Iron deficiency/anemia in tumor patients receiving chemotherapy - results of a cohort study

To date, there are only a few studies in Germany that examine the reality of iron deficiency/anemia treatment for tumor patients who are undergoing chemotherapy. As part of a European prospective observational study, a prevalence of anemia of 40% (at the start of the study) and 67% (during the course of the study) was measured in over 15,000 tumor patients in 2001/02. In addition, the proportion of patients with anemia therapy and the distribution of the different therapy options were recorded. Of these patients, almost 40% were treated with antianemic preparations, with ESA having the highest proportion among the treatment options (Ludwig et al. 2004). In addition, Steinmetz and colleagues (2016) collected data from almost 1,000 cancer patients in Germany regarding demographic and disease-specific characteristics as well as the distribution of antianemic treatment options. It was found that the majority of patients received blood transfusions to treat the anemia and that both ESA and IV iron played a rather minor role in the treatment. The aim of this cohort study is therefore to investigate the care situation of patients with tumor disease and iron deficiency/anemia therapy. In order to better understand the reality of care in Bavaria (1/7 of those insured by statutory health insurance (GKV) in Germany), patient characteristics and disease-specific therapy options were analyzed using diagnostic and billing data as part of a PHARAO project run by the Bavarian Association of Statutory Health Insurance Physicians (KVB). analyzed.

>> The data basis for this cohort study was the routine data from the KVB. Across health insurance companies, these contain both the prescription data issued by the outpatient doctors in Bavaria and the diagnosis data of all those with statutory health insurance in Bavaria (N=10.4 million; corresponds to around 83% of the Bavarian population). The recipe data is available on a platform that is physically separate from the other routine data. For data protection reasons, all master data, such as: B. the insurance numbers, anonymized. Due to identical anonymization in both databases, the data could still be merged using data linkage.
Within the study period from January 1, 2012 to December 31, 2013, all patients who received chemotherapy were initially identified. This was defined using the special pharmaceutical central number (PZN) 9999092 or the Anatomical-therapeutic-chemical classification system (ATC) codes V70BA “Cytostatic preparation” or L01* “Antineoplastic agents”.
It was then examined whether the identified patients had received iron deficiency/anemia therapy. A distinction was made between blood transfusions (Uniform Assessment Standard (EBM) code 20110/20111), iron-containing preparations (ATC code B03A* “Iron-containing preparations”) and/or ESA (ATC code B03XA* “Other antianemics”). These patients were analyzed for their demographic characteristics and the type, duration and timing of iron deficiency/anemia therapy. In addition, a subcohort of patients was identified who received a confirmed tumor diagnosis in each quarter of the analysis period, were treated with cytostatic therapy and treated with iron at any time during the study period. For these patients, both the duration of iron therapy and the type of iron therapy were examined, stratified according to cytostatic drug groups. All outcomes were analyzed using descriptive statistics.
A detailed study concept with a description of the project was approved by the Higher Insurance Office before the start of the study (§287(1) SGB V).
Results
A total of N=60,835 patients were identified who received at least one prescription for cytostatic therapy during the study period. This corresponds to around 0.6% of those with statutory health insurance in Bavaria.
42.5% of all identified patients receiving chemotherapy were male and 51.6% were female (no assignment was possible for the remaining patients due to missing information). The average age of the entire cohort was 65 years, although at 66 years old, the male patients were 2 years higher than the female patients.
A total of 20.3% of all patients receiving chemotherapy also received iron deficiency/anemia therapy (n=12,356). The patients in the iron deficiency/anemia therapy cohort were on average three years older than the patients in the basic cohort without iron deficiency/anemia therapy (67 vs. 64 years).
Of those patients with iron deficiency/anemia therapy, 46.1% received blood transfusions alone, 29.4% received iron and 6.9% received ESA monotherapy, 17.6% of patients were treated with combination therapy, including 2.7% with a combination made of ESA and iron (see Fig. 1).
As a result, 40.8% of patients receiving iron deficiency/anemia therapy were treated with iron; Either as monotherapy or in combination with blood transfusions and/or ESA. About two-thirds of patients (67.8%) received iron deficiency/anemia therapy for 1-2 quarters, 23.4% for 3-4 quarters, 6.6% for 5 throughout the study period (8 consecutive quarters). -6 quarters and a share of 2.2% for 7-8 quarters. The iron or ESA therapy was given at 78.9% in the same quarter as the chemotherapy and at 21.1% afterwards. All blood transfusions were performed in the same quarter(s) as chemotherapy.
For the subcohort of patients with chemotherapy for whom a confirmed tumor diagnosis was available quarterly (n=3,780), the use of iron preparations (oral vs. iv vs. oral & iv iron) and the administration of iron preparations were examined according to chemotherapy drug groups. In a total of 5,631 quarters of therapy with iron therapy, 67.6% oral iron, 30.2% IV iron and 2.1% a combination of oral and IV iron were prescribed (see Fig. 2).
