Background
Anemia is pervasive among patients with cancer, affecting approximately 30% to 90% of those with solid tumors and 26% to 85% of those with gynecologic malignancies.1 –3 The etiology of anemia in patients with cancer is multifactorial, involving tumor-specific and treatment-related elements.1,4,5 Chronic inflammation associated with cancer and cancer-related cytokines can mediate the suppression of erythropoietin production and the sequestration of iron, contributing to anemia. Acute blood loss from cytoreductive surgery, renal impairment from chemotherapy, and bone marrow impairment from chemotherapy, radiation, or other treatments may also contribute to cancer-associated anemia.1
Anemia in patients with cancer has been associated with increased morbidity and mortality.2,3,6 Often presenting as shortness of breath, lethargy, palpitations, or syncope, the symptoms of anemia may be disruptive to daily function and contribute to diminished quality of life. Numerous studies have shown associations between anemia and worse response to treatment and survival in a variety of cancers, including ovarian, endometrial, cervical, and vulvar malignancies.1,7 –11 Among gynecologic cancers, anemia has been associated with poor local tumor control, potentially related to tumor hypoxia–mediated resistance to treatment.1,12
Although anemia is prevalent in patients with cancer, evidence suggests that the workup and treatment of anemia in the oncology context is lacking. In a prospective study of 15,000 patients with cancer, 39% had anemia at initial presentation; however, only 40% of those with anemia received treatment.2 The current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Growth Factors recommend that patients with a hemoglobin (Hgb) level ≤11 g/dL should undergo prompt evaluation for possible causes of anemia, including iron, nutritional, and hemolysis studies, to guide clinical management.4 Our objectives were to determine the prevalence of anemia among patients with gynecologic cancer at Vanderbilt University Medical Center (VUMC) and to assess compliance with the NCCN Guidelines for the evaluation and management of anemia.
Methods
Study Design and Data Abstraction
We conducted a retrospective cohort study of all patients with newly diagnosed gynecologic cancers treated at VUMC between 2008 and 2018 using the Synthetic Derivative, a deidentified database of Vanderbilt’s electronic medical records created for research purposes.13 Tumor registry (TR)–confirmed patients with gynecologic cancer were identified using ICD-O codes. In addition to a TR-confirmed diagnosis of ovarian, fallopian tube, primary peritoneal, uterine, cervical, vulvar, or vaginal cancer, inclusion criteria included age of 18 through 89 years, initial care at our institution, and Hgb measured within ±180 days of diagnosis. Exclusion criteria included recurrent disease, dual primary cancer, history of other malignancy, initial care at another institution, noninvasive disease, and borderline tumors of the ovary. Primary tumor site, date of diagnosis, and stage were obtained directly from the TR data. All other data were obtained through either manual review or data extraction within the Synthetic Derivative, with all cancer treatment data restricted to 180 days after TR diagnosis. Initial Hgb level was defined as the Hgb measurement closest to the TR date of diagnosis within 180 days before or after diagnosis, favoring any values before initiation of oncologic treatment. We identified patients with anemia or bleeding diatheses before cancer diagnosis using phenome-wide association study codes and confirmed them through manual chart review.14 Prediagnosis oral iron intake was obtained by review of medication records. All other laboratory values and treatment information were abstracted from the 180 days after diagnosis.
Clinical Definitions
Anemia was defined according to the NCCN Guidelines as Hgb level ≤11 g/dL. It was graded according to CTCAE version 5.0 as grade 1 (Hgb ≤ lower limit of normal to 10 g/dL), grade 2 (Hgb <10 to 8 g/dL), and grade 3 (Hgb <8 g/dL).15 Microcytic anemia was defined as mean corpuscular volume <80 fL and macrocytic anemia was defined as mean corpuscular volume >100 fL. Iron deficiency was defined according to the NCCN Guidelines as follows. Absolute iron deficiency, or the depletion of total body iron stores, corresponded to ferritin level <30 ng/mL and transferrin saturation (TSAT) <20%. Possible functional iron deficiency, or sufficient stored iron with possibly low bioavailable iron, corresponded to ferritin level >500 to 800 ng/mL and TSAT <50%.4 Functional iron deficiency was not determined in our cohort because this condition primarily arises in patients who have received erythropoietin-stimulating agents, which are not in common use among patients with gynecologic cancer at our institution. In accordance with our institution’s laboratory reference values, vitamin B12 deficiency was defined as levels <213 pg/mL and folate deficiency as levels <5.9 ng/mL. Iron evaluation was defined as at least 1 laboratory test completed for iron level, total iron binding capacity, or ferritin level within 180 days after diagnosis. Other nutritional evaluation was defined as laboratory tests being completed for vitamin B12 or folate level within 180 days after diagnosis. Hemolysis evaluation was defined as laboratory tests for haptoglobin or lactate dehydrogenase level being completed within 180 days after diagnosis. Any anemia evaluation was defined as the presence of any iron evaluation or laboratory tests for vitamin B12, folate, lactate dehydrogenase, or haptoglobin level within 180 days after diagnosis. Treatment of anemia was defined as blood transfusion, intravenous iron, oral iron, vitamin B12, or folate supplementation within 180 days after diagnosis.
