Trends in Treatment of Head and Neck Cancer in Germany: A Diagnosis-Related-Groups-Based Nationwide Analysis, 2005–2018

Simple Summary Surgery, radiotherapy, and chemotherapy/immunotherapy as monotherapy or in combination are the pillars of the treatment of head and neck cancer (HNC). Nation-wide population-based data on treatment rates per population and year for HNC are sparse. The data of virtually all HNC cases (apart from thyroid cancer) treated as inpatients in Germany between 2005 and 2018 were analyzed. Treatment rates for nearly all treatment types increased for cancer of the oral cavity, oropharynx, and salivary glands. Treatment rates for nasopharyngeal cancer in both sexes and hypopharyngeal cancer in men mainly decreased. In women, surgery for hypopharyngeal cancer decreased, but radiotherapy, chemotherapy, or in combination, increased. Laryngeal cancer showed a mixed picture: Surgery and neck dissection decreased in men and remained unchanged in women, whereas radiotherapy, chemotherapy, or in combination, remained unchanged in men, but increased in women. Changes in treatment are dependent on the subsites and are different for men and women for several subsites. Abstract Advances in head and neck cancer (HNC) treatment might have changed treatment strategies. This study determined, with focus on gender disparity, whether treatment rates have changed for inpatients in Germany between 2005 and 2018. Nation-wide population-based diagnosis-related groups (DRG) data of virtually all HNC cases (1,226,856 procedures; 78% men) were evaluated. Poisson regression analyses were used to study changes of annual treatment rates per German population. For surgery, the highest increase was seen for women with cancer of the oral cavity (relative risk (RR) 1.14, 95% confidence interval (CI) 1.11–1.18, p < 0.0001) and the highest decrease for men with laryngeal cancer (RR 0.90, CI 0.87–0.93). In women with oropharyngeal cancer, the highest increase of radiotherapy rates was seen (RR 1.18, CI 1.10–1.27, p < 0.0001). A decrease was seen in men for hypopharyngeal cancer (RR 0.93, CI 0.87–0.98, p = 0.0093). The highest increase for chemotherapy/immunotherapy was seen for women with oropharyngeal cancer (RR 1.16, CI 1.08–1.24, p < 0.0001), and a decrease in men with hypopharyngeal cancer (RR 0.93, CI 0.88–0.97, p = 0.0014). Treatment patterns had changed for nearly all subsites and therapy types. There were relevant gender disparities, which cannot be explained by the DRG data.


Introduction
Head and neck cancer (HNC) is the seventh most common type of cancer worldwide [1]. HNC represents a diverse group of tumor entities covering several anatomical subsites in the upper aerodigestive region. These entities differ greatly in terms of etiology, risk factors, histology, and therapeutic management. About half of the patients are still diagnosed at advanced stage [2,3]. In most cases, a monotherapeutic approach (surgery alone

Material and Methods
All hospitalizations for the years 2005-2018 in this study covering virtually all hospitals in Germany were analyzed. The structure of DRG data supplied by the Federal Bureau of Statistics (DESTATIS) has been described elsewhere in detail [12] (more information about the data source is available on https://www.forschungsdatenzentrum.de/en/ health/drg; last access: 22 September 2021). Ethics approval was not needed. The authors used anonymized data supplied by the German Federal Bureau of Statistics (DESTATIS). The anonymization of such data is regulated in § 16 Bundesstatistikgesetz (German Federal Statistics Act). All authors had access to the study data and reviewed and approved this study.

