Abstract
Background: Primary radio(chemo)therapy [R(C)T] is a treatment option for advanced oropharyngeal squamous cell carcinoma (OSCC). Nevertheless, early diagnostics of treatment failure is problematic. Cytokeratin fragment 19 (CYFRA 21-1), an established marker in the management of pulmonary cancer, might be helpful here. Hence, in this study the impact of CYFRA 21-1 as an indicator for treatment failure and tumor recurrence (TR) in OSCC after R(C)T was analyzed. Patients and Methods: The data of 77 patients with advanced OSCC and R(C)T were retrospectively examined. For determination of CYFRA 21-1 at the time of diagnosis and after R(C)T, an electrochemiluminescence immunoassay was used. Tumor residuals and tumor recurrence were pathologically verified after detection by radiological imaging and endoscopy. The mean follow-up was 44.4 months. Results: After R(C)T, 48 (62%) patients showed locoregional control and 29 (38%) patients experienced locoregional failure. No statistical difference in the CYFRA 21-1 level between groups both before (p=0.75) and after R(C)T (p=0.85) was found. Nevertheless, in cases of TR in follow-up, the CYFRA 21-1 level was significantly higher (p≤0.01). The occurrence of TR was significantly associated with a CYFRA 21-1 elevation at this time (p≤0.01). However, CYFRA 21-1 failed to show a suitable discriminative ability for TR (area under the curve=0.57). Conclusion: In OSCC, CYFRA 21-1 does not seem to be a useful marker for locoregional failure after R(C)T. Nevertheless, a higher level immediately after R(C)T and in the further course of the disease may be associated with TR in individual patients.
In the United States approximately 136,000 patients develop oropharyngeal cancer (OSCC) each year, accounting for about 2.8% of all patients with cancer (1). In Europe the incidence of OSCC is estimated to be five in 100,000 population (2). In this context, an increasing proportion of OSCC in head and neck cancer (HNSCC) has been observed in recent years increasing from 20% in the 1980s to about 70% currently in the United States and Europe (3, 4). Differences in incidence of OSCC may be attributed to a change in risk factors. Whereas in the past tobacco use and alcohol consumption, as well as poor dental status, malnutrition and different pollutants, were also typical risk factors for developing OSCC (5-8), nowadays human papilloma virus (HPV) is increasingly gaining in importance (3, 9, 10). In patients with HPV-associated tumors, the altered risk profile also implies slightly different clinical characteristics compared to HPV-negative tumors. Patients with HPV-associated tumors are usually younger, have smaller primary tumors as well as more advanced regional disease, and a lower rate of secondary tumors (3, 5, 11-14). Furthermore, the overall survival in these patients is superior to that of patients suffering from HPV-negative tumors, due to a better response to treatment (15). However, regardless of HPV status, the treatment of OSCC is complex and usually requires an interdisciplinary setting. In this context, radio(chemo)therapy [R(C)T] and surgery are suitable options for the treatment of the primary tumor. Nevertheless, despite a relevant progress in the diagnosis and management of OSCC, the prognosis remains poor with a 5-year survival rate of about 50-60%. Regional as well as distant failure in the further course of the disease are main reasons for the poor oncological outcome (16). However, tumor recurrence in the further course of the disease is mostly associated with advanced tumor- and nodal-stage and further clinical and histological parameters e.g., tobacco abuse, histological differentiation, HPV status, lymphangiosis carcinomatosa, extranodal spread and residual tumor at the primary site as well as the neck (17, 18).
