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Tobacco Smoking During Radiation Therapy for Head-and-Neck Cancer Is Associated With Unfavorable Outcome
Abstract
To evaluate the effect of continued cigarette smoking among patients undergoing radiation therapy for head-and-neck cancer by comparing the clinical outcomes among active smokers and quitters.
A review of medical records identified 101 patients with newly diagnosed squamous cell carcinoma of the head and neck who continued to smoke during radiation therapy. Each active smoker was matched to a control patient who had quit smoking before initiation of radiation therapy. Matching was based on tobacco history (pack-years), primary site, age, sex, Karnofsky Performance Status, disease stage, radiation dose, chemotherapy use, year of treatment, and whether surgical resection was performed. Outcomes were compared by use of Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer toxicity criteria.
With a median follow-up of 49 months, active smokers had significantly inferior 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and disease-free survival (42% vs. 65%) compared with the former smokers who had quit before radiation therapy (p < 0.05 for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of Grade 3 or greater late complications was also significantly increased among active smokers compared with former smokers (49% vs. 31%, p = 0.01).
Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcomes. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.
... These observations are consistent with a recent and sole publication negatively linking SHS exposure to HNSCC prognosis [24]. Although the data on SHS impact on patient prognosis are scarce, active tobacco smoking at the time of HNSCC diagnosis has been consistently associated with lower rates of complete response to platinum-based induction chemotherapy and radiotherapy [23,42,43]. HNSCC patients who are active smokers during radiation therapy also have significantly lower locoregional control, disease-free survival, and five-year overall survival, than former smokers or never-smokers [43,44]. ...
... Although the data on SHS impact on patient prognosis are scarce, active tobacco smoking at the time of HNSCC diagnosis has been consistently associated with lower rates of complete response to platinum-based induction chemotherapy and radiotherapy [23,42,43]. HNSCC patients who are active smokers during radiation therapy also have significantly lower locoregional control, disease-free survival, and five-year overall survival, than former smokers or never-smokers [43,44]. Given the similarity of the composition of mainstream and SS smoke, our data strongly suggest that like active smoking, exposure to SHS during HNSCC patient's cisplatin treatment may reduce the therapeutic efficacy and lead to poor prognosis. ...
Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers’ saliva and treated with cisplatin (0.01–100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC50, and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells’ capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.
... Prognostic factors reported in clinical studies are: age (9)(10)(11); T-staging (12)(13)(14); N-staging (12)(13)(14)(15); clinical stage (16)(17)(18); tumor volume (19)(20)(21); histological type (12,20,22); radiotherapy technique (22); total dose of radiotherapy (19,20,23); number of chemotherapy cycles (24); albumin level (25); hemoglobin level (13,26); thrombocyte-lymphocyte ratio (27,28); lymphocyte-monocyte ratio (21,29); neutrophil-lymphocyte ratio (29)(30)(31); and EBV status (32,33). The negative impact of cigarette smoking on survival has been reported for various types of tumors (34)(35)(36)(37)(38)(39)(40)(41)(42)(43). The evidence on the role of smoking in the prognosis of patients with nasopharyngeal carcinoma is sparse, reported mainly from endemic areas of occurrence. ...
... The negative impact of cigarette smoking on survival has been reported for various types of tumors (34)(35)(36), including head and neck cancers (37)(38)(39)(40)(41)(42)(43). As cigarette smoking is an adverse lifestyle factor contributing to global cancer deaths (44), its prognostic value for nasopharyngeal carcinoma has also recently attracted research attention. ...
Background/aim:
To evaluate the effectiveness of curative (chemo)radiotherapy in patients with nasopharyngeal carcinoma and to identify prognostic factors influencing treatment outcomes.
Patients and methods:
We conducted a retrospective study of 73 consecutive patients, treated with definitive (chemo)radiotherapy from 2002 to 2019 (median stage III/IV 78%). The median total dose of radiotherapy achieved was 70 Gy. Concomitant chemotherapy was given to 82% of patients.
Results:
The five- and ten-year locoregional controls were 73% and 72%, respectively; the five- and ten-year distant controls were 93% and 93%, respectively. The five- and ten-year overall survival rates were 46% and 34%, respectively. A multivariate analysis identified age, smoking, and the initial response to treatment as the strongest prognostic factors in predicting survival.
Conclusion:
Smoking ≤5 years before starting curative (chemo)radiotherapy for nasopharyngeal carcinoma was shown to be an independent negative prognostic factor for overall survival with a four-fold higher risk of death compared to non-smokers.
... In general, cigarette smoking during radiation therapy for various cancers was reported to be associated with poor therapeutic results [2,3], and it was hypothesized that smoking induces hypoxia in the tumor environment and attenuates the effect of radiation on tumors [4][5][6]. Especially for head and neck tumors, several studies reported that smoking was an important factor that worsens the prognosis for overall survival (OS) rate, local control rate, and complications [7][8][9][10]. However, these studies included head and neck tumors of all regions, and the effects on tumors in individual regions remain unknown. ...
... This retrospective study analyzed the effect of the complete smoking cessation on definitive radiation therapy for early stage glottic carcinoma and confirmed there were significant differences in local control and survival between the complete smoking cessation and no smoking cessation patients by monitoring expiratory CO. Several studies have assessed the effects of smoking on radiation therapy [2,7,8,10]. However, these studies used medical interviewing or monitoring of cotinine, which is a metabolite of nicotine, for evaluating smoking cessation. ...
Background
Previous studies reported that cigarette smoking during radiation therapy was associated with unfavorable outcomes in various cancers using medical interviewing or monitoring of cotinine. Here, we evaluated the effect of smoking cessation on definitive radiation therapy for early stage glottic carcinoma by monitoring expiratory carbon monoxide (CO).
Material and methods
We enrolled 103 patients with early glottic carcinoma (T1N0/T2N0 = 79/24) who underwent conventional radiotherapy between 2005 and 2016. The median age was 70 years. Pathologically, all patients had squamous cell carcinoma. Since 2009, we confirmed smoking cessation before radiation therapy by medical interviews. Since 2014, we measured expiratory CO to strictly monitor smoking cessation. The patients were divided according to diagnosis years: ‘no cessation’ (2005–2008), ‘incomplete cessation’ (2009–2013), and ‘complete cessation’ (2014–2016). We retrospectively analyzed the local recurrence rate and disease-free survival (DFS).
Results
The median follow-up period was 60.1 months (range, 1.9–110.0 months). The 2-year local recurrence rate in the ‘complete cessation’ group was 5.3% and tended to be lower than that in the ‘incomplete cessation’ group (13.7%) and ‘no cessation’ group (21.2%). Multivariate analysis revealed that ‘no cessation’ was a risk factor for DFS (hazard ratio [HR] = 4.25) and local recurrence rate (HR = 16.5, p < .05) compared to ‘complete cessation.’
Discussion
We confirmed that the ‘complete cessation’ group had better prognosis than the ‘no cessation’ group by monitoring expiratory CO during radiation therapy for early stage glottic carcinoma. Moreover, monitoring expiratory CO was easier and more suitable than conventional methods for evaluating smoking cessation because it provided real-time measurements.
... Additionally, the treatment efficacy of HNSCC is also impaired in current smokers. Where the five-year overall survival (OS) of smokers were significantly less compared to matched nonsmokers (22% difference in 5 year -OS) (Chen et al. 2011). Chen et al also reported a higher radiotherapy related toxicity rate and a significantly higher rate of post-surgical complications in current smokers (Chen et al. 2011). ...
... Where the five-year overall survival (OS) of smokers were significantly less compared to matched nonsmokers (22% difference in 5 year -OS) (Chen et al. 2011). Chen et al also reported a higher radiotherapy related toxicity rate and a significantly higher rate of post-surgical complications in current smokers (Chen et al. 2011). There has been a significant reduction in tobacco smoking in Australia, United Kingdom, and the United States of America (Jethwa and Khariwala 2017). ...
Head and neck cancer is debilitating with poor patient outcomes associated with advanced stages of disease. There is a paucity of clinically validated biomarkers capable of early detection of head and neck cancer
This thesis investigated the use of exhaled breath and circulating blood as minimally invasive methods of detecting head and neck cancer. Findings indicated that exhaled volatile breath compounds and circulating blood microRNAs are capable of accurately detecting head and neck cancer.
Five studies were published during the candidature indicating the feasibility, high sensitivity and high specificity for both blood and breath tests. Hence, showing promise as minimally invasive detection methods for head and neck cancer to improve patient outcomes in the future.
... Tobacco, particularly tobacco smoke, is rich in polycyclic aromatic hydrocarbons and nitrosamines, which are known human carcinogens [5,7]. These toxic chemicals are associated with a strongly increased risk of HNSCC [5,7], negatively affect the pharmacodynamics of anticancer drugs [8][9][10], and reduce the efficacy of radiation [11,12] and immune therapy [13,14]. Tobacco smoking, both before and after cancer diagnosis, is an established negative prognostic factor for patients with HNSCC [4,14]. ...
We studied the gene-expression patterns in specimens of tumor and peritumor tissue biopsies of 26 patients with head and neck carcinomas depending on smoking status. Histological and immunohistochemical examinations verified that all tumors belonged to the “classical” subgroup of head and neck carcinomas, and the HPV-negative tumor status was confirmed. The expression of 28 tumor-associated genes determined by RT-PCR was independent of patients’ sex or age, TNM status, degree of differentiation, or tissue localization. Moreover, in peritumor tissue, none of the 28 genes were differentially expressed between the groups of smoking and nonsmoking patients. During oncotransformation in both studied groups, there were similar processes typical for HNSCC progression: the expression levels of paired keratins 4 and 13 were reduced, while the expression levels of keratin 17 and CD44 were significantly increased. However, further investigation revealed some distinctive features: the expression of the genes EGFR and TP63 increased significantly only in the nonsmoking group, and the expression of IL6, CDKN2A, EGF, and PITX1 genes changed only in the smoking group. In addition, correlation analysis identified several clusters within which genes displayed correlations in their expression levels. The largest group included 10 genes: TIMP1, TIMP2, WEE1, YAP, HIF1A, PI3KCA, UTP14A, APIP, PTEN, and SLC26A6. The genetic signatures associated with smoking habits that we have found may serve as a prerequisite for the development of diagnostic panels/tests predicting responses to different therapeutic strategies for HNSCC.
... These findings are in keeping with the known unfavourable outcomes associated with tobacco smoking during radiotherapy in head and neck cancer. 30 There is limited data regarding the impact of HIV status in NPC in the literature. In this study, we observed that an HIV-positive status was a significant favourable prognostic factor for OS. ...
Background: Data on treatment outcomes of Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC) largely comes from endemic regions. There is limited literature regarding the epidemiology and treatment outcomes of EBV-associated NPC in South Africa.Aim: The aim of the study was to compare overall survival (OS) of EBV positive and EBV negative NPC patients.Setting: Groote Schuur Hospital, South Africa.Methods: Data were collected on all patients with histologically confirmed NPC over an 11-year period, including prevalence of EBV, OS, disease-free survival (DFS), loco-regional control (LRC), and impact of treatment interruptions on OS.Results: There were 53 patients in total. Non-keratinising carcinoma was the primary histological subtype (86.8%). The majority of patients had EBV positive NPC (47.2%). The 2- and 5-year OS of EBV positive patients treated with curative intent were significantly higher than EBV negative patients, 84.0% versus 34.0% and 45.0% versus 17.0%, respectively (hazard ratio [HR] 0.25, 95% confidence interval [CI]: 0.10–0.63, p = 0.002). Two-year DFS was 55.0% versus 43.0% (HR: 0.59, 95% CI: 0.18–1.98, p = 0.38) and 2-year LRC were 76.2% versus 46.2% (HR: 0.40, 95% CI: 0.12–1.36, p = 0.13) for EBV positive and EBV negative patients respectively.Conclusion: Treatment of EBV-associated NPC is associated with superior OS compared to EBV negative tumours.Contribution: Epstein-Barr virus was found to be a significant prognostic factor associated with superior OS compared to EBV negative NPC. These findings correlate with literature from endemic and non-endemic regions.
... Bearing in mind malignant neoplasms of the head and neck are common around the world, in its turn, smoking is involved in carcinogenesis, tumor progression, and therapeutic interventions as an independent risk factor of HNSCC (Jethwa and Khariwala 2017). The large-sample cohort study (n = 25,471) indicated smoking patients had a twofold higher risk of developing HNSCC than non-smokers (Hashibe et al. 2007), which compared with the former smokers with HNSCC, Chen et al. found that current smokers had a significantly worse 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and diseasefree survival (42% vs. 65%) during radiation therapy (Chen et al. 2011). What is more, HNSCC patients undergoing surgery had a six-fold complication rate if they had a history of tobacco use compared to non-smokers (Hatcher et al. 2016). ...
