Abstract
Background
An association between Hepatitis C virus (HCV) infection and oropharyngeal cancers (OPCs) has been reported; however, the clinical significance of this epidemiological finding remains unknown. We therefore analyzed the oncologic outcomes of HCV-infected patients with OPCs.
Methods
In this retrospective cohort study, all patients with OPCs seen at MD Anderson (1/2004–12/2015) were reviewed. HCV infection was defined as detectable HCV RNA in serum. Risk of 5-year overall survival (OS) and progression-free survival (PFS) was compared between HCV-infected and uninfected patients.
Results
We studied 161 patients. Most of the patients were white (141; 88%), male (132; 82%) and had tumor stage 3 or 4 (147; 92%). The OPC involved tonsils (83; 52%), base of tongue (67; 42%) or soft palate (11; 7%). The median follow-up time after OPC diagnosis was 3 years (range: 1–13 years). HCV-infected (n=25) and HCV-uninfected patients (n=136) were comparable in regards to smoking and alcohol status. In multivariate analysis, HCV was associated with increased cancer-specific mortality [hazard ratio (HR): 2.15, 95% confidence intervals (CI): 1.08–6.85; P=.02] and risk of OPC progression [HR: 5.42, 95% CI: 2.64–11.14; P=.0008] independent of age and cirrhosis status. Antivirals were administered after OPC diagnosis in 8 of the 25 HCV-infected patients (32%). HCV-infected patients that received antivirals had better 5-year OS (70% versus 12%; P = .005) and PFS (72% versus 19%; P = .005) than the ones who did not.
Conclusions
Early detection of HCV is important in patients with OPC since this infection may affect their oncologic outcomes.
Keywords: oropharyngeal cancer, hepatitis C virus, head and neck cancer, antivirals, overall survival
Background
Hepatitis C virus (HCV) is a globally prevalent pathogen and a leading cause of morbidity and death.[1] HCV is carcinogenic and associated with the development of hepatocellular carcinoma and non-Hodgkin lymphomas.[2] In addition, HCV seropositivity or HCV infection seems to increase the risk of mortality from several cancers including rectal, liver, pancreas, lung, esophagus, thyroid and prostate. [3–6] Recently, we reported that chronic HCV infection is associated with head and neck cancers, particularly human papillomavirus (HPV) positive oropharyngeal cancers (OPCs).[7] Additional studies from the United States[8] and Europe[9] confirm such findings but the clinical significance of these epidemiological observation remains unknown. Patients with OPC are a distinct group of patients with specific treatment modalities. Therefore, we studied the impact of HCV infection on the oncologic outcomes of OPC patients.
Methods
In this retrospective cohort study, the medical records of OPC patients seen at The University of Texas MD Anderson Cancer Center from January 2004 to December 2015 were reviewed. Baseline assessments included standard clinical laboratory testing, smoking and alcohol history assessment, measurement of serum HCV RNA levels and HCV genotype. Smoking-related information collected included smoking status (never, former, or current smoker). Former smokers were those who had quit at least one year before cancer diagnosis. Alcohol-related information collected included drinking status (never, former, or current drinker). Former drinkers were those who had quit at least one year before cancer diagnosis.
HCV RNA levels were measured by means of COBAS AmpliPrep/COBAS TaqMan HCV test (version 1.0 and 2.0, Roche Molecular Systems, Branchburg, NJ). Patients who tested positive for HCV antibody (anti-HCV) with detectable HCV RNA were considered “HCV-infected”, while those who tested negative for anti-HCV were considered “HCV-uninfected”. Patients who tested positive for anti-HCV with HCV RNA either undetectable or never tested were excluded as such patients could have false positive anti-HCV or spontaneous viral clearance. Cirrhosis was diagnosed on the basis of liver biopsy or a combination of clinical findings (e.g., ascites, encephalopathy or jaundice) and radiologic findings (e.g., hepatic nodularity) and serum biomarkers (Prometheus Fibrospect II [Prometheus Laboratories, San Diego, CA]). We compared 5-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) between HCV-infected and uninfected patients. OS was calculated from the date of cancer diagnosis to the time of death, last date of follow-up, or completion of 5 years of follow-up, whichever came earlier. PFS was calculated from the date of cancer diagnosis to the date of disease progression, death, last date of follow-up, or completion of 5 years of follow-up, whichever came earlier. DFS was calculated from the date of last treatment received to the date of relapse, death, last date of follow-up, or completion of 5 years of follow-up, whichever came earlier. DFS was calculated only for patients who achieved complete remission after first line treatment.
