic therapy at the time of progression.
Eighteen percent of patients in the combination group received subsequent anti-PD-1 therapy at progression compared with 62% in the ipilimumab monotherapy arm. The median time to initiation of the subsequent therapy was not reached in the combination arm and was 6.1 months in the ipilimumab-alone arm.
When assessing efficacy of combination immunotherapy by PD-L1 status, there was nodifference in the ORR at the 1-month data cutoff and no difference in PFS or OS at 2 years between patients who were defined as PD-L1-positive versus those defined as PD-L1-negative.
Treatment-related adverse events were consistent with the initial reports, with higher rates of gastrointestinal and hepatic adverse events of any grade with the combination compared with monotherapy.
Grade 3/4 treatment-related AEs occurred in 54% of patients treated with the combination regimen versus 20% with ipilimumab alone. AEs led to discontinuation in 37% of patients treated with the combination regimen compared with 9% for ipilimumab alone.
Lauren M. Green
Chest radiation to treat a pediatric cancer is a well-known risk factor for gettingbreast cancer in adulthood, and research has now unearthed two specific genetic variants that may help to identify those survivors who are most at risk.
“This is the first study that provides evidence that germline genetics outside the context ofhigh-risk syndromes can modify the risk for breast cancer in childhood cancer survivors treated with chest radiation therapy,” said Lindsay M.Morton, PhD, reporting the study results at the 2016 AACR Annual Meeting held April 16-20 in New Orleans. Abstract 2691
“In addition, for patients who have already been treated, the results could be used to identifythe survivors who have the highest risks of developing breast cancer and therefore might benefit the most from screening.”
The specific variants were found to increase breast cancer risk only in women who received 10 or more Gy of chest radiotherapy, reported Morton, a senior investigator with the National Cancer Institute’s Radiation Epidemiology Branch. A variant at position q41 on chromosome1 was associated with nearly a 2-fold increase in risk, Morton said, and one at position q23 on chromosome 11 was associated with a nearly 3-fold increased risk for each copy of the risk alleles. These variants did not increase breast cancer risk in survivors who had not received radiotherapy to the chest as part of their cancer treatment, however.
Morton said the findings, if elucidated and confirmed in subsequent studies, have the potential to impact cancer and survivorship care for the nation’s growing number of childhood cancer survivors—currently estimated to number 420,000—particularly the women among them.
The researchers conducted genomic DNA analyses of more than 3400 blood or saliva samples drawn from 2 large groups of childhood cancer survivors who had been followed for a median 25 years: the Childhood Cancer Survivor Study, which includes children diagnosed with cancer between 1970 and 1986, and the St. Jude Lifetime Cohort, which includes children diagnosed between 1962 and 2001.
Of the 207 breast cancer cases diagnosed across the two cohorts, the majority (65%) had Hodgkin lymphoma as their first primary childhood cancer, 10% had leukemia, and the remaining had a mix of other childhood cancer types.
Investigators compared the genotypes for survivors who developed breast cancer against those who did not. “About two-thirds of the cases had at least 10 Gy of radiation to their breasts during the course of their childhood cancer radiotherapy,” Morton noted. She added that the median age of breast cancer diagnosis in the population was 39. “These are breast cancer cases that are being seen at a much younger age than you would see in the general population.”
Morton explained the mechanisms behind the two single nucleotide polymorphisms (SNPs, or “snips”) found to be implicated in increasing breast cancer risk in the ≥10-Gy group. The chromosome 1 marker, PROX1, is involved inembryonic development, cellular proliferation,and migration, and alterations are present in about 13% of breast tumor cells, Morton said. The chromosome 11 marker, TAGLN, is involved in cellular migration and is overexpressed in breast tumors compared with normal breast tissue.
“Our top association was for a marker on chromosome 1q41 … there was a very significant difference in the genotype distribution at this particular location among the childhood cancer survivors who developed breast cancer compared with those who did not,” said Morton. “The relative risk for developing breast cancer was nearly 2-fold for each copy of the risk allele … but there was no effect on risk among childhood cancer survivors who had not received chest radiotherapy.”
Similar results were seen for the marker on chromosome 11q23, Morton noted, but “unlike the chromosome 1 snip, which was a relatively common one, the chromosome 11 snip was a relative rare marker,” only present in 2% to 3% of controls. This snip conferred about a 2.6-fold increased risk for breast cancer, again restricted to those childhood cancer survivors who had received at least 10 Gy of radiation to the breast, Morton continued.
Morton cautioned that, because they were generated in a “discovery” study, these early findings will require replication before evaluation in the clinic. Among the unanswered questions, she said, is the relationship between the genotypeand the risk from the lower radiation levels patients are typically treated with today.
Other factors to consider include the effect of the child’s age at treatment and whether an individual’sbreast cancer molecular subtype affects the level of increased risk.
“Once all of this work is done—the laboratory studies and additional replication—we think that these studies have tremendous potential for the future,” concluded Morton. “There is the possibility that understanding genetic susceptibility could impact frontline therapy decisions. It may alter the risk-and-benefit calculation for receipt of radiotherapy for a childhood cancer patient who is being diagnosed today.
“For the many survivors who are already out there, these data also could impact the screening recommendations.”
Lauren M. Green
A study of more than 2400 women with early-stage breast cancer has found that those who fasted 13 hours or more at night reduced their risk of breast cancer recurrence, findings that suggest prolonging the nightly fasting interval may offer a relatively safe nonpharmacologic way for women with early breast cancer to lower their risk of disease recurrence.
Nightly fasting less than 13 hours was not significantly associated with a higher risk of breast cancer mortality, however. The patient cohort for this study was drawn from participants in the Women’s Healthy Eating and Living (WHEL) study conducted between 1995 and 2007.
This randomized, controlled trial involved 3088 women with early-stage invasive breast cancer and evaluated whether a low-fat diet focused on vegetables, fruit, and fiber reduced breast cancer recurrence risk and mortality.
The present study looked at invasive breast cancer recurrence and new primary breast tumors during an average of 7.3 years of follow-up and death from breast cancer or any cause during an average 11.4 years of surveillance.
Data were gathered from the participants’ telephone self-reports of their recall of their dietary patterns over the previous 24 hours, taken at baseline, year 1, and year 4.
Participants were aged a median 52.4 years. They reported a mean fasting duration of 12.5 hours per night and 4.4 eating episodes, defined as the number of times per day that they consumed ≥25 kcal at a single time point. Approximately 33% of participants reported eating episodes after 8 pm.
A nightly fast of less than 13 hours was associated with a 36% higher risk of breast cancer recurrence, compared with fasting ≥13 hours per night. Additionally, each 2-hour increase in nightly fasting was associated with significantly lower hemoglobin A1C levels.
Another interesting research finding involved sleep quality: the investigators found that prolonged fasting at night was associated with longer sleep duration, a finding in line with previous research that consuming foods late at night may interfere with circadian rhythms.
The authors noted that limited data exist from previous small studies involving humans that signal a positive impact from intermittent fasting regimens on risk factors for poor breast cancer outcomes, among them, glucose regulation, inflammation, obesity, and sleep.
The researchers concluded that although the study findings “have broad and significant implications for public health, randomized trials are needed to adequately test whether prolonging the nightly fasting interval can reduce the risk of chronic disease.”
Marinac CR, Nelson SH, Breen CI, et al. Prolonged nightly fasting and breast cancer prognosis [published online before print March 31, 2016]. JAMA Oncol.