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Adjuvant Radiotherapy and Chemoradiation in Elderly Patients with Squamous Cell Carcinoma of the Head and Neck

Background: Radiotherapy and chemoradiation are well-established therapies for patients with squamous cell carcinoma of the head and neck (SCCHN). In aging societies, also the incidence of SCCHN in elderly patients is rising. Because of the underrepresentation of elderly patients in scientic trials, we evaluated the feasibility of adjuvant radiotherapy and chemoradiation in patients with SCCHN aged >70 years.

In Germany, the Robert Koch Institute (RKI) in cooperation with the "Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V." (Society of Epidemiological Cancer Registries in Germany) publishes German cancer statistics every two years. In 2014, 12,830 new cases of tumours of the oral cavity and pharynx (9,130 in men, 3,700 in women) were diagnosed as well as 3,500 new cases of malignant tumours of the larynx (2,980 in men and 520 in women) (Robert-Koch-Institut 2017).
The aetiology of head and neck cancer is multifactorial. The main risk factors are smoking, alcohol consumption, human papilloma virus (HPV), premalignant lesions (for example, leukoplakia) and premalignant conditions (inherited conditions or acquired immunode ciency) (Shaw und Beasley 2016) (Blot et al. 1988) (Sankaranarayanan et al. 1998).
Cancer of the head and neck occur heterogeneously, and locally advanced SCCHN are frequent (Magnes et al. 2017). One therapeutic option for locally advanced SCCHN is multimodal treatment consisting of resection followed by postoperative or adjuvant radiotherapy or chemoradiation (Marur und  Therefore, the aim of the present analysis was to evaluate the results and the feasibility of adjuvant radiotherapy or chemoradiation in a collective of elderly patients with SCCHN who were aged 70 years and older.  Survival curves for 60 months were created with Kaplan-Meier-plots and analysed with log-rank-tests.

Methods
An univariate as well as a multivariate analysis were conducted. Positive and negative predictive factors were identi ed by means of the Cox regression model.

Results:
Feasibility Radiotherapy was well tolerated by the patients. In this survey, 62 (87.3%) patients underwent radiotherapy and chemoradiation as planned without interruption. Treatment had only to be interrupted for 2 or more days for 9 (12.7%) of 71 patients. 65 (91.5%) patients could complete radiotherapy with a dose of 95% of the initially prescribed radiation dose. Because of premature discontinuation of radiotherapy, 6 (8.5%) patients received less than 95% and 4 (5.6%) patients less than 80% of the prescribed dose. Median dose for all patients was 64 Gy (IQR: 60-66 Gy).
Of 71 patients, 9 (12.7%) received simultaneous adjuvant or postoperative chemoradiation. 6 (66.6%) of the 9 patients received 75% or more and 8 (88.8%) of the 9 patients 50% or more of the initially planned dose. 1 patient received less than 25% of the prescribed chemotherapy dose because of the premature termination of chemoradiation. Most of the postponed cycles were shifted due to temporary bone marrow toxicity, especially leukopenia and neutropenia.

Acute Toxicity
In this survey, we also evaluated the side effects of radiotherapy and chemoradiation, such as enoral mucositis, dysphagia, dermatitis caused by radiation, loss of weight, leukopenia, thrombopenia, anaemia, renal failure and xerostomia. Side effects were analysed after 6 weeks and after 3, 6 and 12 months according to the dates of follow-up examination. 37 patients (52.1%) developed acute toxicity CTC grade III or IV after radiotherapy or chemoradiation. Analysis by means of the Chi²-test showed that simultaneous chemoradiation did not result in any signi cantly higher degree of acute toxicity than radiotherapy alone.
The most frequent acute side effect of radiation was enoral mucositis. 24 (33.8%) patients developed therapy-induced toxicity CTC grade III or higher. After 6 weeks, 3 (4.2%) patients were still affected by mucositis. [ Table 2]

