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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.
Upon completion, participants should be able to:
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METHOD OF PARTICIPATION
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This pilot trial conducted between January 2014 and April 2015 evenly randomized 30 breast cancer survivors, whose diagnoses ranged from stage 0-III. Half were assigned to a fatigue reduction diet (FRD) rich in fruit, vegetables, whole grains, and omega-3 fatty acid–rich foods for 3 months; the other half followed a general health curriculum (GHC). Participants were asked to maintain the same number of calories they typically consumed.
The study’s primary outcome was change in fatigue from baseline to 3 months (measured by the Brief Fatigue Inventory). All participants completed questionnaires at the beginning and end of the study to determine the severity and impact of fatigue and sleep quality.
Researchers met with the FRD participants on 3 occasions, and during the 3-month study a registered dietician made 6 telephone counseling calls. This group was also given checklists to keep track of their target foods. The control group had the same schedule of in-person and telephone counseling, but their sessions focused on general health topics (eg, oral health, healthy skin, and preventing colds and flu), and there was no mention of diet.
FRD participants reported an average 44% decrease in fatigue during the study compared with 8% in the GHC control group. The FRD group also saw nearly a 50% improvement in sleep quality, whereas the GHC group experienced no change in that area.
Both groups maintained the same body mass index during the study, suggesting it was the diet, and not weight loss, that reduced fatigue.
For the majority of the intervention, patients in the FRD group were able to meet their food goals. The researchers also looked at participants’ serum nutrient levels and discovered an increase in the types of nutrients found in the foods they wanted the individuals to eat, such as carotenoids, lutein, lycopene, and omega-3 fatty acids. They also found the ratio of omega-3 to omega-6 fatty acids increased. Omega-6 fatty acids are found in fried foods, cakes, mayonnaise, and many processed or fast foods, which promote inflammation and can compete with omega-3 fatty acids.
“Most people have too much omega-6s,” lead investigator Suzanna M. Zick, ND, MPH, of the University of Michigan School of Public Health, explained. “The FRD diet could provide a nontoxic treatment strategy for persistent fatigue,” concluded the authors, who are planning a larger study.
Karen Masino, MS, CNP, ACNP-BC, AOCNP, RN, RDN, LDN, STAR®
Cancer-related fatigue is the most commonly reported symptom in patients through all phases of the cancer trajectory and can persist for years after completion of treatment, affecting all aspects of function and quality of life.
As clinicians we all understand and support efforts to help cancer survivors recover from cancer treatment side effects. After recovery, the evidence supports encouraging a healthy diet as standard education for all cancer survivors to reduce the risk of recurrence and developing chronic comorbid illness.
Achieving and complying with a better quality meal pattern, however—as with any intervention involving lifestyle change—can be very difficult. Several organizations provide educational resources, such as the American Cancer Society (cancer.org), American Institute for Cancer Research (AICR.org), and oncologynutrition.org.
An important strategy is to individualize the education provided to the patient. This can be accomplished by first of all evaluating the present meal pattern, understanding the motivation of the patient to make changes and then translating the science of nutrition into actionable food choices and meal patterns that are understandable and achievable for the patient. Registered dietitian/ nutritionists can be very helpful in providing this guidance and education to patients within the context of providing comprehensive survivorship care.
Though previous studies have shown a link between exercise and improved outcomes in early-stage CRC, this is the first to show an association in patients with nonlocal metastases.
The prospective cohort study nested within the National Cancer Institute–sponsored randomized Alliance control trial included 1231 patients with mCRC who received chemotherapy and self-reported their physical activity via a questionnaire. Researchers then determined each patient’s level of activity based on metabolic equivalent task (MET)-hours per week, which assesses energy expended during physical activity.
Overall, the patients who spent more time participating in moderate physical activities such as walking, cleaning, or gardening had reduced rates of cancer progression and death. Patients who reported an engagement in physical activity equivalent to ≥30 minutes of moderate exercise daily, or ≥18 MET-hours per week had a 19% reduction in mortality and a 16% reduction in cancer progression.
The study also found that patients who spent ≥5 hours per week doing non-vigorous activity, such as walking or yoga, had a 25% reduction in mortality. However, there was no association found between vigorous activity, such as running or playing sports, and cancer outcomes.
