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Comorbidity Assessment in Patients With Oral Squamous Cell Carcinoma: Can Imaging Techniques (Fludeoxyglucose Positron-Emission Tomographic Computed Tomography and Contrast-Enhanced Computed tomography) Provide Additional Information?

      Purpose

      This study evaluated the role of imaging staging examinations (positron-emission tomographic computed tomography [PET/CT] and contrast-enhanced computed tomography [ceCT]) for the assessment of the comorbidity status of patients with oral squamous cell carcinoma (OSCC). A binary null hypothesis was drafted: 1) imaging staging examinations do not augment knowledge about the comorbidity status of patients with OSCC and 2) there is no difference between PET/CT and ceCT in this regard.

      Materials and Methods

      A retrospective cohort study design was selected to address the research question. Patients with histologically confirmed OSCC who underwent whole-body staging by PET/CT or ceCT from 2012 through 2015 were considered for inclusion according to predefined criteria. Data collection was performed by the review of patient charts and histology, radiology, and nuclear medicine reports. The Charlson Comorbidity Index (CCI) was chosen to quantify comorbidity and was calculated before and after staging and then compared. The type of imaging staging examination (PET/CT or ceCT) served as the predictor variable and the CCI was determined as the primary outcome variable. Descriptive and inferential statistics were computed for the variable scale. The significance level was set at a P value less than or equal to .05.

      Results

      The sample was composed of 178 patients (71 women, 107 men; average age, 64.2 yr) of whom 109 (61%) underwent PET/CT and 69 (39%) underwent ceCT staging. The pre- and post-staging CCI notably differed. Neither imaging technique showed superior results.

      Conclusion

      Relevant and otherwise covert comorbidities can be found by the performance of imaging staging examinations. This enables clinicians to better assess the peri-therapeutic risk and prognosis of patients with OSCC. Therefore, a detailed evaluation of incidental findings on imaging studies is warranted and recommended.
      Long-term exposure to risk factors, such as smoking and alcohol consumption, can predispose oral tissues to oral squamous cell carcinoma (OSCC).
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      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      The detrimental effects of such exposure do not only manifest within the oral cavity by mucosal alterations or carcinogenesis. Virtually all other organ systems develop serious harm from tobacco extracts, nitrosamines, and alcohol depending on duration and dosage, with special vulnerability of the entire upper aerodigestive tract, the vascular and immune systems, and the genitourinary and hepatobiliary tracts.
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      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
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      Patients with OSCC usually exhibit a large burden of comorbidity with a high prevalence of vascular and lung disease.
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      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
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      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      There is evidence that comorbidity has a negative impact on the survival of patients with cancer.
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      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
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      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
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      Synchronous cancers and distant metastatic spread of the primary malignancy can change the therapeutic schedule or the protocol from curative to palliative.
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      Because the initiation of oncologic treatment after primary cancer diagnosis bears no delay, little time remains for the scrutiny of a comorbidity. In many cases, exploration of the patients' medical history confirming pathologies that have already been diagnosed and simple routine examination procedures, such as electrocardiography, laboratory work, or chest radiography, remain the only potentially incomplete source of information about the level of comorbidity.
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      More detailed investigations to disclose comorbidity might be too costly and time consuming.
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      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      Thus, comprehensive and fast whole-body screening examinations to detect a hidden comorbidity are warranted.
      Clinical and imaging staging examinations are among the first steps of every oncologic treatment plan.
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      Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part 2: Remote extension assessment and exploration for secondary synchronous locations outside of the upper aerodigestive tract. 2012 SFORL guidelines.
      Currently, contrast-enhanced computed tomography (ceCT) and fluorodeoxyglucose positron-emission tomographic computed tomography (18FDG-PET/CT) are commonly used for primary staging in patients with OSCC.
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      When using whole-body scans, ceCT and 18FDG-PET/CT frequently visualize incidental findings.
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      Incidental PET/CT findings in the cancer patient: How should they be managed?.
      The clinical implications of incidental findings on imaging studies have been suggested in previous studies and proved to be of relevance for the comorbidity assessment of patients with various cancers.
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      Literature searches failed to find studies that have explored the application of staging imaging studies, such as ceCT and 18FDG-PET/CT, for the analysis of the comorbidity level of patients with OSCC.
      The purpose of this study was to clarify the following 2-fold research question: can imaging staging examinations, namely 18FDG-PET/CT or ceCT, provide additional, previously covert information about the comorbidity status and presence of synchronous malignancies in patients with OSCC and, if so, is there a difference between 18FDG-PET/CT and ceCT? It was hypothesized that no such benefit of imaging staging examinations exists and that the performance of 18FDG-PET/CT and ceCT in this clinical setting would be similar. The specific aims of the study were to 1) identify an appropriate patient cohort, 2) gather demographic, general medical, and disease-specific data, 3) evaluate the results of diagnostic imaging studies for staging with respect to comorbidity, 4) evaluate the benefit of diagnostic imaging studies for the determination of comorbidity and the detection of distant metastases and synchronous cancers of patients with OSCC, and 5) compare the performance of 18FDG-PET/CT and ceCT in this respect.

