Overall Survival in Stage III and IV High-Risk Head and Neck Squamous Cell Carcinoma Patients who received Adjuvant Chemotherapy and Radiation without Cisplatin

Objectives: Microscopically involved resection margins and/or extracapsular spread represent the most significant prognostic factors for poor outcome in head and neck cancer. Purpose of this study was to estimate overall survival, and assess impact of demographic and clinicopathologic variables on survival in stage III and IV high-risk patients who received chemoradiation other than Cisplatin Methods: Retrospective review Results: The final cohort of 18 eligible patients had a median age of 66 years and males were 66.66%. Median survival was 20.5 months. Patients were trichotomized into three age groups for comparison; ≤60 years, 61-70 years, ≥71 years. A superior overall survival was observed with advanced age (HR, 4.02; 95%CI, 1.33-12.17, p=0.016). Overall survival was significantly lower in patients with high Charlson comorbidity scores of 3-8 when compared to those with low scores of 0-2 (HR, 25.6; 95%CI, 2.78-236.7, p=0.0009). Young patients had high comorbidity scores (CCI > 2) based on the age-groups; ≤60 years (60%), 61-70 years (28.57%), ≥71 years (none). Tumor stage, positive resection margins, extracapsular spread, perineural involvement, lymphovascular invasion, tumor grade, high-risk human papillomavirus, body mass index, smoking and alcohol did not affect overall survival significantly. Conclusions: Young age and severe comorbidity should be considered when treating high-risk head and neck cancer squamous cell carcinoma patients with adjuvant chemoradiation therapy other than Cisplatin due to inferior overall survival.


Introduction
Standard therapeutic management options for head and neck squamous cell carcinomas (HNSCC), which depend on the tumor site, stage, and patient's age and performance status, include surgery, chemotherapy, radiation or a combination of treatments.Historically surgery and/or radiation therapy (RT) were the mainstay of loco-regional treatment in patients with locally advanced resectable disease but rates of local-regional recurrence and distant metastasis were high and long-term prognosis remained poor (Bernier, Vermorken & Koch, 2006).In contrast, adjuvant chemoradiation therapy (CRT) following the surgical resection has been shown to improve overall survival (OS) in operable HNSCC (Bernier et al., 2006, Harari et al., 2014, Bernier & Cooper, 2005, Bernier et al., 2004, Bonner et al., 2006).Multiple pathologic high-risk prognostic factors have been proposed in the literature, mainly on the basis of retrospective analyses, that can affect recurrence and OS in HNSCC.These include microscopically involved surgical margins of resection, extracapsular extension of disease from a lymph node, perineural extension, vascular embolisms, and/or involvement of two or more lymph nodes.It has been substantiated that microscopically involved resection margins and/or extracapsular spread (ECS) of tumor from neck nodes represent the most significant prognostic clinical factors for poor outcome (Bernier & Cooper, 2005).
Supporting data for combined CRT as adjuvant treatment emerged from two independent, large-scale, prospective randomized trials conducted by the European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG).The EORTC 22931 and RTOG 9501 studies were similar in design.They compared addition of concomitant high-dose Cisplatin to RT with RT alone in patients with resected, poor-risk HNSCC (Bernier & Cooper, 2005).Bernier et al. (2005) combined the EORTC and RTOG data to demonstrate that ECS and/or microscopically involved surgical margins were the risk factors for which impact of CRT was most significant.Based on the compelling evidence, concurrent CRT with high-dose Cisplatin is believed to be more effective than adjuvant RT alone in postoperative setting for patients at high-risk of developing a recurrence.This validated combined approach is currently considered as standard therapeutic approach for the high-risk category of HNSCC patients (Bernier et al., 2006, Bernier & Cooper, 2005).
Despite demonstrated benefit of high-dose Cisplatin, its use is nonetheless of concern for many physicians.Combination regimens are associated with higher rates of severe reactions especially involving the mucosa and skin.Late toxic effects, notably dysphagia, are also common.Intravenous rehydration, narcotics for pain management, increased need for nutritional support and invasive procedures for that purpose must be implemented.These imply the need for a considerable intensified supportive care which makes its administration difficult in some settings.A considerable proportion of high-risk HNSCC patients are not considered good candidates for high-dose Cisplatin because of advanced age, renal insufficiency, auditory dysfunction, coexisting conditions, or poor performance status making it an unfavorable option as these patients may be prone to such adverse events (Bernier et al., 2006, Harari et al., 2014, Bernier & Cooper, 2005, Bernier et al., 2004, Bonner et al., 2006).
Alternatively a promising strategy involves incorporation of other targeting agents like cetuximb (Harari et al., 2014).Cetuximab is a monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR).Bonner et al. (2006Bonner et al. ( , 2010) ) demonstrated that weekly cetuximab plus high dose RT increases both the duration of locoregional disease control and survival in locally advanced head and neck cancer without increasing the common toxic effects associated with radiotherapy to head and neck.
There is lack of data regarding survival in patients with poor-risk HNSCC who received adjuvant chemoradiation therapy other than Cisplatin.The objectives of present study were to estimate the OS in patients with stage III and IV high-risk HNSCC who received chemotherapy other than Cisplatin and RT after surgery and assess the impact of demographic and clinicopathologic variables on OS.

