Chemotherapy-related cognitive impairment affects many—and some say most—patients during the time they receive chemotherapy and for up to one-third of patients afterward.
—Arif Kamal, MD, MHS
Recent studies have yielded useful results that clinicians can put into practice, some right now, to help improve the quality of life for patients with cancer. Concerns addressed included cachexia, pain, “chemobrain,” and fertility preservation. At the Best of ASCO®/Chicago meeting, Arif Kamal, MD, MHS, of Duke University, Durham, North Carolina, summarized the major findings from key patient and survivor studies presented at the 2015 ASCO Annual Meeting.
Stemming the Cachexia Cascade
The first two studies presented found that anamorelin, an orally active ghrelin receptor agonist, increased lean body mass among patients with inoperable stage III or IV advanced non–small cell lung cancer (NSCLC) and cachexia.1 This is “an outcome of importance,” Dr. Kamal said, because loss of lean body mass among patients with advanced cancer often “leads to a cascade of events,” including reduced physical functioning and quality of life for these patients and “reduces our ability to give them chemotherapy that extends their lives or improves their lives.” There are “very few therapeutic options to stop this cascade when it goes into effect,” he added.
A total of 979 patients in the two studies (ROMANA 1 and 2) were randomly assigned to anamorelin at 100 mg orally once daily or placebo. The patients were mostly male, over 60 years old, weighed between 60 and 70 kg, and were predominantly white. Most patients were receiving concomitant platinum-based doublet therapy.
After 12 weeks, patients receiving anamorelin had an increase in lean body mass, 1.10 vs –0.44 kg for those receiving placebo (P < 0.001) in ROMANA 1 and 0.75 vs –0.96 kg for those receiving placebo (P < .001) in ROMANA 2. Patients assigned to anamorelin also had a significant increase in body weight (2.2 vs 0.14 kg, P < .001 in ROMANA 1) and (0.95 vs –0.57 kg, P < .001) in ROMANA 2) and improvement in their anorexia/cachexia symptoms (4.12 vs 1.92, P < .001 in ROMANA 1) and (3.48 vs 1.34, P = .002 in ROMANA 2).
There was no difference in handgrip strength, used as a surrogate measurement of physical function and one of the co-primary efficacy endpoints of the study. “There was no immediate change in survival or difference in survival seen,” Dr. Kamal noted, “but the extension study is ongoing, and that will be an important outcome.”
Anamorelin was well tolerated, although there was a “slight increase” in nausea, Dr. Kamal noted. The most frequent drug-related adverse events were hyperglycemia and diabetes. (Clinical trial information: NCT01387269 and NCT01387282)
Less Frequent Dosing of Zoledronic Acid
Administering zoledronic acid every 3 months is just as good as every month for reducing bone pain and skeletal-related events in patients with bone metastases, according to a phase III Alliance study.2
“This is not the first trial to look at this issue,” Dr. Kamal said, “but what makes this trial unique is that it is not limited to specific populations” with a single type of cancer but included patients with breast and prostate cancer, as well as multiple myeloma. “This is the first time that a plasma cell disorder has been included in one of these trials,” Dr. Kamal noted. The 1,822 study participants included 833 with breast cancer, 674 with prostate cancer, and 270 with myeloma.
The mean age of the patients was 65 years old. Patients were required to have creatinine clearance ≥ 30 mL/min, and dose adjustments were based on calculated creatinine clearance. The mean creatinine clearance at baseline was 91 mL/min. All patients were encouraged to take calcium and vitamin D.
The noninferiority trial randomized 911 patients to each of the two dosage groups from the beginning of the trial. Over the 24 months of the study, those in the monthly dosing group received a median total zoledronic acid dose of 56 mg, and those in the every-3-month group received a median total dose of 24 mg. This was less than a threefold difference due to more delays in the monthly dosing group, 62% vs 37% in the every-3-month group.
Skeletal-related events occurred among 29.5% of patients receiving zoledronic acid monthly vs 28.6% of those receiving it every 3 months, demonstrating noninferiority. “This matches conclusions seen in the other trials regarding noninferiority of the administration of zoledronic acid from once a month to once every 3 months,” Dr. Kamal observed. “Optimal dosing has not yet been determined,” Dr. Kamal said. (Clinical trial information: NCT00869206)
The Effects of ‘Chemobrain’
“Chemotherapy-related cognitive impairment affects many—and some say most—patients during the time they receive chemotherapy and for up to one-third of patients afterward,” Dr. Kamal reported. “Chemotherapy-related cognitive impairment is not one clinical entity,” he added, but impacts multiple domains, including executive function, memory, concentration, and attention.
Using “an extensive battery of neuropsychological assessments of executive function, as well as blood collection to look at biomarkers,” as Dr. Kamal noted, researchers compared 366 women with nonmetastatic breast cancer with an equal number of controls.3 Exclusion criteria included neurodegenerative disease or any primary central nervous system disease/disorder. The mean age of patients was 52 years, and most were white.