      Materials and Methods

       Study Design and Sample Selection

      A retrospective cohort study was designed and implemented to address the research question. All patients who presented to the Department of Oral and Maxillofacial Surgery of the Ludwig Maximilians University of Munich (Munich, German) from January 2012 through December 2015 for primary staging of OSCC and who fulfilled the inclusion criteria were enrolled in the study. The following inclusion criteria were defined: 1) patients older than 18 years, 2) presentation with histologically confirmed OSCC within the predefined boundaries,
      • Tapia J.L.
      • Goldberg L.J.
      The challenges of defining oral cancer: Analysis of an ontological approach.
      3) primary manifestation of OSCC, 4) the presence of a whole-body 18FDG-PET/CT or ceCT as the staging examination, and 5) adherence to follow-up examinations for at least 6 months. Patients with 1) recurrent OSCC, 2) allergies to contrast agents or intolerance to tracers, and 3) a history of systemic chemotherapy or radiation therapy to the head and neck region were excluded. The study protocol and preparation followed approved quality requirements.
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies.
      • Dodson T.B.
      A guide for preparing a patient-oriented research manuscript.
      The study was conducted in concordance with ethical guidelines and received internal review board approval (ethics committee of the Ludwig Maximilians University of Munich, number 323-15).

       Data Collection

      At presentation, the medical record of each patient was explored by questioning and review of previous treatment reports. Furthermore, basic laboratory workups and basic clinical examination procedures (chest, heart, and abdominal auscultation) were performed. The detected comorbidities were noted and the comorbidity level was assessed as suggested by the Charlson Comorbidity Index (CCI).
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation.
      The CCI was chosen because it has been validated for OSCC and its prognostic relevance has been established in previous studies.
      • Habbous S.
      • Harland L.T.
      • La Delfa A.
      • et al.
      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      • Paleri V.
      • Wight R.G.
      • Silver C.E.
      • et al.
      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      • Habbous S.
      • Chu K.P.
      • Harland L.T.
      • et al.
      Validation of a one-page patient-reported Charlson comorbidity index questionnaire for upper aerodigestive tract cancer patients.
      The CCI records 19 items, including cardiovascular disease (myocardial infarction, congestive heart failure, and arterial occlusive disease), renal disease, liver disease, endocrine pathology, secondary cancer, and immunologic pathologies and attributes a score from 1 to 6 depending on the comorbidity (eg, congestive heart failure = 1, distant metastasis = 6).
      • Paleri V.
      • Wight R.G.
      • Silver C.E.
      • et al.
      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation.
      The maximum CCI score is 37. However, a CCI score higher than 2 is associated with decreased survival in patients with OSCC.
      • Habbous S.
      • Harland L.T.
      • La Delfa A.
      • et al.
      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      • Reid B.C.
      • Alberg A.J.
      • Klassen A.C.
      • et al.
      Comorbidity and survival of elderly head and neck carcinoma patients.
      • Habbous S.
      • Chu K.P.
      • Harland L.T.
      • et al.
      Validation of a one-page patient-reported Charlson comorbidity index questionnaire for upper aerodigestive tract cancer patients.
      After primary comorbidity investigation and CCI scoring, the patients underwent 18FDG-PET/CT or ceCT as the oncologic staging examination. The following protocols were applied for image acquisition.