Statistical Analysis
Measures of frequency and descriptive statistics were conducted in R version 3.4.4 (R Foundation for Statistical Computing). Univariate and multivariable regression were performed using SAS 9.4 (SAS Institute Inc) to evaluate the associations between clinical characteristics and anemia prevalence, evaluation, and treatment. Adjustments included age, race, surgery, radiation, chemotherapy, and disease stage. Patients with anemia at initial presentation were included within the group of patients with anemia within 6 months of diagnosis, unless otherwise noted. P<.05 was interpreted as statistically significant.
Results
Baseline and Oncologic Treatment Characteristics
A total of 939 patients met inclusion criteria (Table 1). Median age at diagnosis was 60 years (interquartile range, 52–68 years). Most patients were White (88%) and of non-Hispanic ethnicity (97%). The most common malignancy was uterine cancer (n=496; 53%), followed by ovarian (n=258; 27%), cervical (n=126; 13%), and vulvar or vaginal (n=59; 6%) cancers. Most patients (n=535; 57%) presented with early-stage disease and 398 (42%) presented with late-stage disease. A small percentage of patients (n=58; 6.2%) were noted to have anemia or a bleeding diathesis at any time before TR diagnosis, with most anemias being unspecified (supplemental eTable 1, available with this article at JNCCN.org). Fewer than 3% of patients had oral iron intake, as determined by medication lists, before TR diagnosis, with the last notation of medication occurring on average 4 years before cancer diagnosis. Fewer than 1% of all patients had prior oral iron present on medication lists within 1 year of diagnosis. Most patients received treatment for their cancer, including surgery (n=705; 75%), adjuvant chemotherapy (n=242; 26%), radiation (n=175; 19%), and neoadjuvant chemotherapy (n=48; 5%). Only 13% of patients did not undergo any oncologic therapy. Surgical procedure details are listed in supplemental eTable 2. The median estimated blood loss across all patients who had surgery was 250 mL. This was highest among patients with ovarian cancer (500 mL) and lowest among those with vulvar and vaginal cancers (100 mL).
Patient and Treatment Characteristics
Prevalence of Anemia and Anemia Characteristics
A total of 857 patients had an Hgb measurement taken at initial presentation, with a median Hgb of 12.7 g/dL (Table 2). Of these, 186 (20%) were noted to have anemia, with a median Hgb of 9.8 g/dL. Severity of anemia included 87 patients (47%) with grade 1 anemia, 76 (41%) with grade 2 anemia, and 23 (12%) with grade 3 anemia. Among the 186 patients who had anemia at initial presentation, 39% had uterine cancer, 30% had ovarian cancer, 26% had cervical cancer, and 5% had vulvar or vaginal cancer. When the population of patients with anemia at initial presentation was evaluated based on disease site, 15% of those with uterine cancer, 22% of those with ovarian cancer, 38% of those with cervical cancer, and 15% of those with vulvar or vaginal cancer had anemia at initial presentation. Most patients who had anemia at initial presentation had normocytic anemia (n=126; 68%).