As a well-known behavioral risk factor for human health, smoking is involved in carcinogenesis, tumor progression, and therapeutic interventions of head and neck squamous cell carcinoma (HNSCC). The stratification of disease subtypes according to tobacco use is expressively needed for HNSCC precision therapy. High-throughput transcriptome profiling by RNA sequencing (RNA-seq) from The Cancer Genome Atlas (TCGA) was collected and collated for differential expression analysis and pathway enrichment analysis to characterize the molecular landscape for non-smoking HNSCC patients. Molecular prognostic signatures specific to non-smoking HNSCC patients were identified by the least absolute shrinkage and selection operator (LASSO) analysis and were then verified via internal and external validation cohorts. While proceeding to immune cell infiltration and after drug sensitivity analysis was further carried out, a proprietary nomogram was finally developed for their respective clinical applications. In what it relates to the non-smoking cohort, the enrichment analysis pointed to human papillomavirus (HPV) infection and PI3K-Akt signaling pathway, with the prognostic signature consisting of another ten prognostic genes (COL22A1, ADIPOQ, RAG1, GREM1, APBA2, SPINK9, SPP1, ARMC4, C6, and F2RL2). These signatures showed to be independent factors, and the related nomograms were, thus, constructed for their further and respective clinical applications. While the molecular landscapes and proprietary prognostic signature were characterized based on non-smoking HNSCC patients, a clinical nomogram was constructed to provide better HNSCC patient classification and guide treatment for non-smoking HNSCC patients. Nonetheless, there are still significant challenges in the recognition, diagnosis, treatment, and understanding of the potentially efficient mechanisms of HNSCC with no tobacco use.
... Intense smoking (as defined as >20 cigarettes/day) was also an independent prognostic factor for OS among patients with oral cavity cancer. On the contrary, among patients with laryngeal cancer, low educational level was rather a deleterious prognostic factor for OS; moreover, the intensity of alcohol drinking was the prognostic factor for both of the OS and head-and-neck-cancer-specific survival [63]. ...
Squamous cell carcinoma of head and neck (SCCHN) is the most common cancer arising in the head and neck region. Smoking and heavy alcohol drinking are still the well-established causes of most cases worldwide; however, human papillomavirus (HPV) infection is the concerning cause in the Western world. The different pathogenesis, pathophysiology, and prognosis between HPV-driven and non-HPV SCCHN would lead to the different treatment approaches. Breakthroughs in radiation techniques, better organ-preserving surgical strategies, and multidisciplinary management modalities are the major reasons for the curability rate among patients with early and locally advanced SCCHN. Unfortunately, among patients with advanced, recurrent, or metastatic diseases, the treatment remains an area of need. Such patients usually die within a few years. The immune checkpoint inhibitors have been shown to provide astonishingly better survival, but only among a small and not definitely known proportion of patients. Investigating the more specific biomarkers predicting the treatment response and novel therapeutic options is warranted. In this review, we highlight the latest advances in pathophysiology, treatment, and the future direction of researches.
... We also emphasize to our patients that an important reason to abstain from smoking is that the smokers have lower rates of response during radiotherapy and significantly lower survival rates than nonsmokers. 19,[25][26][27][28][29] Preoperative radiotherapy with doses over 60 Gy and previous surgery are considered risks for free flap loss 1,6,23,30 and wound complications. 6 Radiotherapy causes macro-and microscopic alterations in blood vessels, which can subsequently lead to free flap loss. ...
Background Free flap reconstruction is the gold standard in head and neck reconstructions. The current article analyzes failed free flaps in the head and neck region during an 11-year period in a single center aiming to discover factors that could be influenced in order to reduce the risk for flap failure.
Methods During the 11-year study period, 336 patients underwent free flap reconstruction at Tampere University Hospital, Tampere, Finland. The patients' average age was 62 years (range 14–92 years). Note that 201 (61.5%) of the patients were women and 135 (38.5%) men. Medical records were reviewed for demographics, comorbidities, neoadjuvant and adjuvant therapies, free flap type, area of reconstruction, and intraoperative and postoperative complications. Statistical analyses were performed.
Results Ten (3%) of the 336 free flaps failed. Patients' age, comorbidities, smoking, dosage of anticoagulation, free flap type, or the location of the defect did not influence the risk of flap failure. All lost flaps were postoperatively followed by clinical monitoring only. In contrast, 89% of all flaps had both Licox (Integra LifeSciences Corp, NJ) and clinical follow-up postoperatively. In six (60%) of the failed cases, a second free flap surgery was performed as a salvage procedure, with a survival rate of 83.3%.
Conclusion Our free flap success rate of 97% is in accordance with that of other centers that perform head and neck reconstructions. According to our findings, free flap reconstructions can be successfully performed on elderly patients and patients with comorbidities. Smoking did not increase the flap loss rate. We encourage the use of other methods in addition to clinical monitoring to follow the flaps after head and neck free flap reconstructions. All flap types used have high success rates, and reconstruction can be conducted with the most suitable flaps for the demands of the defect.
... Tobacco smoking has been shown to reduce the efficacy of radiation therapy among patients with head and neck cancer. [1][2][3][4] Given the importance of smoking, a secondary analysis of the Radiation Therapy Oncology Group 0129 trial established 10 pack-years of smoking as a threshold of risk stratification for survival in the context of human papillomavirus (HPV). 5 The 10 pack-year threshold has been incorporated to identify patients potentially eligible for treatment deintensification. ...
Importance:
After 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear.
Objective:
To estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer.
Design, setting, and participants:
This single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022.
Exposures:
Heavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic.
Main outcomes and measures:
Overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF).
Results:
A total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01).
Conclusions and relevance:
In this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.
... Multiple risk factors, including host genetics, Epstein-Barr virus (EBV) infection, and environmental factors, had been confirmed to contribute to the development of NPC [2]. Tobacco is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC) [3], and has proven to be a significant predictor of a poor prognosis for patients with a wide variety of malignancies [4,5], including head and neck tumors [6,7] such as oropharyngeal and laryngeal carcinomas [8,9]. ...
Background
This retrospective study was performed to determine the prognostic potential of smoking and its combination with pre-treatment plasma Epstein-Barr virus (EBV) DNA levels in patients with nasopharyngeal carcinoma (NPC).
Methods
Medical records of 1080 non-metastatic NPC patients who received intensity-modulated radiotherapy were reviewed. Male patients were categorized as never and ever smokers, and the smoking amount, duration, and cumulative consumption were used to evaluate dose-dependent effects. Survival outcomes were assessed using Kaplan-Meier survival analysis and the multivariate Cox regression analysis. Propensity score matching (PSM) was constructed.
Results
The 5-year overall survival (OS) was worse for ever smokers than never smokers, and significantly decreased with the increase of smoking amount, duration, and cumulative consumption. Compared with never smokers, the multivariate-adjusted hazard ratio (HR) of death was higher in ever smokers (HR = 1.361, P = 0.049), those smoked ≥20 cigarettes/day (HR = 1.473, P = 0.017), those smoked for ≥30 years (HR = 1.523, P = 0.023), and those cumulative smoked for ≥30 pack-years (HR = 1.649, P = 0.005). The poor prognostic effects of smoking was also confirmed in the PSM analysis. The combination of cumulative smoking consumption and pre-treatment EBV DNA levels was proven to be an independent poor prognostic factor for male NPC, and the risk of death, progression, and distant metastases gradually increased with both factors ( P < 0.001).
Conclusions
Combination of smoking and pre-treatment EBV DNA levels as a predictor of poor prognosis could further improve the risk stratification and prognostication for NPC.
... A relationship between past or current tobacco uses on mucositis risk is unclear. Reports of tobacco smoking having no effect on the rate of acute radiation-associated toxicities including mucositis [32] are contradicted by reports that tobacco use is protective of oral mucositis [33,34] or that smoking adds the risk of mucositis [35,36]. ...
Oral complications of cancer therapy are common, markedly symptomatic, negatively impact patients' quality of life, and add significantly to the cost of care. Patients' risk of treatment-related toxicities is not uniform; most patients suffer at least one side effect, while others tolerate treatment without any. Understanding those factors which impact risk provides opportunities to customize cancer treatment plans to optimize tumor kill and minimize regimen-related toxicities. Oral mucositis (OM) is an iconic example of a clinically significant and common complication of head and neck radiotherapy. Individuals' OM risk is governed by the cumulative impact of factors related to treatment, the tumor, and the patient. In addition to OM risk prediction, a second opportunity to apply precision medicine will evolve as viable treatment options become available. Patients vary widely in how well or poorly they respond to specific treatments. What works well in one individual, might fail in another. Prospective determination of the likelihood of a patient's response or non-response is based on a range of biological interactions. Coupled with risk determination, the application of precision medicine will allow caregivers, patients, and payers to integrate risk/benefit to optimize the probability that the best treatment is be given to the most appropriate patients.
... Smoking among individuals with a cancer diagnosis is associated with increased treatment toxicity, diminished effectiveness of cancer treatment, increased risk of recurrence and diagnosis of second primary cancer [5][6][7][8][9][10][11][12]. Additionally, persistent smoking for those with a cancer diagnosis can cause increased risk of complications from surgery, radiation, and chemotherapy [13][14][15][16][17][18][19] and contribute to poor quality of life and decreased survival rates [1,20,21]. As such, promoting smoking cessation among individuals with a cancer diagnosis is a critical aspect of high quality cancer care [1,[22][23][24][25]. ...
Background
Persistent smoking among patients diagnosed with cancer is associated with adverse clinical outcomes, yet an evidence-based tobacco use intervention has not been well-integrated into cancer care in community oncology settings. This paper describes the protocol of a nation-wide clinical trial conducted by the ECOG-ACRIN National Cancer Institute (NCI) Community Oncology Research Program (NCORP) Research Base to assess the effectiveness of a virtual tobacco treatment intervention and the process of implementing tobacco treatment in NCORP community oncology settings.
Methods/design
This two-arm, multisite (n: 49 NCORP sites) hybrid type 1 effectiveness-implementation randomized controlled trial compares the effectiveness of a Virtual Intervention Treatment (VIT) versus an Enhanced Usual Control (EUC) among English and Spanish speaking patients recently diagnosed with cancer, reporting current smoking and receiving care at a participating NCORP Community or Minority/Underserved Site. The VIT includes up to 11 virtual counseling sessions with a tobacco treatment specialist and up to 12 weeks of nicotine replacement therapy (NRT). The EUC arm receives a referral to the NCI Quitline. The primary study outcome is biochemically confirmed 7-day point prevalence smoking abstinence. Moderators of treatment effect will be assessed. The study evaluates implementation processes from participating NCORP site staff via survey, administrative, and focus group data, including reach, acceptability, appropriateness, fidelity, feasibility, adoption, cost and sustainability outcomes.
Discussion
This trial will generate findings about the effectiveness of an evidence-based virtual tobacco treatment intervention targeting patients diagnosed with cancer and illuminate barriers and facilitators that influence implementing tobacco treatment into community oncology settings nationally. In the era of COVID-19, virtual care solutions are vital for maximizing access and utilization of tobacco treatment delivery.
Trial registration
ClinicalTrials.gov (NCT03808818) on January 18th, 2019; Last update posted: May 21st, 2020.
... One of these factors is problem alcohol use, a known risk factor for the development of HNC; continued alcohol use after diagnosis is associated with several negative outcomes including cancer recurrence, significant physical comorbidities, and poor psychosocial outcomes including depression and reduced HNC-specific HRQOL [14][15][16][17][18]. Estimates suggest that upwards of thirty percent of HNC patients demonstrate problem alcohol use and many continue to consume alcohol into the survivorship period [19][20][21]. Similarly, tobacco use is an etiologic factor in HNC development and continued use after diagnosis is associated with second primary cancer, elevated risk of cancer recurrence, poor response to treatment, and negatively impacted HRQOL [22][23][24][25]. These two behaviors often co-occur and together act to multiply risk for a host of negative outcomes in HNC [26]. ...
Purpose:
Problem alcohol and tobacco use in patients with head and neck cancer (HNC) frequently co-occur and each are associated with poor outcomes including health-related quality of life (HRQOL). The purpose of this descriptive exploratory study was to identify the prevalence of these co-occurring behaviors and associations with HNC-specific HRQOL within the first year of diagnosis in a large sample of patients with HNC.