       18FDG-PET/CT Image Acquisition Protocol

      The PET/CT image generation algorithm followed previously validated and published standards.
      • Schramm N.
      • Rominger A.
      • Schmidt C.
      • et al.
      Detection of underlying malignancy in patients with paraneoplastic neurological syndromes: Comparison of 18F-FDG PET/CT and contrast-enhanced CT.
      A 64-detector row PET/CT machine (scanner 1: Siemens Biograph 64, Siemens Healthcare, Erlangen, Germany; scanner 2: Discovery 690, GE Healthcare, Garching, Germany) was used to obtain the PET/CT studies that were acquired 1 hour after the infusion of 18F-fluoro-2-deoxy-D-glucose equivalent to 250 MBq. Furthermore, the intravenous drug protocol during imaging included butyl scopolamine 20 mg for the decrease of smooth muscle FDG enhancement and a loop diuretic (furosemide 20 mg) to secure tracer elimination. PET/CT was performed only when patients had refrained from food and liquid intake for a minimum of 6 hours to prevent false-positive results as a consequence of increased blood sugar levels (>150 mg/dL).
      A whole-body ceCT scan (100 to 190 mAs, 120 kV, 2.5-mm collimation, 1.5 pitch, Iomeprol 350 mg/mL [Bracco SpA, Milan, Italy], body weight–adapted administration, 1.5 mL/kg body weight, 2.5-mL/second infusion speed) was obtained 80 seconds before the PET scan (6 bed positions, 11-cm field of view, 144 × 144 matrix, 3-dimensional mode, 2.5 minutes per bed position), the data of which were used to correct for attenuation. All obtained images (ceCT, PET with and without attenuation correction, and PET/CT) were analyzed in all available planes.

       CT Image Acquisition Protocol

      All whole-body CT examinations were performed on clinical 64-row multidetector CT scanners (2009 to 2012, Brilliance 64CT, Philips Healthcare, Hamburg, Germany; from 2013, Optima 660, GE Healthcare) with the patient supine. Technical parameter settings included a tube charge of 120 kVp, collimation of 64 × 0.5 mm (effective primary reconstruction slice thickness, 0.625 mm), rotation time of 0.5 to 0.7 second, tube current with automatic exposure control as recommended by the manufacturer, filtered back-projection without (until 2012) or with (from 2013) 40% iterative image reconstruction, soft tissue and lung reconstruction algorithms, and reformatted slice thicknesses of 2.5 to 5.0 mm for soft tissue structures and 2.5 to 3.0 mm for lung structures in axial image reconstructions. Invariably, coronal and sagittal images were reconstructed with a slice thickness of 3.0 mm. Unless contraindicated, intravenous contrast medium with iodine 350 mg/mL was applied at a flow rate of 3 mL/second, followed by normal saline solution 40 mL at 3 mL/second. Contrast medium volume was weight-adapted for CT of the chest and abdomen from 70 to 90 mL for the first bolus and fixed at 40 mL for the head and neck for the second bolus. CT scans of the chest and abdomen were obtained with the patient's arms rested overhead and delay times from the start of contrast medium injection of 33 seconds for the chest and 75 seconds for the abdomen. Subsequently, CT scans of the head and neck were performed with the patient's arms rested along the chest and a delay time of 55 seconds. Routinely, 3% mannitol solution 1 L was administered over 1 hour as oral contrast medium; rectal contrast medium was not routinely given. After reconstruction, CT images were transferred to the institutional picture archiving and communication system (Syngo version W7 and earlier; Siemens Medical Solutions, Erlangen, Germany) for evaluation, documentation, and archiving.

       Assessment of Incidental Findings and CCI Review After Oncologic Staging Examination

      All images were reviewed by at least 2 board-certified radiologists and nuclear medicine physicians. Incidental findings were recorded and evaluated for clinical relevance. Figures 1 and 2 display examples of incidental findings on examined imaging studies. In cases of uncertainty, patients were referred to the appropriate clinical departments for clarification of the imaging findings. 18FDG-PET/CT and ceCT have been validated for the detection and diagnosis of vascular, cardial, pulmonary, abdominal, rectoabdominal diseases and secondary malignancies with various sensitivities and specificities.
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      • et al.
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      • Levine M.S.
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      • et al.
      Benign and malignant lesions of the stomach: Evaluation of CT criteria for differentiation.
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      • Williams H.T.
      • Aldridge B.A.
      • et al.
      Incidental PET/CT findings in the cancer patient: How should they be managed?.
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      • Ghesani N.V.
      • Zuckier L.S.
      Physiology and pathophysiology of incidental findings detected on FDG-PET scintigraphy.
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      • et al.
      18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease.
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      • et al.
      Comparison of whole-body PET/CT, dedicated high-resolution head and neck PET/CT, and contrast-enhanced CT in preoperative staging of clinically M0 squamous cell carcinoma of the head and neck.
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      • et al.
      Role of chest CT scanning in the management of patients presenting with head and neck cancer.
      Previously unknown comorbidities discovered on the imaging studies were added to each patient chart and the CCI score was recalculated with respect to the new findings.
      Figure thumbnail gr1
      Figure 1Axial contrast-enhanced computed tomogram showing perihepatic ascites, liver cirrhosis, and an intrahepatic tumorous process as incidental findings in a patient with oral squamous cell carcinoma.
      Figure thumbnail gr2
      Figure 2Axial fludeoxyglucose positron-emission tomographic computed tomogram showing a lesion in the transverse colon suspicious for malignancy as an incidental finding in a patient with oral squamous cell carcinoma that was histologically confirmed as adenocarcinoma of the colon.