Only patients with OPC were studied as this is a more homogeneous group with standardized non-surgical treatment, removing surgical and pathologic variables as potential confounders in the survival analyses. OPC progression was identified either clinically or radiologically. Follow-up began at the date of OPC diagnosis and ended at the date of death or last follow-up visit. The effect of antiviral treatment (AVT) (either interferon-based or interferon-free regimens) on the survival outcomes among HCV-infected OPC patients was explored.
We extracted data on demographics, cigarette smoking and alcohol consumption at the time of cancer diagnosis. The smoking-related information collected, included smoking status (never, former or current smoker) and duration of smoking in pack-years (number of cigarette packs smoked per day multiplied by number of years smoking). Former smokers were those who had quit at least one year prior to diagnosis. Alcohol-related information included drinking status (never, former or current drinker). OPCs were considered to be HPV-positive if they were positive for p16 protein expression according to immunohistochemistry - as defined in pathology reports.
Descriptive statistics were used to characterize the study population. Categorical variables were compared using chi-square or the Fisher’s exact test. Continuous variables were compared using the Wilcoxon-rank sum test. Survival probabilities in the HCV-infected and uninfected patients were compared using a log-rank test. Multivariable Cox regression models were used to determine the association of HCV infection, risk of death and disease progression after adjusting for potential confounders. In the final multivariable analysis only OPC-specific mortality was analyzed. We did not analyze all-cause mortality as the differences in outcome between HCV-infected and HCV-uninfected patients could be due to uncontrolled confounding covariates.
Furthermore, to determine whether AVT affects the oncologic outcomes in HCV-infected patients, patients treated with AVT after OPC diagnosis were compared with those who were not treated, using a log-rank test. P values less than .05 were considered statistically significant.
Results
We studied 178 OPC patients. Seventeen patients (10%) with positive anti-HCV antibody and undetectable or never tested where excluded. Further analysis was performed in the remaining 161 patients, 25 (16%) of whom were HCV-infected and 136 (84%) of whom were uninfected. By definition, all the 25 HCV-infected patients had anti-HCV and detectable HCV RNA. The median follow-up time after OPC diagnosis was 3 years (interquartile range [IQR]: 1.8–4.7 years). The demographic, hepatic, virologic and oncologic characteristics of the HCV-infected and uninfected patients are compared in Table 1. Eighty-six (53%) of the patients were HPV-positive, 22 (14%) were HPV-negative, and 53 (33%) had unknown HPV statuses. HPV-related OPCs were equally distributed in HCV-infected and uninfected patients. Only 2 patients in the entire cohort (1%) were infected with HIV.
Table 1.
Demographics and cancer characteristics of OPC patients according to HCV infection status.