Methods:
Cross-sectional study examined prevalence of co-occurring problem alcohol and tobacco use at diagnosis in a large sample of patients with HNC (N = 1327). Problem alcohol use was assessed using the Short Michigan Alcoholism Screening Test (SMAST); patients were classified as current/previous/never smokers based on self-reported tobacco use. HNC-specific HRQOL was assessed using the Head and Neck Cancer Inventory (HNCI), measured at diagnosis and 3 and 12 months postdiagnosis.
Results:
Three hundred twenty-five of 1327 (24.5%) scored 3 + on the SMAST at diagnosis, suggesting problem alcohol use and nearly 30% (28.4%) were current smokers. Of those with problem alcohol use, 173 (53.2%) were also current smokers. In total, 173 of 1327 (13.0%) exhibited both behaviors at diagnosis. Covariate-adjusted mean HNCI scores suggest that patients classified as both problem drinkers and current smokers have lower HRQOL scores during the first year postdiagnosis in multiple HNC-specific domains.
Conclusion:
HNC patients should be screened for alcohol and tobacco use at diagnosis. Multimodal behavioral health interventions may provide one avenue for improved access and outcomes, particularly for patients at distance, and deserve further study in HNC.
... In the current model, the lack of co-morbidity parameters might explain the reduced prediction power in the hypofractionated patients since these patients are evaluated by the oncologist to be a more frail group. Smoking has been shown to be one of the leading causes of larynx cancer [23], and even smoking during RT has also been shown to reduce the efficacy of the treatment [24]. Thus inclusion of smoking in a future model might be warranted. ...
Introduction
Prediction models are useful to design personalised treatment. However, safe and effective implementation relies on external validation. Retrospective data are available in many institutions, but sharing between institutions can be challenging due to patient data sensitivity and governance or legal barriers. This study validates a larynx cancer survival model performed using distributed learning without any sensitive data leaving the institution.
Methods
Open-source distributed learning software based on a stratified Cox proportional hazard model was developed and used to validate the Egelmeer et al. MAASTRO survival model across two hospitals in two countries. The validation optimised a single scaling parameter multiplied by the original predicted prognostic index. All analyses and figures were based on the distributed system, ensuring no information leakage from the individual centres. All applied software is provided as freeware to facilitate distributed learning in other institutions.
Results
1745 patients received radiotherapy for larynx cancer in the two centres from Jan 2005 to Dec 2018. Limiting to a maximum of one missing value in the parameters of the survival model reduced the cohort to 1095 patients. The Harrell C-index was 0.74 (CI95%, 0.71-0.76) and 0.70 (0.66-0.75) for the two centres. However, the model needed a scaling update. In addition, it was found that survival predictions of patients undergoing hypofractionation were less precise.
Conclusion
Open-source distributed learning software was able to validate, and suggest a minor update to the original survival model without central access to patient sensitive information. Even without the update, the original MAASTRO survival model of Egelmeer et al. performed reasonably well, providing similar results in this validation as in its original validation
... Studies suggest that smoking is associated with the formation and recurrence of colorectal adenomatous polyps [8] and with increased colorectal cancer incidence and mortality [2,[9][10][11][12][13]. Across cancer types, continued smoking limits the effectiveness of cancer treatments; increases the risk of complications from treatment and of developing cancer recurrence or secondary malignancies; and is associated with poorer quality of life and worse overall survival [5,[14][15][16][17][18][19][20]. ...
Background
Continued smoking after a cancer diagnosis limits the effectiveness of treatment, increases the risk of cancer recurrence or secondary malignancies, and is associated with poorer quality of life and survival. A cancer diagnosis may provide a meaningful timepoint for quitting, but the prevalence and characteristics of continued smoking through survivorship are poorly understood.
Methods
In the multi-regional Cancer Care Outcomes Research and Surveillance (CanCORS) cohort, we examined smoking rates and factors associated with continued smoking at long-term follow-up among lung and colorectal cancer patients. This paper builds upon previous CanCORS participant data addressing quit rates and associated characteristics at baseline and 5 months post-diagnosis.
Results
At long-term follow-up (median 7.3 years post-diagnosis [IQR = 5.9–8.7]), 16.7% of lung cancer and 11.6% of colorectal cancer survivors continued to smoke combustible cigarettes. Factors independently associated with continued smoking at long-term follow-up included being male, younger, not married or partnered, having Medicare, Medicaid/other public or no insurance, more depression symptoms, smoking more cigarettes per day, and having a history of lung disease (p < .05). Continued smoking did not vary by lung vs. colorectal cancer diagnosis.
Conclusion
Of active smokers at the time of diagnosis, an important minority of lung and colorectal cancer survivors continued to smoke well into survivorship. Understanding characteristics associated with continued smoking after a cancer diagnosis may help inform the development of tobacco treatment programs for cancer patients and survivors.
Implications for survivors
While addressing smoking cessation at the time of diagnosis is critical to ensure better long-term treatment outcomes and quality of life, it is essential to continue smoking cessation discussions and efforts throughout care and survivorship.
... Insbesondere Larynxkarzinome sind überproportional häufig mit Tabakrauchen assoziiert. Fortgesetzter Tabakkonsum im Rahmen sowie nach erfolgter Tumorbehandlung eines Kopf-Hals-Tumors erhöht außerdem das Risiko für ein Tumorrezidiv und die Ausbildung eines Zweitkarzinoms [11,12]. Neben der negativen Beeinflussung des Überlebens zeigt sich ein kausaler Zusammenhang zwischen posttherapeutischer Fibrose und Tabakkonsum bei Patienten und Patientinnen mit Kopf-Hals-Tumoren [13]. ...
Every year, around 127,000 people in Germany die as a result of smoking tobacco. These include 85,000 people with tobacco-related cancer. However, about a quarter of the adult population in Germany still smokes—often even when a tobacco-related disease develops. Many smokers do not achieve abstinence without support. This article provides an overview of evidence-based tobacco cessation strategies and also describes the potential of tobacco cessation in the context of adjuvant therapy for tumor diseases. Finally, health policy challenges for tobacco cessation care are highlighted. A variety of psychological and pharmacological intervention methods for tobacco cessation are effective. Patients who smoke with tobacco-related diseases should be offered tobacco cessation therapy. As an adjuvant therapy in cancer treatment, it is comparatively inexpensive, with significant benefits for disease recovery and quality of life for those affected. To date, however, it has been offered in Germany only as a poorly regulated preventive measure. Tobacco cessation is of great importance as an adjuvant therapy for tumor diseases. In order to improve the quality of life of a large number of people with tobacco-related diseases, as well as for health economic reasons, it is urgently necessary that it become established and financed as a nationwide routine process in medical care.
... Kontynuowanie palenia po otrzymaniu diagnozy nowotworowej wpływa na zwiększone ryzyko powstawania komplikacji podczas leczenia. Obniża się reakcja pacjenta na radioterapię i chemioterapię, wzrasta ryzyko nawrotu choroby oraz powstawania nowych guzów nowotworowych, co składa się na pogorszenie jakości życia pacjentów oraz szans na wyleczenie [Chen 2011]. ...
Cancers are already a common disease in the society of the XXI century. They are responsible for the high mortality rate of the human population. Their presence is associated with the occurence of various types of air pollution, including tobacco smoke and dust pollution. Tar substances present in tobacco smoke are the main factor responsible for the development of lung and laryngeal cancer, and indirectly for the
occurrence of breast cancer, cardiovascular diseases and other diseases. The cumulative nature of substances contained in tobacco smoke is responsible for DNA strand damages, chromosomal aberrations or the induction of mutations that cause oncogenesis. Air pollution with dust particles is mainly related to the
industrialisation and is responsible for the presence of carcinogenic compounds in the atmosphere. The presence of polycyclic aromatic hydrocarbons (PAHs), including benzo(a)pyrene, in the air leads to the development of cancers. Its ability to accumulate in tissues is responsible for a strong correlation between the concentration of this compound and the occurrence of lung tumors.
... While the exact mechanism remains to be elucidated, this observation may be attributable to smoking-associated tissue hypoxia, which is detrimental for both radiation tumoricidal effect and neuronal regeneration. 19,20 Apart from the forementioned patient factors, neurological recovery of different cranial nerves also varied. The optic nerve had the lowest recovery potential. ...
Objectives
Cranial neuropathy is a common presenting symptom of advanced T4 nasopharyngeal carcinoma (NPC). Data on neurological outcomes after modern intensity-modulated radiotherapy (IMRT) and chemotherapy are scarce.
Materials and Methods
Case records of consecutive T4 NPC patients who received definitive IMRT in two tertiary oncology centers in 2004-2019 were reviewed. Patterns of cranial neuropathies at disease presentation were recorded. Time to neurological recovery and the rate of subsequent re-palsy were estimated by the Kaplan-Meier method. Clinical predictors were analyzed using multivariable Cox regression.
Results
During the study period, 257 T4 NPC patients presented with 504 individual cranial neuropathies. The median time from neuropathy onset to NPC diagnosis was two months (IQR, 1-4 months). Cranial nerves (CN) VI (56.4%), V2 (47.9%), and V3 (29.2%) were most frequently involved. At a median follow-up of 6.4 years, the crude partial and full recovery rates of neuropathies were 111 (22%) and 289 (57.3%) , respectively. CN III, IV, and VI had the highest 5-year full recovery rate (72.7%), followed by CN V1-3 (60.3%), XII (48.6%), and II (18.2%) (p<0.001). Positive smoking history, optic nerve involvement, and longer duration of neuropathy were independent negative predictors for neurological recovery. After full recovery, re-palsy was observed in 6.9% (20/289) of the nerves, 60% of which co-occurred with local NPC recurrences.
Conclusion
Durable recovery of most cranial neuropathies in advanced T4 NPC was observed in the era of modern IMRT and effective systemic chemotherapy. Both patient and disease factors affected the chance of neurological recovery. Re-palsy of recovered nerves should prompt careful evaluation for local recurrence.
... Due to physical properties of BT, locally delivered doses can exceed the prescription dose up to 200% in close proximity to the source position, resulting in higher strain to surrounding normal tissues, albeit to small volumes. It is also worth noting that the BT cohort had significantly more smoking patients, as smoking is associated with worse outcomes and increased late toxicity rates in HNC treated with radiation therapy 22 . ...
Background and purpose
Primary radiotherapy is often preferred for early-stage cancer of the nasal vestibule (CNV), combining high disease control with preservation of nasal anatomy. However, due to practice variation and an absence of comparative trials, no consensus exists on preference for brachytherapy (BT) or external beam radiotherapy (EBRT). We compared these modalities in terms of disease control, nose preservation rates and toxicity.
Materials and methods
Medical records of 225 patients with T1-T2 squamous cell carcinoma of the nasal vestibule treated with 3D image-guided primary radiotherapy between Jan 2010 and Dec 2016 in 6 Dutch institutions were reviewed retrospectively.
Results
153 of 225 patients were treated with BT, 65 with EBRT and 7 with other modalities. Median follow-up was 46 months. Overall 3-year local control (LC) and regional control (RC) were 87% and 89%. Five-year disease-specific survival (DSS) and overall survival (OS) were 94% and 82%. Three-year survival with preserved nose (SPN) was 76%.
BT provided higher 3-year LC (95% vs 71%, p<0·01) and SPN compared with EBRT (82% vs 61%, p<0·01). Multivariable and propensity-score-matched cohort analyses confirmed better outcomes after BT. No difference was seen in DSS or OS. Five-year incidence of CTCAE 5.0 grade ≥2 toxicity was higher after BT (20% vs 3%, p=0·03) and consisted mostly of radiation ulcers. 50% of all late toxicity recovered.
Conclusion
In this largest-to-date multicenter analysis of T1-T2 CNV, BT achieved superior LC and SPN compared with EBRT. Grade 1-2 radiation ulcers occurred more frequently after brachytherapy, but were transient in half the cases. Considering these results, BT can be recommended as first-line treatment for T1-T2 CNV.
... It is well known that smoking and alcohol contribute significantly to the development of laryngeal dysplasia and cancer. It has also been shown in several studies that smoking during radiation therapy is associated with unfavorable outcomes with one study by Chen et al. showing a decrease in 5-year survival rate (23% vs 55%), locoregional control (58% vs 69%), and disease-free survival (42% vs 65%) compared to smokers who quit prior to the initiation of radiation therapy [6]. A more recent study by Al-Mamgani et al. showed poor local control, lower overall survival rates, and a worse voice handicap index along with increased risk of second primary tumors [7]. ...