“Patients should know that even as little as 30 minutes of moderate activity per day may improve outcomes for colorectal cancer patients,” noted lead study author Brendan Guercio, MD, of Brigham and Women’s Hospital, Boston. Guercio said these findings suggest that even light activities, which many patients with mCRC may be able to participate in, can be associated with improved outcomes.
The most important question to address regarding the findings of the study was the role of confounders, Guercio said.
“In other words, is physical activity making people healthier, or were individuals who were sicker than others just exercising less?”
To address this issue, regression analyses were used to calculate hazard ratios for disease progression and mortality for levels of self-reported physical activity after adjusting for potential confounders, including comorbidities, weight change over the prior 6 months, ECOG performance status, body mass index, chemotherapy received, tumor KRAS status, gender, and age.
Additional trials and more prospective clinical studies are needed to confirm the link between physical activity and outcomes in mCRC. A randomized clinical trial is currently ongoing to compare patients who exercise during treatment with those who do not, with the hope of confirming the impact of physical activity on cancer outcomes.
Laura Metcalfe, MSN, RN, APN-C, AOCNS
I was not as surprised to read the results of this study as I might have been a year ago. We have known for many years that physical activity lowered the risk both of being diagnosed with colon cancer, as well as having a colon cancer recurrence. Therefore, for many years we have recommended daily aerobic exercise of at least 30 minutes to all of our early-stage and colon cancer survivors as something they can, and should, do to decrease their risk of recurrence.
Exercise recommendations for survivors include at least 150 minutes per week of aerobic exercise and 2 days a week of strength training. (CA Cancer J Clin. 2012; 62:242-274) We have not, however, been routinely recommending exercise for those patients with metastatic colorectal cancer (mCRC), as no data had suggested a benefit. Of course, if patients asked about exercise, we did not discourage it and even recommended it for the mental health benefit and to improve appetite, sleep, and overall well-being.
We had a similar experience with vitamin D supplementation. We have advised all of our early-stage and colon cancer survivors to begin daily vitamin D supplementation of at least 2000 IU based on studies dating as far back as 2008, when a meta-analysis revealed that colon cancer incidence could be reduced by 72% with vitamin D levels of 32 ng/mL or higher. (Cancer Epidemiol Biomarkers Prev; 2008;17:2958-2969) Again, we were not routinely checking vitamin D levels on those patients with metastatic disease or advising vitamin D supplementation for them.
A 2015 study by researchers at Dana-Farber, however, found that patients with mCRC who had high levels of vitamin D prior to treatment survived longer on average than patients with lower levels of vitamin D. Based on that study, we began monitoring vitamin D levels in those patients on treatment for mCRC and recommending supplementation for them, as well as for survivors.
Now, this current study shows that exercise can also benefit those patients with mCRC, not just survivors. This tells me that those things that can lower one’s risk of colon cancer and help survivors prevent their risk of recurrence can also help those with mCRC do better, as evidenced by longer overall survival. It seems we may have been doing our mCRC patients a disservice by not giving them the same recommendations as our patients with early stage colon cancer.
Anything we can do to help our patients live not only longer but better with their cancer is something we, as oncology nurses, should be embracing. In my experience, patients are always interested in what they can do to help fight their cancer. Whatever we can do to empower our patients and give them a sense of control in a world that feels very out of control can only be a benefit. I will certainly be more proactive in recommending physical exercise for all of our colorectal patients now, no matter what stage or phase of treatment.
Among patients with metastatic renal cell carcinoma (mRCC), those who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate when treated with checkpoint inhibitor immunotherapy than those who had not received antibiotics (2.3 months vs 8.1 months, respectively). Previous preclinical studies using mouse models have suggested an association between antibiotics and the efficacy of immune checkpoint blockade agents. (Science. 2015;350:1079-1084)
“This is the first analysis evaluating the impact of antibiotics on outcome in mRCC patients treated in the era of immune checkpoint blockade,” said investigator Lisa Derosa, MD, PhD candidate, of the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.
Researchers analyzed 80 patients with mRCC who were being treated with checkpoint inhibitors on trials at the Gustave Roussy Cancer Institute. Immunotherapy treatments included single-agent anti–PD-1/PD-L1 therapy (n = 67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor (n = 10), and a combination of anti–PD-L1 therapy and bevacizumab (Avastin) (n = 3).