| Variable | Total cohort N=161 |
HCV-infected N=25 |
HCV-uninfected N=136 |
P value* |
|---|---|---|---|---|
| Demographics | ||||
| Age at cancer diagnosis, median (IQR) | 62 (56–68) | 59 (55–63) | 63 (56–70) | .02 |
| Race/ethnicity, n (%) | .30 | |||
| White | 141 (88) | 23 (92) | 118 (87) | |
| Black | 9 (6) | 2 (8) | 7 (5) | |
| Hispanic | 11 (6) | 0 (0) | 11 (8) | |
| Male sex, n (%) | 132 (82) | 21 (84) | 111 (82) | .77 |
| Cigarette smoking status, n (%) | .09 | |||
| Never smoker | 49 (30) | 7 (28) | 42 (31) | |
| Former smoker | 63 (40) | 6 (24) | 57 (42) | |
| Current smoker | 49 (30) | 12 (48) | 37 (27) | |
| Median pack-years of smoking (IQR) | 33 (18–50) | 35 (20–44) | 30 (18–50) | .26 |
| Alcohol consumption status, n (%) | .08 | |||
| Never drinker | 73 (45) | 8 (32) | 65 (48) | |
| Former drinker | 39 (25) | 8 (32) | 31 (23) | |
| Current drinker | 49 (30) | 9 (36) | 40 (29) | |
| Cancer characteristics | ||||
| Pathology of OPC, n (%) | >.99 | |||
| SCC | 147 (91) | 22 (88) | 125 (92) | |
| Lymphoepithelioma | 7 (4) | 1 (4) | 6 (4) | |
| Adenocarcinoma | 4 (2) | 2 (8) | 2 (1) | |
| Neuroendocrine | 3 (2) | 0 (0) | 3 (2) | |
| Site of OPC, n (%) | .82 | |||
| Tonsils | 83 (51) | 14 (56) | 69 (51) | |
| Base of Tongue | 67 (42) | 9 (36) | 58 (43) | |
| Soft palate | 11 (7) | 2 (8) | 9 (6) | |
| Tumor Stage, n (%)¥ | .13 | |||
| 1 | 4 (2) | 0 (0) | 4 (3) | |
| 2 | 10 (6) | 4 (16) | 6 (4) | |
| 3 | 17 (11) | 3 (12) | 14 (10) | |
| 4 | 130 (81) | 18 (72) | 112 (83) | |
| Type of treatment, n (%)§ | ||||
| Radiation | 154 (96) | 23 (92) | 131 (96) | .29 |
| Chemotherapy | 134 (83) | 21 (84) | 113 (83) | >.99 |
| Neck dissection | 32 (20) | 2 (8) | 30 (22) | .17 |
| Chemotherapy drug class, n (%)± | >.99 | |||
| Alkylating agents | 121 (75) | 17 (68) | 104 (76) | |
| Antimetabolites | 107 (66) | 18 (72) | 89 (65) | |
| Antimicrotubular | 116 (72) | 17 (68) | 99 (73) | |
| EGFR inhibitor | 42 (26) | 6 (24) | 36 (26) | |
| Median follow-up time in years, (IQR) | 3 (1–5.5) | 2.5 (1.3–3.9) | 4 (2–5.5) | .01 |
| Median number of appointments after treatment initiation, (IQR) | 7 (3–12) | 9 (7–14) | 6 (4–9) | .07 |
| Overall mortality | 124 (77) | 23 (92) | 101 (74) | .003 |
| OPC-related mortality | 111 (69) | 20 (80) | 91 (66) | .01 |
Abbreviations: EGFR, epidermal growth factor receptor; IQR, interquartile range; OPC, oropharyngeal cancer; SCC, squamous cell carcinoma.
Categorical variables were compared using Pearson’s chi-squared test or Fisher’s exact test and continuous variables were compared using Wilcoxon rank-sum test. All statistical tests were two-sided.
Tumor stage was assessed based on the TNM system
Patients may have received multiple treatment modalities. Neck dissection was performed as salvage therapy in patients with persistent nodal disease.
Patients may have received combination treatment with multiple drug classes. Alkylating agents included cisplatin and carboplatin; Antimetabolites included fluorouracil, pemetrexed, methotrexate and gemcitabine; Antimicrotubular agents included docetaxel and paclitaxel; EGFR inhibitors included cetuximab, erlotininb and panitumumab
In univariate analysis, HCV-uninfected patients had better 5-year OS and PFS rates than did HCV-infected ones (26% versus 8% ; P = .003 and 73% versus 48%; P = .0008, respectively). After first-line cancer treatment 113 patients (70%) achieved complete remission. Nine were HCV-infected and 104 uninfected. In these patients DFS rates were similar (77% in the HCV-uninfected versus 65% in the HCV-infected; P = .15). Multivariable Cox regression analysis demonstrated that HCV infection was associated with a twofold increase in risk of death due to OPC (hazard ratio, 2.1 [95% confidence interval (CI), 1.0–4.1]) and a threefold increase in risk of OPC progression at 5 years (hazard ratio, 3.1 [95% CI, 1.5–6.4]) independent of age and cirrhosis status (Figures 1 and 2).
Figure 1.
Five year cancer-specific mortality in HCV-infected and HCV-uninfected patients with OPCs.
