Controlling Pegfilgrastim Bone Pain
Abstract & Commentary
By Gary R. Shapiro, MD, Medical Director, Cancer Center of Western Wisconsin, New Richmond, Wisconsin. Dr. Shapiro reports no financial relationships relevant to this field of study.
Synopsis: This randomized, placebo-controlled, Phase 3 clinical trial showed that the majority of patients treated with pegfilgrastim experience bone pain, and that taking 500 mg of naproxen twice a day decreases its incidence and severity.
Source: Kirshner JJ, et al. Prevention of pegfilgrastim-induced bone pain: A phase III double-blind placebo-controlled randomized clinical trial of the University of Rochester Cancer Center Clinical Community Oncology Program Research Base. J Clin Oncol 2012;30:1974-1979.
Five hundred ten cancer patients (nonmyeloid) at 17 community-based sites were enrolled in the study; 257 received naproxen and 253 placebo. The majority were white (89%) women (86%) with breast cancer (67%). Their mean age was 56.2 years, and only 27% had received previous chemotherapy. Patients with a history of gastrointestinal bleeding or ulcers, recent heart surgery, elevated serum creatinine, and those taking nonsteroidal anti-inflammatory drugs (NSAIDs) or therapeutic doses of aspirin or warfarin were excluded from the study.
The patients were randomly assigned to take 500 mg of naproxen (n = 257) or placebo (n = 253) before their first dose of pegfilgrastim, and then twice a day (with food) for 5 days (up to 8 days if they were still experiencing pain). The pegfilgrastim was given on day 2, 3, or 4 of the chemotherapy cycle. In this double-blind study, both groups of patients filled out pain questionnaires and recorded the severity (0 to 10) and duration of their pain before and for 5 days after they received pegfilgrastim.
Pain reached its peak at 3 days post-pegfilgrastim in both groups, but it was less intense (mean 5 day AUC 6.04 vs 7.71; P = 0.037) and of shorter duration (1.92 vs 2.40 days; P = 0.009) in the patients who took naproxen. Naproxen also decreased overall pain incidence from 71.3% to 61.1% (P = 0.020), and severe pain (> 5/10) from 27.0% to 19.2% (P = 0.048).
That granulocyte colony-stimulating factors (GCSFs) cause bone pain is no surprise to practicing oncologists. That so many of our patients (almost three quarters!) suffer this side effect may, however, come as a shock. Sensitizing oncologists to this fact may be even more important than Kirshner's report that taking naproxen 500 mg twice a day for 5 to 8 days reduced the incidence of pain by 10% (severe pain by 8%), the intensity of pain by 22%, and the duration of pain by half a day. Even with this preventive regimen, just over 60% of patients still experienced pain, and almost 20% reported that the pain was severe. Clearly, new strategies are needed to prevent and treat this too often debilitating side effect of what has become an essential component of many chemotherapy regimens.
Clinical trial data support the use of primary prophylactic GCSFs when the risk of febrile neutropenia is in the range of 20% or higher.1 Although most commonly used regimens have a risk less than this, an increasing number fall into this category, especially the dose-dense regimens that have proven so effective in the adjuvant treatment of breast cancer (the overwhelming majority of the patients in the Kirshner study).
Older adults (a group that was not well represented in Kirshner's study) comprise another growing group of cancer patients in whom the use of GCSFs is of critical importance. The risk of myelosuppression increases significantly by age 65, and primary prophylaxis with GCSF is now recognized as an important adjunct to chemotherapy in this population.1,2 Studies have repeatedly shown that non-frail older patients benefit from and are able to tolerate commonly used chemotherapy regimens as well as younger patients, especially when adequate supportive care is provided.3 As in their younger counterparts, dose reductions significantly compromise chemotherapy, and the use of GCSF in these circumstances increases efficacy as well as decreases morbidity.
Although 49 of the original 510 patients dropped out of Kirshner's study (equally split between the two groups), none appeared to have done so because of pegfilgrastim-induced bone pain. However, given the prevalence of significant bone pain in patients receiving pegfilgrastim, it is likely that there are those in day-to-day practice who just cannot tolerate the regimen and choose to either discontinue treatment or opt for compromised doses over pegfilgrastim-based regimens. This may be particularly true in older individuals who often have unacceptable side effects (lethargy, confusion, falls, constipation) from opioid analgesic medications. Even if they choose to "tough it out" without the stronger pain relievers, the impact of this pain on quality of life may be profound for both older and younger patients.
Amgen's official website4 informs patients that: "The most common side effect you may experience is aching in the bones and muscles. If this happens, it can usually be relieved with a nonaspirin pain reliever, such as acetaminophen." Unfortunately, there are no studies to confirm this, and, given the number of patients in Kirshner's study who still had bone pain after naproxen prophylaxis, it seems unlikely that acetaminophen will do any better. If it did, it would certainly be less toxic.
Though the design of Kirshner's study had many strengths, it did not provide adequate information about the well-known side effects of naproxen. Gastrointestinal and renal toxicity from NSAIDs are relatively common (especially in older patients), but they usually take some time to develop. NSAID-related side effects were not seen in Kirshner's study, but the patients were only asked about serious adverse events during the first cycle of chemotherapy. It would be wrong (perhaps even dangerous) to generalize the absence of these side effects to standard care where patients are given multiple cycles of chemotherapy over many months. Since most of the patients in this study were relatively young, healthy, white women with breast cancer, it is also difficult to extrapolate these findings to other cancer diagnoses and patient groups.
Nevertheless, this study does provide good evidence that naproxen may be useful in diminishing the impact of pegfilgrastim-induced bone pain in some patients. Until we understand more about its toxicity over the entire course of chemotherapy, it should be used judiciously in only selected patients. Since the majority of cancer chemotherapy patients receiving GCSFs will have significant bone pain, oncologists should pay particular attention to the published guidelines, and, when they do use GCSFs, assess and treat pain proactively and aggressively.
1. 2006 Update of ASCO Practice Guideline recommendations for the use of white blood cell growth factors: Guideline summary. J Clin Oncol 2006;24:3187-3205.
2. Repetto L, et al. EORTC Cancer in the Elderly Task Force guidelines. Eur J Cancer 2003;39:2264-2272
3. Chen H, et al. Can older cancer patients tolerate chemotherapy? A prospective pilot study. Cancer 2003;97:1107-1114.
4. Neulasta.com Web Site. What are the most common side effects of Neulasta® (pegfilgrastim)? http://www.neulasta.com/starting-chemo-with-neulasta/white-blood-cell-counts.html?src=ppc&WT.srch=1&SRC=2.