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Men under the age of 65 who get less than 7 hours of sleep each night have a greater risk of dying of prostate cancer, according to findings from a study at the AACR Annual Meeting held April 2 to 5.
The role of getting sufficient sleep is increasingly recognized as essential to health. Sleep provides the downtime the body needs to repair and restore vital functions, cells and tissues.
Following on previous research suggesting an association between shorter sleep duration and fatal prostate cancer, researchers from the American Cancer Society (ACS) in Atlanta examined data from 2 large, longterm cohort studies, the Cancer Prevention Study-I (CPS-I) and the Cancer Prevention Study-II (CPS-II). They determined that shorter sleep duration was associated with an increased risk of death from the disease, but only in men ≤65 years.
The ACS Cancer Prevention Studies are part of its intramural research program. The CPS-I cohort, launched in the 1950s, included nearly 1 million men. In 1982, the CPS-II cohort was established and recruited 1.2 million participants and includes a subgroup focused on nutrition.
From the CPS-I study, 407,649 men were followed from 1950 through 1972; 416,040 men from the CPS-II study were followed from 1982 through 2012. All men were cancer-free when the studies began, and researchers excluded anyone with sleep information that could not be determined. In CPS-I, 1546 men died of prostate cancer, and CPS-II, 8704 men died of the disease during the first 8 years of follow-up.
Sleep-related behaviors such as sleep duration, shift work, and insomnia were self-reported by study participants.
Examining the deaths from prostate cancer more closely, researchers found that during the first 8 years of follow-up, men ≤65 years who slept 3 to 5 hours per night had a 55% greater risk of dying of prostate cancer than men who slept for 7 hours (relative risk [RR], 1.61; CI, 1.10-2.37).
Additionally, men in this age group who had 6 hours of sleep per night had a 29% higher risk than those who averaged 7 hours (RR, 1.25; CI, 0.99-1.58). For men ≥65 years, no difference was reported in the risk of death from prostate cancer, no matter how much sleep they got.
“While these results are intriguing, and contribute to a growing body of evidence that circadian rhythm–related factors might play a role in prostate carcinogenesis, more research is needed to better understand the biologic mechanisms,” said Susan M. Gapstur, PhD, MPH, vice president of epidemiology at ACS and lead author on the study, in a statement.
“If confirmed in other studies, these findings would contribute to evidence suggesting the importance of obtaining adequate sleep for better health.”
Gapstur explained that sleep deprivation and the associated presence of light at night, such as the use of electronics like cell phones and televisions, can inhibit the production of melatonin—a hormone that affects sleep cycles. She added that producing low amounts of melatonin can cause increased genetic mutations, greater oxidative damage, reduced DNA repair, and immune suppression.
Less sleep also may contribute to the dysregulation of genes involved in tumor suppression. Regarding sleep duration and death from prostate cancer in older men, Gapstur said the reasons remain unclear. However, she believes it may be related to the natural decline in nocturnal melatonin levels with age, possibly reducing the relative impact of sleep deprivation.
“These findings support evidence that factors related to circadian rhythms may increase fatal prostate cancer risk,” the authors noted in their abstract.
“The observed association between short sleep duration and higher risk of fatal prostate cancer only during the first 8 years of follow-up suggests that short sleep duration could affect later stages of prostate carcinogenesis.”
Study authors noted 2 limitations of the study: self-reporting of data and the fact that data were collected only at the start of the study and thus may not reflect changes in sleep habits.
Lauren M. Green
Long-term survival in patients with metastatic non–small cell lung cancer (NSCLC) receiving the immune checkpoint inhibitor nivolumab (Opdivo) has proven to be much higher than expected, with 16% of these patients surviving after 5 years, which is equivalent to about 4 times what would be expected with chemotherapy.
What explains the extended survival of these 16 patients remains an important area of further investigation, as the analysis found that nothing really stood out to predict who will become longterm survivors, and the survivors themselves had diverse baseline characteristics.