At the time of recruitment, the patients with breast cancer had not yet received any chemotherapy but were about to start. Within 1 week of starting chemotherapy and 4 weeks post chemotherapy, these patients underwent psychological testing in several domains, including executive function, verbal, memory, language, and learning. The patients also completed cognition self-reports.
“This is a large study, certainly for this type of research,” Dr. Kamal said. Comparing patients before and after chemotherapy showed “across-the-board” changes in cognition, he added, with patients performing worse on all neuropsychological measures than controls. The largest effects were seen on the cognition self-report.
Increased cognitive impairment was associated with increases in inflammatory biomarkers, with statistically significant increases in MCP-1 and interleukin-1 beta. This supports the hypothesis that inflammation mediates chemotherapy-induced cognitive impairment.
“We often have patients come and talk to us about the changes they are having in cognitive function, and although we inherently know this to be true, there is very little, or not enough, evidence to demonstrate that this is a measurable thing,” Dr. Kamal noted. “I think it is important that as oncologists we not only listen to our patients, but validate their concerns” with data from this and other studies. (Clinical trial information: NCI UG1CA18996, K07CA168886)
Reducing Late Mortality in Childhood Cancer
An update of the Childhood Cancer Survivor Study found that modifying therapy for childhood cancer to reduce the occurrence of late effects has resulted in a significant reduction in late mortality, including cardiac and pulmonary deaths.4 Although recurrence of cancer is the most common cause of death initially, deaths due to other causes increase over time.
“When we look at cause-specific late mortality among these survivors, there is a plateau that occurs over time in terms of having a recurrence or progression of that primary cancer,” Dr. Kamal noted. “As we reach that plateau,” he said, there are other health and treatment-related issues “that we need to keep an eye on.”
Overall childhood cancer survival “has been improving decade by decade,” Dr. Kamal said, and there are now an estimated half a million survivors of childhood cancer. (The updated study was reported in the July 10 issue of The ASCO Post.)
Dr. Kamal pointed to trends in cancer-related therapy over time. For example, the use of radiation has declined from the 1970s through the 1990s. During that same period, the percentage of patients receiving anthracyclines increased, but the total cumulative doses decreased. “We are getting a little more intelligent in how we are using our doses,” Dr. Kamal revealed.
Results from a study among women aged 24 to 45 with stage I to III breast cancer “essentially confirmed the safety of concurrent aromatase inhibitor and ovarian stimulation” to preserve fertility, Dr. Kamal stated. The study found that controlled ovarian stimulation with letrozole supplementation “is unlikely to cause substantially increased recurrence risk in breast cancer, even in the presence of BRCA gene mutations, and it results in the preservation of fertility in a majority of women.”5 There were no differences in survival whether a woman had or did not have BRCA mutations or received such treatment before or after breast surgery.
Among 337 women, who enrolled in the study during fertility preservation consultation before chemotherapy, 120 elected to undergo ovarian stimulation with letrozole prior to chemotherapy; the remaining 217 served as controls. Those choosing ovarian stimulation with letrozole for fertility preservation were younger and had less frequent lymph node involvement.
At a mean follow-up after diagnosis of 4.9 years for those in the ovarian stimulation with letrozole group and 6.2 years for the controls, the hazard ratio for recurrence among women choosing ovarian stimulation with letrozole was 0.77, and survival was not compromised compared with controls (P = .61).
“Neither BRCA gene mutation status (P = .18) nor undergoing fertility preservation before breast surgery (P = .56) affected survival,” the authors reported. “Likewise, none of the tumor characteristics including the receptor status affected survival.”
Among the 33 women attempting pregnancy with frozen embryos (15 using a gestational carrier), 17 had at least one child. The fertility preservation rate was 51.5%, and the live birth/embryo transfer rate was 45.0%. “The live birth rate was similar to an age-matched control group from a national in vitro fertilization database,” the researchers reported. “There were no recurrences among women who conceived.” (The data on pregnancy and birth were recently published in the Journal of Clinical Oncology.6)
Based on the study results, the authors advocated making ovarian stimulation with letrozole more widely available for young women with breast cancer, even before undergoing breast surgery. (Clinical trial information: NCT00504699)
‘Let Them Eat Fruit’
Do so-called neutropenic diets, which restrict fresh raw fruits, raw vegetables, raw meat, or soft cheeses, reduce the risk of infection for patients with cancer being treated with chemotherapy? A meta-analysis to determine whether a neutropenic diet was more effective than a regular diet of foods prepared within standardized U.S. Food and Drug Administration food safety guidelines identified four studies comparing regular and neutropenic diets.7
The three randomized trials and one observational study encompassed 918 patients with cancer or stem cell transplants. The primary outcomes were mortality of any cause, major infections (pneumonia, bacteremia, fungemia, or pneumonia accompanied with bacteremia or fungemia), and the composite outcome of neutropenic fever or major infections as defined here, minor infections, or fever.