Opinion Statement
Dysplasia and early laryngeal cancer lie on a spectrum of cellular changes. These start with early changes to the cells including epithelial hyperplasia and expand to dysplasia, squamous cell carcinoma in situ and finally developing in to invasive cancer. Dysplasia can range from low to high grade, with each being treated in a different manner. Treatment options are typically determined by where the dysplasia/invasive cancer lie on this spectrum along with the site within the larynx. Hyperkeratosis, mild dysplasia and moderate dysplasia typically involve primary endoscopic excision. Severe dysplasia and squamous cell carcinoma in situ involve primary endoscopic resection with the addition of possible laser resection and/or ablation. At this stage, surgery will be followed by close surveillance. Finally, early laryngeal cancer such as T1 and T2 lesions is typically more involved. Treatment depends on the site and degree of involvement of the structures, along with spread to surrounding structures. Typical treatment options of more involved early laryngeal cancer can range from radiation therapy, endoscopic transoral laser resection, endoscopic transoral robotic resection to open resection. Often times, my choice of treatment will be aimed at voice preservation but patient preference will also play a role in the decision making between treatment modalities. Chemotherapy and immunotherapy are typically not used in early stage laryngeal cancer.
... e results showed that infection rates after SL were high, and univariate analysis demonstrated risk variables that had a significant correlation with infection, so the antibiotic regimen is probably ineffective. Other authors [41][42][43][44][45][46][47][48] presented an overview of current evidence-based best practices in the use of prophylactic antibiotics in head and neck cancer surgery; indeed, this type of patient is at high risk of developing complications after surgery. ...
Background:
The Health Technology Assessment (HTA) is used to evaluate health services, manage healthcare processes more efficiently, and compare medical technologies. The aim of this paper is to carry out an HTA study that compares two pharmacological therapies and provides the clinicians with two models to predict the length of hospital stay (LOS) of patients undergoing oral cavity cancer surgery on the bone tissue.
Methods:
The six Sigma method was used as a tool of HTA; it is a technique of quality management and process improvement that combines the use of statistics with a five-step procedure: "Define, Measure, Analyze, Improve, Control" referred to in the acronym DMAIC. Subsequently, multiple linear regression has been used to create two models. Two groups of patients were analyzed: 45 were treated with ceftriaxone while 48 were treated with the combination of cefazolin and clindamycin.
Results:
A reduction of the overall mean LOS of patients undergoing oral cavity cancer surgery on bone was observed of 40.9% in the group treated with ceftriaxone. Its reduction was observed in all the variables of the ceftriaxone group. The best results are obtained in younger patients (-54.1%) and in patients with low oral hygiene (-52.4%) treated. The regression results showed that the best LOS predictors for cefazolin/clindamycin are ASA score and flap while for ceftriaxone, in addition to these two, oral hygiene and lymphadenectomy are the best predictors. In addition, the adjusted R squared showed that the variables considered explain most of the variance of LOS.
Conclusion:
SS methodology, used as an HTA tool, allowed us to understand the performance of the antibiotics and provided variables that mostly influence postoperative LOS. The obtained models can improve the outcome of patients, reducing the postoperative LOS and the relative costs, consequently increasing patient safety, and improving the quality of care provided.
... However, none of these parameters fully explain the differences in treatment response for individual patients undergoing radiotherapy. Other patient characteristics, such as smoking status, age, and nutritional status [19,20] are also considered to be factors that influence radiotherapy response and prognosis, but it is still difficult to predict which patients will be completely relieved and which will not. This condition makes the treatment of a large number of patients inadequate, ineffective, or unnecessary. ...
Background
HNSCC (head and neck squamous cell carcinoma) is a heterogeneous disease for which radiotherapy is a main treatment. As intrinsic radiosensitivity and immune status affect the initial and effective stage of the radiation-induced cancer immunity cycle, respectively, it is important to consider both of them when we select patients who can benefit from radiotherapy.
Material/Methods
Our study included all HNSCC patients with complete survival and radiotherapy information in TCGA database. Patients were divided into RS (radiosensitive), RR (radioresistant), immune, and non-immune groups according to their RSI (radiosensitivity index) and immune score calculated by the ESTIMATE algorithm. Survival analysis was performed to compare OS (overall survival) between patients receiving and not receiving radiotherapy. GO and KEGG pathway enrichment analysis was performed for functional analysis. Univariate Cox and ridge regression analysis were performed to construct a predictive gene signature based on the combined stratification.
Results
Only patients in the RS-immune group could benefit from radiotherapy, and the survival analysis results remained consistent after we performed propensity score matching between patients receiving and not receiving radiotherapy. The differentially expressed genes between the RS-immune and non-RS-immune groups were mainly enriched in pathways related to immune process. The 3-gene signature we built exhibited predictive value in training and validation cohorts when treated as a binary or continuous variable.
Conclusions
The combined stratification of intrinsic radiosensitivity and immune status was superior to considering intrinsic radiosensitivity or immune status alone and could be used in preclinical evaluation to select patients or to decide whether radiotherapy sensitizers and immunotherapy should be used at the same time.
... Perhaps, one of the most potent and available strategies to tackle tumour hypoxia is smoking cessation. Studies have shown that current smokers have the highest risk of disease recurrence and toxicity from RT compared to "never smokers" [77][78][79][80]. Evidence exists that smoking cessation could reverse blood hypoxia levels immediately to the level of "never smokers" and the LRC of such "recent quitters" appears to revert to a similar level as "never smokers" [81]. ...
The majority of head and neck squamous cell carcinoma (HNSCC) is now classified into two major types: HPV-mediated [HPV(+)] and HPV-negative [HPV(−)]. Within this paradigm, the 8th edition TNM staging system effected modification about what is considered “locally-advanced” HNSCC. Two phase-III trials (RTOG 1016 and De-ESCALATE HPV) disappointingly showed that cetuximab is not as effective in HPV(+) oropharyngeal cancer (OPC) compared to cisplatin with radiotherapy. The recent NRG HN002 de-escalation trial demonstrated the presence of outcome heterogeneity within “low-risk” HPV(+) OPC, some of which continue to benefit from cisplatin combined with reduced-dose radiotherapy. Moreover, distant metastasis (DM) has consolidated its position as the leading cause of death in HPV(+) OPC and strategies to mitigate it are necessary. Unanswered questions and ongoing-emerging concepts exist in both HPV(+) and HPV– diseases. These include understanding the importance of risk under the rubric of extranodal extension (ENE), including degrees of pathological ENE (pENE), and emerging knowledge about radiologic ENE (rENE). Strategies addressing modification of biological phenomena have become paramount and includes hypoxia modification (such as smoking cessation). In addition, contemporary evidence suggests that immunotherapy improves survival in recurrent/metastatic settings, and it is now also being explored in primary disease presentations in combination with (chemo-)radiotherapy. Induction chemotherapy achieves DM reduction in nasopharyngeal cancer but has only been explored minimally in HPV(+) OPC. Evidence that loco-regional management can be de-intensified following a favorable response to induction treatment would provide an attractive option for HPV(+) OPSCC patients while also addressing risk of developing distant disease.
... Previous studies also reported higher late toxicity outcomes in smokers. [30][31][32] The largest differences were seen for coughing, use of tube feeding, nutritional supplements, and painkillers. Toxicity profiles per tumor site allow for the evaluation of site specific symptoms. ...
Purpose
Radiotherapy is an effective but burdensome treatment for head and neck cancer (HNC). We aimed to characterize the severity and time pattern of patient-reported symptoms and quality of life in a large cohort of HNC patients treated with definitive radiotherapy, with or without systemic treatment.
Material and methods
859 HNC patients treated between 2007 and 2017 prospectively completed the EORTC QLQ-HN35 and QLQ-C30 questionnaires at regular intervals during and after treatment for up to 5 years. Patients were classified into three subgroups: early larynx, infra-hyoideal, and supra-hyoideal. Outcome scales of both questionnaires were quantified per subgroup and time point by means of average scores and frequency distribution of categorized (none, mild, moderate, severe) severity. Time patterns and symptom severities were characterized. Toxicity profiles were compared using linear mixed model analysis. Additional toxicity profiles based on age, HPV-status, treatment modality, smoking status, tumor site and treatment period were characterized as well.
Results
The study population consisted of 157 early larynx, 304 infra-hyoideal, and 398 supra-hyoideal patients. The overall compliance rate was 83%. Generally, the EORTC QLQ-HN35 symptoms showed a clear time pattern, with increasing scores during treatment, followed by a gradual recovery in the first 2 years. Distinct toxicity profiles were seen across subgroups (p<0.001), with generally less severe symptom scores in the early larynx subgroup. The EORTC QLQ-C30 functioning, quality of life and general symptoms showed a less evident time pattern and less pronounced differences in average scores between subgroups, although differences were still significant (p<0.001). Differences in average scores were most pronounced for role functioning, appetite loss, fatigue, and pain.
Conclusion
We established patient-reported toxicity and quality of life profiles that showed different patterns for three subgroups of HNC patients. These profiles provide detailed information on the severity and persistency of various symptoms as experienced by patients during and after definitive radiotherapy. These profiles can be used to inform future patients and may serve as a benchmark for future studies.
... Current or former tobacco use is not only associated with a higher rate of comorbidities and second primary cancers but also leads to a higher disease-specific mortality and several studies have shown that the risk of death is approximately twice as high in current or former smokers compared to non-smokers [59,61,63]. Furthermore, it has been known for a long time that patients with HNSCC who continue to smoke during radiotherapy have lower response rates and shorter survival compared to patients who quit smoking before treatment [64,65]. ...
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.
... Risk factors for HNSCC include human papillomavirus (HPV), tobacco use, and alcohol consumption (Brunin et al., 1999). Smokers are at a higher risk than non-smokers for OSCC and are more likely to have unfavorable outcomes with reduced survival (Chen et al., 2011;Hatcher et al., 2016). The incidence of OSCC is rising, and outcomes are poor, with a 5-year survival rate of only 50% (Chaturvedi et al., 2013). ...
Oral squamous cell carcinoma (OSCC) is the most common subsite of head and neck cancer, with a 5-year survival rate of only 50%. There is a pressing need for animal models that recapitulate the human disease to understand the factors driving OSCC carcinogenesis. Many laboratories have used the chemical carcinogen 4-nitroquinoline-1-oxide (4NQO) to investigate OSCC formation. The importance of the 4NQO mouse model is that it mimics the stepwise progression observed in OSCC patients. The 4NQO carcinogen model has the advantage that it can be used with transgenic mice with genetic modification in specific tissue types to investigate their role in driving cancer progression. Herein, we describe the basic approach for administering 4NQO to mice to induce OSCC and methods for assessing the tissue and disease progression.
... "1" symptomatic and ambulatory cares for self "80" normal activity with effort; some activities "70" able to care for self but unable to do normal activities "2" ambulatory >50% of the time; occasional assistance "60" requires occasional assistance; cares for most needs "3" ambulatory ≤50% of the time; nursing care needed "50" requires considerable assistance "40" disabled; requires special assistance "30" severely disabled "4" bedridden "20" very sick; requires active supportive treatment "10" moribund and understanding and experience which will help in tailoring the treatment plan to each individual distinctly. This individualized approach cannot be implemented unless there are multidisciplinary tumor board meetings, which are crucial for clinicians practicing oncology and hence provides teambased practice keeping the patient in mind [2][3][4]. This is best done before initiating the treatment. ...
Oral Cavity Squamous Cell Carcinoma (OSCC), is a heterogenous disease with respect to risk factors, geographic predelictions, treatment response and outcome. Although non-surgical treatment is employed in other head and neck sub-sites, surgery is the primary treatment modality to treat oral cancers followed by adjuvant treatment either in the form of radiation or chemoradiation based on the risk features on final histopathology. It is utmost importance that all the patients before undergo treatment are discussed and treatment plan is formulated in a multidisciplinary tumor board. This chapter intent to elaborate the basic surgical principles involved in management of different sub-sites of oral cavity as well as reconstruction of the defects.
... It is also well established that cigarette smoking has negative implications on cancer outcomes, including increasing disease progression, incidence of second primary tumors, and treatment-related toxicity, and reducing patient survival 7-12 . Smoking at the time of diagnosis has been shown to increase resistance to radioand chemo-therapy 7,13 and tumor recurrence 9,11,14,15 . Alarmingly, data show that about 60% of lung and head and neck cancer patients, who were cigarette smokers before their diagnosis, continued to smoke during treatment 16 . ...