The study is the first to report long-term survival rates in patients with metastatic NSCLC treated with an immune checkpoint inhibitor. It suggests that, “for a small subset of patients, immunotherapy can work for a very long time,” according to study author Julie Brahmer, MD, who reported at the 2017 AACR Annual Meeting.
Brahmer, an associate professor of oncology at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, presented updated results from the phase Ib CA209-003 dose-escalation cohort expansion trial which involved 129 patients with heavily pretreated, advanced NSCLC who were randomized to receive nivolumab once every 2 weeks for up to 2 years. The results Brahmer presented at AACR are based on approximately 5 years of follow-up. Overall survival (OS) at 1 year was 42%; at 2 years, 24%; 3 years, 18%; and at 5 years, 16%.
Twelve of the 16 long-term survivors had partial responses, which includes both early and late responses. Nine patients completed the maximum of 2 years of nivolumab, “but there were 4 patients who actually stopped therapy early due to adverse events and have not required any further treatment, even though they didn’t get the full 2 years of therapy,” Brahmer explained.
Overall, 12 of the 16 patients received no further therapy after nivolumab and remained without evidence of progressive disease at the time of their last follow-up. Of the 4 patients who received subsequent therapy, however, one stopped after 2 years, but then the disease progressed about 1 year later, at which time the patient was retreated with nivolumab and had a response that lasted about 1 more year before progression again. A second patient stopped therapy and had local progression wherein the right lower nodule was resected, and “this patient has not required further therapy,” said Brahmer.
Five-year OS was very similar between patients whose tumors expressed <1% PD-L1 (n = 30), and those with ≥1% (n = 38), at 20% and 23%, respectively, Brahmer reported. Of the 13 patients whose tumors expressed ≥50% PD-L1; however, their 5-year OS was 43%. PD-L1 status was not evaluable in 61 patients, but their estimated 5-year OS rate was 10%.
The researchers also analyzed other characteristics of all treated patients compared with the 5-year survivors, but, “in general, there is really no difference,” Brahmer said. Most patients were former or current smokers with similar tumor histology: 54 patients in the total cohort had squamous NSCLC and 74 had non-squamous; the histology of 16 long-term survivors was evenly divided between the 2. “Interestingly, however, 2 of the 16 patients had EGFR mutations,” noted Brahmer. “Typically, we don’t expect these patients to do well with immunotherapy.”
"This is the longest follow-up to date on patients with lung cancer receiving this therapy,” noted press conference moderator Suzanne Topalian, MD, professor of surgery and director of the Melanoma Program at Johns Hopkins Medicine. “The 5-year overall survival really quadrupled the survival we would otherwise expect if these patients had received chemotherapy.”
The research sheds additional light on the important topic of how long patients should remain on immunotherapy. These findings, said Brahmer, suggest that “we can shorten the time patients require therapy, but we really need to be able to identify those patients who develop ‘memory cells’ to continue to combat their tumor long term.”
Samantha Siegel, MSN, APN-C, OCN
The introduction of immunotherapy to oncology treatment has truly begun to change the way we treat patients, as well define prognosis in terminal illnesses. Specifically, nivolumab (Opdivo), which is an anti–PD-1 immune checkpoint inhibitor, has increased survival for many patients whose life expectancy was less than 1 year.
Many patients who do respond, as the study shows, tend to do so for a prolonged period of time, and it is important to evaluate these individual responses and for the treating physicians and advanced practice nurses to have a solid understanding of immunotherapy drugs. Familiarity with the drugs and associated clinical trials lends itself to appropriate use of these agents and superior patient management.
The treatment duration for immunotherapy remains elusive, making it exceptionally important to recognize immune-related adverse events and recognize that these toxicities can occur beyond the termination of treatment. Side effects such as pneumonitis, thyroiditis, hepatitis, nephritis, dermatitis, and colitis, can occur at any point during treatment. Although toxicities tend to increase with combination immunotherapy, single-agent immunotherapy can certainly be toxic. From a nursing perspective, it is imperative that patients receiving these drugs are fully educated on the treatment for toxicities and understand that all healthcare practitioners involved in their care need to be aware that they are receiving or have received immunotherapy.
