Age‐adjusted comorbidity and survival in locally advanced laryngeal cancer

The purpose of this study was to quantify the relationship among age, pretreatment comorbidity, and survival outcomes in patients with locally advanced laryngeal cancer.

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title: Competing Causes of Death and Second Primary Tumors in Patients with Locoregionally Advanced Head and Neck Cancer Treated with Chemoradiotherapy
abstract: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy.  We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis.  Median follow-up of surviving patients was 5.2 years (2–10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2)  Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.

title: The impact of comorbidity on the survival of patients with squamous cell carcinoma of the head and neck
abstract: In North America, cigarette smoking and/or alcohol consumption not only cause head and neck cancer, they also cause many of the other diseases, illnesses, and conditions, also known as comorbidities, frequently found in our patients. Comorbidities can influence treatment decision making and treatment outcome. The aim of this study is to quantify the increased risk of comorbidity in our patients.

title: Predictors of competing mortality in advanced head and neck cancer.
abstract: Death from noncancer causes (competing mortality) is an important event in head and neck cancer, but studies identifying predictors of this event are lacking. We sought to identify predictors of competing mortality and develop a risk stratification model for competing events.  Patients were treated on consecutive prospective clinical trials involving organ-preserving chemoradiotherapy and surgery. We used multivariable competing risks regression models to analyze factors associated with the cumulative incidence of competing mortality, locoregional and distant failure, and second malignancies as first events.  Median follow-up was 52 months median for survivors. The 5-year cumulative incidence of competing mortality was 19.6% (95% CI, 15.8 to 23.4). On multivariable analysis, competing mortality was associated with female sex (hazard ratio [HR], 1.72; 95% CI, 1.13 to 2.63), increasing age (HR, 1.30; 95% CI, 1.04 to 1.62), increasing Charlson Comorbidity Index (HR, 1.24; 95% CI, 1.05 to 1.47), decreasing body mass index (HR, 0.33; 95% CI, 0.13 to 0.84), and decreasing distance traveled to the treating center (HR, 0.65; 95% CI, 0.44 to 0.98). Patients with zero, one, two, and > or = three risk factors had 5-year competing mortality of 8.9% (95% CI, 3.0% to 14.8%), 12.4% (95% CI, 7.0% to 17.8%), 22.1% (95% CI, 14.5% to 29.7%), and 39.3% (95% CI, 28.6% to 50.1%), respectively.  Competing mortality in advanced head and neck cancer is associated with several demographic and health status characteristics. Analyses of risk factors for competing mortality may be useful in outcomes reporting and designing clinical trials.

title: The impact of comorbidity on the survival of patients with laryngeal squamous cell carcinoma
abstract: In survival analysis, the combined Charlson comorbidity index (CCI) can be considered as a prognostic factor independent of the tumor node metastasis (TNM) classification, tumor stage, and tumor location. Severe comorbidity was the factor that had the greatest impact on prognosis in cases of initial tumor.  To study the influence of comorbidity on the survival of patients undergoing surgery for larynx cancer.  This was a retrospective study of the survival of 231 patients with laryngeal cancer who underwent surgery between 1995 and 2002. The CCI was used to assess comorbidity, the Kaplan–Meier method was used for survival analysis, and the Cox proportional risk regression model was used to identify independent prognostic factors.  The multivariate analysis of specific mortality showed that patients classified as having severe comorbidity (CCI) were more likely to die (adjusted hazard ratio (adjHR) 1.85, 95% confidence interval (CI) 1.07–3.17). This difference was more important in patients with early tumor stages than in those with advanced stages.

title: The significance of comorbidity in advanced laryngeal cancer
abstract: Cancer patients often have concurrent diseases and conditions known as comorbidities. The aim of this project is to demonstrate the significance of comorbidity in the treatment and outcomes of advanced laryngeal carcinoma.