Methods
We collected data by retrospective medical record review in patients diagnosed with poor-risk HNSCC between January 1, 2008 and January 31, 2015, who received treatments at Southern Illinois University School of Medicine (SIU-SOM) and affiliated hospitals.Study approval was obtained from the Institutional Review Board (IRB) i.e. the Springfield Committee for Research Involving Human Subjects (SCRIHS).
Patients diagnosed with HNSCC and treated at SIU-SOM were identified using a database based on the ICD -9 codes.Inclusion criteria were (1) Patients with stage III and IV HNSCC (Oral cavity, oropharynx, larynx and hypopharyngeal) (2) Presence of pathologic high-risk features including either ECS of the disease and/or microscopically involved mucosal margins of resection (3) Adjuvant chemotherapy regimen other than Cisplatin and RT (4) Availability of electronic pathology reports and therapy records.Exclusion criteria consisted of (1) Histology other than SCC (2) Carcinoma in situ only (3) Tumors not amenable to a surgical resection (4) CRT or RT given prior to surgery (5) History of recurrent HNSCC (6) Treatment with a palliative intent and (7) Unavailable electronic medical records.
In eligible cases, the reasons not to use Cisplatin were; clinical judgment that patient would not be able to tolerate Cisplatin or patients refusing Cisplatin.Data collection included the demographic variables, clinicopathological features and treatments.Age at the time of diagnosis, sex, ethnicity, tumor staging, histologic grade, adverse pathologic features (extracapsular extension, microscopically involved surgical margins, perineural infiltration, lymphovascular invasion), clinically enlarged lymph nodes, smoking status, high-risk Human Papillomavirus (HPV) status, alcohol consumption, co-morbid conditions, body mass index (BMI), details of surgery, chemotherapy, RT and OS were recorded.
Common Terminology Criteria for Adverse Events (CTCEA version 4.0, 2010) was used to document grade 3-4 toxicities related to chemoradiotherapy or RT.Chemotherapy toxicity including hypomagnesemia (Magnesium level < 1.2 mg/dL), skin rash (involving >10% of body surface area), anemia, thrombocytopenia and infections were recorded.Radiation toxicity due to mucositis, pigmentation, erythema, esophagitis, thrush and osteomyelitis was documented.
Patients were trichotomized into three age groups for comparison (≤60 years, 61-70 years, ≥71 years).Ethnicity was classified into Caucasians and others.American Joint Committee on Cancer's sixth (American Joint Committee on Cancer, [AJCC], 2002) and seventh (AJCC, 2010) editions, corresponding to the year of diagnosis, of the AJCC Cancer Staging Manual was used for tumor staging.Pathology reports were used to determine the T and N class.Patients were categorized into current, never, or former based on smoking and alcohol consumption status at the time of diagnosis.The high-risk HPV status was recorded from pathology reports.WHO classification of BMI (WHO, 2000) was used for categorization of patients into underweight, normal weight, overweight, class I obesity and class II obesity.Charlson Comorbidity Index (Hall, Ramachandran, Narayan, Jani & Vijayakumar, 2004, Singh et al., 1997) was used to calculate the comorbidity score and stratify patients based on CCI score.All patients underwent surgery of the primary site including tumor excision, total/partial pharyngectomy, or laryngopharyngectomy ± neck dissection for nodal metastasis.Adjuvant chemotherapy regimens included Cetuximab, Carboplatin, Carboplatin+5-Fluorouracil+Cetuximab, and Paclitaxel+5-Fluorouracil+Hydroxyurea.
Overall survival was the primary outcome measure, defined as survival calculated (in months) from the date of diagnosis to death from any cause, and patients were censored at the last date known to be alive or June 30, 2016 whichever came first.
All statistical analysis was performed using the SPSS software program (version 16.0; SPSS Inc.).Study endpoint was OS.Survival analysis was conducted by Kaplan-Meier estimation and Cox proportional hazards regression methods.All baseline characteristics were analyzed as univariable prognostic factors, and impact of these variables on survival was evaluated using the log-rank test.Hazard ratios and 95%CI were calculated for the strength of association.The p-value was considered to be statistically significant at <0.05
Young patients had high comorbidity scores based on the age-groups.In age-group ≤60 years, 3 out of 5 patients (60%) had a CCI score greater than 2. In 61-70 years age-group, 2 out of 7 patients (28.57%) had a CCI score of above 2 while in patients ≥71 years, none had a CCI score of above 2.