       Study Variables

      The following variables were gathered from patients' charts, previous treatment documentation, clinical examination, and radiology, nuclear medicine, and pathology reports: demographic data (age, gender), exposure to risk factors (smoking, tobacco), type of imaging staging examination (18FDG-PET/CT or ceCT), tumor and nodal status as suggested by the American Joint Committee on Cancer,
      • Paleri V.
      • Mehanna H.
      • Wight R.G.
      TNM Classification of Malignant Tumours 7th Edition: What’s new for head and neck?.
      presence and location of distant metastasis, synchronous cancer as defined by de Mones et al,
      • de Mones E.
      • Bertolus C.
      • Salaun P.Y.
      • et al.
      Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part 2: Remote extension assessment and exploration for secondary synchronous locations outside of the upper aerodigestive tract. 2012 SFORL guidelines.
      and the CCI score before and after the imaging staging examination.
      All variables were coded on appropriate scales. The following variables were coded on a dichotomous scale: gender, type of imaging staging examination, presence or absence of distant metastasis, and synchronous cancers. An ordinal scale was chosen for tumor and nodal status and the CCI score and the variable age was coded on an interval scale.
      Type of imaging staging examination (18FDG-PET/CT or ceCT) was determined as the predictor variable and CCI score after the imaging staging examination served as the primary outcome variable. All other variables were considered secondary outcome variables.

       Statistical Analysis

      All data were tabulated and statistically analyzed using SPSS 23.0 for Windows (IBM Corp, Armonk, NY). Descriptive and inferential statistics were computed. The following statistical tests were applied for the variable scale: χ2 test, Mann-Whitney U test, Kruskal-Wallis test, and t test. Correlation coefficients were calculated where appropriate. The significance level was set at a P value less than or equal to .05.