title: The Impact of Comorbidity and Age on Survival with Laryngeal Cancer
abstract: Previous studies have evaluated the effects of comorbidity on survival in patients with cancer. We applied the Charlson comorbidity index (CCI) to a cohort of patients with laryngeal cancer to validate its use and to assess the prognostic impact of age. Our study population consisted of 152 patients with laryngeal cancer who were seen over a 10-year period. Patients were assigned CCI scores and were categorized into low- and high-grade comorbidity groups for comparison. Age adjustments were performed by adding 1 point to the Charlson score for each decade over the median age. Low- vs. high-grade comorbidity was a valid predictor of survival independent of TNM (tumor, nodes, and metastases) stage. Low-grade comorbidity was present in 126 patients; their median survival was 41 months. High-grade comorbidity was present in 26 patients; their median survival was 8 months (p = 0.0002). The addition of the age factor to the CCI did not improve our prognostic ability. There was no difference in CCI groups with respect to tobacco and alcohol use, gender, treatment modality, or mean time to recurrence. The incidence and severity of complications were also similar in the two groups. We conclude that the CCI is a strong predictor of survival inpatients with laryngeal cancer. The confounding effects of comorbidity should be considered in the TNM staging of laryngeal cancer to improve our prognostic ability. Further investigations are necessary to assess the validity of this index inpatients with other head and neck cancers.

title: Impact of comorbidity on the outcome of laryngeal squamous cancer
abstract: Comorbidity has been shown to be a determinant in treatment selection and survival in various cancers. We have previously shown that the Adult Comorbidity Evaluation—27 index is applicable in a United Kingdom setting, and the process of comorbidity grading by retrospective notes evaluation is an accurate and reliable process.

title: Importance of Comorbidity in Head and Neck Cancer
abstract: Patients with head and neck cancer are staged according to the morphology of the tumor with little or no attention given to the importance of the other diseases, illnesses, or conditions. These other conditions are generally referred to as comorbidities. Although not a feature of the cancer itself, comorbidity is an important attribute of the patient with cancer. Comorbidity has direct impact on the care of patients, selection of initial treatment, and evaluation of treatment effectiveness. The objective of this thesis is to demonstrate the importance of comorbidity in head and neck cancer. Specifically, the aims are 1) to demonstrate the burden of comorbidity among head and neck cancer patients by comparing the incidence of none, mild, moderate, and severe comorbidity among patients with head and neck cancer to patients with cancers of the colorectum, lung, breast, gynecological sites, or prostate, 2) to demonstrate the independent impact of comorbidity on overall survival, and 3) to demonstrate the importance of comorbidity in the assessment of initial treatment effectiveness.

title: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer.
abstract: We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation.



Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy.



After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease.



These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.

title: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.
abstract: Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown.



We randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx.



A total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 percent, P<0.001). The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin (78 percent, vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone). Both of the chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups. The rate of high-grade toxic effects was greater with the chemotherapy-based regimens (81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin, vs. 61 percent with radiotherapy alone). The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy.



In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.

title: Population-based study of competing mortality in head and neck cancer.
abstract: Patients with head and neck cancer (HNC) are at high risk of death resulting from noncancer causes and second malignancies (ie, competing mortality). Variation in competing mortality risk complicates individual treatment choices and design and interpretation of clinical studies.



Using the Surveillance, Epidemiology, and End Results registry, we identified 34,568 patients with nonmetastatic squamous cell carcinoma of the head and neck diagnosed between 1994 and 2003. We developed a multivariable competing-risk regression model to stratify patients according to competing mortality risk and evaluate the impact of this risk on power loss in clinical studies.



The 5-year cumulative incidences of all-cause mortality, HNC-specific mortality, and competing mortality were 51.3% (95% CI, 50.8% to 51.9%), 23.8% (95% CI, 23.3% to 24.2%), and 27.6% (95% CI, 26.8% to 28.3%), respectively. Factors associated with increased competing mortality were increasing age, male sex, black race, unmarried status, localized disease, higher socioeconomic status, nonsurgical treatment, and hypopharyngeal, nasopharyngeal, and oral cavity subsites. The 5-year cumulative incidences of competing mortality for patients in low-, medium-, and high-risk score tertiles were 20.0% (95% CI, 18.8% to 21.3%), 27.7% (95% CI, 26.3% to 29.1%), and 33.7% (95% CI, 32.2% to 35.2%), respectively. Compared with patients with low competing mortality risk, relative sample sizes required to show benefit of a treatment regarding all-cause mortality were 12% and 42% higher in the medium- and high-risk groups, respectively.