Anemia Characteristics
Among all patients with cancer, the median nadir Hgb level within 6 months of diagnosis was 9.8 g/dL. Among patients who had anemia within 6 months of diagnosis (n=625; 67%), the median nadir Hgb level was 8.7 g/dL, with 124 patients (20%) with grade 1 anemia, 301 (48%) with grade 2 anemia, and 200 (32%) with grade 3 anemia. Similar to the distributions of anemia at initial presentation, most of these patients had normocytic anemia (n=526; 84%). In addition, among all patients who had anemia within 6 months of diagnosis, 44% had uterine cancer, 35% had ovarian cancer, 15% had cervical cancer, and 6% had vulvar or vaginal cancer (data not shown). When the population of patients with anemia within 6 months of diagnosis was evaluated based on disease site, 56% of those with uterine cancer, 86% of those with ovarian cancer, 72% of those with cervical cancer, and 59% of those with vulvar or vaginal cancer had anemia within 6 months of diagnosis (data not shown).
Among 671 patients with pretreatment Hgb values available who did not have anemia at initial presentation, 384 (57%) ultimately developed anemia within 6 months of diagnosis. Among surgical patients, postoperative anemia was common, with 269 (50%) of surgical patients who initially did not have anemia noted to develop anemia within 30 days of surgery. This persisted beyond the postoperative period, with 120 of these patients remaining anemic or developing a subsequent anemia in the 6 months after diagnosis.
Compliance With NCCN Guidelines
Among all 939 patients, 241 (26%) underwent anemia evaluation within the 6 months after diagnosis (Table 3). Of these 241 patients, 87 (36%) underwent evaluation for iron deficiency or anemia of chronic disease with iron studies, 58 (24%) underwent evaluation for other nutritional causes of anemia, and 167 (69%) underwent evaluation for hemolysis. Among those who had iron studies completed, 8 (9%) had absolute iron deficiency and 8 (9%) had possible functional iron deficiency. Among patients with other nutritional studies completed, 3 (5%) had vitamin B12 deficiency and 6 (10%) had folate deficiency. Among all patients, 283 (30%) had some treatment for anemia, including blood transfusion (n=213; 75%) or iron (n=68; 24%), vitamin B12 (n=47; 17%), or folate supplementation (n=7; 2%).
Compliance With NCCN Guidelines: Evaluation and Treatment of Anemia
Among 625 patients with anemia within the 6 months after diagnosis, 209 (33%) had any evaluation for anemia, including iron (n=80; 38%), other nutritional (n=50; 24%), and hemolysis (n=146; 70%) studies. Prevalence of absolute and possible functional iron deficiency was low (both 9%) among patients with anemia who had iron studies performed. Among patients with anemia with other nutritional studies completed, 3 (6%) had vitamin B12 deficiency and 6 (12%) had folate deficiency. Treatment of anemia was initiated in 260 (42%) patients with anemia. Among these patients, almost half (n=124; 48%) had a prior evaluation of anemia. Blood transfusion was the most common intervention (n=205; 79%) followed by iron (n=62; 24%), vitamin B12 (n=37; 14%), and folate supplementation (n=7; 3%). Approximately 68% of patients with grade 3 anemia in the 6 months after diagnosis underwent blood transfusion, and 52% of all transfusions occurred within 7 days before or after surgery. Of 16 patients with possible functional or absolute iron deficiency, 4 (25%) received iron treatment and 9 (56%) received any treatment for anemia, including transfusion, iron, or other nutritional supplementation.
Associations With Cancer Site
Anemia, any evaluation of anemia, iron evaluation, and treatment of anemia were significantly associated with type of gynecologic cancer (Table 4). In multivariable models that included adjustment for age at diagnosis, race, surgery, radiation, chemotherapy, and stage of disease, patients with uterine cancer had approximately 50% lower odds of having anemia within 6 months of diagnosis, any evaluation of anemia, iron evaluation, any treatment of anemia, or blood transfusion compared with patients with other gynecologic cancers. Patients with ovarian cancer had 50% higher odds of receiving treatment for anemia and more than 2-fold higher odds of having anemia within 6 months of diagnosis, any anemia evaluation, or any iron evaluation compared with patients with other gynecologic cancers. After adjustment of the models, patients with cervical cancer had almost 2-fold higher odds of receiving treatment for anemia and blood transfusion compared with other cancers of interest. Compared with women with other gynecologic cancers, patients with vulvar and vaginal cancer did not have significant associations with odds of anemia or anemia treatment, but did have approximately 60% lower odds of anemia evaluation.