Survival And Response
Our study population of 71 patients showed an overall survival rate of 87% after 12 months, 67% after 24 months and 41% after 60 months [ Figure 1] Median overall survival for patients with tumour recurrence (local relapse or metastatic spread) during follow-up was 21 months (IQR: 18-54 months). Median survival of patients without relapse was 65 months (IQR: 23-120 months) and thus signi cantly longer than for patients with tumour recurrence (log rank-test: p = 0.001).
Local tumour was 99% after 12 months, 88% after 24 months and 76% after 60 months. 13 of the 71 patients had local tumour recurrence (median after 25 months (IQR: 15.0-65.0). [ Figure 2] A subgroup analysis showed a median overall survival rate of 24 months during follow-up for both patients with local relapse (IQR: 18-54 months) as well as for patients with metastatic spread (IQR: 14-25 months). According to the log rank-test for both subgroups this result is signi cant in comparison to the remaining patients (local relapse: p = 0.039; metastatic spread: p = 0.002).

Univariate And Multivariate Analysis
In view of the overall survival rate, these results were signi cant with regard to the KPS. First, patients with a KPS of 60% or less before, during or after radiotherapy had signi cantly worse overall survival (p = 0.019) than patients with a KPS of 70-100%. This fact was con rmed in the univariate analysis of KPS after radiotherapy, in which especially a KPS of 50% or less was associated with signi cantly worse overall survival (KPS 30%: p = 0.000, KPS 40%: p = 0.000, KPS 50%: p = 0.001). Furthermore, univariate analysis yielded a signi cantly worse overall survival rate during follow-up for patients with tumour recurrence (local recurrence or metastatic spread) (p = 0.002) and for patients with metastatic spread (p = 0.001).
Univariate evaluation showed a trend towards an association between dysphagia after radiotherapy, especially dysphagia CTC grade III 6 months after the end of radiotherapy (p = 0.071), and slightly worse overall survival. A tendency was also apparent for an association of low haemoglobin values (anaemia CTC III or higher) before radiotherapy (p = 0.067), tumour recurrence at the beginning of radiotherapy (p = 0.101) and an increased UICC-status (UICC IVb: p = 0.084) with worse overall survival.
Multivariate analysis yielded a signi cant association of tumour recurrence (local recurrence or metastatic spread) during follow-up (p = 0.02) and dysphagia CTC grade III 6 months after the end of radiotherapy (p = 0.036) with overall survival.

Conclusion:
Malignancies of the head and neck area are among the most frequent malignant tumours, but elderly patients have been underrepresented in scienti c surveys so far. The aim of the present examination was to evaluate the feasibility and results of radiotherapy or chemoradiation in patients aged > 70 years with head and neck tumours.
The feasibility of radiotherapy and chemoradiation in our collective of elderly patients was good.
Especially local tumour control was satisfactory.
Careful patient selection regarding comorbidities and the Karnofsky performance status is essential. But continuous progress in radiation techniques over the past few years has signi cantly reduced the frequency of toxicities. The factor age does not seem to in uence overall survival because there was no obvious difference between elderly patients and younger or unselected patients.
Our results suggest that de-intensi cation of treatment just because of age has to be reconsidered critically.
Further research is needed to better assess cancer therapy, particularly in elderly and frail patients.