Treatment with oral iron preparations is the most common treatment across all chemotherapy drug groups. Treatment with oral iron took place in approximately 20% of all chemotherapy quarters and treatment with IV iron in approximately 10%. Less than 1% of patients were treated with oral and IV iron in all drug groups (see Fig. 3).
discussion
In this cohort study, the reality of care with regard to iron deficiency/anemia therapy in tumor patients receiving chemotherapy was examined over the course of two years (Q1/2012 to Q4/2013) in the Bavarian SHI population using routine data from the KVB and prescription data from outpatient doctors in Bavaria examined. It was found that around one in five patients was treated with iron deficiency/anemia therapy either in parallel or following their chemotherapy. The duration of iron deficiency/anemia therapy was 1-2 quarters for the majority of patients. Three forms of therapy for iron deficiency/anemia in tumor patients receiving chemotherapy have been used: blood transfusions, ESA and iron preparations. Combinations of the different therapies have also been observed. Overall, almost half of the patients with iron deficiency/anemia therapy received blood transfusions, around 30% received iron monotherapy and 6.9% received ESA monotherapy. Only 4.7% of all iron deficiency/anemia patients were treated with both ESA and iron. Among iron preparations, oral iron preparations were prescribed significantly more frequently than IV preparations. The combination of oral and IV preparations is rarely used in the treatment of chemotherapy-associated iron deficiency/anemia.
These results are in close agreement with the results of the German prospective cohort study by Steinmetz and colleagues mentioned at the beginning. Of N=962 anemic cancer patients, only 6% received treatment with a combination of ESA and IV iron. 15% and 20% of the patients were treated with IV iron or ESA monotherapy (Steinmetz et al. 2016).
International randomized clinical trials show that patients who receive ESA therapy and additional IV iron show a significant improvement in Hb levels compared to patients with oral iron or no additional iron therapy (Hedenus et al. 2007; Auerbach et al. 2004). By Steinmetz et al. In 2013, a German non-interventional study showed that the improvement in hemoglobin (Hb) levels in anemic cancer patients was comparable between patients with IV iron carboxymaltose monotherapy and with combination therapy with ESA (Steinmetz et al. 2013).
A study by Kanuri et al. According to this, there is also an improvement in the quality of life. For every gram increase in the Hb value, the quality of life score (FACT-An questionnaire) also increases by 3.1 points (Kanuri et al. 2016).
An examination of the direct relationship between increased quality of life with combination therapy with ESA and IV iron vs. ESA and oral iron yielded ambivalent results. While studies by Auerbach and colleagues (Auerbach et al. 2004, 2010) were able to demonstrate such a significant effect in favor of the combination therapy of ESA and IV iron, other studies did not show any significant effect (Bastit et al. 2008; Steensma et al. 2011).
limitations
The KVB data includes all billing data from outpatient healthcare in Bavaria. However, data from inpatient care are not available. Furthermore, there is no information regarding the laboratory tests (e.g. Hb levels or iron status) performed on the patients. It was therefore not possible to make a statement about Hb values in the course of this cohort study, nor was it possible to determine the severity of the iron deficiency. Based on this, it was approximated that the patients had a corresponding indication due to the prescription of iron preparations and ESAs or the implementation of blood transfusions.
Although all prescribed and redeemed drug prescription data are available in full, there may be an underestimation regarding iron medication and therapy, as the data does not contain any information on so-called “over the counter” (OTC) preparations.
In addition, an analysis of diagnoses from outpatient care is only possible on a quarterly level - not on a daily basis - as these are only documented quarterly for billing reasons.
Conclusion
Overall, the study showed that iron preparations are very important in the treatment of iron deficiency/anemia in patients receiving chemotherapy, although the administration of blood transfusions accounts for the highest proportion of care in these patients. Although various studies demonstrate a significantly better hematological response in patients with chemotherapy-induced anemia to ESA therapy with additional administration of iv iron compared to ESA therapy without iv iron (Hedenus et al. 2007; Auerbach et al. 2010; Henry et al . 2007), therapy with a combination of ESA and IV iron plays a rather subordinate role in care. Few patients receive such treatment. Accordingly, both the therapy recommendation from 2012 of the S3 oncology guideline and the G-BA's therapy advice that IV iron preparations should be administered parallel to the administration of ESA in chemotherapy-treated patients with functional or storage iron deficiency have not yet been fully implemented in the reality of care . However, in view of the publication by Steinmetz et al. In 2013, a combined therapy of ESA and IV iron only takes place if the use of ESA is medically necessary. The heavy use of oral preparations in iron therapy must be viewed critically in conjunction with the current guideline recommendations (Steinmetz et al. 2013).
The ESMO Clinical Practice Guideline from 2018 recommends the use of oral iron only if CRP <5 mg/L, as malignant diseases or chemotherapy itself cause inflammatory processes that reduce the absorption capacity of oral iron (Aapro et al. 2018) . With regard to the even greater limitation of the recommendation of ESA and oral iron, the current care situation for patients with malignant diseases should be re-analyzed. <<