A majority of the enrolled patients were male (65%), 88% had clear-cell histology, and 80% of the patients had prior nephrectomy. Twenty-one percent had favorable disease by International mRCC Database Consortium (IMDC) risk standards, 57% had intermediate IMDC risk, and 22% had poor-risk disease. Sixteen patients (20%) had received antibiotics up to 1 month prior to starting treatment with immunotherapy, including mostly betalactamases or fluoroquinolones.
At a median follow-up of 6 months, overall survival (OS) results were not yet able to be reached in the overall population, but a negative trend was already noted for patients who received prior antibiotics. The objective response rate also favored patients who had not received antibiotics.
In a subgroup of 62 patients who were treated with nivolumab (Opdivo) monotherapy, patients who had not taken antibiotics showed a greater PFS rate, which also achieved statistical significance. OS in the nivolumab monotherapy subgroup was also significantly higher in patients who had not taken recent antibiotics.
“This research shows that antibiotic therapy may have a direct impact on how well the PD-1 inhibitor nivolumab works in patients with kidney cancer,” said Sumanta K. Pal, MD, who moderated the presentation.
A multivariate analysis for prognostic risk factors showed a hazard ratio of 4.17 (95% CI, 1.92-9.08) for patients who had not received antibiotics compared with those who had received them (P <.001). Patients with a lower Karnofsky performance status also showed an increased hazard ratio (HR, 5.23; 1.57-17.4; P <.005).
“Immune based therapies for cancer may have a complex interplay with the host’s microbiome,” commented Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”
Derosa stated that the data were preliminary but the findings encourage longer follow-up and further studies to confirm the hypothesis of the study.
“These observations have some consistency with preclinical observation,” Pal said. “We may be able to offer some insights as to whether or not bacterial composition of the gut could affect clinical outcomes and that might help us guide antibiotic usage.” Pal also suggested that these findings are not yet mature enough to impact clinical practice.
The researchers plan to enroll additional patients in this study to investigate the mechanism of action. Other studies exploring the relationship between antibiotics and the efficacy of immunotherapy agents in lung cancer and kidney cancer are ongoing.
Kathleen Madden, RN, MSN, FNP-BC, AOCNP, AHNP
The complex interrelationship of immune system function with the gastrointestinal system (GI) is an expanding area of science and research being evaluated more closely in the rapidly evolving era of immunotherapeutics.
Recently, the Gustav Roussy Cancer Institute in Villejuif, France, conducted and presented a retrospective analysis of 80 patients with metastatic renal cell carcinoma (mRCC) on varying clinical trials of PD-1/PD-L1 inhibitors as single agents or in combination with CTLA-4 or bevacizumab. The analysis demonstrated a negative correlation between antibiotic therapy prior to the start of treatment on trials with checkpoint inhibitors. The investigation, motivated by preclinical mouse models, revealed patients treated with antibiotic therapy experienced a statistically shorter duration of progression-free survival (PFS).
Sixteen patients were treated with broad spectrum antibiotics within 1 month prior to initiating checkpoint inhibitor therapy. Although overall survival could not be evaluated, at the 6-month median follow-up, a negative trend was identified in patients with prior antibiotic use, which calls into question that if normal gut flora are altered, does this correlate with efficacy and duration of response to checkpoint inhibitor therapy? Conversely, in a subgroup of patients treated with monotherapy nivolumab who did not receive antibiotic therapy, they demonstrated a greater PFS rate which was statistically significant.
Sumanta Pal, MD, co-director of the Kidney Cancer Program at City of Hope, stated that antibiotic therapy may be influential in the composition and behavior of gut bacterial flora which could potentially impact efficacy of immunotherapy. This relationship involving the GI tract and immunotherapy, though not fully understood, poses interesting scientific and clinical questions and has been identified as an area for further exploration in the matrix of immune checkpoint inhibitor therapy.
Lauren M. Green
In this retrospective analysis involving 19 patients, 8 (42%) were able to remain off additional systemic therapy for more than 6 months, and of these, 6 patients continue to be free from progression, according to Rana R. McKay, MD, presenting at the 2017 Genitourinary Cancer Symposium.
“What we’ve demonstrated is that despite these patients stopping their treatment, there is a subset of them who continue to have disease that is in check and controlled, despite their not being on any therapy,” said McKay, an assistant professor at UC San Diego School of Medicine. “When the durable responders stopped their therapy due to a toxic event, they were able to remain off any therapy with their disease being controlled.”