Discussion:
In this survey, we consciously decided to focus on elderly patients aged > 70 years with head and neck cancer who had been treated with radiotherapy or chemoradiation at the University Medical Centre Regensburg. Our aim was to investigate this heterogenous patient collective under therapy to analyse how these patients tolerated treatment and how to deal with the demands and challenges of real world data. Many other studies have focused on pre-selected patient collectives. Such (pre-)selection of patients may falsify the results of surveys and overlook the special requirements in treating elderly or frail patients, which is one reason for the lack of su cient data on such patients.
For elderly patients with head and neck tumours radiotherapy and chemoradiation represent important and effective treatment options (National Comprehensive Cancer Network 2020). Elderly patients should not be deprived of radiotherapy or chemoradiationjust because of their age (Metges et al. 2000;Kunkler et al. 2014;Wasil et al. 2000). We underline this assumption because of the good feasibility of radiotherapy and chemoradiation in our patient collective.
However, it is necessary to take a closer look at the collective of elderly patients with SCCHN.
Comparison of subgroups is di cult, because postoperative patients with intermediate risk tumours usually only receive radiotherapy (National Comprehensive Cancer Network 2020). Nearly all high-risk patients in our collective would have received simultaneous chemoradiation if they had been younger. In reality only t patients in our collective received simultaneous chemoradiation pursuant to present guidelines, since some elderly and frail patients were not intended to be able to tolerate simultaneous chemotherapy according to the data of "Meta-analysis of chemotherapy in head and neck cancer (MACH-NC)". (Blanchard et al. 2016). In accordance to the data of the MACH-NC meta-analysis elderly patients in our collective who had risk factors (ECS, more than 3 lymph nodes affected, less than 5 mm margin), comorbidities or a low Karnofsky performance status received radiotherapy alone although -according to oncological guidelines -simultaneous chemoradiation should also be conducted -at least theoretically. general condition was classi ed in accordance to the Karnofsky performance status and comorbidities. Thus therapeutic decisions had to be made individually for each patient.
As already mentioned feasibility of radiotherapy and chemoradiation in our collective was good, consequently treatment had only to be interrupted for 2 or more days in 9 (12.7%) patients. Reasons for the interruption of radiotherapy were mostly acute toxicity or other medical complications such as infections. Some interruptions were due to patient incompliance or organisational problems. 65 patients were able to complete radiotherapy with 95% of the initially prescribed radiation dose (91.5%). 4 patients We also cannot con rm the hypothesis that elderly patients generally have a worse prognosis than collectives of younger patients or patients of different age groups. Data on elderly patient collectives are generally still insu cient (Wasil et al. 2000).
Our patients treated with simultaneous chemoradiation generally had worse outcome than the patients only treated with radiotherapy. Median survival of patients undergoing simultaneous chemotherapy was 21 months. Patients without simultaneous chemotherapy had a median survival rate of 51 months. In the log rank-test this result was not signi cant (p = 0.219). This result is due to the fact that patients who qualify for simultaneous chemotherapy have a poor prognosis and considerable risk factors (ECS, more than 3 lymph nodes affected, less than 5 mm margin). The majority of our patients had locally advanced tumour (UICC stadium IVa), hence the poor overall survival rate was not surprising.
For these reasons, comparison of these patient groups is di cult. On the one hand, simultaneous chemotherapy and radiotherapy is more effective (Forastiere et  Furthermore, our univariate evaluation showed a trend towards an association of dysphagia after radiotherapy, especially dysphagia CTC grade III 6 months after the end of radiotherapy, a low haemoglobin value (anaemia CTC III or higher) before radiotherapy (p = 0.067), tumour recurrence at the beginning of radiotherapy and an increased UICC-status with poor overall survival. The haemoglobin value is also known as a negative predictive marker in unselected non-elderly patients (Dietl et al. 2005).
The purpose of this survey was to evaluate the treatment feasibility of radiotherapy or chemoradiation in an unselected patient collective. To assess the reality and authenticity of the treatment of elderly patients as closely as possible, we decided to include the patients in the described unselected manner. Consequently conclusions could be drawn with regard to feasibility and toleration of radiotherapy and chemoradiation.
The feasibility of radiotherapy and chemoradiation in our collective of elderly patients was good. We However, their patient collective was smaller than ours. The implementation of intensity-modulated radiation and the subsequent dose reduction and thus protection of organs at risk has increased the compatibility of radiotherapy in the head and neck area (Kunkler et al. 2014).
Our patient collective was larger and less heterogenous than those in other surveys. Each of our patients received adjuvant radiotherapy or chemoradiation, and our patient collective is representative because it resembles clinical reality.
Chemoradiation was not signi cantly less well tolerated by our elderly patients than by younger patients, Nevertheless, careful patient selection regarding comorbidities and the Karnofsky performance status is necessary (Sanabria et al. 2007). Our next prospective studies on radiotherapy and chemoradiation of elderly patients with head and neck cancer will particularly focus on frail patients.

Declarations -Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Ethics Committee of the University of Regensburg.
-Consent for publication Not applicable -Availability of data and material The datasets generated and analysed during the current study are not publicly available due to data protection regulations for the personal and con dential patient data but are available anonymised from the corresponding author on reasonable request.
-Competing interests Figure 1 Overall survival of the whole sample Local tumour control after adjuvant radiotherapy / chemoradiation