Statistical Analysis
The population of Germany of the years 2005-2018 was used to calculate the treatment rates. Population data were provided by the German Federal Bureau of Statistics (DESTATIS). Negative binomial regression models with log link were performed to conduct an analysis over time. Here, the dependent variable was the number of cases and the logarithm of the population at risk was taken as an offset. Time from 2005 was used as covariate. Relative risks (RR) with 95% confidence intervals (CI) are reported. For all statistical tests, significance was two-sided and set to p < 0.05. All calculations were carried out using SAS version 9.4 (SAS Institute, Cary, NC, USA  Figure S1 illustrates the changes of the treatment rates over time for the different types of treatments and separately for the head and neck cancers subsites. Overall, the highest average biopsy rate was seen for laryngeal cancer (5.32 ± 0.70 per 100,000 per year) and cancer of the oral cavity (4.88 ± 0.79). The same was seen for the frequency of surgery of the primary tumors with a surgery rate of 10.96 ± 0.48 for laryngeal cancer and of 10.25 ± 0.74 for cancer of the oral cavity. The neck dissection rates were dominated by neck dissection for cancer of the oral cavity (5.34 ± 0.41). In general, the neck dissection rates were much lower than the primary surgery rates. Radiotherapy rates were headed by cancer of the oral cavity (5.95 ± 0.54), followed by oropharyngeal cancer (4.13 ± 0.44). The chemotherapy/immunotherapy rates were dominated by oral cavity cancer (5.82 ± 0.59), oropharyngeal cancer (4.15 ± 0.42), and hypopharyngeal cancer (4.08 ± 0.39). In general, the treatment rates were much higher for men than for women. The treatment rates over  Figure 1. The frequency ranking was different between both sexes for the biopsy and primary surgery rates: Laryngeal cancer led biopsies and primary surgery in men and oral cavity was in second place, whereas it was vice versa in women. The ranking of the frequencies between the subsites was not different for both sexes concerning neck dissection, radiotherapy, and chemotherapy/immunotherapy.    Table 2 summarizes the treatment rates for each subsite for both sexes, and based on the regression analyses, if these rates have increased, decreased, or were unchanged over the years. Furthermore, the changes of treatment rates in percentage between the first year, 2005, and the last year, 2018, are listed.

Gender Differences in Change of Therapy Strategies between 2005 and 2018
The biopsy rates increased over time for all subsites (RR 1.09-1.37; all p < 0.0001), but less noticeable for hypopharyngeal cancer in men (RR 1.07; p < 0.05; Table 3).