Tobacco smoking is the leading preventable cause of cancer. Moreover, continued smoking during cancer therapy reduces overall survival. Aware of the negative consequences of tobacco smoking and the challenges of smoking cessation, cancer patients are inquiring whether they should switch to electronic cigarettes (e-cigarettes). To obtain evidence-based data to inform this decision, we examined the effects of e-cigarette aerosol exposure on cisplatin resistance in head and neck cancer cells. Our results show that cancer cells exposed to e-cigarette aerosol extracts and treated with cisplatin have a significant decrease in cell death, increase in viability, and increase in clonogenic survival when compared to non-exposed cells. Moreover, exposure to e-cigarette aerosol extracts increased the concentration of cisplatin needed to induce a 50% reduction in cell growth (IC50) in a nicotine-independent manner. Tobacco smoke extracts induced similar increases in cisplatin resistance. Changes in the expression of drug influx and efflux transporters, rather than activation of cell growth-promoting pathways or DNA damage repair, contribute to e-cigarette induced cisplatin resistance. These results suggest that like combustible tobacco, e-cigarette use might increase chemotherapy resistance, and emphasize the urgent need for rigorous evaluation of e-cigarettes health effects to ensure evidence-based public health policies.
Objective
To determine the effect of tobacco cessation following laryngeal cancer diagnosis on response to first‐line therapy, laryngectomy‐free survival, and overall survival in patients who were current smokers at the time of diagnosis.
Study Design
Retrospective, case‐control study.
Setting
OU Stephenson Cancer Center, National Cancer Institute‐Designated Cancer Center.
Methods
We included 140 patients diagnosed with laryngeal squamous cell carcinoma, who were current smokers at the time of diagnosis, and were treated with first‐line definitive radiation or chemo/radiation with the intent to cure. The association between patient characteristics and treatment response was assessed using the χ ² test and logistic regression analysis. Survival outcomes were analyzed using Kaplan‐Meier methods and Cox proportional‐hazards models.
Results
Of the 140 current smokers, 61 patients (45%) quit smoking prior to treatment initiation. In adjusted logistic regression analysis, quitters had 3.7 times higher odds of achieving a complete response to first‐line therapy than active smokers (odds ratio: 3.694 [1.575‐8.661]; P = .003). In the adjusted Cox proportional‐hazards model, quitters were 54% less likely to require salvage laryngectomy within 7 years of diagnosis than active smokers (hazard ratio: 0.456 [0.246‐0.848]; P = .013). Quitters had a statistically significant increase in 7‐year overall survival compared to active smokers ( P = .02).
Conclusion
This is the first study to show that in newly diagnosed laryngeal cancer patients who are current smokers at the time of diagnosis, tobacco cessation significantly increases therapy response, laryngectomy‐free survival, and overall survival. These data stress the importance of systematically incorporating tobacco cessation programs into laryngeal cancer treatment plans.
Background
Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer.
Methods
A modified Cancer Patient Tobacco Use Questionnaire (C‐TUQ) was administered to patients enrolled in nine ECOG‐ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression.
Results
A total of 740 patients completing the C‐TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69–7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64–10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02–0.58; p = .0086) versus those in the least disadvantaged neighborhoods.
Conclusions
Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.
This is a comprehensive review of the most prevalent risk for the development of chronic obstructive pulmonary disease (COPD) from direct and second-hand tobacco smoke exposure. The large amounts of reactive oxygen species present in tobacco smoke increase oxidative stress. The compelling evidence suggests that oxidative stress plays a critical role in the pathogenesis of COPD via processes including oxidative damage, mitochondrial dysfunction, and inflammation. Since patients with COPD are more likely to develop lung cancer, this review also emphasizes how oxidative stress and potentially related mechanisms link COPD and lung cancer.KeywordsTobaccoCigaretteSecond-hand smokeCOPDOxidative stressMitochondrial dysfunctionInflammationLung cancerEpigenetics
Nursing burnout has been linked to stress, anxiety, and depression. Increased stress and anxiety have been closely related to burnout. This study's major goal has been to determine the association of these variables in the context of nursing practice. This descriptive correlational study aimed at determining the relationship between stress, anxiety, and depression with burnout among the 307 purposive nurse samples from participating government and private hospitals in Manila, Pampanga, and Tarlac, Philippines collected between March and June 2020 using a 21-item Depression Anxiety Stress Scale (DASS-21) and a 16-item Oldenburg Burnout Inventory (OLBI) instruments. Mostly with a normal level of stress, anxiety, and depression, the nurses had been also found to have a moderate level of overall burnout and were moderately disengaged, and exhausted. Using IBM SPSS v.26, the study utilized Pearson product-moment correlation which found that nurses’ stress had significant relationships (p=.000) with burnout, disengagement, and exhaustion; anxiety to burnout, disengagement, and exhaustion; and depression with burnout, disengagement, and exhaustion. The degree of stress, anxiety, and depression has significantly shown direct correspondence which calls for a deeper examination of sources and factors. Nurses' experience of burnout is associated with the service-oriented features of the profession. The emphasis is on the need for treatments to guarantee that burnout does not lead to higher staff turnover, degraded health care, decreased productivity, and decreased professional fulfillment. A systems approach to burnout prevention and treatment should investigate the relevant factors that are addressed in the organizational, group, and individual efforts. This study offers a remarkable hypothetical underpinning for nurses' ability to handle stressful workplace situations with resilience and professionalism.
Electronic cigarette (EC) usage or vaping has seen a significant rise in recent years across various parts of the world. They have been publicized as a safe alternative to smoking; however, this is not supported strongly by robust research evidence. Toxicological analysis of EC liquid and aerosol has revealed presence of several toxicants with known carcinogenicity. Oral cavity is the primary site of exposure of both cigarette smoke and EC aerosol. Role of EC in oral cancer is not as well-researched as that of traditional smoking. However, several recent studies have shown that it can lead to a wide range of potentially carcinogenic molecular events in oral cells. This review delineates the oral carcinogenesis potential of ECs at the molecular level, providing a summary of the effects of EC usage on cancer therapy resistance, cancer stem cells (CSCs), immune evasion, and microbiome dysbiosis, all of which may lead to increased tumor malignancy and poorer patient prognosis. This review of literature indicates that ECs may not be as safe as they are perceived to be, however further research is needed to definitively determine their oncogenic potential.
Purpose of review:
Excellent outcomes following contemporary treatment of human papillomavirus (HPV)-positive oropharyngeal carcinoma (HPV+ OPC) have prompted the exploration of deintensification approaches to minimize treatment-related toxicities. This review describes the landscape of deintensification to date (up to November 2022).
Recent findings:
Although several deintensification trials have been published, none are practice changing. Three phase III randomized-controlled trials studying cetuximab and radiation therapy vs. standard chemoradiotherapy all showed inferior outcomes. Although some phase II trials reported favourable outcomes, they are often single-arm trials without an adequate control arm, thereby limiting the ability to modify practice.
Summary:
Substantial effort has been expended to explore deintensification options for selected HPV+ OPC patients aiming to avoid unnecessary toxicity. Strategies have included replacing cisplatin with cetuximab, reduced chemotherapy or radiotherapy intensity, reduction of radiotherapy volumes and risk stratification after trans-oral surgery or following induction chemotherapy. Challenges remain in the current deintensification landscape, including identifying the most suitable candidates along with a choice of most appropriate deintensification strategies. Promising selection criteria included either static baseline features or kinetic characteristics of clinical-biological parameters. Practice-changing trials remain elusive, and the search continues to attempt optimization of the therapeutic ratio for these patients.
Introduction:
Individuals living with severe mental illness (SMI) have a reduced life expectancy of approximately 15-20 years compared to the general population1,2. Individuals with SMI and comorbid cancer have increased cancer related mortality rates compared to the non SMI population. This scoping review examines the current evidence in relation to the impact on cancer outcomes where individuals have a pre-existing SMI.
Methods:
Scopus, PsychINFO, PubMed, PsycArticles and the Cochrane Library were searched for peer reviewed research articles, published in English language between 2001 and 2021. Initial title and abstract screening, followed by full text screening sourced articles reporting on the impact of SMI and cancer on: stage at diagnosis, survival, treatment access or quality of life. Articles were quality appraised, and data were extracted and summarised.
Results:
The search yielded 1226 articles, 27 met the inclusion criteria. The search yielded no articles that met the inclusion criteria that were from the perspective of the service user or that were focused on the impact of SMI and cancer quality of life. Three themes were developed following analysis: Cancer related mortality, stage at diagnosis, and access to stage appropriate treatment.
Discussion:
The collective study of populations with comorbid SMI and cancer is complex and challenging without a large-scale cohort study. The studies yielded through this scoping review were heterogenous and often study multiple diagnoses of SMI and cancer. Collectively these indicate that cancer related mortality is increased in the population of individuals with pre-existing SMI and the SMI population are more likely to have an increased likelihood of metastatic disease at diagnosis and less likely to receive stage appropriate treatment.
Conclusions:
Individuals with pre-existing SMI and cancer have increased cancer specific mortality. Comorbid SMI and cancer is complex, and individuals with SMI and cancer are less likely to receive optimal treatments, experience increased interruptions and delays to treatment.
Objective:
Transoral robotic surgery (TORS) has become an effective treatment for early-stage oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to analyze the clinical safety and efficacy of TORS for human papilloma virus (HPV)-positive and HPV-negative OPSCC in China.
Methods:
Patients with OPSCC of pT1-T2 stage who underwent TORS from March 2017 to December 2021 were analyzed.
Results:
A total of 83 patients (HPV-positive, n = 25; HPV-negative, n = 58) were included. The median age of the patients was 57.0 years and 71 were men. The majority of primary tumor sites were palatine tonsils (52, 62.7%) and base of tongues (20, 24.1%). Three patients have a positive margin. A total of 12 (14.5%) patients received tracheotomies, the average duration of tracheostomy tube use was 9.4 days, and nasogastric tube was 14.5 days. No patient had a long-term tracheotomy. The 3-year overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for all 83 patients were 89.5%, 80.1%, and 83.3%, respectively. The OS at 3 years between the HPV-positive group and HPV-negative group were 100% versus 84.3% (P = .07), while the DFS and RFS between two groups also showed no significant difference. Among multivariate cox regression analysis of all potential risk factors, smoking was the significant risk factors for disease recurrence (P < .05).
Conclusion:
Transoral robotic surgery achieved encouraging oncologic outcomes and safety in T1-T2 stage OPSCC treatment, regardless of HPV status.
Level of evidence:
4.
Background/purpose:
Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC.
Material and methods:
We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT.
Results:
All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions.
Conclusion:
The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.
Introduction:
Tobacco cessation is a critical but challenging intervention for cancer patients. Our National Cancer Institute-designated Comprehensive Cancer Center instituted a tobacco cessation program in 2019. This manuscript reports on the first 2 years of our experience.
Methods:
Patients were referred to the program by their care team, and a certified tobacco treatment specialist contacted patients remotely and provided behavioral therapy and coordinated pharmacotherapy. We retrospectively captured data from patients with a cancer diagnosis referred to the tobacco cessation program. Univariate and multivariable logistic regression analyses with the backward elimination approach were performed to determine factors associated with patient acceptance of referral to the tobacco cessation program. Tobacco cessation rates after referral to the program were also captured.
Results:
Between July 2019 and August 2021, 194 patients were referred to the tobacco cessation program. Of the 194 patients referred, 93 agreed to enroll in the tobacco cessation program (47.9%), of which 84 requested pharmacotherapy (90.3%). Twenty-four were able to cease tobacco use (25.8%). Only 7 patients out of the 101 patients (6.9%) who declined cessation services were successful (p < 0.001). On univariate logistic regression, race (p = 0.027) and marital status (p = 0.020) were associated with referral acceptance. On multivariable analysis, single patients (odds ratio [OR] = 0.33) and Caucasian patients (OR = 0.43) were less likely to accept a referral.
Conclusions:
Access to tobacco cessation services is a critical component of comprehensive cancer care. Our experience highlights the need to understand patient-specific factors associated with engagement with a tobacco cessation program during cancer treatment. The use of pharmacotherapy is also a critical component of successful tobacco cessation.
Introduction:
Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT.
Patients and methods:
Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria.
Results:
Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively-primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (P= 006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, P= .10) and smoking (HR 1.60, p = .06) as non-significantly associated with an increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, P=.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI.
Conclusions:
Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.
Head and neck squamous cell carcinoma (HNSCC) patients who are current smokers when diagnosed have inferior clinical outcomes compared to never-smokers or previous smokers. However, the impact of quitting after HNSCC diagnosis has not been quantified. In this retrospective, case-control study (n = 134), the odds of complete response to first-line therapy were 3.7 times higher among smokers at diagnosis who quit before treatment initiation (quitters; n = 55) than among those continuing to smoke (p = 0.03). Disease-free survival was also higher among quitters (aHR, 0.33; 95 % CI, 0.12–0.90; p = 0.029). Quitters were 67 % less likely to die of all causes than active smokers (aHR, 0.33; 95 % CI, 0.15–0.71; p = 0.004). These data show for the first time that, smoking cessation after HNSCC diagnosis is predictive of higher therapy efficacy and long-term survival.