In this context, an early diagnosis of residual tumor or tumor recurrence is highly important and could potentially be achieved by using a suitable tumor marker. Cytokeratin fraction 21-1 (CYFRA 21-1) was first described in 1981 by Wu and Rheinwald (19) and is an established marker for non-small cell carcinoma of the lung (20). CYFRA 21-1 is a soluble fragment of cytokeratin 19 which weighs about 40 kDa and belongs to the type I keratin, a sort of intermediate filament in epithelial cells (19). CYFRA 21-1 is expressed by benign and malignant epithelium, with a higher level in the lower aerodigestive tract. Therefore, patients with non-small-cell carcinoma of the lung were found to have higher serum CYFRA 21-1 concentrations than patients with HNSCC (21). Up to now, the usage of CYFRA 21-1 as a serum marker in the clinical management of HNSCC has been controversially discussed. In particular, the question for a suitable cut-off remains debatable, with values varying from 1.0 ng/ml to 3.3 ng/ml (22-24). Nevertheless, there is common agreement about worse overall- and disease-free survival for patients with HNSCC with elevated CYFRA 21-1 concentrations (22, 23, 25). Previous trials revealed that CYFRA 21-1 might be suitable for finding a tumor recurrence or metastasis during follow-up, while it seems to be inappropriate for the initial diagnosis of HNSCC (21, 26). Due to the fact that in primarily surgically treated patients the tumour is completely removed, it should be assumed that the CYFRA 21-1 level normalizes quickly. However, in patients treated by R(C)T, a slight increase or lack of decrease of CYFRA 21-1 level was observed in patients with residual tumor, even when such tumor was not noted by radiological imaging (27, 28). On the basis of these studies, we previously published a study that included 180 patients with OSCC treated at our hospital, evaluating the usage of CYFRA 21-1 as a marker during follow-up. In the present study, we re-evaluated a selected subgroup of patients treated by primary R(C)T. The aim of the present study was to demonstrate the use of CYFRA 21-1 as an indicator for residual disease after R(C)T as well as tumor recurrence during follow-up. The associations between the CYFRA 21-1 level and different tumor characteristics, as well as disease-free and overall survival were analyzed.
Patients and Methods
Clinical data and inclusion criteria. In this study, we retrospectively evaluated the data of 77 patients treated by primary R(C)T (70 by primary R(C)T and seven by primary RT) for histologically proven OSCC between 2003 and 2015. Only patients with at least one measurement of CYFRA 21-1 before and up to 6 weeks after the end of R(C)T were included in this study. Patients with cancer of unknown primary or a secondary tumor at the time of diagnosis were not included. Approval was obtained from the Ethic Committee of the Medical Faculty of the Philipps-Universität Marburg (number: ek_mr_03_05_19_hoch-2). Informed consent was obtained from all participants included in the study.
Diagnostics and tumor staging. At time of first presentation, a clinical and endoscopic examination of the upper airways was performed and regional lymph nodes were assessed by sonographic imaging in all cases. In patients with suspicion of regional or distant metastases at primary diagnosis and in cases of advanced tumor stage, magnetic resonance imaging of the neck and computed tomography (CT) of the chest were performed. All tumors were staged according to the seventh TNM classification by the International Union against Cancer (29).
Treatment modalities. All patients included in this study were treated by primary radiotherapy (n=77). When there was a clinical indication and the general condition of the patient was sufficient, additional chemotherapy concomitantly or before RT was performed (n=70). Radiotherapy consisted of 66 to 72 Gy, with a mean value of 68 Gy. Chemotherapy consisted of five different treatment protocols including 5-fluorouracil with mitomycin C; 5-fluorouracil with cisplatin; cetuximab with cisplatin; cetuximab with cisplatin, docetaxel and carboplatin; as well as a cetuximab monotherapy. Before 2010, nearly all patients were treated by salvage neck dissection (ND) after R(C)T. In this context the extent of ND (radical, modified radical, or selective) depending on the clinical and radiological presentation of residual neck lymph node metastasis. Since 2010, salvage ND has been performed only in patients with clinical suspicion of residual neck metastasis.