Association of Cancer Site With Anemia, Anemia Evaluation, and Anemia Treatment
Associations With Cancer Stage
A chi-square test of independence was performed to examine the relationship between stage of disease and anemia at initial presentation and within 6 months of diagnosis. Stage of disease and anemia at both time points were significantly associated, with advanced stage (III and IV) being strongly associated with the presence of anemia and early stage being strongly associated with the absence of anemia (initial presentation, χ2 [3, N=851] = 69.59; P<.001; within 6 months of diagnosis, χ2 [3, N=933] = 117.03; P<.001). Maximum grade of anemia within 6 months of diagnosis was similarly associated with cancer stage (χ2 [9, N=933] = 182.87; P<.001), with early-stage (stage I) disease being strongly associated with no anemia (grade 0) and advanced-stage disease being strongly associated with severe anemia (grade 3).
Discussion
Anemia in patients with cancer often has a multifactorial etiology, including disease-specific mechanisms such as bone marrow infiltration and inflammation-driven iron sequestration, and treatment-specific mechanisms such as chemotherapy-, immunotherapy-, or radiotherapy-induced myelosuppression or nephrotoxicity.4 Prompt recognition, evaluation, and treatment of anemia is critical to optimize outcomes, because anemia is an independent prognostic factor for survival in a variety of cancers.3 Given the complex nature of anemia in patients with cancer, the NCCN Guidelines recommend a workup for anemia to include evaluation of the mean corpuscular volume, reticulocyte count, and iron status, and consideration of other causes, such as hemorrhage, hemolysis, nutritional deficiency, renal dysfunction, treatment-induced, inherited, hormonal, or inflammatory.4 The NCCN Guidelines also recommend that anemia treatment be guided by the determined cause, although blood transfusion may be considered for asymptomatic patients with comorbidities (eg, cardiac or pulmonary dysfunction) and should be performed for symptomatic patients per AABB guidelines.16
In this study, we aimed to determine the prevalence of anemia among patients with gynecologic cancer at our institution and assess compliance with NCCN Guidelines for evaluation of anemia in patients with an Hgb measurement ≤11 g/dL. We found that less than one-third of patients with gynecologic cancers had anemia at initial presentation, but more than half had anemia by 6 months after diagnosis. At both initial presentation and within 6 months of diagnosis, most of the anemia in our cohort was normocytic. Although normocytic anemia may suggest anemia of chronic disease, bone-marrow suppression, or acute blood loss, we did not see an increase in the prevalence of microcytic anemia by 6 months, as would be expected in chronic blood loss or iron deficiency. Thus, in this cohort, most of the anemia likely occurred because of a combination of chronic disease and treatment-induced myelosuppression. The presence and severity of anemia were significantly associated with cancer stage, with prevalence and grade of anemia increasing with advanced disease stage. Patients with ovarian cancer had significantly higher odds of anemia within 6 months of diagnosis in both the unadjusted and adjusted models. This finding may be accounted for by the higher levels of blood loss during cytoreductive surgery in combination with myelosuppressive adjuvant chemotherapy.
Despite a high prevalence of anemia among all patients with gynecologic cancer, evaluation of anemia was only performed in 33% of patients with anemia, and treatment for anemia was initiated in 42% of these patients. Among patients with anemia within 6 months of diagnosis, those with ovarian cancer had higher odds of receiving treatment for anemia. This association was attenuated but remained significant after adjustment for oncologic treatment, possibly because of the frequency with which these patients are monitored as they have follow-up and evaluation during chemotherapy, allowing for more opportunities for intervention. Patients with cervical cancer also had higher odds of receiving treatment for anemia and blood transfusion. This finding may be multifactorial and associated with increased vaginal bleeding at presentation; multimodality treatment that may exacerbate anemia, including surgery, chemotherapy, and radiation; and lower thresholds for transfusion due to the need for radiotherapy, given that anemia is associated with worse outcomes.12 Accordingly, higher rates of treatment in this group likely occurred specifically because of higher transfusion rates; among the 48 patients with cervical cancer who initially presented with anemia, 28 (58%) underwent blood transfusion and only 5 (10%) received iron therapy.