      Results

      In total, 178 patients (71 women, 107 men) with an average age of 64.2 ± 7.6 years were included in the study. Most patients (136 of 178; 76%) presented with OSCC of limited stages and a CCI score of at least 1. The most commonly confirmed comorbidities before the imaging studies were cardiovascular diseases (congestive heart failure, peripheral artery disease, and hypertension). In 109 patients, staging was achieved by 18FDG-PET/CT and 69 patients underwent ceCT. Many previously unknown comorbidities were found on the imaging studies, which led to a considerable increase of the average CCI score. Lung emphysema, abdominal pathologic processes, vascular disease, and synchronous cancers were the most frequently and newly detected comorbidities by imaging. Distant metastases and synchronous cancers were found in approximately 10% of patients at primary presentation, 3 of whom had a distant metastatic spread and a secondary cancer. The predilection sites of synchronous cancers were the oropharynx, hypopharynx, and larynx (n = 5), the lung (n = 4), the esophagus (n = 3), and the bowels (n = 4). Further synchronous cancers presented in the gynecologic, endocrinologic, and lymphatic organs. Further details are presented in Table 1.
      Table 1Tabulation of Descriptive Statistical Parameters of Entire Study Sample
      Variable
      Sample size, N178
       Women, n (%)71 (39)
       Men, n (%)107 (61)
      Age (yr), average ± SD64.2 ± 7.6
      Risk factor exposure (alcohol ± smoking), n (%)148 (83)
      pT status, n (%)
       pT163 (35)
       pT244 (26)
       pT328 (15)
       pT443 (24)
      pN status, n (%)
       pN061 (34)
       pN156 (32)
       pN246 (26)
       pN315 (8)
      Distant metastasis, n (%)19 (10.6)
       Lung11
       Mediastinal lymph nodes4
       Liver2
       Bone1
       Adrenal gland1
      Synchronous malignancies, n (%)24 (13.4)
      Staging examination, n (%)
      18FDG-PET/CT109 (61)
       Contrast-enhanced CT69 (39)
      Charlson comorbidity index before staging examination, average (range)1.05 (0-12)
      Charlson comorbidity index after staging examination, average (range)1.85 (0-12)
      Abbreviations: 18FDG-PET/CT, fludeoxyglucose positron-emission tomographic computed tomography; CT, computed tomography; SD, standard deviation.
      The comparison of patients in the ceCT and PET/CT groups did not show any relevant differences for age, gender, tumor and nodal status, risk factor exposure, and CCI score before staging. The 2 staging modalities (ceCT and PET/CT) added important information about the comorbidity status of patients and the CCI score after staging was notably higher. Neither staging modality showed superior performance for comorbidity, distant metastasis, and synchronous cancer detection (Table 2).
      Table 2Tabulation of Outcome Variables With Respect to the Predictor Variable, Type of Staging Examination
      Variable18FDG-PET/CTceCTP Value
      Total number10969N/A
      Gender, n (%).632
      By χ2 test.
       Women45 (41)26 (38)
       Men64 (59)43 (62)
      Age (yr), average ± SD64.3 ± 7.964.1 ± 7.9.171
      By t test.
      pT status, n (%).068
      By χ2 test.
       pT146 (42)17 (25)
       pT223 (21)21 (30)
       pT318 (17)10 (15)
       pT421 (20)21 (30)
      pN status, n (%).005
      By χ2 test.
       pN033 (30)28 (40)
       pN145 (41)11 (16)
       pN222 (20)24 (35)
       pN39 (9)6 (9)
      Distant metastasis, n (%)15 (14)4 (6).094
      By χ2 test.
      Synchronous malignancies, n (%)12 (11)12 (17).225
      By χ2 test.
      CCI score before staging examination, average (range)1.01 (0-7)1.12 (0-12).691
      By Mann-Whitney U test.
      CCI score after staging examination, average (range)1.71 (0-9)2.09 (0-12).444
      By Mann-Whitney U test.
      Note: Percentages apply to totals in columns.
      Abbreviations: 18FDG-PET/CT, fludeoxyglucose positron-emission tomographic computed tomography; CCI, Charlson Comorbidity Index; ceCT, contrast-enhanced computed tomography; N/A, not applicable; SD, standard deviation.
      By χ2 test.
      By t test.
      By Mann-Whitney U test.
      The burden of comorbidity as indicated by the pre- and post-staging CCI scores was not notably associated with any of the other study variables (Table 3). The occurrence of synchronous cancer was not related to increased CCI scores in general or in particular when the pre- and post-staging CCI scores were considered. A higher pN status was significantly correlated with the diagnosis of distant metastases in patients with OSCC (P = .037 by χ2 test).
      Table 3Tabulation of Secondary Outcome Variables With Respect to the Primary Outcome Variable, Charlson Comorbidity Index
      VariableBefore Staging ExaminationAfter Staging Examination
      CCI Score, Average (Range)P ValueCCI Score, Average (Range)P Value
      Gender.403
      By Mann-Whitney U test.
      .445
      By Mann-Whitney U test.
       Women0.79 (0-5)1.62 (0-5)
       Men1.22 (0-12)2.01 (0-12)
      Average age (yr)−0.092
      Pearson correlation coefficient.
      NS−0.003
      Pearson correlation coefficient.
      NS
      pT status.355
      By Kruskal-Wallis test.
      .364
      By Kruskal-Wallis test.
       pT10.92 (0-7)1.67 (0-7)
       pT21.23 (0-12)1.8 (0-12)
       pT30.68 (0-7)1.82 (0-9)
       pT41.3 (0-7)2.21 (0-7)
      pN status.489
      By Kruskal-Wallis test.
      .489
      By Kruskal-Wallis test.
       pN00.84 (0-6)1.85 (0-6)
       pN10.95 (0-7)1.57 (0-7)
       pN21.28 (0-12)2.22 (0-12)
       pN31.60 (0-7)1.60 (0-7)
      Distant metastasis.691
      By Mann-Whitney U test.
      .454
      By Mann-Whitney U test.
       M01.01 (0-12)1.80 (0-12)
       M+1.37 (0-7)2.32 (0-7)
      Synchronous malignancies.609
      By Kruskal-Wallis test.
      .680
      By Kruskal-Wallis test.
       No1.01 (0-7)1.78 (0-7)
       Yes1.33 (0-12)2.33 (0-12)
      Abbreviations: CCI, Charlson Comorbidity Index; NS, not significant.
      By Mann-Whitney U test.
      Pearson correlation coefficient.
      By Kruskal-Wallis test.

