LAS VEGAS—Chemotherapy-induced peripheral neuropathy (CIPN) and cancer-related fatigue are two challenging common clinical problems for oncology nurses, topics that were explored here at the Oncology Nursing Care conference, a meeting formerly called Critical Issues & Trends.
Researchers hypothesize that paclitaxel acute pain syndrome may actually be an indicator of chemotherapy-induced peripheral neuropathy, said Charles Loprinzi, MD, the Regis Professor of Breast Cancer Research and Co-director of the Mayo Cancer Center Prevention and Control Program at Mayo Clinic and Chair of the North Center Cancer Treatment Group (NCCTG).
In an email exchange after the meeting, Debra Barton RN, PhD, AOCN, FAAN, one of the conference chairs and Associate Professor of Oncology at the Mayo Clinic and NCCTG Program Coordinator and Investigator, said that learning whether paclitaxel acute pain syndrome is a predictor of future neuropathy will help to focus prevention studies to the correct population to more efficiently find solutions to the problem.
Another speaker, David Cella, PhD, Professor and Chair of the Department of Medical Social Sciences at the Feinberg School of Medicine and Cancer Control Program Leader at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, noted that fatigue is an especially troubling symptom to many cancer patients.
Dr. Cella said that although the use of erythropoiesis-stimulating agents (ESAs) is often helpful in treating fatigue associated with anemia, many practitioners are not impressed with this therapy due to what they view as marginal benefits, in addition to the potential side effects.
Dr. Barton agreed: “I think that at this time, we really need to be aware of the FDA position on these agents. ESAs should not be used off label in a broad set of circumstances because there are risks.”
PAPS or CIPN?
Paclitaxel acute pain syndrome (PAPS), commonly described as myalgia or arthralgia, may actually be due to nerve pathology via sensitization of nociceptors, said Dr. Loprinzi, citing a study that he and his colleagues conducted published in the Cancer Journal (2007;13:399-403). Patients who received paclitaxel did not describe joint or muscle pain, but instead described their pain as “radiating, shooting, aching, stabbing, and pulsating,” which may indicate neuropathy, the study authors hypothesized.
In an ongoing study presented at the most recent ASCO Annual Meeting (Abstract 9135), Dr. Loprinzi and colleagues studied 90 women receiving weekly paclitaxel at 70-90 mg/m2, without a concomitant neurotoxic agent. Patient questionnaires evaluated the incidence and severity of paclitaxel associated acute pain and sensory neuropathy every week for 12 weeks.
For Cycle 1, pain peaked on Day 4 and was an average of 1.5-2 on a scale of 0 to 10 for severity. Newer data of patients receiving paclitaxel at 175 mg/m2 every three weeks showed average pain scores of 4, with many patients reporting pain scores of 7-10, Dr. Loprinzi said.
Over a 12-week period, researchers collected chemotherapy-induced peripheral neuropathy data using a tool assessing autonomic, motor, and sensory subscales. They found sensory neuropathy to be the most troublesome in patients, he said.
Pain, numbness and tingling in hands and feet, components of sensory neuropathy, also worsened in patients over the course of 12 weeks, with numbness and tingling being more of a problem than pain.
Additionally, patients who had pain scores of 0 to 4 during the first week had less neuropathy at 12 weeks than patients with scores of 5 to 10 in the first week, supporting the theory that patients with pain are actually experiencing neuropathy, Dr. Loprinzi noted.
Because chemotherapy-induced peripheral neuropathy has no clinically proven treatment, nurses need to be well versed on rehabilitation and adaptive functioning that can help patients cope, Dr. Barton said. Nurses can educate patients how to assess CIPN for themselves and how to keep their providers informed about the extent of their symptoms to avoid irreversible functional loss. Fortunately, therapy for CIPN may soon be available, she said.
Dr. Barton recently conducted a study of topical baclofen, amitriptyline, and ketamine in polaxamer-lecithin organogel (BAK-PLO) in patients with chemotherapy-induced peripheral neuropathy and found a trend for improvement in sensory and motor subscales versus placebo.
In the study (Support Care Cancer 2010 May 25. Epub ahead of print), the greatest improvements were observed with relief of symptoms of tingling, cramping, and shooting or burning pain in the hands, as well as with difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity.
“My hope is that we can replicate this study using a slightly higher dose and better formulation, which will result in more meaningful relief for patients,” said Dr. Barton. Because it is a treatment strategy, not a prevention strategy, it isn't going to help avoid the problem. “But hopefully it will give substantial relief to patients who have suffered with pain and discomfort from CIPN who have not found relief with other things.”
Another potential approach to chemotherapy-induced peripheral neuropathy may be the MC5-A Calmare patient-specific cutaneous electrostimulation pain-control device designed to reduce pain intensity, as reported in a small study at the most recent ASCO Annual Meeting (Abstract 9029). In that study of 16 patients, the CIPN pain score fell by 59% over 10 days and no toxicities were observed.
Dr. Loprinzi noted that his facility has treated a handful of patients with this technology: “We've seen some amazing decreases of shooting and burning pain, numbness and tingling. It's not proven, but there's something going on here, I'm pretty sure.”
Another recent study that was started by Dr. Loprinzi and his colleagues suggests that calcium and magnesium (CaMg) therapy may help relieve CIPN in patients with colon cancer taking adjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX), as reported at the 2008 ASCO Annual Meeting (Abstract 4009). After 104 of the planned 300 patients were enrolled, however, the study was closed due to reports from another trial, L-9444 suggesting that CaMg decreased treatment efficacy.