As long-term survival increases, the entire concept of lung cancer treatment may change. Although prognosis for stage IV disease has always been quite grim, healthcare practitioners are now seeing survival benefits beyond anything that could have been expected with conventional chemotherapy. Initial pathology and staging workups have also started to change to include PD-L1 testing. This allows for stage IV patients to get immunotherapy as a first-line cancer therapy.
It is clear that further research is needed on long-term responses with immune checkpoint inhibitors, but their discovery has certainly changed the face of oncology and brought hope to many patients who are terminally ill.
Lauren M. Green
A landmark analysis of findings from the international, multicenter, phase III EF-14 trial testing the efficacy and safety of tumor treating fields (TTFields; Optune) for the treatment of glioblastoma multiforme (GBM) has found that for patients who used the device, their risk of death was reduced by 37% and their overall survival (OS) extended by a median of 5 months. The results were presented at the 2017 AACR Annual Meeting held April 2 to 5.1
Two-, 3-, 4-, and 5-year overall and progression-free survival (PFS) rates for patients who received TTFields with adjuvant temozolomide (TMZ; Temodar) were significantly improved over patients who received TMZ alone, reported Roger Stupp, MD, professor of neurological surgery at Northwestern University Feinberg School of Medicine and associate director for strategic initiatives at the Robert H. Lurie Comprehensive Cancer Center.
He deemed these findings a “clear improvement,” in a setting like GBM where the prognosis is so poor and thus requires a “thinking out of the box” strategy like TTFields. He said that this final analysis of EF-14 suggests that electric fields therapy should be considered as part of the standard of care for all patients with newly diagnosed GBM.
Interim findings from EF-14, based on the experience of 315 patients,2 led to the FDA’s approval of the device in 2015 for use in combination with adjuvant TMZ, as a treatment for patients with newly diagnosed GBM following surgery, chemotherapy, and radiation.
TTFields are low-intensity electric fields alternating at an intermediate frequency (200kHz) that are thought to exert anticancer effects by blocking cell division. For patients with GBM, the TTFields are delivered continuously to the brain by a patient-operated, medical device that is worn continuously for at least 18 hours throughout the day.
Stupp said that patients learned how to use the device very quickly, and in his 10 years of experience studying it, he has found it to be well tolerated. In EF-14, adherence was >75% over the course of a median number of 8.2 TTFields/ TMZ 1-month cycles of therapy. Most of the side effects in the experimental arm, he said, were due to the chemotherapy rather than the device, which is associated with skin reactions that are usually mild.
The EF-14 trial enrolled patients from July 2009 to December 2014, and the findings reported at AACR were as of the data cutoff December 28, 2016. A second-generation, lighter version of the device was approved by the FDA in July 2016, weighing 2.7 lbs or about half the size and weight of the original.
A total of 695 patients with grade IV GBM who had completed standard treatment involving surgery, TMZ, and radiation, were randomized within 7 weeks of their last radiation dose to either TMZ with TTFields (n = 466) or TMZ alone (n = 229). To be included in the study, participants had to have a Karnofsky performance score ≥70 and nonprogressive disease. Patient characteristics were similar between the 2 arms: the median age in the 2 groups was approximately 56.5 years, and most patients were male (68.5%). The trial’s primary endpoint was PFS based on blinded central radiology review, with OS as the secondary endpoint.
PFS was 6.7 months with TTFields/TMZ versus 4.0 months in the TMZ-only arm (hazard ratio [HR], 0.63; CI, 0.52-0.76; P = .00005). Median PFS after diagnosis was 11.2 months in the experimental arm compared with 7.8 months in the control group. Median OS was 20.9 months with TTFields versus 16.0 months with TMZ only (HR, 0.63; CI, 0.53-0.76; P = .00006).
MGMT is a clinically significant molecular marker in this setting, and patients whose tumors have methylated MGMT generally have a better prognosis. In this trial, among the 41% of patients who had methylated MGMT, OS was 31.6 months in the TTFields arm compared with 21.2 months in the control group. For patients with unmethylated MGMT, the survival benefit with TTFields was smaller (16.9 vs. 14.7 months).