      Discussion

      The purpose of this study was to evaluate the benefit of imaging staging examinations for comorbidity assessment of patients with OSCC. The specific aim was to analyze possible differences between 18FDG-PET/CT and ceCT in this respect. A binary null hypothesis was formulated: 1) imaging staging examinations do not increase knowledge about the comorbidity status of patients with OSCC and 2) the information gained from 18FDG-PET/CT and ceCT in this regard would be similar. Further objectives of this work were to select an appropriate patient cohort, to gather suitable data from patient charts and radiology and pathology reports, to determine the comorbidity status and presence of distant metastases and synchronous cancers of the patient cohort before the performance of oncologic staging with an applicable tool, and to measure the importance of incidental imaging findings for the accuracy of comorbidity estimation.
      The results of the study support the alternative hypothesis that imaging staging examinations contribute to and enhance the comorbidity analysis of patients with OSCC. The incidental findings on the imaging studies were of such relevance that they warranted a marked upstaging of the CCI score. The comorbidity, distant metastasis, and synchronous cancer detection rates of 18FDG-PET/CT and ceCT were equal.
      The implications of comorbidity on the therapeutic success, complication rate, and prognosis of patients with head and neck squamous cell carcinoma (HNSCC) have been discussed.
      • Habbous S.
      • Harland L.T.
      • La Delfa A.
      • et al.
      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      • Yung K.C.
      • Piccirillo J.F.
      The incidence and impact of comorbidity diagnosed after the onset of head and neck cancer.
      • Singh B.
      • Bhaya M.
      • Zimbler M.
      • et al.
      Impact of comorbidity on outcome of young patients with head and neck squamous cell carcinoma.
      • Reid B.C.
      • Alberg A.J.
      • Klassen A.C.
      • et al.
      Comorbidity and survival of elderly head and neck carcinoma patients.
      • Jones A.S.
      • Morar P.
      • Phillips D.E.
      • et al.
      Second primary tumors in patients with head and neck squamous cell carcinoma.
      • Wutzl A.
      • Ploder O.
      • Kermer C.
      • et al.
      Mortality and causes of death after multimodality treatment for advanced oral and oropharyngeal cancer.
      The patient cohort in this study presented with a CCI score of at least 1 even before meticulous examination procedures were initiated, which is considered a relevant burden.
      • Habbous S.
      • Harland L.T.
      • La Delfa A.
      • et al.
      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      • Sanabria A.
      • Carvalho A.L.
      • Vartanian J.G.
      • et al.
      Comorbidity is a prognostic factor in elderly patients with head and neck cancer.
      Most patients with HNSCC have comorbidity in at least 1 other organ system.
      • Paleri V.
      • Wight R.G.
      • Silver C.E.
      • et al.
      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      Therefore, distinct knowledge about pathologic processes not related to the primary cancer site is inevitable.
      • de Mones E.
      • Vergez S.
      • Barry B.
      • et al.
      Initial staging for squamous cell carcinoma of the mouth, larynx and pharynx (except nasopharynx). Part 3: General assessment. 2012 SFORL recommendations.
      • Jones A.S.
      • Morar P.
      • Phillips D.E.
      • et al.
      Second primary tumors in patients with head and neck squamous cell carcinoma.
      Because the detailed examination of each organ system can be tedious and potentially insufficient, the value of the systematic evaluation of incidental findings on imaging studies has been recognized,
      • Liu Y.
      • Ghesani N.V.
      • Zuckier L.S.
      Physiology and pathophysiology of incidental findings detected on FDG-PET scintigraphy.
      • Rominger A.
      • Saam T.
      • Wolpers S.
      • et al.
      18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      the benefit of which has been proved for treatment planning in various malignancies.
      • Beatty J.S.
      • Williams H.T.
      • Aldridge B.A.
      • et al.
      Incidental PET/CT findings in the cancer patient: How should they be managed?.
      • Adams H.L.
      • Jaunoo S.S.
      Clinical significance of incidental findings on staging positron emission tomography for oesophagogastric malignancies.
      • Ichikawa T.
      • Saito K.
      • Yoshioka N.
      • et al.
      Detection and characterization of focal liver lesions: A Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.
      The imaging staging examinations in this study showed an abundance of previously covert comorbidities. In consequence, the post-staging (“real”) CCI score was considerably higher, which is of clinical and prognostic importance.
      • Paleri V.
      • Wight R.G.
      • Silver C.E.
      • et al.
      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      To the best of the authors' knowledge, this study is the first to investigate the role of 18FDG-PET/CT and ceCT for the comorbidity analysis of patients with OSCC.
