Implication of comorbidity on the initiation of chemotherapy and survival outcomes in patients with locoregionally advanced nasopharyngeal carcinoma

Background To assess the impact of comorbidity on the initiation of chemotherapy and its ultimate treatment outcomes in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods Data on 1316 patients with NPC treated between February 2003 and January 2007 was retrospectively reviewed. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) system. The association of various factors with chemotherapy was evaluated. And treatment outcomes of chemoradiotherapy regimes in patients with comorbidity were compared. Results Comorbidity was present in 42.2% of patients; mild, moderate and severe comorbidity were observed in 33.6%, 8.1% and 0.5% of patients, respectively. Comorbidity (as indicated by ACE-27 score) was a negative prognostic factor for overall survival (OS) (hazard ratio HR=1.577; P < 0.001) and disease-free survival (DFS) (HR=1.509; P < 0.001). In stage III-IV NPC, T classification, N classification, age, sex and hemoglobin before treatment were significant predictors of the initiation of chemotherapy (P < 0.05). Additionally, in stage III-IV patients with comorbidity (ACE >0), 5-year OS for the concomitant chemoradiotherapy group (CCRT) was 74.5% vs. 56.9% in the radiotherapy (RT) only group (P = 0.008), the 5-year DFS rate was 64.0% in the CCRT group vs. 49.4% for RT only (P = 0.015). Conclusions Comorbidity should be assessed during treatment strategy decision-making to improve survival in NPC. Concomitant chemoradiotherapy is feasible and effective in patients with comorbidity in locoregionally advanced stages.


INTRODUCTION
Nasopharyngeal carcinoma (NPC) has a distinct epidemiology and geographic distribution, with the highest incidence of 20-50 cases per 100,000 males in Southern China [1].Radiotherapy (RT) is the primary Clinical Research Paper www.impactjournals.com/oncotargettreatment modality for non-disseminated NPC due to its anatomical location and radiosensitivity [2]; however, the results with radiotherapy alone for locoregionally advanced NPC patients are usually unsatisfactory with 5-year overall survival (OS) rates of 67%-77% in stage III-IVB [3].Various chemoradiotherapy (CRT) strategies have been explored, including concomitant chemoradiotherapy (CCRT), induction chemotherapy (IC) and adjuvant chemotherapy (AC) [4].
At present, standard clinical practice is to stage NPC according to the tumor-node-metastasis (TNM) staging system, which is based on the anatomic extent of the tumor and excluded patient-based prognostic factors.Comorbidity which is defined as the presence of medical ailments not caused by the primary tumor may add difficulty to treatment decisions for the use of chemotherapy [5].In addition, as CRT strategies are widely used, it may exacerbate comorbidity, which may ultimately compromise survival or quality of life [6].Therefore, The risks, decision making and potential benefit of CRT are necessary to assess for NPC patients with comorbidity before treatment.
Previous studies showed that patients with comorbidities received less, similar or more frequent uses of chemotherapy in different solid tumor [6].However, little is known about outcome of CRT in patients with comorbidity, as comorbidities are generally not considered in the design of cancer data sets or assessed in observational research on the selection of CRT [7].For NPC patients, no studies have investigated the impact of

RESULTS
The median follow-up was 75.

Differences of the patients with or without comorbidity
The overall distribution of stage I, II, III and IVA-B diseases was 8.7%, 25.4%, 36.9% and 29.0%, respectively.There was no association between disease stage and comorbidity, as indicated by ACE-27; however, the stage III-IV NPC patients with comorbidity (ACE-27 > 0) significantly received decreased chemotherapy compared with patients without comorbidity (67.6%vs.74.0%;P = 0.037).Furthermore, the significant associations were also observed between comorbidity and gender, age and type of radiotherapy (P < 0.05; Table 1).

Factors associated with initiation of CRT in advanced stage disease
For stage III-IV NPC patients, T classification, N classification, age, sex and hemoglobin before treatment and comorbidity (with vs. without) were significantly associated with the initiation of CRT in univariate analysis (P < 0.05; Table 4).And the T classification, N classification, age, sex and hemoglobin before treatment were significantly associated with the initiation of CRT in multivariable logistic regression (P < 0.05; Table 4).Furthermore, patients with a higher renal system burden and substance abuse were less likely to receive CRT (P = 0.068; P = 0.017; Table 4).

DISCUSSION
Patients with comorbidities present considerable challenges to cancer management because they are often excluded from clinical trials.To our knowledge, this is a single-institutional study with the largest sample size to report the impact of comorbidity on the uptake of chemotherapy in NPC patients.