The analysis is based on patients with mRCC who received treatment at 1 of 5 academic centers but had ceased PD-1/PD-L1 inhibitor therapy due to an irAE. Reasons for stopping therapy included joint pain, eye problems, diarrhea, and organ inflammation. Most of the patients (63%) had received their PD-1/PD-L1 treatment as monotherapy, and the remainder had their immunotherapy in combination with other systemic treatments, McKay noted.
Patients were a median age of 68 years, and the majority (n = 14) were men. Five patients (26%) had aggressive disease according to common diagnostic criteria, and more than half of the overall group (58%) had had prior systemic therapy.
“The patients in this cohort experienced a wide spectrum of adverse events affecting different organ systems,” McKay explained, among them, pneumonitis, myositis, nephritis, hepatitis, pericarditis, and myocarditis. Sixteen patients (84%) needed steroids to manage their irAEs, and 2 required additional immunosuppressive agents to treat their symptoms, McKay said. At the time of the analysis, 10 patients were experiencing ongoing toxicity.
In addition to the 8 durable responders, 3 patients were deemed “immediate progressors,” that is, they required additional treatment less than 4 months after discontinuing their PD-1/PD-L1 therapy; the 8 other patients stopped responding 4 to 6 months after discontinuing treatment.
Among the durable responders, the median time on treatment prior to their therapy discontinuing was 11 months, and the median time off treatment was 20 months, McKay said. For the immediate progressors, however, the median time on treatment was much shorter (4 months), and the median time off treatment was 2 months.
The authors cautioned that although the study findings are novel and compelling, the number of participants is small, and prospective studies are needed to further explore how immunotherapy can be customized.
“Larger studies are warranted to evaluate the need for continuous drug dosing in all patients, identify patients in which continuous dosing is not required, and to evaluate long-term outcomes in this population,” they concluded.
Accordingly, McKay said that the planned phase II OMNIVORE study will examine the optimized management of nivolumab based on response in patients with mRCC, with an eye toward elucidating what clinical characteristics may be linked to a durable immunotherapy response.
“This is really important work,” noted Sumanta Pal, MD, co-director of the Kidney Cancer Program at City of Hope, given the veritable “tidal wave” of new immunotherapies he said that unfortunately also carry a risk of irAEs. “If a patient has immune-related side effects, the impact can be serious, but there is also the possibility that they could have a protracted benefit from the drug in terms of their cancer remaining dormant or shrinking.”
“More broadly,” Pal said, “these findings call into question the current standard of continuous treatment with immunotherapy.” However, he added, “Further research is needed to validate this phenomenon.”
Rajni Kannan, MS, RN, ANP-BC
Unlike chemotherapy, the amount of immunotherapy needed for patients to not only respond, but also to have a durable response, is individualized. The activation of the immune system to target cancer cells varies—some patients respond rapidly, whereas others have slow regression of their disease. How much is enough? This is a question that is still being actively researched.
Patients who have severe immune-related adverse events (irAEs) can experience regression of their disease and/or durable response even after treatment has been discontinued. These irAEs can occur anytime during treatment; thus, side effects can affect discontinuation early on or several months after the initiation of treatment. It is hypothesized that the immune system once activated by immunotherapy continues to remain activated against tumor cells even when treatment has been halted. The science behind the continued response is still unknown.
Many studies are being conducted to determine the right amount of maintenance immunotherapy and the length of treatment needed. New studies are suggesting that a set dose of the immunotherapy agents may provide the same responses compared with weight-based dosing. With immunotherapy agents being used in more disease states, research continues to improve our treatment plans and side effect management.
In the multicenter trial, which initially enrolled 760 men with biochemical recurrence after radical prostatectomy, patients were randomly assigned to treatment with bicalutamide or placebo for 2 years, along with 6.5 weeks of RT.
After a median follow-up of 13 years, the actuarial rate of overall survival (OS) at 12 years was 76.3% for patients treated with bicalutamide compared with 71.3% for patients in the placebo group.
The 12-year incidence of death from prostate cancer was 5.8% versus 13.4%, respectively. The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group and 23.0% in the placebo group.
“Our study indicates that hormonal treatments should be incorporated into the management of men who need radiation therapy after surgery for prostate cancer,” senior author Howard Sandler, MD, chair of the Department of Radiation Oncology at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai in Los Angeles, said in a statement, and it is expected the findings will change the standard of care for this patient population experiencing a postoperative recurrence.