Discussion
This study is a retrospective review of high-risk stage III and IV HNSCC patients who were treated at a single tertiary care institute and OS was evaluated.The salient observations are as follows: (1) High-risk stage III and IV HNSCC patients who received adjuvant chemoradiation therapy other than Cisplatin had a median OS of 20.5 months (2) Patients ≤60 years of age had worse OS (3) Patients with higher CCI scores had distinctively inferior OS.Majority of patients ≤60 years of age had high CCI scores (4) Our analysis did not show a statistically significant difference in OS for the variables including sex, tumor stage, microscopically involved surgical margins, perineural infiltration, ECS, lymphovascular invasion, clinically enlarged lymph nodes, smoking, high-risk HPV, alcohol consumption, BMI, and therapy toxicities.
The present study is important because HNSCC patients who have the high-risk disease are at increased risk for recurrence and poor survival.Literature is scarce regarding the impact of stratified variables on outcomes in high-risk HNSCC.Bonner et al. (2010) showed a higher OS with Cetuximab plus high dose RT compared with RT alone as a primary treatment in locally advanced head and neck cancer.In the postoperative setting, Amini et al. (2016) showed no added benefit of CRT on survival after resection of salivary gland carcinomas.
Retrospective comparisons between Cisplatin and Cetuximab have shown mixed results.Strom et al. (2015) found no difference in OS and locoregional control between Cisplatin every 3 weeks or weekly Cetuximab with RT.However, several other retrospective studies have reported better survival with use of Cisplatin concurrently with radiation for definitive therapy of locally advanced head and neck cancer (Riaz et al., 2016, Ley et al., 2013, Levy et al., 2014).A meta-analysis demonstrated that concomitant Cisplatin-based CRT is associated with better OS than Cetuximab+RT in locally advanced HNSCC, probably attributable to better loco-regional disease control (Petrelli et al., 2014).However, no prospective study has yet been published comparing Cisplatin/RT to Cetuximab/RT, and no retrospective or prospective data has been reported on the use of Cetuximab in high risk head and neck cancer patients post-operatively.Bonner et al. (2010) has demonstrated the superiority of cetuximab plus RT over RT alone in the primary treatment setting, while CONCERT-2 (Giralt et al., 2015) and HN.6 (Siu et al., 2017) have shown mixed results with regards to panitumumab (another mAb against EGFR) versus cisplatin in the primary treatment setting.Bernier et al. (2004) observed a median time to death of 72 months in patients treated with postoperative irradiation and Cisplatin vs 32 months after RT alone in locally advanced head and neck cancer.Median OS in our study was 20.5 months.The difference in OS is likely related to study design, setting and highly selected patient population.
Advanced age has generally been associated with worse OS in multiple studies (Chen, Harris, Hara, Sirjani & Divi, 2016, Choi et al., 2016) although in our study advanced age correlated with a superior OS.The higher OS was observed in an individual as well as a stratified approach based on the age-groups.Young patients had high comorbidity scores, which may be the contributing factor to poor survival in those patients.Further studies are warranted given the limited sample size and inclusion of Carboplatin-based regimens in addition to Cetuximab in our study.It would be intriguing if our findings are confirmed on a large-scale because adjuvant CRT other than Cisplatin may be an alternate option for geriatric patients with stage III or IV high-risk HNSCC who do not tolerate and/or are poor candidates for Cisplatin.
Comorbidity strongly influences the outcomes of cancer patients through direct consequences of comorbid conditions and affecting the tolerability for chemotherapy (Skillington, Kallogjeri, Lewis Jr. & Piccirillo, 2016).Multiple studies have shown adverse relationship of comorbidity with OS (Paleri, Wight & Davies, 2003, Datema, Ferrier, van der Schroeff & Baatenburg de Jong, 2010).Our analysis inherently focused on the high-risk HNSCC population and we used an individual as well as a stratified approach to study the outcome.Our findings corroborate with those of Skillington et al. (2016) that OS is negatively affected by severe comorbidity.We suggest judicious use of adjuvant CRT in patients with severe comorbidities.Continued research for agents that are better tolerated should be pursued for patients with high-risk HNSCC and severe coexisting illnesses.Mell et al. (2010) reported an inferior OS in women.Median OS was higher in males in our study but not statistically significant.Mixed results exist as to whether positive resection margins impact survival (Haque, Contreras, McNicoll, Eckberg & Petitti, 2006, Binahmed, Nason & Abdoh, 2007, Brandwein-Gensler et al., 2005).Majority of the studies associate positive resection margins with poor survival.ECS has long been recognized as a pertinent adverse prognostic factor in HNSCC at all sites (Kharytaniuk et al., 2016).Pathologic features including ECS, perineural infiltration, and lymphovascular invasion have been associated with poor locoregional control (Langendijk, Slotman, van der Waal, Doornaert, Berkof & Leemans, 2005).In our study, the median survival was lower in patients with ECS or lymphovascular invasion and higher in patients who had clear margins of resection or perinerual infiltration, but these differences did not reach statistical significance.
Patients with HPV-associated HNSCC show better survivals as compared to HPV-negative tumors (Fakhry et al., 2008, Ang et al., 2010).High-risk HPV didn't impact OS in our study, and the disparity is likely due to fewer cases with documented HPV-status.A review of literature showed that patients with higher BMI had increased OS as compared to underweight and normal weight patients (Hollander, Kampman & van Herpen, 2015).Our study cohort did not show any correlation between BMI and OS.There was unequal distribution of patients in the categories based on WHO BMI classification.Increased alcohol consumption and smoking have been associated with unfavorable outcomes in HNSCC (Chen et al., 2011, Miller, Day & Ravenel, 2006, Mayne, Cartmel, Kirsh & Goodwin Jr., 2009, Deleyiannis, Thomas, Vaughan & Davis, 1996).We did not observe any correlation between smoking or alcohol intake and OS.Interestingly, patients who experienced grade ≥ 2 Cetuximab-induced skin rash had better OS than those with grade 1 or no rash (Bonner et al., 2010).Grade 3-4 chemotherapy or irradiation-induced toxicity had no impact on survival in our study.
Our study is limited by its retrospective design and the external validity of our results may be limited to patients treated in similar tertiary care settings.Sample size was small and the long study period may have included outdated supportive care practices.Nonetheless, our observations are important and should contribute to current literature on outcomes after adjuvant treatments for stage III and IV high-risk HNSCC patients.