Follow-up. In order to monitor responses to therapy, in most patients (n=70, 91%) a radiological imaging through CT, positron-emission tomography–CT or magnetic resonance imaging of the initial tumor side and the neck was performed 10-12 weeks after R(C)T. At the same time, all patients were further evaluated by endoscopy of the upper aerodigestive tract with biopsies. Subsequent follow-up examinations consisted of endoscopic examination of the upper aerodigestive tract followed by ultrasound of the head and neck. Within the first 2 years after initial tumor diagnosis, the patients were revaluated every 4 to 8 weeks. Examination intervals were extended from 3 months (year 3 after diagnosis) to 6 months (year 4 after diagnosis) and then to 12 months after the fifth year from initial diagnosis. In cases of suspicion of tumor recurrence or a secondary tumor, further diagnostics consisting of magnetic resonance imaging and CT of the neck or thorax and fine-needle aspiration cytology of sonographically suspicious lymph nodes, were performed.
Measurement of CYFRA 21-1. The serum CYFRA 21-1 concentration was measured in all patients at the time of diagnosis and at about 2 months after the end of R(C)T. In 62 cases (77.5%), further measurements of CYFRA 21-1 were performed during the follow-up, especially at time of clinical suspicion of tumor progression or residual disease. For the measurement of CYFRA 21-1, two monoclonal antibodies (KS 19-1 and BM 19-21) were used after centrifuging and cooling 6-ml venous blood samples at –80°C. The Enzymum-Test® CYFRA 21-1 (Roche Diagnostics, Rotkreuz, Switzerland) electrochemiluminescence immunoassay test kit was used to determine the serum CYFRA 21-1 concentration. According to the manufacturer’s instructions, the cut-off value was set at 3.3 ng/ml, which is also recommended in the follow-up for detection of a disease progression in patients with lung cancer. Tumor recurrence after initial successful R(C)T occurred at a mean time interval of 20.6 months. For comparative analysis to patients without tumor recurrence after successful R(C)T, the CYFRA21-1 level at the same period of time was used in both groups.
Statistical analysis. All analyses were performed using Stata 14.0 (StataCorp LLC, College Station, TX, USA). The difference in CYFRA 21-1 values between various groups was measured using two-sample Wilcoxon rank-sum (Mann–Whitney) test. Linear regression was assessed between the CYFRA 21-1 values at the time of diagnosis across T-, N- and M-stage, histological grading and age at the time of diagnosis. The presence or absence of residual tumor was taken as a binominal outcome variable, wherein the T-, N- and M-stage, histological grading, age, gender, HPV status and CYFRA 21-1 values before and after R(C)T were taken as independent variables in a logistic regression analysis. Initially, univariate logistic regression was performed, then a forward stepwise analysis and ultimately a multivariate model was built. Similarly, logistics regression was used where the outcome variable was the presence or absence of recurrent tumor. Furthermore, factors associated with overall and disease-free survival of the patients were analyzed by Cox regression. Kaplan– Meier curves were used for graphic evaluation of the overall survival. The sensitivity and specificity of CYFRA 21-1 was calculated by using receiver operator curves. The ideal cut-off value for detecting recurrence using CYFRA 21-1 after R(C)T was calculated using the method stated by Liu, which defines the optimal cut-off point by maximizing the product of sensitivity and specificity (30). A p-value of less than 0.05 was considered statistically significant.
Results
Patients and follow-up. In total, 77 patients underwent primary R(C)T with curative intention; 64 (83%) of them were male. 70 patients were treated by radiochemotherapy and 7 by RT alone. The mean±SD age of the patients at the time of diagnosis was 58±9.8 years (range=38.2-91.6 years). A unilateral or bilateral salvage ND was performed in 54 cases. Forty-eight (62%) patients experienced locoregional control (LRC) after R(C)T, while 29 (38%) patients suffered from locoregional failure (LRF) after R(C)T. A total of 37 (77%) out of the 48 successfully treated patients were tumor-free in their further course and 11 (23%) experienced tumor recurrence. Clinical and histological data of the patients included in this study are listed in Table I. The median duration of follow-up for this study was 44.4 months (range=5-104 months).