      However, the efficacy of 18FDG-PET/CT and ceCT in the detection of distant metastases and synchronous cancers has been examined previously.
      • Sarrion Perez M.G.
      • Bagan J.V.
      • Jimenez Y.
      • et al.
      Utility of imaging techniques in the diagnosis of oral cancer.
      • Adams H.L.
      • Jaunoo S.S.
      Clinical significance of incidental findings on staging positron emission tomography for oesophagogastric malignancies.
      • Rodrigues R.S.
      • Bozza F.A.
      • Christian P.E.
      • et al.
      Comparison of whole-body PET/CT, dedicated high-resolution head and neck PET/CT, and contrast-enhanced CT in preoperative staging of clinically M0 squamous cell carcinoma of the head and neck.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      • Ong T.K.
      • Kerawala C.J.
      • Martin I.C.
      • et al.
      The role of thorax imaging in staging head and neck squamous cell carcinoma.
      • Kim S.A.
      • Roh J.L.
      • Kim J.S.
      • et al.
      18F-FDG PET/CT surveillance for the detection of recurrence in patients with head and neck cancer.
      • Suenaga Y.
      • Kitajima K.
      • Ishihara T.
      • et al.
      FDG-PET/contrast-enhanced CT as a post-treatment tool in head and neck squamous cell carcinoma: comparison with FDG-PET/non-contrast-enhanced CT and contrast-enhanced CT.
      • Lee J.R.
      • Choi Y.J.
      • Roh J.L.
      • et al.
      Preoperative contrast-enhanced CT versus (1)(8)F-FDG PET/CT evaluation and the prognostic value of extranodal extension for surgical patients with head and neck squamous cell carcinoma.
      • Blatt S.
      • Ziebart T.
      • Kruger M.
      • et al.
      Diagnosing oral squamous cell carcinoma: How much imaging do we really need? A review of the current literature.
      Most studies have concluded that 18FDG-PET/CT is superior to other imaging techniques for metastasis and synchronous cancer detection.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      • Suenaga Y.
      • Kitajima K.
      • Ishihara T.
      • et al.
      FDG-PET/contrast-enhanced CT as a post-treatment tool in head and neck squamous cell carcinoma: comparison with FDG-PET/non-contrast-enhanced CT and contrast-enhanced CT.
      • Gourin C.G.
      • Watts T.L.
      • Williams H.T.
      • et al.
      Identification of distant metastases with positron-emission tomography-computed tomography in patients with previously untreated head and neck cancer.
      In contrast, no differences between 18FDG-PET/CT and ceCT for distant metastasis and synchronous cancer identification were shown in this study.
      In accordance with the literature,
      • Houghton D.J.
      • Hughes M.L.
      • Garvey C.
      • et al.
      Role of chest CT scanning in the management of patients presenting with head and neck cancer.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      • Suenaga Y.
      • Kitajima K.
      • Ishihara T.
      • et al.
      FDG-PET/contrast-enhanced CT as a post-treatment tool in head and neck squamous cell carcinoma: comparison with FDG-PET/non-contrast-enhanced CT and contrast-enhanced CT.
      • Spector J.G.
      • Sessions D.G.
      • Haughey B.H.
      • et al.
      Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx.
      the predilection site of distant metastasis of OSCC in the examined patient cohort was the lung and the most synchronous cancers appeared in the aerodigestive tract, esophagus, and colon. As previously described, metastatic lesions and synchronous cancers are present in approximately 10 to 15% of patients with HNSCC.
      • de Mones E.
      • Bertolus C.
      • Salaun P.Y.
      • et al.
      Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part 2: Remote extension assessment and exploration for secondary synchronous locations outside of the upper aerodigestive tract. 2012 SFORL guidelines.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      • Ong T.K.
      • Kerawala C.J.
      • Martin I.C.
      • et al.
      The role of thorax imaging in staging head and neck squamous cell carcinoma.
      • Spector J.G.
      • Sessions D.G.
      • Haughey B.H.
      • et al.
      Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx.
      This confirms the external validity of the present findings.
      The following drawbacks of the study have to be discussed. The retrospective design of the study bears a considerable risk of bias.
      • Hess D.R.
      Retrospective studies and chart reviews.
      Thus, the results of this study might provide only initial hints for the potential application of imaging staging examinations in comorbidity analysis of patients with OSCC that have to be validated in future studies.
      The CCI was chosen as the appropriate tool for comorbidity quantification in this study because it has been validated for its applicability and prognostic relevance in patients with head and neck cancer.
      • Habbous S.
      • Harland L.T.
      • La Delfa A.
      • et al.
      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      • Paleri V.
      • Wight R.G.
      • Silver C.E.
      • et al.
      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      • Ma C.Y.
      • Ji T.
      • Ow A.
      • et al.