The prevalence of comorbidity for NPC in south China
Comorbidities occur in 33%-65% of patients with head and neck cancer, with cardiovascular and pulmonary diseases most common [7][8][9][10][11][12][13]. In our research, 42.2% of patients with NPC had comorbidity; however, the most common comorbidities were gastrointestinal disease, which, according to the ACE-27, includes liver disease.This was not surprising as southern China has one of the highest incidences of chronic hepatitis B virus (HBV) infection, with hepatitis B surface antigen (HBsAg) positivity rates of 10-12% in the general population [14].Therefore, chronic HBV infection may be an important gastrointestinal comorbidity in patients with NPC in southern China.An increased frequency and severity of comorbidity were noted with increasing age and in male patients.Piccirillo et al. also reported that increased age was associated with an increasing number and severity of comorbidities [15] with similar results obtained in other studies [13,16,17].In this study, the second most frequent comorbidity was substance abuse, mainly in male patients.

Factors associated with the initiation of chemotherapy in advanced stage NPC
Age, T classification, N classification, pretreatment hemoglobin were independent predictive factors for initiation of CRT; in agreement with previous studies demonstrating elderly patients tend to receive less intensive treatment [18].However, The reduction in the use of CRT was only in patients with renal disease.Chemotherapy strategies for NPC include cisplatin, the use of which is limited by its severe acute and chronic nephro-, oto-and neuro-toxicity [19].In everyday practice, the initiation of CRT is not primarily determined by comorbidity conditions, but renal disease.

Implications of CRT in patients with comorbidity
Little is known about the toxicity and outcomes of CRT regimes in patients with s comorbidity, as these patients are often excluded from clinical trials.Our results indicate CCRT improved OS compared to RT only for patients with mild, moderate and severe comorbidity.Nevertheless, adding IC or AC to CCRT had no significant OS benefit.CCRT also improved OS compared to RT alone in patients with comorbidity (ACE > 0).Therefore, if patients with advanced NPC and comorbidity desire curative treatment, we consider CCRT to be the most appropriate approach; further studies are required to identify more intensive systemic approaches and novel agents, such as molecular-targeted agents, to improve the treatment outcomes for these patients.Moreover, patients with comorbidity should receive complete supportive care during treatment to ensure optimal outcome.ACE-27 requires no special technological expertise and can be applied by any healthcare professional.Comorbidity assessment could easily be included in research into prognostic factors and could represent a major confounder in clinical trials.
Since this was a retrospective sample, we had no control over the nature and quality of the medical records.Nevertheless, the records were detailed and provided accurate information on the patients' clinical characteristics.More importantly, these results clearly demonstrate that comorbidity must be routinely considered with other significant prognostic factors in both clinical work and research.This study also justifies the need for prospective collection of comorbidity data in routine clinical practice.

CONCLUSIONS
Comorbidity information should be incorporated into treatment strategy decision-making processes, to aid patient consultation and improve clinician decisionmaking.Concomitant chemoradiotherapy is feasible and effective in patients with comorbidity in locoregionally advanced stages.

Patient selection
Between February 2003 and January 2007, 1403 newly-diagnosed patients with non-metastatic, histologically-proven NPC at Sun Yat-sen University Cancer Center (Guangzhou, People's Republic of China) were retrospectively reviewed.Of these, 87 were excluded due to a lack of substantial data on comorbidity; the remaining 1316 cases were included.This retrospective analysis of the patient data was approved by the ethics committee of Sun Yat-sen University Cancer Center.Written consent was waived, while oral consent from the patients was obtained via telephone and documented by telephone recording.
All patients completed pretreatment evaluations, including complete medical history, physical examination, MRI of the nasopharynx and neck, hematology and biochemistry profiles, abdominal ultrasonography, chest radiography and whole body bone scan using single photon emission computed tomography (ECT); 139 (10.6%) patients also underwent positron emission tomography CT (PET-CT).All patients were restaged according to the 7th edition of the International Union against Cancer/ American Joint Committee on Cancer (UICC/AJCC) system [20].All MRI records were separately reviewed by

Figure 1 :
Figure 1: Kaplan-Meier estimates of survival for the 1316 study patients with nasopharyngeal cancer, according to ACE27 grade.A. Overall survival, B. disease-free survival.

Table 2 : Presence and severity of comorbidity in the study population of 1316 patients with NPC Disease classification according to ACE-27 Grade 1: mild Grade 2: moderate Grade 3: severe
Abbreviation: ACE-27, Adult Comorbidity Evaluation-27.

Table 3 : Multivariate analysis of the impact of all variables on survival
Abbreviation: ACE-27, Adult Comorbidity Evaluation-27; CI, confidence interval; HR, hazard ratio.*According to the 7th AJCC/UICC staging system.‡ Multivariate P values were calculated using an adjusted Cox proportional-hazards model.The following parameters were included in the Cox proportion hazard model by backward elimination: age, gender, World Health Organization (WHO) histological grade, T classification, N classification, radiotherapy (conformal vs. 3D and intensity modulated radiation therapy), use of chemotherapy (with vs. without) and ACE-27.www.impactjournals.com/oncotarget