By the end of this chapter, the reader will:
Introduction
This study developed and piloted the first online training package to support implementation and delivery of brief smoking cessation interventions for therapeutic radiographers in four radiotherapy departments in England.
Methods
A previously reported systematic literature review and data analysis from the previously reported pre-focus group questionnaire and focus groups enabled the development of an online training package. The questionnaire was repeated by the participating therapeutic radiographers following completion of the training resource (n = 31). The results of the comparative questions from the pre and post questionnaires were analysed using the Statistical Package for Social Sciences (SPSS Version 24).
Results
In total, 43 therapeutic radiographer participants completed the pre-questionnaire and 31 participants continued to complete the post questionnaire, having completed the online training package. The previously conducted focus groups identified several barriers to the delivery of smoking cessation, that were addressed through the development of an online training package. Following the completion of the training; therapeutic radiographers had increased knowledge and confidence regarding smoking cessation, the number of therapeutic radiographers who believe that smoking cessation is part of their role increased and therapeutic radiographers more routinely have conversations about smoking cessation.
Conclusion
The training resource improved therapeutic radiographers’ knowledge and confidence and increased awareness of the role of the therapeutic radiographer in the provision of smoking cessation interventions. Challenges remain that continue to prevent some therapeutic radiographers from delivering smoking cessation interventions and strong leadership and implementation of strategy and guidance is essential to ensure wider implementation. Recording and measuring impact of interventions remains an area to be addressed, alongside cultural changes and reassurance around the therapeutic relationship.
Implications for practice
This training tool has proven to be effective in the sample within this study and should be disseminated and evaluated more widely across radiotherapy provision within the United Kingdom.
This open access book discusses the most current issues in head and neck cancer with a focus on current trends such as biomarkers, precision medicine and immunotherapy. New approaches in the diagnosis such as liquid biopsies and imaging biomarkers to predict radiotherapy toxicity as well as approaches in the surgical management of head and neck cancers are discussed. The book discusses medical and surgical approaches in both primary, recurrent and metastatic disease and also covers approaches for rare head neck cancers.
Readers will learn about the latest drug developments and epidemiological aspects in cancers ranging from head and neck squamous cell cancer to nasopharynx cancer.
Edited by a team of world leaders in head and neck cancer, this volume serves as an easy reference to the head and neck oncology practitioner and provides a contemporary overview for specialists the field. The chapters are based on the latest data presented at the 7th Trends in Head and Neck Oncology Conference and reflect the most up-to-date information in the field.
Purpose of this review of medical literature is to present the immediate side effects of radiation therapy for head and neck cancer and their treatment. The likelihood and severity of these immediate side effects depends on a number of factors, including the total dose of radiation delivered, over what time it was delivered and what parts of the head and neck received radiation. Early side effects include: inflammation of the oropharyngeal mucosa (mucositis), painful swallowing (odynophagia), difficulty swallowing (dysphagia), hoarseness, lack of saliva (xerostomia), orofacial pain, laryngeal radionecrosis, dermatitis, hair loss, nausea, vomiting, inadequate nutrition and hydration, and weight loss. These complications can interfere with, and delay treatment. Most of these side effects generally dissipate over time. In conclusion, radiation treatment for the head and neck cancer causes significant early side effects. Many of these side effects present difficult challenges to the patients. Their recognition and treatment can significantly improve the patients' health, long-term survival and quality of life. The review provides information that can assist head and cancer survivors deal with radiation side effects.
Background
Smoking status at point of diagnosis is not used in defining risk groups for human papillomavirus (HPV)‐associated oropharyngeal cancer (OPC) despite its prognostic value in head and neck cancer.
Methods
Retrospective analysis of consecutive patients treated with chemoradiotherapy between January 2005 and July 2017 was performed with multivariable analysis to explore the impact of smoking status at diagnosis (current/former/never) on overall survival (OS), cancer‐specific survival (CSS) and progression‐free survival (PFS).
Results
Median follow‐up was 61 months. Four hundred and four patients were included. Current smokers had inferior OS versus never and former smokers [adjusted HR 2.37 (95% CI 1.26–4.45, p < 0.01) and 2.58 (95% CI 1.40–4.73, p < 0.01), respectively] and inferior PFS versus never smokers [adjusted HR 1.83 (95% CI 1.00–3.35, p = 0.04)]. Smoking status did not predict for CSS.
Conclusion
Detailed smoking behavior should be considered in refining risk groups in HPV‐associated OPC treated with radiotherapy and in future trial design eligibility and stratification.
Objectives
While smoking is associated with worse outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), the magnitude of this association is unclear given the heterogenous smoking definitions and outcomes. Our objective was to investigate the association between smoking, survival, and recurrence in HPV-related OPSCC using multiple smoking metrics reported in the literature.
Materials and methods
This was a retrospective cohort study of 375 adults with p16+ OPSCC undergoing surgical resection (n = 272) or definitive chemoradiation (n = 103) at a tertiary academic institution from 2006 to 2017. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), disease-specific survival (DSS), and recurrence. We used multiple smoking metrics commonly cited in previous studies, including ever versus never smokers, current versus former/never smokers, ≤10 versus >10 pack-year, ≤20 versus >20 pack-year, and continuous pack-year.
Results
There were 375 patients, median age 58 years, with 326 (87%) males, and median follow-up of 52 months. Of all smoking metrics, >20 pack-year history was the strongest predictor of both OS (HR 2.24, 95% CI: 1.19–4.20) and DFS (HR 1.67, 95% CI: 1.04–2.66) on univariable and multivariable analysis after adjusting for age, overall stage, and comorbidities. Patients with >20 pack-year smoking history were also more likely to have recurrence (HR 1.59, 95% CI: 0.95–2.67) after adjusting for overall stage.
Conclusion
Heavier smoking >20 pack-years was the strongest smoking metric associated with 2-times worse survival and recurrence. Our findings suggest that >20 pack-year smoking history may be a more useful cutoff for risk stratification models but requires further validation.
Purpose
Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OPSCC) is extremely radiosensitive. Radiotherapy plus high-dose cisplatin remains the standard of care but causes long-term toxicity. Treatment de-intensification approaches that reduce toxicity while maintaining survival are desirable for HPV-related OPSCC.
Methods and Materials
We conducted a single-arm, multicentre, phase 2 trial. Patients with newly diagnosed, biopsy-proven, American Joint Committee on Cancer (seventh edition) stage III or IV OPSCC positive for both p16 and HPV DNA were eligible. Patients with T4, N3, or T1N1 disease were excluded. Smoking history was not included in eligibility criteria. Patients received intensity-modulated radiation therapy (IMRT) of 70 Gy in 35 fractions or 70.4 Gy in 32 fractions without chemotherapy. The primary endpoint was complete response (CR) or complete metabolic response (CMR) 10 weeks after IMRT completion.
Results
Between September 13, 2013 and November 15, 2016, 39 patients were enrolled according to a two-stage Simon design. Twenty-three (59%) patients had smoked for >10 pack-years. Thirty-six (92%) patients had tumors genotyped as HPV16. Thirty-seven (95%) patients received full-dose radiotherapy and 35 (90%) had CR or CMR. Median follow-up was 51 months (interquartile range 41–63). One (3%) patient had regional recurrence and three (8%) had distant metastasis. One patient died of disease. Two-year progression-free survival was 94% (95% confidence interval 81–99) and 2-year overall survival was 100%. Common grade 3 adverse events during IMRT included mucositis in ten (26%) patients and dysphagia in seven (18%) patients. None were dependent on a feeding tube at 1 month after IMRT completion. No grade 3 or 4 late adverse events were observed.
Conclusions
IMRT alone is associated with excellent response as well as reduced toxicity. IMRT alone could be a treatment option for carefully selected patients with locally advanced ‘true’ HPV-related OPSCC. Further studies are warranted.
Subcutaneous wound-tissue oxygen (PsqO2) tension in eight volunteers fell rapidly and significantly in response to smoking, and remained low for 30 to 50 minutes. Sham "smoking" had no effect. These data suggest that a typical "pack-per-day" smoker experiences tissue hypoxia during a significant portion of each day. The degree of hypoxia found in these subjects has been associated with poor wound healing in animal and human studies. The onset and duration of tissue hypoxia paralleled the well-established plasma pharmacokinetics of nicotine. This suggests that peripheral vasoconstriction, induced by the adrenergic effects of nicotine, may contribute to the observed decrease in PsqO2.
The pattern of cigarette smoking of 41 patients receiving continuous, hyperfractionated, accelerated radiotherapy for locally advanced head and neck cancer was examined to determine any relationship with the duration of mucositis. The uniformity of the treatment given made it possible to perform an analysis of the factors influencing the duration of the mucositis. There was no correlation with age, sex or weight loss prior to treatment. A highly significant correlation was shown with smoking during and/or after treatment (p = 0.014) and with the volume of mucosa irradiated (p = 0.025). Both appeared to act independently. It is important to encourage patients to cease smoking totally, prior to radiotherapy, to minimize the duration of mucositis associated with radiotherapy.
The effect of acute carbon monoxide (CO) breathing on blood oxygenation and tumour hypoxia was related to the radiation response of the C3H/Tif mammary carcinoma. Blood gas analysis showed that CO breathing caused a time- and dose-dependent formation of carboxyhaemoglobin (HbCO), a significant left shift of the oxygen dissociation curve and a reduction in tumour blood perfusion. These factors all contributed to a marked drop in tumour oxygen supply. In agreement with this, tumour hypoxia was found to be significantly increased: Microelectrode PO2 measurements showed a clear relationship between CO concentration and the proportion of low PO2 measurements (< or = 5 mmHg). The fraction of clonogenic hypoxic cells increased from 8% in air-breathing animals to 13%, 18% and 54% with 75,220 and 660 p.p.m. CO respectively. The tumour hypoxia resulted in significant radiation modification. The local tumour control after single-dose and fractionated irradiation gave TCD50 enhancement ratios (relative to air-breathing controls) of 0.90, 0.85 and 0.89 for single dose and five or ten fractions given in 5 days (P < 0.005 for all values). For 15 fractions in 5 days with 6- 6- and 12 h intervals, the TCD50 was similar in CO- and air-breathing mice, presumably as a consequence of insufficient reoxygenation during the short inter-fraction intervals. It is concluded that elevated HbCO levels to increased tumour hypoxia and that the induced hypoxia has a significant impact on the local tumour control also after fractionated irradiation.
Smoking is a risk factor for several cancers and may also limit the efficacy of treatment. In this study, we evaluated the influence of cigarette smoking during radiation therapy on the efficacy of treatment in patients with head and neck cancer.
Using a questionnaire, we obtained information on smoking behavior at base line and weekly during therapy in 115 patients with head and neck cancer who were treated with radiation therapy with or without fluorouracil. The side effects of therapy were evaluated weekly, and response was assessed 13 weeks after treatment was completed. The main outcomes measured were treatment response and survival.
The prognostic variables were similar among the patients who smoked and those who did not smoke during treatment. The 53 patients who continued to smoke during radiation therapy had a lower rate of complete response (45 percent vs. 74 percent, P = 0.008) and poorer two-year survival (39 percent vs. 66 percent, P = 0.005) than the 62 patients who did not smoke or who had quit before treatment. Among the nonsmoking patients, mortality was influenced by the length of time between quitting and treatment, with a risk reduction (relative to that for patients who continued to smoke) of 40 percent for patients who had quit less than 12 weeks before diagnosis and of 70 percent for patients who had quit more than 1 year before diagnosis. After adjustment for other variables with proportional-hazards regression analysis, smoking remained an independent prognostic factor (P = 0.002), with a relative risk of 2.5 (95 percent confidence interval, 1.4 to 4.4) favoring the patients who abstained from smoking. The results could not be explained by the type of chemotherapy received, the presence of coexisting morbid conditions, differences in the side effects of radiation, or the number of interruptions of treatment.
Patients with head and neck cancer who continue to smoke during radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy.