Multiple factors affect risk of competing mortality among patients with HNC. Risk stratification would be useful to identify patients most likely to benefit from treatment intensification.

title: Cancer-Specific Mortality and Competing Mortality in Patients with Head and Neck Squamous Cell Carcinoma: A Competing Risk Analysis
abstract: BackgroundThe objective of this study was to estimate probabilities of cancer-specific death and competing death for patients with head and neck squamous cell carcinoma (HNSCC). In addition, we attempted to construct competing risk nomograms to predict prognosis for patients with HNSCC using a large population-based cohort.MethodsPatients diagnosed with nonmetastatic HNSCC between 2000 and 2010 were identified from the Surveillance Epidemiology and End Results Program to form the analytic cohort. We estimated cumulative incident function (CIF) of cancer-specific mortality and competing mortality. Nomograms for predicting probability of death were built with proportional subdistribution hazard models.ResultsThe study cohort included 23,494 patients with HNSCC. The 5-year CIF for cancer-specific death and competing death were 26.7 % (95 % confidence interval [CI] 26–27.3 %) and 12.7 % (95 % CI 12.2–13.3 %), respectively; 10-year CIF were 32.8 % (95 % CI 31.9–33.6 %) and 23 % (95 % CI 22.1–24 %), respectively. On multivariate analysis, increasing cause-specific mortality was associated with increasing age, increasing tumor size, black race, single status, advanced T and N classifications, and high tumor grade. Increasing probability of competing mortality had a relationship with increasing age, male, black race, single status and nonradiotherapy. Models showed good accuracy with c-index of 0.73 for cause-specific mortality model and 0.69 for competing mortality model.ConclusionsWe constructed competing risk nomograms for HNSCC using population-based data. The model used for building nomograms represented good performance. These nomograms can serve to guide management of patients with HNSCC.

title: Long‐term outcomes after multidisciplinary management of T3 laryngeal squamous cell carcinomas: Improved functional outcomes and survival with modern therapeutic approaches
abstract: The purpose of this study was to evaluate the long‐term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers.

title: Noncancer health events as a leading cause of competing mortality in advanced head and neck cancer.
abstract: The survival of patients with head and neck squamous cell carcinoma (HNSCC) can be affected by noncancer health events (NCHE) as well as by index cancer progression and second primary cancer (SPC). This study aimed to investigate the risk factors for NCHE and noncancer mortality (NCM) in patients with advanced-stage HNSCC.



This cohort study involved 600 consecutive patients with overall stage III to IV HNSCC who were treated between 2001 and 2010 at our tertiary referral hospital. NCHE was defined as re-admission (i.e. after the primary treatments for the index tumors) due to noncancer-related causes. The incidences of NCHE and NCM and their risk factors were analyzed by using cumulative incidence and cause-specific hazard functions.



During a median follow-up period of 54 months, 224 (37.3%) and 55 (9.2%) of the 600 patients had NCHE and NCM, respectively. The 5-year index cancer mortality, SPC mortality, and NCM rates were 23.8%, 4.2%, and 8.9%, respectively. Multivariate analyses revealed that body mass index <20 kg/m(2) (P = 0.018), Charlson comorbidity index (CCI) ≥1 (P < 0.001), tumor recurrence (P < 0.001), SPC occurrence (P < 0.001), and initial chemotherapy (P = 0.049) were independent NCHE predictors. Older age (P < 0.001), CCI ≥1 (P = 0.008), tumor recurrence (P < 0.001), and SPC occurrence (P = 0.047) were independent NCM predictors. Patients with respiratory NCHE were at a higher risk of NCM than patients with other NCHE types (P < 0.001).



