Symptom burdens related to chemotherapy-induced anemia in stage IV cancer
Background Chemotherapy-induced anemia (CIA) is associated with many symptoms that negatively impact quality of life. However, a systematic examination of symptoms in patients with CIA is lacking.
Objective To describe the occurrence of a comprehensive list of symptoms in patients with stage IV malignancies by CIA status.
Methods Patients diagnosed with stage IV non-Hodgkin lymphoma, breast, and lung cancer at Kaiser Permanente Southern California (2010-2012) were eligible. CIA was defined as hemoglobin <10 g/dL after the initiation of chemotherapy. Standardized record review evaluated the occurrence of symptoms for all patients who developed CIA (n = 402), and a random sample of patients who did not develop CIA (n = 98). The prevalence of each symptom and the distribution of number of symptoms per patient were described overall and by anemia grade.
Results Mean number of symptoms during chemotherapy for patients who did and did not develop CIA was 6.8 and 4.1, respectively (P < .01). Fatigue (90%), dyspnea or shortness of breath (58%), nausea or vomiting (56%), and loss of appetite (56%) were documented in >50% of patients who developed CIA, whereas only fatigue (77%) was noted in >50% patients without CIA. Several symptoms, including depression, diarrhea, dizziness or lightheadedness, and dyspnea, particularly demonstrated a clearly increasing prevalence with declining hemoglobin level. The mean number of symptoms per patient increased as CIA grade increased (3.6 symptoms for grade 2, and 5.4 symptoms for grades 3 and 4, respectively).
Limitations No causal relationship was examined due to descriptive design.
Conclusions High-grade CIA correlates with an increased symptom burden in patients with stage IV malignancies.
Funding Amgen Inc, maker of ESA used in the treatment of anemia
Accepted for publication October 26, 2018
Correspondence Chun Chao, PhD; Chun.R.Chao@kp.org
Disclosures Hairong Xu and Bhakti Mehta were employees of Amgen during study execution and received salary and stock as part of employment. Amgen provided research support to Kaiser Permanente to perform this study who, in turn, employed or contracted with the non-Amgen authors. Authors did not report any other potential conflicts of interest.
©2018 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0432
Data collection
Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded.
The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.
Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.13
,Statistical analysis
Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.
Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.
The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.
All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