“What they found was really no change in the major infection rate with the neutropenic diet. Additionally, the risk of mortality was no different on a neutropenic diet,” Dr. Kamal said.
“These results persisted after omitting the observational study from analysis,” the investigators noted. Analyzing the composite outcome of any infection or fever “found a slightly potentially increased risk” with the neutropenic diet,” Dr. Kamal added.
The results of the meta-analysis matched the results of the individual studies, Dr. Kamal noted. “For all of us who see these patients on the hospital side, this is an important piece of evidence that is starting to put this issue to rest—the folklore around the neutropenic diet is disproven. I would say let them eat fruit if they want to.”
The study authors called for larger randomized controlled studies. However, “In the meantime, it may be time to relax the restrictions of the neutropenic diet to attain better nutrition.”
Menthol May Be Worth Trying
Topical menthol can be useful for preventing chemotherapy-induced neurotoxicity, according to a phase II open-label study of patients with colorectal cancer being treated with regimens that include oxaliplatin.8 This is a follow-up to a phase II study finding that menthol reduced existing chemotherapy-induced neurotoxicity in 75% of patients.
Derived from mint leaves, menthol “functions as an agonist of transient receptor potential melastatin-8 (TRPM-8). TRPM-8 is distributed in peripheral nerves and has been shown to be associated with cold hypersensitivity, noxious cold and sensory disturbance. It is also related to the occurrence of chemotherapy-induced neurotoxicity,” the investigators explained.
In this preventive phase II study, patients applied 1% topical menthol twice daily to their hands and feet from the start of regimens containing oxaliplatin. “This is a single layer, about ¼-inch thick,” of an over-the-counter preparation,” Dr. Kamal explained.
The study included 32 patients with colorectal cancer starting oxaliplatin-containing regimens: 22 in the adjuvant setting and 10 in the metastatic setting. The treatment regimens included capecitabine (Xeloda) and oxaliplatin (CapeOx), CapeOx plus bevacizumab (Avastin); and FOLFOX (folinic acid, fluorouracil, oxaliplatin) plus cetuximab (Erbitux).
Eight patients terminated or changed their chemotherapy regimens before reaching a cumulative oxaliplatin dose of 500 mg/m2, which is reported to cause grade 2+ chemotherapy-induced neurotoxicity, and were excluded from analysis. Among those assessed, the frequency of grade 2 chemotherapy-induced neurotoxicity was 12.5% at the cumulative oxaliplatin dose of 500 mg/m2. “This was significantly lower than the expectation value (25%),” the authors stated.
No adverse events were reported from menthol application. Dr. Kamal said that the reduction in grade 2 peripheral neurotoxicity means “over-the-counter menthol may be worth trying.”(Clinical trial information: UMIN000009655) ■
Disclosure: Dr. Kamal reported no potential conflicts of interest.
1. Temel JS, Currow DC, Fearon K, et al: Phase III trials of anamorelin in patients with advanced non-small cell lung cancer and cachexia (ROMANA 1 and 2). 2015 ASCO Annual Meeting. Abstract 9500. Presented June 1, 2015.
2. Himelstein AL, Qin R, Novotny PJ, et al: CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs longer interval dosing of zoledronic acid in metastatic cancer. 2015 ASCO Annual Meeting. Abstract 9501. Presented June 1, 2015.
3. Janelsins MC, Yao S, Mustian KM, et al: Chemotherapy-related cognitive impairment, and neurotransmitter signaling, longevity, and inflammation pathways in 366 breast cancer patients and 366 age-matched cancer-free controls: A prospective, nationwide, longitudinal URCC NCORP study. 2015 ASCO Annual Meeting. Abstract 9503. Presented June 1, 2015.
4. Armstrong GT, Yasui Y, Chen Y, et al: Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. 2015 ASCO Annual Meeting. Abstract LBA2. Presented May 31, 2015.
5. Oktay K, Turan V, Kim J: Long-term safety of fertility preservation by ovarian stimulation and concurrent aromatase inhibitor treatment in women with breast cancer. 2015 ASCO Annual Meeting. Abstract 9521. Presented May 30, 2015.
6. Oktay K, Turan V, Bedoschi G, et al: Fertility preservation success subsequent to concurrent aromatase inhibitor treatment and ovarian stimulation in women with breast cancer. J Clin Oncol 33:2424-2429, 2015.
7. Sonbol MB, Firwana B, Diab M, Witzig TE: Evaluating the effect of neutropenic diet on infection and mortality rate in cancer patients: A meta-analysis. 2015 ASCO Annual Meeting. Abstract 9619. Presented May 29, 2015.
8. Nakamura K, Nakamura M, Onikubo T, et al: Phase II study of preventive effect of topical menthol for chemotherapy-induced peripheral neurotoxicity. 2015 ASCO Annual Meeting. Abstract 9610. Presented May 29, 2015.