It is estimated that cigarette smoking kills over 1 000 000 people each year by causing lung cancer as well as many other neoplasmas. p53 mutations are frequent in tobacco-related cancers and the mutation load is often higher in cancers from smokers than from nonsmokers. In lung cancers, the p53 mutational patterns are different between smokers and nonsmokers with an excess of G to T transversions in smoking-associated cancers. The prevalence of G to T transversions is 30% in smokers' lung cancer but only 12% in lung cancers of nonsmokers. A similar trend exists, albeit less marked, in laryngeal cancers and in head and neck cancers. This type of mutation is infrequent in most other tumors aside from hepatocellular carcinoma. At several p53 mutational hotspots common to all cancers, such as codons 248 and 273, a large fraction of the mutations are G to T events in lung cancers but are almost exclusively G to A transitions in non-tobacco-related cancers. Two important classes of tobacco smoke carcinogens are the polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines. Recent studies have indicated that there is a strong coincidence of G to T transversion hotspots in lung cancers and sites of preferential formation of PAH adducts along the p53 gene. Endogenously methylated CpG dinucleotides are the preferred sites for G to T transversions, accounting for more than 50% of such mutations in lung tumors. The same dinucleotide, when present within CpG-methylated mutational reporter genes, is the target of G to T transversion hotspots in cells exposed to the model PAH compound benzo[a]pyrene-7,8-diol-9,10-epoxide. As summarized here, a number of other tobacco smoke carcinogens also can cause G to T transversion mutations. The available data suggest that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.
Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non-small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation.
We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum.
Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20. To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P < 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P < 0.001), exon 21 (P < 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon 19 mutations (P = 0.047) when female never smoker was set as a reference.
Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.
The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospective clinical trial.
We prospectively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group (ECOG) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and standard fractionation radiation therapy. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis. The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age, ECOG performance status, stage, and other covariables was estimated by use of a multivariable Cox proportional hazards model. All statistical tests were two-sided.
Genomic DNA of oncogenic HPV types 16, 33, or 35 was located within tumor cell nuclei of 40% (95% confidence interval [CI] = 30% to 50%) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR. Compared with patients with HPV-negative tumors, patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%, difference = 27%, 95% CI = 9.3% to 44.7%, P = .01) and after chemoradiation treatment (84% vs 57%, difference = 27%, 95% CI = 9.7% to 44.3%, P = .007). After a median follow-up of 39.1 months, patients with HPV-positive tumors had improved overall survival (2-year overall survival = 95% [95% CI = 87% to 100%] vs 62% [95% CI = 49% to 74%], difference = 33%, 95% CI = 18.6% to 47.4%, P = .005, log-rank test) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression (hazard ratio [HR] = 0.27, 95% CI = 0.10 to 0.75), and death from any cause (HR = 0.36, 95% CI = 0.15 to 0.85) than those with HPV-negative tumors.
For patients with HNSCC of the oropharynx, tumor HPV status is strongly associated with therapeutic response and survival.
To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer.
Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status.
EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002).
Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.
Learning Objectives
After completing this course, the reader will be able to:Discuss the prognostic significance of intratumoral hypoxia and low hemoglobin levels in patients receiving curative-intent radiation for head and neck or cervical cancer.Describe the potential relationship between anemia and intratumoral hypoxia in patients with solid tumors.List possible interventions for improving intratumoral oxygenation and radiosensitivity in the radiation oncology setting.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO2 levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for “low” should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO2 thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.
• Subcutaneous wound-tissue oxygen (Psqo2) tension in eight volunteers fell rapidly and significantly in response to smoking, and remained low for 30 to 50 minutes. Sham "smoking" had no effect. These data suggest that a typical "pack-per-day" smoker experiences tissue hypoxia during a significant portion of each day. The degree of hypoxia found in these subjects has been associated with poor wound healing in animal and human studies. The onset and duration of tissue hypoxia paralleled the well-established plasma pharmacokinetics of nicotine. This suggests that peripheral vasoconstriction, induced by the adrenergic effects of nicotine, may contribute to the observed decrease in Psqo2.
(Arch Surg. 1991;126:1131-1134)
Background:
Patients with head and neck cancer who continue to smoke after diagnosis and treatment are more likely than patients who quit to experience tumor recurrence and second primary malignancies. Therefore, information about patients' smoking status and the factors associated with continued tobacco use are important considerations in the comprehensive care patients with head and neck cancer.
Methods:
Study participants were 144 patients with newly diagnosed squamous cell carcinomas of the upper aerodigestive tract who underwent surgical treatment, with or without postoperative radiotherapy or chemotherapy, 3-15 months before assessment of their postoperative tobacco use.
Results:
Among the 74 patients who had smoked in the year before diagnosis, 35% reported continued tobacco use after surgery. Compared with patients who abstained from smoking, patients who continued to use tobacco were less likely to have received postoperative radiotherapy, to have had less extensive disease, to have had oral cavity disease, and to have had higher levels of education. Hierarchical regression analysis indicated that most of the explained variance in smoking status could be accounted for on the first step of analysis by disease site. Interest in smoking cessation was high, and most patients made multiple attempts to quit.
Conclusions:
Although the diagnosis of a tobacco-related malignancy clearly represents a strong catalyst for smoking cessation, a sizable subgroup of patients continue to smoke. Patients with less severe disease who undergo less extensive treatment are particularly at risk for continued tobacco use. These data highlight the importance of developing smoking cessation interventions designed to meet the demographic, disease, treatment, and tobacco-use characteristics of this patient population.
BACKGROUND
Epidemiologic studies have indicated that environmental and personal habits, particularly tobacco use and alcohol abuse, are major etiologic factors in the induction and progression of head and neck squamous cell carcinomas (HNSCC). Molecular studies have focused on HNSCC related to smoking but not those associated with smokeless tobacco.METHODS
The authors studied immunohistochemical evidence of alterations of p53, cyclin D1, and Rb in 34 human oral carcinomas related to tobacco use. They also examined p53 and H-ras using single strand conformation polymorphism (SSCP) and sequencing analysis.RESULTSOverexpression of cyclin D1 was found in 41% of cases, and accumulation of p53 was found in 59%. Only 9% of the samples did not show Rb staining. In SSCP and sequencing analysis, 17 cases showed mutations in the conserved region of the p53 gene. No mutations were detected in codons 12, 13, or 61 of the H-ras gene.CONCLUSIONS
Overexpression of cyclin D1 and p53 mutations are common alterations in HNSCC. In contrast, the loss of Rb function seems to occur infrequently, and mutations in the H-ras gene apparently do not play a role in this cancer. HNSCC associated with smokeless tobacco contained the same alterations as those related to smoking. Cancer 1998;83:204-212. © 1998 American Cancer Society.
In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed.
For random samples of size N the product-limit (PL) estimate can be defined as follows: List and label the N observed lifetimes (whether to death or loss) in order of increasing magnitude, so that one has \(0 \leqslant t_1^\prime \leqslant t_2^\prime \leqslant \cdots \leqslant t_N^\prime .\) Then \(\hat P\left( t \right) = \Pi r\left[ {\left( {N - r} \right)/\left( {N - r + 1} \right)} \right]\), where r assumes those values for which \(t_r^\prime \leqslant t\) and for which \(t_r^\prime\) measures the time to death. This estimate is the distribution, unrestricted as to form, which maximizes the likelihood of the observations.
Other estimates that are discussed are the actuarial estimates (which are also products, but with the number of factors usually reduced by grouping); and reduced-sample (RS) estimates, which require that losses not be accidental, so that the limits of observation (potential loss times) are known even for those items whose deaths are observed. When no losses occur at ages less than t the estimate of P(t) in all cases reduces to the usual binomial estimate, namely, the observed proportion of survivors.
To retrospectively evaluate the prognostic value of smoking and drinking status in patients with head-and-neck squamous cell carcinomas.
All patients with all stages and sites were included if complete information was available on baseline smoking and alcohol behavior (never, former, active), disease stage, primary site, radiation dose, sex, and age. Treatment was radiotherapy in 973 patients, postoperative radiotherapy in 469, and chemoradiotherapy in 429. Statistical analysis was performed with Kaplan-Meier and Cox methods.
Data from 1,871 patients were available. At baseline, 9% of patients never smoked, 40% were former smokers, and 51% were active smokers; 20% never drank, 25% were former drinkers, and 55% were active drinkers. Smoking was associated with inferior local control and survival. For local control, the hazard ratio (HR) of active smokers vs. former smokers was 1.5 (p = 0.0001). For survival, the HRs of former smokers and active smokers vs. those who never smoked were also statistically significant (1.3 and 1.7, respectively, p = 0.000001). Alcohol drinking was associated with local control (p = 0.03), and was associated with survival. For survival, HRs of former and active drinkers compared with those who never drank were, respectively, 1.1 (p = 0.01) and 1.28 (p = 0.001). Adjusted 5-year local control and survival rates for those who never smoked and never drank were 87% and 77%, respectively, and for those who were both active smokers and active drinkers were 72% (p = 0.007) and 52% (p = 0.0009), respectively.
Smoking and drinking at baseline were associated with poor outcomes in these patients.
The histories of 14 patients in whom osteoradionecrosis developed were compared with those of 28 patients who had similar tumors and/or treatment and were not afflicted with osteoradionecrosis. 1. Fourteen of 15 episodes of bone complications occurred in the mandible, and 70% occurred within 1 year after the completion of radiation therapy. 2. A high dose of radiation, with conventional fractionation, did not specifically predispose patients to osteoradionecrosis. Fifty percent of the ORN patients actually received a total dose of 6000 rad or less. Combined radiation therapy and surgery did not seem to significantly increase the risk inasmuch as both groups of patients had similar combinations. In two of four patients who received methotrexate, however, osteoradionecrosis developed during the time of administration. 3. One of the most prevalent negative factors associated with the ORN patients was the continued heavy use of alcohol and tobacco by 86% of them. These strong tissue irritants could have significantly contributed to the breakdown of mucosa and exposure of bone. Alcohol and tobacco could also have potentiated the combined effects of the other negative factors, such as contributing to poor oral hygiene. 4. The ORN patients had poorer oral hygiene than the control group. Seventy-five percent of the patients with teeth who had osteoradionecrosis continued to have poor oral hygiene. In contrast, none of the control patients had poor oral hygiene. 5. A combination of factors relating to stage of tumor and treatment was found in the ORN patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Laryngeal abnormalities following definitive irradiation for carcinoma of the larynx are common. The objective of this study was to identify risk factors for persistent cancer in such patients who were found to have abnormal larynges following definitive irradiation. A retrospective evaluation of 185 consecutive patients undergoing primary irradiation for a glottic or supraglottic laryngeal squamous carcinoma treated between 1976 and 1990 at the Affiliated Hospitals of the Medical College of Wisconsin was performed. From chart review, data concerning site, stage, intent of treatment, smoking history, treatment dose, fraction size, failure patterns, and outcome were obtained. In addition, worrisome signs and symptoms including ulceration, dysphasia, odynophagia, airway distress, aphonia, blood, pain, oedema, aspiration, and pneumonia were recorded. Univariate association with failure and a persistently abnormal laryngeal examination was assessed using the Mantel-Haenszel test. The odds ratio was used to estimate relative risk associated with dichotomous risk factors. Disease-free and overall survival were estimated using Kaplan-Meier methodology. The log rank test was used to compare survival as defined by the levels of various risk factors. Two-year disease-free survival was 83% (T1 = 93%, T2 = 72%, T3/T4 = 66%). Primary failure was associated with the presence of an abnormal examination (P = 0.001), tracheotomy (P = 0.001), symptom index (P = 0.002), aphonia (P = 0.003), advanced T stage (P = 0.03), and lower total dose (P = 0.03). Of 151 patients who survived 6 months disease-free with an intact larynx, an abnormal examination was seen in those with advanced T stage (P = 0.002), supraglottic primary (P = 0.003), symptom index (P = 0.008), eventual failure at the primary site (P = 0.008), continued smoking (P = 0.01), and higher total dose (P = 0.01). The symptom index (total signs and symptoms of airway distress, aphonia, ulceration, pain, oedema, dysphagia, blood production, aspiration, pneumonia, and odynophagia) was correlated with primary failure and continued smoking. Of 37 patients with continually normal examinations, only 1 (3%) failed at the primary site. Of 102 who survived 6 months but with an abnormal examination, 22 (22%) eventually developed a primary failure. Persistently abnormal larynges are common after radiation therapy, yet not all harbour cancer. Risk factors for persistent cancer include stage, airway, total dose, and symptom index. Patients whose larynges return to normal after radiation rarely fail at the primary site.
Epidemiologic studies have indicated that environmental and personal habits, particularly tobacco use and alcohol abuse, are major etiologic factors in the induction and progression of head and neck squamous cell carcinomas (HNSCC). Molecular studies have focused on HNSCC related to smoking but not those associated with smokeless tobacco.
The authors studied immunohistochemical evidence of alterations of p53, cyclin D1, and Rb in 34 human oral carcinomas related to tobacco use. They also examined p53 and H-ras using single strand conformation polymorphism (SSCP) and sequencing analysis.