One or more comorbidities, tumor recurrence, and SPC occurrence were independent predictors of both NCHE and NCM. Patients with respiratory NCHE had a particularly high risk of NCM.

title: Long‐term outcomes after surgical or nonsurgical initial therapy for patients with T4 squamous cell carcinoma of the larynx: A 3‐decade survey
abstract: The current study was conducted to evaluate long‐term disease control, survival, and functional outcomes after surgical and nonsurgical initial treatment for patients with T4 larynx cancer.

title: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
abstract: The objective of this study was to develop a prospectively applicable method for classifying comorbid conditions which might alter the risk of mortality for use in longitudinal studies. A weighted index that takes into account the number and the seriousness of comorbid disease was developed in a cohort of 559 medical patients. The 1-yr mortality rates for the different scores were: "0", 12% (181); "1-2", 26% (225); "3-4", 52% (71); and "greater than or equal to 5", 85% (82). The index was tested for its ability to predict risk of death from comorbid disease in the second cohort of 685 patients during a 10-yr follow-up. The percent of patients who died of comorbid disease for the different scores were: "0", 8% (588); "1", 25% (54); "2", 48% (25); "greater than or equal to 3", 59% (18). With each increased level of the comorbidity index, there were stepwise increases in the cumulative mortality attributable to comorbid disease (log rank chi 2 = 165; p less than 0.0001). In this longer follow-up, age was also a predictor of mortality (p less than 0.001). The new index performed similarly to a previous system devised by Kaplan and Feinstein. The method of classifying comorbidity provides a simple, readily applicable and valid method of estimating risk of death from comorbid disease for use in longitudinal studies. Further work in larger populations is still required to refine the approach because the number of patients with any given condition in this study was relatively small.

title: Validation of the Charlson Comorbidity Index in Patients With Head and Neck Cancer: A Multi‐institutional Study
abstract: Comorbid conditions are medical illnesses that accompany cancer. The impact of these conditions on the outcome of patients with head and neck cancer is well established. However, all of the comorbidity studies in patients with head and neck cancer reported in the literature have been performed using the Kaplan‐Feinstein index (KFI), which may be too complicated for routine use. This study was performed to introduce and validate the use of the Charlson comorbidity index (CI) in patients with head and neck cancer and to compare it with the Kaplan‐Feinstein comorbidity index for accuracy and ease of use. Study design was a retrospective cohort study. The study population was drawn for three academic tertiary care centers and included 88 patients 45 years of age and under who underwent curative treatment for head and neck cancer. All patients were staged by the KFI and the CI for comorbidity and divided into two groups based on the comorbidity severity staging. Group 1 included patients with advanced comorbidity (stages 2 or 3), and group 2 included those with low‐level comorbidity (stages 0 or 1). Outcomes were compared based on these divisions. The KFI was successfully applied to 80% of this study population, and the CI was successfully applied in all cases ( P < 0.0001). In addition, the KFI was found to be more difficult to use than the CI ( P < 0.0001). However, both indices independently predicted the tumor‐specific survival ( P = 0.007), even after adjusting for the confounding effects of TNM stage by multivariate analysis. Overall, the CI was found to be a valid prognostic indicator in patients with head and neck cancer. In addition, because comorbidity staging by the CI independently predicted survival, was easier to use, and more readily applied, it may be better suited for use for retrospective comorbidity studies.

title: Validation of a combined comorbidity index.
abstract: The basic objective of this paper is to evaluate an age-comorbidity index in a cohort of patients who were originally enrolled in a prospective study to identify risk factors for peri-operative complications. Two-hundred and twenty-six patients were enrolled in the study. The participants were patients with hypertension or diabetes who underwent elective surgery between 1982 and 1985 and who survived to discharge. Two-hundred and eighteen patients survived until discharge. These patients were followed for at least five years post-operatively. The estimated relative risk of death for each comorbidity rank was 1.4 and for each decade of age was 1.4. When age and comorbidity were modelled as a combined age-comorbidity score, the estimated relative risk for each combined age-comorbidity unit was 1.45. Thus, the estimated relative risk of death from an increase of one in the comorbidity score proved approximately equal to that from an additional decade of age. The combined age-comorbidity score may be useful in some longitudinal studies to estimate relative risk of death from prognostic clinical covariates.