The double-blind, placebo-controlled trial was conducted between 1998 and 2003 and enrolled patients who had had their prostate gland removed for localized stage T2/T3 disease with no nodal involvement.
Eligible patients were also required to have a detectable PSA level of 0.2 to 4.0 ng/mL at least 8 weeks after surgery. Additionally, patients could not participate in the study if they had previously received chemotherapy, RT, or hormone therapy (other than preoperative short-term hormonal therapy for 2-6 months in some patients [6.4% of those enrolled]).
Salvage RT began within 12 weeks after randomization. A total dose of 64.8 Gy was administered in 36 daily fractions of 1.8 Gy at a rate of 5 sessions per week. Beginning at the initiation of RT, patients were given either 150 mg of bicalutamide or 1 placebo tablet daily.
At the beginning and end of radiation therapy, researchers evaluated patients’ clinical history, physical examination, Karnofsky performance status score, complete blood count, PSA level, serum alanine aminotransferase level, bilirubin level, and reports of any treatment-related adverse events (AEs) at baseline and after completion of RT.
Follow-up evaluations were conducted every 3 months for 2 years, then every 6 months for 3 years, and then on a yearly basis. Bone and CT scans were performed at subsequent biochemical recurrence. Maximum androgen blockade was recommended if metastatic disease was present or if the serum PSA level rose to above 4.0 ng/mL. The 2 groups of patients were well balanced in terms of demographic and tumor-related characteristics. The median age of patients was 65 years, and the median PSA level at study entry was 0.6 ng/mL.
Median interval between surgery and the first detectable PSA level was 1.4 years, and the median interval between surgery and trial entry was 2.1 years.
The primary endpoint was the rate of OS. Prespecified secondary endpoints included disease-specific death, distant metastases, local disease progression, non–disease-specific death, any disease progression including a second biochemical recurrence, and AEs.
A total of 21 patients treated with bicalutamide died from prostate cancer, compared with 46 patients in the placebo group. The cumulative incidence of a second biochemical recurrence at 12 years was 44.0% in the bicalutamide group, compared with 67.9% in the placebo group.
In terms of toxicity, the incidence of late AEs associated with RT was similar between the 2 treatment arms. Gynecomastia was observed in 69.7% of patients in the bicalutamide group, compared with 10.9% of patients in the placebo group.
Frank delaRama, RN, MSN, AOCNS
"I thought I was done with treatment ...” These often are the words that I hear from men who are met with a rising PSA level after having had a prostatectomy. Sometimes this happens a few months after surgery; sometimes it can be many years later. Just as when they were newly diagnosed with prostate cancer, there is a cascade of appointments, including a bone scan or perhaps a CT scan, then meetings with physician specialists in urology, radiation oncology, and medical oncology. If the imaging tests are clear of metastases, the salvage treatment up for discussion is external beam radiation therapy (EBRT), “plus or minus” androgen deprivation therapy (ADT).
Prior to starting ADT, patients learn about the possible side effects from their medical providers and nurse navigators. This list from the 2016 NCCN guidelines can seem imposing and includes: hot flashes, loss of libido and erectile dysfunction, shrinkage of penis and testicles, loss of muscle mass and strength, fatigue, depression, hair loss, osteoporosis, greater incidence of clinical fractures, obesity, insulin resistance, alterations in lipids, and greater risk for diabetes and cardiovascular disease.
As many nurses already know, rarely does any patient experience all the side effects of a given medication, but they have a right to know what might happen. Sharing stories of our other patients who have undergone EBRT and ADT can be helpful for the men considering “plus or minus ADT” by revealing the most common adverse effects and how they may affect quality of life to varying degrees.
What about the plus side? The study presented here offers some compelling data in support of EBRT plus ADT. With the addition of ADT to salvage EBRT, there was a definite beneficial effect on survival and incidence of recurrence. In the words of one of my patients, “one of the side effects is that you may get to live longer.”
As we counsel our patients in treatment decision making, nurses can help ensure that they understand all the possibilities and how it may affect their quality of life. The best tools for us to accomplish this can be as simple as sharing stories (to illustrate the possibilities in a meaningful way), asking questions and listening (to measure our patients’ understanding of the situation), and presenting data from studies like this one to provide tangible evidence in support of a treatment decision.