Patients and treatment characteristics (n=77).
Correlation of CYFRA 21-1 at initial diagnosis with T-, N- and M- stage, histological grading and age. The serum level of CYFRA 21-1 value was significantly elevated in with increasing age (p≤0.01). No significant association with the T-, N-, M- stage or histological grading was found at the time of diagnosis (Table II).
Linear regression modelling for the association of serum cytokeratin fragment 19 (CYFRA 21-1) at the time of oropharyngeal cancer diagnosis with different pathological and clinical characteristics.
CYFRA 21-1 as a marker for LRF in patients treated by R(C)T. The mean CYFRA 21-1 level at the time of initial diagnosis was 3.0±2.4 ng/ml (range=0.41-11.0 ng/ml) for patients with LRC. For the LRF group, the corresponding value was 3.4±2.9 ng/ml (range=0.47-12.0 ng/ml). There was no statistically significant difference (p=0.75) in the CYFRA 21-1 level between the two groups before treatment.
At about 2 months after R(C)T, in patients with LRC, the mean CYFRA 21-1 level was 4.9±13.4 ng/ml (range=0.72-74.0 ng/ml). The equivalent mean CYFRA 21-1 level for the LRF group was 2.3±1.5 ng/ml (range=0.81-7.4 ng/ml). There was no statistically significant difference (p=0.85) in the CYFRA 21-1 level between the two groups after R(C)T.
During the course of treatment, on average, the CYFRA 21-1 level rose by 1.92 ng/ml in patients with LRC. In contrast, an average decrease in CYFRA 21-1 level of 1.10 ng/ml was observed in patients with LRF. However, there was no significant difference between the two groups (p=0.84).
The positive predictive value of CYFRA 21-1 after R(C)T was 0.428 (42.8%) in the 29 patients who suffered from LRF. Therefore, the CYFRA 21-1 value measured after R(C)T had a sensitivity of 31% and a specificity of 75% for detection of LRF.
LRF was not associated with a CYFRA 21-1 level >3.3 ng/ml at the time of diagnosis and after R(C)T, tumor size, nodal invasion, distant metastasis, histological grading, age, gender nor HPV status in the multivariate analysis (Table III).
Linear regression modelling for association between locoregional failure and the listed parameters for the whole patient group (n=77).
CYFRA 21-1 as a marker for tumor recurrence after successful R(C)T (n=48). The following analyses refer to the 48 patients successfully treated by R(C)T.
At initial diagnosis, the mean CYFRA 21-1 level was 2.7±2.3 ng/ml (range=0.41-11.0) among patients classified as tumor-free in the follow-up (n=37) compared to 3.9±2.6 ng/ml (range=0.75-9.6) in the group with tumor recurrence (n=11). There was no statistically significant difference (p=0.09) in the CYFRA 21-1 level at the time of diagnosis between patients who were tumor-free and those who suffered from tumor recurrence.
After R(C)T, the mean CYFRA 21-1 level was 2.2±1.5 ng/ml (range=0.74-8.5 ng/ml) among those patients who were tumor-free compared to 14±26.8 ng/ml (range=0.7-74 ng/ml) among the patients with tumor recurrence. A significant difference (p≤0.01) in the CYFRA 21-1 level between the groups was found.
At the time of tumor recurrence, the mean CYFRA 21-1 level was 14.4±34.8 ng/ml (range=0.97-148 ng/ml) compared to 2.6±3.7 ng/ml (range=0.65-17 ng/ml) in tumor-free patients at the same time. Hence, a statistically significant difference (p≤0.01) was found in the serum CYFRA 21-1 concentration between the two groups.
In this selected group of patients, no analyzed parameter, such as TNM, age, gender, HPV or CYFRA 21-1 >3.3 ng/ml before and after therapy was associated with tumor recurrence in the univariate and multivariate analyses.