Abbreviations: HCV, hepatitis C virus; OPC, oropharyngeal cancer
Shown are Kaplan–Meier estimates of cancer-specific mortality according to treatment group.
Hazard ratios, 95% confidence intervals and p values were calculated using Cox regression model comparing HCV-infected (n=25) and HCV-uninfected (n=136) patients after adjustment for cirrhosis (yes vs no), age at cancer diagnosis (>65 vs <65) and tumor stage (1, 2 vs 3, 4).
Figure 2.
Five year progression-free survival in HCV-infected and HCV-uninfected patients with OPCs.
Abbreviations: HCV, hepatitis C virus; OPC, oropharyngeal cancer
Shown are Kaplan–Meier estimates of progression-free survival according to treatment group.
Hazard ratios, 95% confidence intervals and p values were calculated using Cox regression model comparing HCV-infected (n=25) and HCV-uninfected (n=136) patients after adjustment for cirrhosis (yes vs no), age at cancer diagnosis(>65 vs <65) and tumor stage (1, 2 vs 3, 4).
AVT was administered after OPC diagnosis in 8 of the 25 HCV-infected patients (32%), with 6 of them receiving interferon-free AVT (4 patients received sofosbuvir/ledipasvir fixed-dose combination, and 2 patients received sofosbuvir plus ribavirin). All of these 8 patients had sustained virologic responses 12 weeks after the end of treatment, regarded as cure of HCV infection. In univariate analysis, treated HCV-infected patients had better 5-year OS (70% versus 12%; P = .005) and 5-year PFS (72% versus 19%; P = .005) survival rates than did untreated patients. We observed no statistically significant differences in DFS, but the percentage of AVT-treated patients who were disease-free at 5 years was higher than that of untreated patients (100% versus 57%; P = .33).
Discussion
To our knowledge, this is the first study to analyze the clinical impact of chronic HCV infection on oncologic outcome in patients with OPC. We found that HCV infection is associated with an increased risk of cancer-specific mortality and cancer progression independent of age and cirrhosis status.
Head and neck cancer is the 6th most common type of cancer in the world. [10] OPCs constitute a distinct entity among head and neck cancers. In a large study performed by our group, we found that HCV infection was significantly associated with OPCs, [7] a finding also validated by others[8, 9] but the oncologic significance of such association was unclear.
HCV infection negatively affects the oncologic outcomes of patients with [11–13] or without HCV-associated malignancies.[14] For instance, in patients with advanced hepatocellular carcinoma, underlying HCV was associated with worse outcomes when compared to those without HCV.[4] Also in advanced HCC, HCV eradication before sorafenib era improved OS and post-progression survival. [13] Additionally, HCV-infected patients with diffuse large B-cell non-Hodgkin lymphoma, had worse 5-year OS than HCV-uninfected ones.[15] In our study, we found that HCV infection leads to a poor cancer prognosis in patients with OPCs after adjusting for potential confounders. A previous study regarding the effect of HCV in patients with head and neck cancers did not find any significant impact on oncologic outcomes. However, they included mainly patients with relatively early HCV infection, precluding the analysis of chronic implications. [16]
The higher mortality observed in HCV-associated malignancies such as hepatocellular carcinoma can be attributed to worsening liver function particularly among those with decompensated cirrhosis. However, this is not applicable to HCV-associated NHL where most patients have mild liver disease[17]. Our group and others have demonstrated that viral eradication following AVT improves oncologic outcomes of patients with HCV-associated non-Hodgkin lymphoma suggesting a direct effect of this carcinogenic virus on survival[15, 18] There is also evidence of increased mortality in HCV-infected patients from nonliver-related deaths including renal and cardiovascular deaths, likely from chronic inflammation.[6, 19, 20]. Sustained virologic response with interferon-free regimens is associated with a significant mortality benefit in such patients[21]
This study includes many HCV-infected patients seen before 2013, the year when more effective, less toxic and better tolerated AVT (interferon-free regimens) were introduced in the United States. Even in the general population, the previous standard treatment of HCV with interferon and ribavirin was given to only the minority of infected patients (less than 20%).[22] In our study, most of the patients treated with AVT (6 out of 8) received interferon-free regimens, more effective and safe therapies used at the present time even in cancer patients.[23] Achievement of a sustained virological response has been associated to better overall survival and reduced risk of extrahepatic manifestations.[24, 25]
Our study had some limitations. First, we examined a single institution cohort including a small number of HCV-infected patients. However, they were all proven cases of HCV infection (detectable HCV RNA), which may not be possible in population-based studies. Second, as in every retrospective study there is a risk of confounding bias, which we addressed by performing multivariable analysis to control for independent predictors of survival outcomes. Third, smoking and alcohol history was defined at the time of OPC diagnosis and we were not able to control for potential cessation after diagnosis. Fourth, most patients seen at MD Anderson have stage 4 disease. As a result, the survival rates of our study patients were lower independent of HCV infection status. Fifth, AVT was provided to a small group of patients and results should be interpreted with caution. Patients who were deemed to have better survival were more likely to receive AVT, illustrating a potential selection bias. Sixth, we did not collect information on all comorbidities (e.g.: obesity, diabetes) some of them potentially increasing mortality in our patients.