Notably, reported Stupp, OS was better with TTFields in patients irrespective of age, suggesting that oncologists should consider the device for use in elderly patients. Median OS was 21.6 months in patients <65 years in the TTFields cohort, compared with 17.1 months with TMZ alone; for patients aged 65 and older, median OS was 16.0 months with the device versus 10.9 months among control participants.
Stupp also reported landmark annual survival rates in patients using TTFields. One year after randomization, 73% of patients in the TTFields arm were alive versus 65% of the control participants. At year 2, survival was 43% versus 31%, respectively; year 3, 26% vs 16%; year 4, 20% vs 8%; and 5 years out, 13% of patients with the device survived versus 5% with chemotherapy only. The investigators noted that patients who wore the device longer than 18 hours/day had better outcomes.
Prior to TMZ chemotherapy, 5-year survival rates in GBM were 3.6%, Stupp remarked in his presentation. When TMZ was added to radiation, this improved to 9.8%. Now, however, “EF-14 establishes a new landmark 5-year survival rate of 13%, and long-term remission in GBM is now possible.”
“Although we’re far from where we want to be,” Stupp concluded, “TTFields confer a meaningful additional benefit for these patients,” with all subgroups benefitting from the therapy, including those with the worst prognosis.
He added that the device is being explored for use in treating other solid tumors, including pancreatic cancer and mesothelioma. “These data show the power of this new treatment modality, and we look forward to learning the results of trials testing it in patients with other forms of cancer.”
Life expectancy for patients with myeloma has increased significantly over the past 20 years. In England, the 5-year survival rate increased from 37.1% in 2005-2009 to 42.2% in 2007-2011. Data from the National Cancer Institute’s SEER program show steady improvement in 5-year relative survival in the United States, from 26.3% in 1975 to 52.7% in 2009.
However, longer life expectancy comes with a unique set of problems. The physical health of long-term survivors reflects the effects of disease, comorbidities, frailty, and aging. Moreover, treatment often includes adverse events (AEs), such as permanent organ damage, as patients go through cycles of treatment, remission, and relapse.
To date, there is no comprehensive, multidisciplinary guideline document for the screening, management, and long-term care of patients with myeloma. The UK Myeloma Forum and the British Society for Haematology set out to address the need and published such a guideline in the British Journal of Haematology.
This guideline offer recommendations for screening and management for oncologists, general practitioners, and healthcare specialists in other disciplines, including dentistry and psychology; nurses; social workers; and community groups. All told, as many as 25 practitioners and groups could be involved in managing the late effects of myeloma.
“Our hypothesis is that it will be cost-effective given that nurse- and therapy-led services are significantly less expensive and more comprehensive than medically led care and will lead to a reduction in unplanned/unscheduled appointments with expensive specialists, primary care physicians, and [emergency department] visits,” explained coauthors John A. Snowden, MD, director of blood and marrow transplantation, and Diana Greenfield PhD, RN, professor of cancer survivorship, both at Sheffield Teaching Hospitals NHS Foundation Trust.
“We would like to test our model formally in a research setting and would challenge others to do the same in other health services. What we know is the current medical model, with the focus on the treatment-focused end of the care pathway, remains associated with significant unmet needs and a change in culture and models of care is warranted if we want to optimize patient outcomes at all stages in myeloma.”
The guidelines discuss managing the physical effects of myeloma, recommending annual vaccines for influenza and regular screening for complications such as cardiovascular disease and endocrine disorders. The researchers also advocate for regular dental screenings to address concerns such as dry mouth, hypersensitivity, and problems with speaking or swallowing.
“Maintenance of oral and dental hygiene is relevant to all myeloma patients, whether or not they have undergone [hematopoietic stem cell transplantation],” the researchers wrote. “Regular dental review will not only help identify the risk of bisphosphonate-related osteonecrosis of the jaw, but should also cover a broader range of issues.”