The receiver operating characteristic curve for CYFRA 21-1 value after therapy showed an area under the curve of 0.57, with sensitivity and specificity of 45.5% and 75.7%, respectively, for detection of tumor recurrence in follow-up (Figure 1). The optimal cut-off value with respect to sensitivity and specificity for the 48 successfully treated patients analyzed in this study was 2.55 ng/ml.
CYFRA 21-1 as a prognostic marker for overall and disease-free survival. In total 31 (40.3%) patients died during the follow-up period. In these patients, nodal status ≥2 at the time of diagnosis and CYFRA 21-1 level greater than 3.3 ng/ml after R(C)T were significantly associated with poorer overall survival in the multivariate analysis (p≤0.01) (Figure 2, Table IV). No significant association between the overall survival of the patients and the T- and M-stages, histological grading, age at time of diagnosis, gender, HPV status or CYFRA 21-1 level at diagnosis was found (Table IV).
Receiver operating characteristic curve for cytokeratin fragment 19 (CYFRA 21-1) after treatment. The area under the curve was 0.57 (n=48).
Kaplan–Meier curves for overall survival according to serum cytokeratin fragment 19 (CYFRA 21-1) level after radio(chemo)therapy (p≤0.01).
Multivariate Cox analysis of possibly associated parameters with the overall and disease-free survival.
In total, 40 (51.9%) patients suffered from further tumor manifestation (LRF=29 or tumor recurrence=11) (Figure 3). In these patients, a CYFRA 21-1 level greater than 3.3 ng/ml after R(C)T was significantly associated with poorer disease-free survival in the multivariate analysis (p≤0.01). No significant association between disease-free survival and T-and N-stages, histological grading, age, gender, HPV status or CYFRA 21-1 at diagnosis was found (Table IV).
Kaplan–Meier curves for disease-free survival according to serum cytokeratin fragment 19 (CYFRA 21-1) level after radio(chemo)therapy (p≤0.01).
Discussion
The clinical relevance of CYFRA 21-1 as a marker for diagnosis and tumor recurrence was pointed out by several studies especially for non-small cell carcinoma of the lung (20, 31, 32). However, the clinical impact of CYFRA 21-1 in patients with OSCC is still a matter of controversy. The only two studies that analyzed CYFRA 21-1 as a diagnostic marker in OSCC reported insufficient sensitivity and specificity (33, 34). Nevertheless, the value of CYFRA 21-1 as a diagnostic and prognostic marker has been analyzed in patients with HNSCC by some authors. The results of the former mentioned studies are currently part of a controversial debate about CYFRA 21-1 in the diagnosis and follow-up of HNSCC (22, 23, 35). Use of CYFRA 21-1 has not yet been established in diagnostics of HNSCC and OSCC. Part of the reason for this is that the expression of CYFRA 21-1 ranges from 0.78 ng/ml to 3.35 even in healthy squamous epithelium (36-38). Additionally, it has been observed that malignant epithelium in the lung releases more CYFRA 21-1 than malignant squamous epithelium in the upper aerodigestive tract (39). Hence the expression of CYFRA 21-1 is further influenced by the localization of malignancy in the aerodigestive tract. In this context, Alkotyfan et al. found tumors of the lung expresses higher values of CYFRA 21-1 than tumors in the head and neck. They also noted that the hematocrit and total protein levels might also influence the serum CYFRA 21-1 concentration (34).