Conclusions
In conclusion, early detection of HCV in OPC patients is important as it may affect their oncologic outcomes. Larger studies are warranted to evaluate the impact of HCV and AVT in patients with OPCs or other head and neck cancers.
Table 2.
Baseline hepatic and virologic characteristics according to HCV infection status.
| Variable | Total cohort N=161 |
HCV-infected N=25 |
HCV-uninfected N=136 |
P value* |
|---|---|---|---|---|
| Baseline Hepatic characteristics | ||||
| Median total bilirubin (IQR) | 0.5 (0.4–0.8) | 0.5 (0.4–0.8) | 0.6 (0.4–0.7) | .99 |
| Median ALT (IQR) | 31 (19.5–47.5) | 38 (31.5–69) | 29.5 (18–45) | .006 |
| Median AST (IQR) | 30 (23–49) | 28 (22.5–59) | 30 (23.5–47) | .86 |
| Median albumin (IQR) | 4.2 (3.9–4.4) | 4.2 (3.8–4.4) | 4.1 (3.9–4.4) | .78 |
| Cirrhosis, n (%) | 27 (17) | 10 (40) | 17 (13) | .002 |
| Virologic characteristics | ||||
| HCV genotype, n (%) | ||||
| 1 | 12/25 (48) | |||
| 2 | 1/25 (4) | |||
| 3 | 2/25 (8) | |||
| 4 | 1/25 (4) | |||
| Unknown | 9/25 (36) | |||
| HIV, n (%) | 2 (1) | 2 (8) | 0 (0) | . |
| HBV, n (%) | ||||
| HBsAg + | 3 (2) | 1 (4) | 2 (2) | .40 |
| HBcAb + | 20 (12) | 7 (28) | 13 (10) | .02 |
| HPV, n (%) | 86 (53) | 11 (44) | 75 (55) | .78 |
| HCV treatment received | ||||
| 8 (32) | ||||
| IFN+RBV | 2 (25) | |||
| LDV/SOF | 4 (50) | |||
| SOF + RBV | 2 (25) | |||
| Timing of AVT after HCV diagnosis, median in months (IQR) | 18.3 (12.6–24.8) |
Abbreviations: Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AVT, antiviral treatment; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; IFN, interferon; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response.
Acknowledgments
Funding: This study was supported by the NIH/NCI under award number P30CA016672
Footnotes
Conflict of interest: Dr. Torres is or has been the principal investigator for research grants from Gilead Sciences, Merck & Co., Inc., and Vertex Pharmaceuticals, with all funds paid to MD Anderson. He also is or has been a paid scientific advisor for Gilead Sciences, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Dynavax Technologies, Vertex Pharmaceuticals, Genentech, Novartis, Astellas Pharma, Pfizer Inc., and Theravance Biopharma, Inc.; the terms of these arrangements are being managed by MD Anderson in accordance with its conflict of interest policies. All other authors declare no conflicts of interests stated in regards to this study.
Author contributions: MPE, PM, JH, UB, EMS and HAT organized the study. MPE and MA performed the data collection. YJ, PM and JH performed the statistical analysis. MPE and HAT wrote the manuscript. MPE, MA, PM, JH, YJ, UB, EMS and HAT reviewed and accepted the final form of the manuscript.
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