The guidelines go beyond physical concerns, too, calling for regular assessment of a patient’s mood, anxiety, and cognitive status. The researchers recommend a 4-level model of psychological assessment and support in line with recommendations by the National Institute for Health and Care Excellence. Snowden and Greenfield said that healthcare providers can overlook certain aspects of long-term management, but that the patient’s emotional and psychological wellbeing is as important as physical health.
As expected, there is a lot of screening, monitoring, and testing built into these guidelines. But as Snowden and Greenfield point out, clinicians are tasked with managing a complex, lifelong condition that can affect every aspect of a patient’s life, from sexual function to his or her ability to earn a living, to general happiness. “If you frame it as a hassle, then it will be. If you frame it as addressing and managing the concerns of the patient and anticipating and monitoring of treatment consequences, rather than focusing purely on control of the clinical and laboratory parameters of disease activity, the patient’s needs will be addressed and late effects identified sooner.
Snowden JA, Greenfield DM, Bird JM, et al; UK Myeloma Forum (UKMF) and the British Society for Haematology (BSH). Guidelines for screening and management of late and long-term consequences of myeloma and its treatment. Br J Haematol. 2017;176(6):888-907. doi:10.1111/bjh.14514.
Melissa Baker, RN, MSN, APN-C, OCN
Patients with myeloma are living longer due to the availability of novel chemotherapeutic agents and the use of hematopoietic stem cell transplantation. Therefore, nursing and medical management are shifting from a shorter term palliative approach to a chronic disease one.
Unlike other survivorship guidelines, the British Society for Haematology (BSH) publication provides recommendations emphasizing long-term disease complications with consideration of global issues, such as frailty and geriatric assessment. Similarly, the International Myeloma Foundation Nurse Leadership Board (NLB) developed a health maintenance schedule with an emphasis on survivorship.1
Contrary to the NLB health maintenance schedule which consolidated several guideline documents with recommendations for specific areas of practice, the BSH provides 1 integrated guideline document. Recommendations by both the NLB and BSH are similar, highlighting the importance of health promotion and secondary prevention practices through education and collaboration with patients.
Addressing health maintenance should commence at diagnosis and extend well beyond completion of therapy. Both sets of guidelines recommend screening for cardiovascular disease (eg, hypotension, hypertension, and hyperlipidemia), secondary malignancies, endocrine disorders (eg, diabetes, thyroid dysfunction, and hypogonadism), bone health, oral hygiene (eg, oral dryness, decreased salivation, and bisphosphonate-related osteonecrosis of the jaw), and psychosocial screening, including evaluation of nutritional status, pain, addiction, depression, and quality of life.
Nurses play a pivotal role by offering counseling for lifestyle modification, including diet, weight control, smoking cessation, and appropriate physical activity. Patients with myeloma not only require treatment aimed at disease management but they also need supportive and palliative care to improve quality of life at all disease stages. The BSH guidelines highlight the importance of geriatric and holistic assessments and advocate for the utilization of a multi-disciplinary team to foster better patient-centered healthcare for those living with multiple myeloma.
Bilotti E, Faiman BM, Richards TA, Taiman JD, Miceli TS, Rome SI; International Myeloma Foundation Nurse Leadership Board. Survivorship care guidelines for patients living with multiple myeloma: consensus statements of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(suppl:5-8). doi: 10.1188/11.S1.CJON.5-8.
Patients with stage III or IV melanoma assigned to 10 mg/kg of ipilimumab (Yervoy) lived longer than patients assigned to a lower dose of the drug but at the cost of greater toxicity, according to results from a randomized, double-blind, phase III study published online March 27, 2017, in Lancet Oncology.
In the trial, performed at 87 medical centers in 21 countries, researchers found that median overall survival for 364 patients receiving 10 mg/kg of ipilimumab was 15.7 months, compared with 11.5 months for 362 patients assigned to 3 mg/kg.
However, patients in the 10-mg/kg group had a higher incidence of grade 3/4 treatmentrelated adverse events (TRAEs), including diarrhea (10% vs 6%), colitis (5% vs 2%), increased alanine aminotransferase (3% vs 1%), and hypophysitis (3% vs 2%).