The rates of absolute and possible functional iron deficiency among patients with anemia in our cohort were low (18% total); however, this may be due to the low prevalence of patients with available data. A prospective study to determine the true prevalence of iron deficiency in this population would be prudent. Our data indicate that although the prevalence of anemia in patients with gynecologic cancers is high, few patients undergo comprehensive evaluation as recommended by the NCCN Guidelines. Among all patients with gynecologic cancer, this tendency may be influenced by recent clinical trends toward tolerating lower Hgb values to reduce blood transfusion rates or restrictions on the use of erythropoietin-stimulating agents.4,17
Our results are in concordance with prior studies of anemia in patients with cancer that have shown frequencies ranging from 30% to 90%, with both the prevalence and grade of anemia increasing over the 6 months after diagnosis.18 –20 Although iron deficiency has been reported to occur in up to 40% of patients with cancer, both inside and outside the context of anemia, we found a lower prevalence in our cohort, although there were low rates of completed iron studies.5,19,21,22 In addition, reported rates of iron deficiency vary due to the clinical definitions used; given the links between inflammation and cancer, the ESMO guidelines define iron deficiency as a TSAT <20% or ferritin level <100 ng/mL.23 Moreover, some prior studies of iron deficiency in patients with cancer have used a TSAT <20% to initially define iron deficiency, with a ferritin level of <30 ng/mL corresponding to absolute deficiency and a level of ≥30 ng/mL corresponding to functional deficiency.22 When either of these broad definitions of iron deficiency (TSAT <20% or ferritin level <100 ng/mL) were applied to patients in our cohort who had iron studies available, these definitions yielded up to 69% of patients with any iron deficiency. Although perioperative blood transfusion is associated with morbidity and mortality, prior studies have shown relative frequency in gynecologic oncology.17 In our cohort, 23% of all patients underwent blood transfusion, with most transfusions occurring in the perioperative period. In addition to showing opportunities to improve compliance with NCCN Guidelines, our data provide important opportunities to potentially reduce blood transfusion rates by optimizing preoperative anemia evaluation.
The strengths of our study include involvement of a broad, well-characterized cohort of patients with gynecologic cancer over a period of 10 years at a large tertiary-care institution. We determined the prevalence of anemia before treatment where possible and also assessed the prevalence of anemia within 6 months of cancer diagnosis. Few studies have assessed compliance with NCCN Guidelines, and to our knowledge this is the first to assess compliance specifically with NCCN Guidelines for management of anemia among patients with cancer.
This study has several limitations. As a retrospective study utilizing deidentified data, this research may have had incomplete clinical information. The presence of preexisting anemia, bleeding diatheses, and preexisting oral iron intake may have confounded our results, although these numbers are small. Although we only included patients who had Hgb laboratory tests completed at our institution, information regarding further evaluation, treatment, or care from other facilities may have been missing from our record. Information regarding whether hematology consultation was obtained was not available. Furthermore, although we manually reviewed records to confirm that Hgb levels at initial presentation were recorded prior to surgery or chemotherapy, it was not possible to confirm that these levels were recorded prior to radiation therapy among the 19% of patients who received this treatment, because specific dates of radiation oncology treatments are managed through a separate system at our institution. The specific impact of radiation on the rates of anemia may be further complicated by the use of radiation to control bleeding from gynecologic malignancies; therefore, radiation may potentially increase or decrease rates of anemia.24 Although reticulocyte count may guide anemia evaluation, we were only able to obtain it for <2% of our cohort within our study period, and thus did not include it in our analyses.
Previous randomized controlled trials of iron treatment among patients with gynecologic cancer undergoing chemotherapy or chemoradiation have been promising for primary prevention of anemia, treatment of anemia, and reduction of transfusion rates.25 –29 However, it is unclear whether improvements in quality of life occur with treatment of anemia.25,30 Future work will seek to improve compliance with the NCCN Guidelines for anemia and to assess whether treatment of anemia is associated with improved quality of life and oncologic outcomes. At our institution, a quality improvement project is underway to determine the prevalence of iron deficiency and nutritional anemias and to optimize compliance with the NCCN Guidelines. Potential interventions at our institution include developing laboratory algorithms for reflex iron, vitamin B12, and folate laboratory tests after an anemic Hgb result to facilitate evaluation and guide management, as well as tracking the evaluation of anemia in new patients and those undergoing chemotherapy, who are at increased risk of anemia.
Conclusions
Anemia is pervasive among patients with gynecologic cancer, and compliance with NCCN Guidelines for the evaluation and treatment of anemia may be low. Our data suggest that there are opportunities for improvement in the evaluation and management of anemia among patients with gynecologic cancer.
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