In the present study, a cut-off value of 2.55 ng/ml was found to be the most suitable with respect to sensitivity and specificity for tumor recurrence in follow-up. Additionally, it should be mentioned that the cut-off value optimized in this study was determined on the basis of a very small number of patients (n=48) and is therefore only of limited validity. Nevertheless, the cut-off value of 3.3 ng/ml we used for analysis in this study, based on that defined by the test kit, may be too high in the context of HNSCC and OSCC (35, 40). However, 3.3 ng/ml is an established cut-off value with suitable specificity for HNSCC, especially for the newer and more accurate electrochemiluminescence immunoassay method for CYFRA 21-1 measurement we used in the present study (21, 41-43). Furthermore, even with the cut-off value of 3.3 ng/ml, we were able to find highly significant associations between the CYFRA 21-1 level and different analyzed characteristics. In literature, the nodal stage in HNSCC is considered to be the most likely histopathological parameter correlated with CYFRA 21-1 level at diagnosis (23, 24, 28, 39, 44, 45). In a previous study on CYFRA 21-1 for OSCC, we also found a significant correlation between the CYFRA 21-1 level and the nodal stage (33). However, in the present study we did not confirm these findings. One explanation might be that patients with an advanced tumor stage are referred more often to primary R(C)T and by only analyzing these patients, a selection effect might have influenced the results. In this study, an association between the patient’s age and the CYFRA 21-1 level was found. A possible explanation for this might be that the patient with the highest age at the time of initial diagnosis in the entire cohort also had a relatively high CYFRA 21-1 level (11 ng/ml). Furthermore, the expression of CYFRA 21-1 is higher in metabolically more active epithelial cells and in the case of cell death (38). Cell death might be more common in older patients, which might be a reason for the findings in this study.
Treatment failure or the development of a tumor recurrence in the further course of disease are common reasons for poor overall survival in patients with OSCC (27, 44). Serological markers might be useful for detection of these events and thus improve the overall survival of oncological patients. Doweck et al. found no decrease of CYFRA 21-1 level for about 2-4 months after R(C)T and therefore concluded repetitive cell damage and continuous hematogenic spread of tumor cell fragments as an explanation for this (27). To the best of our knowledge, CYFRA 21-1 for patients with HNSCC treated by primary R(C)T has only been analyzed in one study, by Mrochem-Kwarciak et al. However, the authors found promising results and attributed CYFRA 21-1 with diagnostic benefit for the detection of LRF, and prognostic benefit for disease-free and overall survival in patients with HNSCC (28). They found significant correlation between the lack of a decrease of CYFRA 21-1 and the presence of LRF (28). Nevertheless, the role of CYFRA 21-1 for the subgroup of patients with OSCC treated by primary R(C)T has not yet been examined. In this study, we did not confirm the findings of Mrochem-Kwarciak et al. for patients with OSCC. There was even a tendency for an increase of CYFRA 21-1 concentration after successful therapy, which may indicate higher tumor cell damage due to successful radiation treatment. Furthermore CYFRA 21-1 fails to provide a suitable discriminative ability in these patients, with a low sensitivity for LRF of only 31% i.e., a specificity of 75%, after treatment. However, a possible reason for the difference of this study to others might be that only 42.7% of the patients analyzed by Mrochem-Kwarciak et al. suffered from OSCC, while the majority (n=57, 3%) suffered from laryngeal/hypopharyngeal tumors. Furthermore, Mrochem-Kwarciak et al. found a correlation between the N-stage and CYFRA 21-1 level, in contrast to the present study, which suggests a different metastatic pattern. Since it is known that glottic laryngeal carcinoma, in particular, has a less aggressive metastatic behavior (46). The findings of the present study underline the clinical relevance of new methods for imaging and the importance of endoscopy in monitoring. In literature, positron-emission tomography-CT has shown satisfying results for detection of LRF (47).