Lead author Paolo A. Ascierto, MD, noted that at least in some patients, improved outcomes outweigh the risk for increased toxicity.
“With ipilimumab, with only 4 cycles, we have still the possibility to reach a long-term benefit,” he said. “If it’s true that with 10 mg/kg we have a higher incidence of severe adverse events than with a lower dosage [37% vs 18%], it’s true as well that in refractory patients, where we have no other options to get a long-term benefit, this is superior to the risks.”
Researchers enrolled adult patients with unresectable stage III or IV melanoma from February to July 2012. Eligible patients could have been treated previously, as long as they had not received BRAF inhibitors, CTLA-4 or PD-1 antagonists, or PD-L1 or CD137 agonists.
Patients who had been treated previously were required to undergo a washout period of 4 weeks for all previous anticancer therapy and at least 2 years for systemic immunosuppressive drugs, except for episodic low-dose corticosteroids.
At a minimum follow-up of 43 months, patients in the 10-mg/kg group received a median of 4 doses of ipilimumab in the initial treatment phase, with 58% completing all 4 doses.
Patients in the 3 mg/kg group also received a median of 4 doses, and 67% completed all 4 doses. At the data cutoff of March 2016, 6% of patients in the 10 mg/kg group and 9% in the 3 mg/kg group entered the first retreatment phase. In the initial treatment phase, disease progression and TRAEs were the most common reasons for discontinuation in both treatment groups. Patients in the 3 mg/kg group were more likely to experience progression (43% vs 30%) and patients in the 10 mg/kg group were more likely to leave the study due to TRAEs (24% vs 10%).
About one-third (36%) of patients in the 10mg/kg group proceeded to systemic therapy, including 16% who underwent subsequent immunotherapy (16%) and 10% who proceeded to targeted therapy. The numbers were similar for patients in the 3 mg/kg group: 38% proceeded to systemic therapy, including 14% who received immunotherapy and 13% who had targeted therapy.
Researchers found that a similar proportion of patients with BRAF-positive tumors received subsequent therapy in both dose groups: 54% (43 of 80 patients) in the 10 mg/kg group versus 59% (47 of 79 patients) in the 3 mg/kg group. Patients in the 10 mg/kg group were more likely to receive subsequent anti–PD-1 therapy (19% vs 10%).
Sorafenib-experienced patients with advanced hepatocellular carcinoma (HCC) had long-term responses to nivolumab (Opdivo) of more than 1 year, according to findings from the Check-Mate-040 trial presented at the 2017 International Liver Congress. Abstract GS-010
At a median follow-up of 12.9 months, the objective response rate by blinded independent central review was 14.5%, but 19.3% by investigator assessment. At present, response is ongoing in 71.4% of patients. The 12-month overall survival (OS) rate was 59.9%, and median OS was 16.7 months.
“The durable responses and survival rates that were achieved with nivolumab are very encouraging, particularly as the side effects were manageable,” said Jörg Trojan MD, of Goethe University Hospital and Cancer Center in Frankfurt, Germany.
Trojan presented interim results from the sorafenib-experienced cohort of the phase I/II, multicohort, open-label CheckMate-040 study of nivolumab in patients with advanced HCC who were not candidates for surgery (n = 145). In the dose-expansion portion of the study, the patients received nivolumab at 3 mg/kg every 2 weeks. All patients had previously received sorafenib.
Earlier this year, researchers presented an evaluation of the overall population (N = 262) performed at 9 months that suggested nivolumab could be an option for the treatment of patients with HCC that failed sorafenib; the median duration of response was 9.9 months and the 9-month OS rate was 74%.
Chronic hepatitis infection is an underlying cause in most HCC cases. In this study, nivolumab response was independent of chronic hepatitis B (HBV) and/or hepatitis C (HCV) infection.
The safety profile of nivolumab in patients with advanced HCC was consistent with that reported in other tumor types. Grade 3/4 treatmentrelated adverse events occurred in 16.6% of patients. Fewer than 3% of patients experienced grade 3/4 ALT/AST elevations, and researchers said those conditions were “manageable and reversible” with established algorithms.