Discussion
Overall, the burden of cancer incidence including HNC is rapidly growing worldwide. This reflects both aging and growth of the population as well as changes in the prevalence and distribution of the main risk factors for cancer [13]. Increasing numbers of HNC cases will need increasing numbers of treatment. The presented study is based on secondary data analysis from DRG data. Several countries use the DRG system, but to our knowledge the present study is the first to use DRG data to analyze head and neck treatment trends for over time. This data set, incorporating as a major advantage all hospitalized cases in Germany, is based on reimbursement claims. Hence, and this a limitation of the study, it does not include outpatient treatment [14]. Therefore, the absolute number of treatments for HNC will be higher than presented here. The comprehensive picture of inpatient treatment relies on OPS treatment codes that can be linked to ICD codes. The herein presented treatment rates per 100,000 population and year cannot be transferred par for par to incidence rates as some HNC patients, especially when in advanced stage, might receive several treatments.
As no other DRG-based analysis was performed before, the presented results could only be compared to publications based on other population-based data sources, i.e., mainly on cancer registry data. Like in many other countries, it is the task of population-based cancer registries in Germany to estimate and analyze the number of annual incident cancer cases, cancer deaths, survival rates, and additional indicators of cancer epidemiology, particularly prevalence, incidence, and including the investigation of trends over time. Additionally, it is the task of the clinical cancer registries to collect further clinical data, for instance the TNM staging. Therefore, the presented analysis did not allow a linkage of the presented treatment data to TNM staging or any other clinical data. Due to the German Centre for Cancer Registry Data (https://www.krebsdaten.de; accessed on 22 October 2021), for instance, the average incidence of cancer of the oral cavity between 2005 and 2017 (data of 2018 not yet available) was 24.8 for men and 9.6 for women, respectively. The average incidence of laryngeal cancer between 2005 and 2017 was 8.3 for men and 1.3 for women, respectively. In comparison, the DRG data analyses revealed for cancer of the oral cavity a cumulative treatment rate of 46.6 for men and 18.4 for women, respectively. The cumulative treatment rates for laryngeal cancer were 25.6 and 6.8, respectively. This reflects that most patients receive several procedures and not monotherapy. It is known that the hospitalization rates range between 1 and 2 fold of the incidence rates [15].
An older National Cancer Data Base (NCDB) analysis for the years 1990-2004 showed decreasing numbers of surgery, a decrease of radiotherapy as monotherapy, but a massive increase of radiochemotherapy and a slight increase of surgery combined with radiochemotherapy [16]. Cooper et al. relate these changes mainly to the emergence of data from phase III protocols showing that the addition of chemotherapy to radiation therapy enhances the rate of locoregional control in advanced HNC tumors. A Surveillance, Epidemiology, and End Results (SEER) analysis for the years 1997, 2004, and 2009 showed mainly the same results [17]. We are not aware of newer NCDB or SEER analyses covering actual years with focus on treatment trends. More appropriate is a population-based analysis using clinical cancer registry data from Thuringia, a federal state in Germany, covering the years 1996-2016 [5]. Here, surgery alone (26.5% of all cases), surgery with adjuvant radiochemotherapy (21.2%), surgery with adjuvant radiotherapy (21.0%), and definitive radiochemotherapy/radioimmunotherapy (11.9%) were in descending order the most predominant strategies. Furthermore, the relative frequency of radiotherapy as a single therapy decreased, instead, radiochemotherapy/radio-immunotherapy increased. In contrast to the mentioned NCDB and SEER data, surgery as a single modality, as a primary treatment in combination with radiochemotherapy/radio-immunotherapy increased in Germany. It seems that surgery plays a larger role even for advanced stage tumors in Germany than compared to the United States. Here, we could separately analyze the surgery of the primary and surgery of the neck. It is striking that the neck dissection rates for all localizations were >50% lower than the surgery rates for the primary tumor. This means that an elective neck dissection was probably not performed in many early cancer cases (stage I) with clinical N0. Whereas this is standard of care or at least matter of debate for most head neck subsites, neck dissection is standard for cancer of the oral cavity even for all N0 necks and independent of the T classification. This suggests that part of the cases with cancer of the oral cavity were undertreated. The neck dissection rate is a quality indicator for the treatment of cancer of the oral cavity for the certified head and neck cancer centers in Germany. In 2020, only 76% of the oral cavity cancer cases treated in certified centers received a neck dissection (https://www.onkozert.de/organ/kopf-hals/; last access: 22 September 2021). Even taking into account that some patients refused a neck dissection or it was not indicated because of multimorbidity, an undertreatment can be assumed. This shows that more effort has to be made to improve the clinical guideline adherence.
Finally, the use of chemotherapy/biologicals as part of the treatment concept increased. The increase of biologicals in mainly related to cetuximab introduced in 2006 as checkpoint inhibitors were not introduced before 2017 [6,7]. These German cancer registry data correspond better to the presented results, especially as factors, such as the subsite and gender, have to be considered in the presented SEER and NCDB data. Of main interest are inverse trends. For most therapy types, we revealed increasing treatment rates over time, but especially treatment rates for nasopharyngeal cancer and hypopharyngeal cancer, as well as laryngeal cancer in male patients decreased. This seems to be directly associated to a decreasing incidence of these tumor subtypes in Germany [5].
Although it is well known that females have improved survival in comparison with their male counterparts [18], gender disparities were especially neglected so far when analyzing treatment trends. The above-mentioned Thuringian data showed that treatment decisions were different between male and female patients even for the same tumor type and stage [5]. Understanding these gender disparities is essential to providing appropriate care to HNC patients [18]. Therefore, prospective trials are needed to better analyze the decision making for or against a certain treatment strategy.
Although DRG data is collected prospectively through the routine hospital coding process which collects data from virtually all German hospitals, this study has several limitations. First, this study is retrospective, which could lead to misclassification errors and unmeasured variables. Notably, many clinical but important factors with influence on decision making, such as stage, comorbidity, or age, were not included. The calculated treatment rates can only be seen as a proxy for the incidence rates [15]. Furthermore, the DRG data is primarily collected for reimbursement. Although the data underwent plausibility checks for incorrect codes before release of DESTATIS to researchers, it cannot be excluded that in some cases the coding followed the interest of maximizing the profit more than a proper documentation of the actual treatment [19]. As the complete dataset is subject to this uncontrolled bias, the comparisons between subsets, such as the comparisons between men and women or between subsites, are evenly affected by such a bias.

Conclusions
The German and nationwide DRG statistics provide a unique epidemiological data source for the quantification of treatment rates for HNC. For the first time representative population-based DRG data of 1,226,856 procedures performed between 2005 and 2018 were used to analyze treatment trends in HNC in Germany. HNC is a very heterogeneous type of cancer. Therapy decisions are very different between HNC subtypes and trends over time are dependent on the subtype. Moreover, treatment decision also seems to depend on gender. These differences in decision making between men and women have to be better understood.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/cancers13236060/s1, Figure S1: Annual treatment rates per 100,000 population for head and neck cancer from 2005 to 2018. A: biopsy rates; B: surgery of the primary tumor rates; C: neck dissection rates; D: radiotherapy rates, and E: chemotherapy/immunotherapy rates. Table S1: Change of operation and procedure rates for oral cavity cancer in Germany over the time from 2005 to 2018.

Data Availability Statement:
The datasets used during the current study are available from the corresponding author upon reasonable request.