      Surgical site infection in elderly oral cancer patients: Is the evaluation of comorbid conditions helpful in the identification of high-risk ones?.
      • Sanabria A.
      • Carvalho A.L.
      • Vartanian J.G.
      • et al.
      Comorbidity is a prognostic factor in elderly patients with head and neck cancer.
      • Habbous S.
      • Chu K.P.
      • Harland L.T.
      • et al.
      Validation of a one-page patient-reported Charlson comorbidity index questionnaire for upper aerodigestive tract cancer patients.
      The clinical information for CCI determination is usually gathered from patient questioning and the scrutiny of patient charts, which has been confirmed to provide sufficient data.
      • Habbous S.
      • Harland L.T.
      • La Delfa A.
      • et al.
      Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.
      • Datema F.R.
      • Ferrier M.B.
      • van der Schroeff M.P.
      • et al.
      Impact of comorbidity on short-term mortality and overall survival of head and neck cancer patients.
      • Sanabria A.
      • Carvalho A.L.
      • Vartanian J.G.
      • et al.
      Comorbidity is a prognostic factor in elderly patients with head and neck cancer.
      Recalculation of the CCI score with additional clinical information gained from imaging studies is unprecedented. It could be argued that all comorbidities are not indicated by the CCI score and imaging studies cannot provide satisfactory information to evaluate all CCI categories. However, none of the comorbidity indices suggested in the literature can capture all relevant pathologies
      • Paleri V.
      • Wight R.G.
      • Silver C.E.
      • et al.
      Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice.
      and it must be stressed that the imaging findings might only enhance, but not replace, basic clinical, laboratory, and imaging techniques. Comorbidity assessment can be accurate and comprehensive only if all sources of information are used. Nevertheless, whole-body imaging examination modalities such as 18FDG-PET/CT and ceCT are useful, fast, and cost-effective screening tools that provide important comorbidity information.
      In this study, patients with OSCC underwent 18FDG-PET/CT or ceCT for primary staging. Because these imaging modalities rely on different principles, a direct comparison of these techniques in different patient cohorts might not be entirely reliable. Other studies have performed comparative studies between 18FDG-PET/CT and ceCT by subjecting patients to the 2 techniques consecutively or by evaluating the ceCT and PET components of 18FDG-PET/CT individually.
      • Rodrigues R.S.
      • Bozza F.A.
      • Christian P.E.
      • et al.
      Comparison of whole-body PET/CT, dedicated high-resolution head and neck PET/CT, and contrast-enhanced CT in preoperative staging of clinically M0 squamous cell carcinoma of the head and neck.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      However, these algorithms have disadvantages. Although the consecutive application of ceCT and 18FDG-PET/CT is ethically questionable because of patients' increased radiation, the ceCT phase of 18FDG-PET/CT might not display the same accuracy as ceCT alone.
      • Corrigan A.J.
      • Schleyer P.J.
      • Cook G.J.
      Pitfalls and artifacts in the use of PET/CT in oncology imaging.
      Because rates of distant metastasis and synchronous cancer detection in this study in the 2 groups (18FDG-PET/CT and ceCT) resembled those mentioned in the literature,
      • de Mones E.
      • Bertolus C.
      • Salaun P.Y.
      • et al.
      Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part 2: Remote extension assessment and exploration for secondary synchronous locations outside of the upper aerodigestive tract. 2012 SFORL guidelines.
      • Krabbe C.A.
      • Pruim J.
      • van der Laan B.F.
      • et al.
      FDG-PET and detection of distant metastases and simultaneous tumors in head and neck squamous cell carcinoma: A comparison with chest radiography and chest CT.
      • Strobel K.
      • Haerle S.K.
      • Stoeckli S.J.
      • et al.
      Head and neck squamous cell carcinoma (HNSCC)—Detection of synchronous primaries with (18)F-FDG-PET/CT.
      • Ong T.K.
      • Kerawala C.J.
      • Martin I.C.
      • et al.
      The role of thorax imaging in staging head and neck squamous cell carcinoma.
      • Spector J.G.
      • Sessions D.G.
      • Haughey B.H.
      • et al.
      Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx.
      sufficient validity of the gathered results can be inferred.
      Within the limitations of this study, it can be concluded that imaging staging examinations facilitate, accelerate, and improve the pre-therapeutic diagnostic process in patients with OSCC, which enables clinicians to assess these patients more accurately and provide tailored and individual treatment plans. The performance of ceCT as the imaging modality of choice for primary OSCC staging seems to deliver acceptable accuracy not only for the extent of the primary tumor (local, locoregional, and metastasis), but also for the existence of synchronous cancers and relevant comorbidity.

      Press Release

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