title: Validity of the Age-Adjusted Charlson Comorbidity Index on Clinical Outcomes for Patients with Nasopharyngeal Cancer Post Radiation Treatment: A 5-Year Nationwide Cohort Study
abstract: To characterize the impact of comorbidity on survival outcomes for patients with nasopharyngeal carcinoma (NPC) post radiotherapy (RT).  A total of 4095 patients with NPC treated by RT or RT plus chemotherapy (CT) in the period from 2007 to 2011 were included through Taiwan’s National Health Insurance Research Database. Information on comorbidity present prior to the NPC diagnosis was obtained and adapted to the Charlson Comorbidity Index (CCI), Age-Adjusted Charlson Comorbidity Index (ACCI) and a revised head and neck comorbidity index (HN-CCI). The prevalence of comorbidity and the influence on survival were calculated and analyzed.  Most of the patients (75%) were male (age 51±13 years) and 2470 of them (60%) had at least one comorbid condition. The most common comorbid condition was diabetes mellitus. According to these three different comorbidity index (CCI, ACCI and HN-CCI), higher scores were associated with worse overall survival (P< 0.001). The Receiver Operating Characteristic (ROC) curve was used to assess the discriminating ability of CCI, AACI and HN-CCI scores and it demonstrated the predictive ability for mortality with the ACCI (0.693, 95% CI 0.670–0.715) was superior to that of the CCI (0.619, 95% CI 0.593–0.644) and HN-CCI (0.545, 95%CI 0.519–0.570).  Comorbidities greatly inﬂuenced the clinical presentations, therapeutic interventions, and outcomes of patients with NPC post RT. Higher comorbidity index scores accurately was associated with worse survival. The ACCI seems to be a more appropriate prognostic indicator and should be considered in further clinical studies.

title: Bayesian Model Selection in Social Research
abstract: It is argued that P-values and the tests based upon them give unsatisfactory results, especially in large samples. It is shown that, in regression, when there are many candidate independent variables, standard variable selection procedures can give very misleading results. Also, by selecting a single model, they ignore model uncertainty and so underestimate the uncertainty about quantities of interest. The Bayesian approach to hypothesis testing, model selection, and accounting for model uncertainty is presented. Implementing this is straightforward through the use of the simple and accurate BIC approximation, and it can be done using the output from standard software. Specific results are presented for most of the types of model commonly used in sociology. It is shown that this approach overcomes the difficulties with P-values and standard model selection procedures based on them. It also allows easy comparison of nonnested models, and permits the quantification of the evidence for a null hypothesis of interest, such as a convergence theory or a hypothesis about societal norms.

title: Predictive factors of survival and treatment tolerance in older patients treated with chemotherapy and radiotherapy for locally advanced head and neck cancer.
abstract: To report outcomes and predictive factors of overall survival, hospitalization and treatment completion rates in elderly patients with locally advanced head and neck cancer treated with concurrent chemoradiotherapy (CRT).



A retrospective analysis of patients aged 70years or older treated with concurrent CRT for locally advanced head and neck cancer was conducted. Univariate and multivariate analysis as well as competing risk survival analysis were used to determine predictors of mortality. Logistic regression was used to predict for hospitalization and treatment completion rates.



In total, 129 patients were included. Median follow-up was 27months (range: 1.7-125months). Completion rate of combined CRT was 84%. Actuarial OS and DSS at 4years were 56% and 75%. Hospitalization rate was 36%. On multivariate analysis, a Karnofsky performance status (KPS) ⩽80 was predictive of mortality. Using competing risks, KPS ⩽80 and weight loss >5% were predictive of cancer mortality whereas Charlson score ⩾3 was predictive of mortality due to other causes. On logistic regression, patients with abnormal renal function and lower body mass index were more likely to be hospitalized during their treatment course. Charlson score and chemotherapy regimen were predictive of treatment completion.



Concurrent CRT may be a feasible treatment option for healthier older patients at the cost of high hospitalization rates. Pre-treatment factors linked to physiological age such as KPS ⩽80, Charlson score ⩾3, abnormal renal function should be considered at the time of treatment decision.