Since then, though, Dr. Loprinzi said, an independent monitoring committee found that response data for Study L-9444 may not have been analyzed properly, but because of the questions still surrounding CaMg therapy, he and his colleagues have opened up a new trial, CTSU N08CB, evaluating this treatment.
Vitamin E may also benefit people with cisplatin-induced neuropathy, according to the literature, Dr. Loprinzi said, but he and his colleagues have not seen any benefit for paclitaxel-induced neuropathy.
Other treatments being evaluated include glutathione, acetyl L-carnitine, venlafaxine, and alpha-lipoic acid.
Research by Dr. Cella and his colleagues has found that fatigue was the symptom of most concern to patients with advanced cancer and that patients who did not experience fatigue had better quality-of-life scores than those who did report the symptom (JNCCN 2008;6:448-455).
Fatigue, though, remains under-recognized and under-treated, he said, noting that one survey conducted in the United States shows that while 32% of cancer patients report experiencing fatigue every day, 77% of the time their physicians offered no treatment or prescribed only bed rest (Oncologist 2000;5:353-360 and 2003;8:27-30).
Dr. Cella explained that the management of fatigue often involves correction of potential etiologies such as anemia, and that while anemia may not be the leading cause of cancer fatigue, it is treatable.
Still, treating anemia may not always address fatigue due to the symptom's many other causes—for example, cytokine storms, sleep disorders, deconditioning from not exercising, nutritional changes, prior or current depression, emotional state, and the patient's financial situation. Chemotherapy and radiation may also cause fatigue, he added.
ESAs: Current Status
Overall, improvements in fatigue with erythropoiesis-stimulating agents (ESAs) do not bring patients to the normal fatigue levels seen in the general population, Dr. Cella said.
“This is partly why some people in the treatment community are not terribly impressed with the benefits [of these agents] against fatigue and other side effects of anemia. The benefits are demonstrable, but not huge. They certainly don't get people back to normal.”
In a study of patients with nonmyeloid malignancies, epoetin alfa therapy resulted in significant increases in hemoglobin levels and improvements in functional status and fatigue, as assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Questionnaire (JCO 2001;19:2875-2882). Additionally, improvements in quality of life correlated with increased hemoglobin levels.
In another analysis (JCO 2003;21:366-373), Dr. Cella and colleagues found that epoetin alpha resulted in improvement in FACT-An fatigue subscale scores in patients with cancer and anemia, while the scores became worse in those taking placebo. The levels of improvement with epoetin alpha were just below those of a comparison populations of patients with a history of cancer or a history of anemia.
Another trial of epoetin alpha vs placebo in cancer patients published two years later demonstrated similar results in quality of life and fatigue scales (JCO 2005;23:2597-2605), he noted.
In an assessment of five randomized clinical trials (Annals Oncol 2004;15:979-986), Dr. Cella and other researchers found that in cancer patients on and off chemotherapy, increasing hemoglobin with darbopoetin was associated with meaningful improvements in fatigue. Higher hemoglobin was also associated with improved physical, functional, emotional, and overall well-being.
Furthermore, in an article in press, Dr. Cella and his colleagues found that of 10 review studies, nine did find evidence of benefits in reducing fatigue or improving quality of life in patients using ESAs. Five studies concluded that there was a clear benefit, while four found that benefit was inconclusive or potentially marginal. Three studies found benefit to be clinically meaningful.
However, “it's not like all the trials have shown benefit with erythropoiesis stimulating agents as far as fatigue and quality of life,” said Dr. Cella, citing JCO 2005;23:2606-2617.
The Food and Drug Administration position on ESAs in oncology patients is that these agents provide no benefit for fatigue or health-related quality of life. Recommended use is limited to helping patients avoid transfusion and to treat chemotherapy-induced anemia. Furthermore, ESAs should be used only when cure is not a treatment goal, the agency says.
Based on reviews of the literature, the Cochrane Collaboration and Blue Cross/Blue Shield Association Technology Evaluation Center have concluded there is a small but meaningful effect of ESAs on fatigue, said Dr. Cella. “So, they singled out fatigue and not other aspects of quality of life.”
ASCO and the American Society of Hematology adopted this view in their clinical guidelines on ESAs, although fatigue was not mentioned in the executive summary (JCO 2008;26:132-149), Dr. Cella noted.
Regarding the National Comprehensive Cancer Network guidelines, he said that they are under continuous review and modification and heavily based on a safety-and-efficacy balance, especially due to data that have been well publicized since 2007 on survival disadvantage and tumor progression in cancer patients using ESAs. “As a result, quality of life has not been a priority—My point is that I think quality of life is relevant. It's part of a complicated regulatory and legal and clinical risk-benefit analysis that you need to make with each of your patients.”
Additionally, like the FDA, the NCCN panel is heavily focused on avoiding transfusion, Dr. Cella continued. “I doubt that fatigue will ever make it onto the regulatory radar, in regard to chemotherapy-induced anemia,” he said.
Dr. Barton noted that the NCI's Physician's Data Query editorial board on supportive care is currently revising the summary statement on fatigue and the use of ESAs: “I think it will be a good resource, providing a summary of the FDA position as well as the evidence that is currently published in this area,” she said.