Overexpression of cyclin D1 was found in 41% of cases, and accumulation of p53 was found in 59%. Only 9% of the samples did not show Rb staining. In SSCP and sequencing analysis, 17 cases showed mutations in the conserved region of the p53 gene. No mutations were detected in codons 12, 13, or 61 of the H-ras gene.
Overexpression of cyclin D1 and p53 mutations are common alterations in HNSCC. In contrast, the loss of Rb function seems to occur infrequently, and mutations in the H-ras gene apparently do not play a role in this cancer. HNSCC associated with smokeless tobacco contained the same alterations as those related to smoking.
To define the optimal treatment regimen, patients with T1N0M0 glottic larynx carcinoma were treated with six different radiotherapy (RT) schedules. To assess the influence of patient characteristics, complication rates, and to evaluate the overall larynx preservation.
Out of a consecutive series of 383 patients treated for T1N0M0 glottic larynx carcinoma between 1965 and 1992, 352 evaluable patients were treated with six different "standard" fractionation schedules: 65 Gy (20 x 3.25 Gy), 62 Gy (20 x 3.1 Gy), 61.6 Gy (22 x 2.8 Gy), 60 Gy (25 x 2.4 Gy), 66 Gy (33 x 2 Gy) and 60 Gy (30 x 2 Gy). The median follow-up of all patients was 89 months. Patient factors analyzed included: age, sex, concurrent illness, smoking habits, tumor localization and extension, tumor differentiation, the effect of tumor biopsy or stripping of the vocal cord, and the presence of visible tumor at the start of radiotherapy. Treatment parameters evaluated were: year of treatment, beam energy, treatment planning, field size, fractionation schedule, fraction size, number of fractions, total dose, treatment time and treatment gap, the use of wedges, and neck diameter.
The overall 5-year actuarial locoregional control was 89%, varying between 83 and 93% for the different schedules. Univariately, local control decreased with increasing treatment time. This could not be explained by the confounding variables sex, tumor extension, and field length (p = 0.0065). Adjusted for these variables, 5-year local control percentage decreased from 95% (SE 2%) for 22-29 days to 79% (SE 6%) for treatment time > or = 40 days. The overall complication rate (grade I-IV) at 5 years was 15.3%, and varied between the different schedules, from 7 to 17%. No relation was found between complications and treatment factors. Patients who continued smoking had a higher complication rate than those who never smoked or stopped smoking, univariately as well as adjusted for tumor extension, macroscopic tumor, and neck diameter (p = 0.0038). Twenty-eight percent (SE 6%) of the patients who continued smoking had complications at 10 years, compared to about 13% (SE 4%) of those who stopped before or after RT. No evidence was found for any other relation between complications and patient or tumor factors. Severe edema and necrosis (grade III and IV) were not observed in the 2 Gy fraction schedules. A laryngectomy was performed in 36 patients: 30 for recurrence, 3 for complications (at 40, 161, and 272 months), and 3 for a second primary. The overall larynx preservation was 90% at 10 years, and for the different schedules it was 20 x 3.25 Gy: 97%; 20 x 3.1 Gy: 96%; 22 x 2.8 Gy: 92%; 25 x 2.4 Gy: 89%; 33 x 2 Gy: 78%; and 30 x 2 Gy: 80%.
Overall treatment time is the most significant factor for locoregional control of T1 glottic cancer. A schedule of 25 x 2.4 Gy appeared to be the optimal treatment schedule considering both tumor control and long term toxicity. The complication rate was increased in patients who continued smoking.
Tumours of head and neck belong to the most frequent types of cancer world-wide. In Poland, mortality from larynx cancer among males has been continuously increasing during the last decades up to 8.4 deaths per 100,000 men in 1993, which exceeds epidemiological records from other countries. The aetiology of laryngeal cancer is strongly associated with exposure to carcinogens present in tobacco smoke. The review describes a sequence of molecular and cellular events from carcinogenic exposure, DNA adduct formation, detection of mutations in the p53 gene, loss of heterozygosity (LOH) in chromosomal loci encoding the p53 and p16 genes, and loss of control of the cell cycle. The section concerning DNA adducts includes a discussion of the role of such confounders as exogenous exposure, the age and sex of the subject, and disease progression. The significance of genetic factors as individual risk determinants is discussed in relation to bleomycin-induced chromosome instability and in connection with the occurrence of defects in genes encoding detoxifying enzymes. The question concerning the substantial difference between men and women in larynx cancer morbidity and mortality remains open, even when the significantly higher adduct formation in male DNA compared with female material was taken into account. Preliminary experiments suggest a role of the frequently observed loss of the Y-chromosome.
The study objective was to confirm a previous finding that patients with stage III/IV squamous head and neck cancer (SHNC) who smoke during radiotherapy (RT) experience reduced survival.
An observational cohort study. Patients' smoking status was assessed weekly by questionnaire plus blood cotinine. Patients were assessed every 3 to 4 months for survival. Logistic regression and Cox proportional hazards analyses were used to detect the independent contribution of smoking on survival.
Of 148 patients, 113 smoked during RT. Blood cotinine and smoking questionnaire responses were highly correlated (Spearman R = .69; p < .0005). Abstainers and very light smokers experienced better survival than light, moderate, and heavy smokers (median, 42 vs 29 months; p = .07). Tumor and nodal status and years smoked were the most important prognostic factors. Smoking during RT was not an independent predictor of survival, but baseline smoking status was (p = .016).
Smoking status should be documented in all future trials of RT in SHNC to allow for pooled analyses with sufficient power to address this question.
To determine which wound-healing factors impact on the severity of radiation skin and oral mucosal reactions in head and neck cancer and to test modifications to the Radiation Therapy Oncology Group (RTOG) acute toxicity scoring system.
A consecutive sample of 53 head and neck cancer patients who were scheduled for curative or palliative radiation therapy. Therapy was planned using traditional computerized techniques. A new RTOG subscale for tongue reactions was developed. Information on potential predictors was collected during the first week of treatment. Reactions were observed and documented each week throughout treatment using the RTOG Acute Reaction Scoring System scores of acute oropharyngeal reactions and various personal factors.
Significant relationships were found between severe skin and oral reactions and age, commencing radiation within 2 months of surgery and smoking. Significant relationships for severe oral mucosal reactions were found with weight at the commencement of treatment, inadequate or poor diet, having had mucositis with previous chemotherapy, and the use of a custom-made Perspex tongue immobilizer.
Three conclusions can be derived from this study: (1) structures within the oral cavity should be considered separately for toxicity scoring, (2) the newly developed tongue RTOG subscale adds accuracy and specificity to the RTOG acute toxicity scoring system, and (3) wound healing factors are an important component of understanding risk for side effects in head and neck cancer treatment.
Although it is known that high levels of cigarette smoke lead to cell death, little is known about the effects of low-to-moderate levels of smoke components that are found in vivo, such as those experienced by cells in tissues. Clinical studies and experimental data show that smokers heal poorly and are more prone to develop fibrotic diseases. Here we show the effects of first-hand cigarette smoke on fibroblasts, cells that are critically involved in these processes. Using doses of smoke found in the tissues of smokers and a variety of cell and molecular approaches, we show that these doses of cigarette smoke do not cause cell death but rather stimulate fibroblasts to produce stress response and survival proteins such as interleukin-8, PKB/Akt, p53, and p21 that in turn contribute to an increase in cell survival. In addition, smoke-treated cells show a decrease in cell migration, which can be explained by the increased cell adhesion and alterations in cytoskeletal elements. We also show that these levels of smoke cause changes in mitochondrial morphology with a minimum loss of function and these changes are the result of exposure to reactive oxygen species. We conclude that the increase in cell survival may lead to a build-up of connective tissue in the area of a wound, potentially leading to delayed healing and/or fibrosis and that the alterations in the cytoskeleton and in cell adhesion result in inhibition of cell migration, a process that could lead to nonclosure of the wound for lack of proper fibroblast migration to form the healing tissue.
To determine if smoking, a known risk factor for a number of cancers including cervical cancer, is associated with poor prognosis in patients with locally advanced cervical carcinoma treated with chemoradiation.
Patients with primary, previously untreated, histologically confirmed stage II-B, III-B or IV-A cervical carcinoma participated in a Gynecologic Oncology Group (GOG) phase III study (GOG 165) and were randomly allocated to receive radiation plus either cisplatin or 5-fluorouracil. Smoking behavior was ascertained using an administered questionnaire and by quantifying urine cotinine concentration. Disease progression was defined as a >or=50% increase in the cross product of the existing tumor compared with previous assessments. Patients were followed until death.
Of 328 enrolled patients, 12 were ineligible, one was inevaluable for reported smoking status and 40 others were inevaluable for cotinine-derived smoking status. Among evaluable patients, 133 (42%) were reported smokers and 111 (40%) were cotinine-derived smokers. The kappa for agreement between the groups was 0.872 (P<0.01). Compared with non-smokers, median survival was 15 months shorter for reported smokers and 20 months shorter for cotinine-derived smokers (P<0.01). After adjusting for covariates, a significant increase in the risk of death (but not disease progression) was observed for reported smokers (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.01-2.27; P=0.04) and cotinine-derived smokers (HR: 1.57; 95% CI: 1.03-2.38; P=0.04).
Smoking predicts worse overall survival in women with locally advanced cervical carcinoma treated with chemoradiation.
There has been concern that the efficacy of radiation therapy may be reduced when patients smoke or take antioxidant vitamins during treatment. Cancer prevention trials with beta carotene supplements documented adverse effects only among smokers. We conducted a randomized trial with alpha tocopherol (400 IU/day) and beta carotene (30 mg/day) supplements among 540 head and neck cancer (HNC) patients treated by radiation therapy. We examined whether smoking during radiation therapy modified the effects of the supplementation on HNC recurrence and on mortality. During the follow-up, 119 patients had a HNC recurrence and 179 died. Cox models were used to test the interaction between smoking and supplementation and to estimate the hazard ratios (HR) for HNC recurrence and death associated with the supplementation. Cigarette smoking either before or after radiation therapy did not modify the effects of the supplementation. In contrast, the interactions between supplementation and cigarette smoking during radiation therapy were statistically significant for HNC recurrence (p = 0.03), all-cause mortality (p = 0.02) and mortality from the initial HNC (p = 0.04). Among cigarette smokers, the HR were 2.41 (95% CI: 1.25-4.64) for recurrence, 2.26 (95% CI: 1.29-3.97) for all-cause mortality and 3.38 (95% CI: 1.11-10.34) for HNC mortality. All corresponding HR among nonsmokers were close to 1. These results could best be explained by the hypothesis that the combined exposures reduced the efficacy of radiation therapy. Particular attention should be devoted to prevent patients from both smoking and taking antioxidant supplements during radiation therapy.
To determine the prevalence of psychosocial distress among patients undergoing radiotherapy (RT) for head and neck cancer and to examine the association between depression and anxiety and demographic and medical variables.
A total of 40 patients (25 men and 15 women) with nonmetastatic head and neck cancer were enrolled in this prospective study and underwent RT administered with definitive (24 patients) or postoperative (16 patients) intent. Twenty patients (50%) received concurrent chemotherapy. All patients completed the Hospital Anxiety and Depression Scale and Beck Depression Inventory-II instrument before RT, on the last day of RT, and at the first follow-up visit. The effect of patient-, tumor-, and treatment-related factors on psychosocial distress was analyzed.
The prevalence of mild to severe pre-RT depression was 58% and 45% using the Hospital Anxiety and Depression Scale-D and Beck Depression Inventory-II scale, respectively. The prevalence of severe pre-RT anxiety was 7%. The depression levels, as determined by the Hospital Anxiety and Depression Scale and Beck Depression Inventory-II instrument increased significantly during RT and remained elevated at the first follow-up visit (p < 0.001 for both). The variables that were significantly associated with post-RT depression included a greater pre-RT depression level, employment status (working at enrollment), younger age (<55 years), single marital status, and living alone (p < 0.05, for all).
The results of our study have shown that an alarming number of patients undergoing RT for head and neck cancer have symptoms suggestive of psychosocial distress even before beginning treatment. This proportion increases significantly during RT. Studies investigating the role of antidepressants and/or psychiatric counseling might be warranted in the future.
bcl-xL, and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer
- Cordell B Kg Kumar
- Lee
- Js
Kumar B, Cordell KG, Lee JS, et al. EGFR, p16, HPV titer, bcl-xL, and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008;26:3128–3137.
Cigarette smoking and cancer of the mouth, pharynx, and larynx
- Moore