Conclusions
Adjuvant chemoradiation therapy other than Cisplatin in high-risk stage III or IV HNSCC patients is associated with a median OS of 20.5 months.Young age and severe comorbidity are prognostic of poor OS.Our results suggest that adjuvant CRT other than Cisplatin should be used with caution in high-risk HNSCC patients although patients with severe co-illnesses may benefit from the addition of Cetuximab.More research in the form of a Phase II multicenter study would be needed to confirm our findings.

Figure 1 .
Figure 1.Kaplan-Meier Survival Curves based on age-groups.Patients with age-group ≤60 years, 61-70 years, ≥71 years were compared to each other and a statistically significant superior OS in older patients was observed (p=0.016).

Figure 2 .
Figure 2. Kaplan-Meier Survival Curves based on age-groups.Patients with age range of 61-70 years are compared to those with ≥71 years at the time of diagnosis.The OS was significantly lower in 61-70 years age group (p=0.049).

Figure 3 .
Figure 3. Kaplan-Meier Survival Curves based on age-groups.Patients with age range of ≤60 years are compared to those with ≥71 years at the time of diagnosis.The OS was significantly lower in the group with age range of ≤60 years (p=0.003).

Figure 4 .
Figure 4. Kaplan-Meier Survival Curves based on the Charlson Comorbidity Index Score.Patients with low scores of 0-2 are compared to those with high scores, 3-8.The OS was significantly higher in the group with scores of 0-2 (p=0.0009).

Table 1 .
Clinical Details of the entire cohort comprising of 18 HNSCC patients who received adjuvant CRT other than Cisplatin Radiation therapy Median OS was 20.5 months in all patients.Median OS in patients who received Cetuximab was 19 months.Mean survival was 29 months in those who got carboplatin, 25.5 months in Carboplatin+5-Fluorouracil+Cetuximab and 8 months in patients who received Paclitaxel+5-Fluorouracil+Hydroxyurea.Median age at diagnosis was 66 years (age-range = 49-80 years).OS was inferior in young patients (HR, 0.91; 95%CI 0.85-0.98,p=0.013).In addition, we conducted an age-group (≤60 years, 61-70 years, ≥71 years) based analysis to assess whether OS was influenced by increased age and observed a statistically significant superior OS in older patients(HR, 4.02; 95%CI, p=0.016).Median OS was 20 months in patients aged ≤60 years, 19 months in patients 61-70 years of age, and 31 months in patients who were ≥71 years.Majority of patients were Caucasians (n=17, 94.44%).As ethnicity was not widely distributed in our study cohort, the OS was not assessed based on it.Males represented two-thirds of our study cohort.We observed no statistical difference in OS between male or female patients (HR, 2.49; 95%CI, 0.61-10.06).Median OS was 21.5 months in males vs 17 months in females (p = 0.184).