The role of CYFRA 21-1 for detection of a tumor recurrence in follow-up is controversially discussed. While for HNSCC, Wollenberg et al. revealed a low sensitivity of only 18% and a specificity of 95% for tumor recurrence (29), others found an elevated CYFRA 21-1 level in 70.4% and 78.9% of analyzed patients, respectively (24, 35, 43). However, in one of our last studies, we found a sensitivity and specificity of 23% and 78% for CYFRA 21-1 at the time of diagnosis and 32% and 87% after treatment, respectively, for patients with OSCC (33). Further studies on OSCC by Alkotyfan et al. also revealed a low sensitivity, of 45%, for CYFRA 21-1 (34). Although Alkotyfan et al. ascribed a good discriminative ability to the CYFRA 21-1 level at diagnosis, we were unable to confirm these findings in analyzing the data of a larger group of patients with OSCC in a previous study (33). To the best of our knowledge, the present study is the first to investigate this question in a selected group of patients with OSCC treated by primary R(C)T. A significant association between an elevated CYFRA 21-1 level after R(C)T and the development of tumor recurrence in the follow-up was observed in this study. Nevertheless, CYFRA 21-1 measurement 2 months after R(C)T failed to show a sufficient sensitivity and specificity for the prediction of tumor recurrence. In this context, it must be mentioned that only patients who were tumor-free after R(C)T were analyzed for the development of a tumor recurrence in their further disease course, which may have led to a selection bias. However, in the present study and former trials for OSCC (33, 34), the CYFRA 21-1 levels were significantly higher at the time of tumor recurrence. Thus, a sudden increase of CYFRA 21-1 concentration in regular follow-up may indicate tumor recurrence and thus further diagnostics should be initiated.
For HNSCC, it is well known that patients with a CYFRA 21-1 level above 3.3 ng/ml have a worse overall survival compared to patients with lower CYFRA 21-1 levels (25, 48). In a previous study on CYFRA 21-1 for OSCC, we confirmed these findings (33). However, the results of the present study agree in shorter overall survival only for those with an elevated CYFRA 21-1 level after R(C)T. In multivariate analysis, besides a CYFRA 21-1 level above 3.3 ng/ml after R(C)T, an advanced N-stage at diagnosis was significantly associated with worse overall survival, which is consistent with the fact that N-status is the most important prognostic factor for HNSCC (16). There is also a broad agreement in the literature that an elevated CYFRA 21-1 level is associated with a shorter disease-free survival in patients suffering from HNSCC (22, 23, 25, 48). However, in the present study, a highly significant correlation between CYFRA 21-1 values above 3.3 ng/ml and a worse disease-free survival was found in the multivariate analysis.
Nevertheless, due to the retrospective modelling of the present study, there are some limitations that need to be noted. Some of the patients were lost to follow-up which led to the fact that CYFRA 21-1 was not determined in all patients in the follow-up period. Furthermore, the CYFRA 21-1 concentration was not measured at defined regular intervals during the follow-up.
Conclusion
To our knowledge, this is the largest study evaluating CYFRA 21-1 as a diagnostic and prognostic biomarker in a subgroup of patients with OSCC treated by primary R(C)T. In this study, the CYFRA 21-1 level did not have a diagnostic or therapeutic benefit for the early detection and prediction of residual tumor after R(C)T. However, an elevated serum CYFRA 21-1 level after R(C)T may be associated with worse overall and disease-free survival although they are having insufficient predictive value for the development of tumor recurrence during follow-up. A sudden increase of CYFRA 21-1 during follow-up may be attributed to a tumor recurrence and should motivate clinicians to undertake further investigations. Large-scale prospective trials are needed to confirm our findings.
Footnotes
Authors’ Contributions
Stefan A. Rudhart: Conceptualization, methodology, writing – original draft preparation, writing – review and editing. Philipp Langen: Investigation, Data acquisition. Francesca Gehrt: Investigation, data acquisition. Kruthika Thanagvelu: Software, formal analysis, statistical analysis. Petar Stankovic: Writing – review and editing. Thomas Wilhelm: Writing – review and editing. Boris A. Stuck: Writing – review and editing, critical revision, final approval and supervision. Stephan Hoch: Conceptualization, supervision, methodology, writing – original draft preparation, writing – review and editing.
Conflicts of Interest
The Authors declare that they have no conflicts of interest.
- Received October 1, 2021.
- Revision received October 22, 2021.
- Accepted October 27, 2021.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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