Valuing Follow-up Programs In Head and Neck Cancer

Head-and-neck cancers (HNCs) are one of the major public health problems for both patients and the health-care providers in India. The clinical manifestations of HNC and its treatment can lead to negative effects on the quality of life (QoL) of the patient. The study is aimed to explore the QoL using the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaires among HNC patients in Western part of India. A cross-sectional prospective study was conducted among 400 HNC patients attending the tertiary cancer center. The QoL was assessed by using the EORTC core questionnaire (EORTC QLQ-C30) and EORTC head- and neck-specific questionnaire (EORTC QLQ-H and N35). The data were explored using means, standard deviation, medians, ranges, and proportions. All the 400 patients had completed the questionnaire having a compliance rate of 100%. There was no missing data at the item level for the EORTC QLQ-C30 questionnaire. While the missing items for EORTC QLQ-H and N35 were: problems while swallowing food, problems with teeth, and sexuality. The mean functional score ranged from 74.22 to 93.49 for EORTC QLQ-C30. The mean symptoms score was found in the range from 3.25 to 81.50 for EORTC QLQ-H and N35. Both questionnaires were comprehensive and well accepted by the patients. These questionnaires provided the information-related disease-specific QoL data, which otherwise is often missed. Health-care providers should not only focus on the clinical effects of treatment but also on QoL issues because it will improve overall patient care and survival.

Understanding of p53 family protein (p53, p63 and p73) networks in head and neck squamous cell carcinoma (HNSCC), can positively influence in cancer screening, diagnosis, treatment and prevention. P53 family proteins are regulating diverse cell signalling pathways at diverse conditions to determine cell fate. At each condition of cells state, how these proteins are controlling cell fate is more complexed due to the presense of several isoforms for each p53 family proteins and their multifaceted interactions. Like other solid tumours, the p53 pathway is disabled by several mechanisms in HNSCC. Despite of the convincing evidence of a high frequency of p53 mutations in HNSCC, a subset of cancers arise in the absence of mutations. The molecular mechaninsms through which p53 lacking mutations subvert its tumor supressor functions in HNSCC still remain uncertain. In fact, some cancers and established cancer cell lines are over-expressing wild type p53 protein makes questionable of p53 role as only a tumor suppressor or it has some other additional functions, even in cancer cells. For an answer of this hypothesis, we have performed detailed molecular characterization, in an invitro model of head and neck cancer, in a broad panel of 12 newly established HNSCC cell lines. In our studies, we found that some head and neck cancer cell lines are accumulating wild p53 protein hyperphosphorylated at serine15 and 392 and it leads to the over expression of DNp73, the mechanism already reported from our laboratory in HPV38 immortalized keratinocytes. To better understand the functions of accumulated wild p53 role in HPV positive and negative cancer cell lines, we have performed p53 knock down by siRNA and the results have showed that p53 knock down inhibited cell proliferation in both HPV positive and negative cancer cells. Moreover, p53 knock down induced significant morphological changes and senescence associated beta galactosidase activity in these cells. Our results pinpoint, wild-type p53 protein accumulated in transformed cell lines has an additional role in cell proliferation other than its well known tumor supressor activity. Moreover, the key role of p53 family network in modulating epidermal growth factor receptor (EGFR) expression and in controlling cell proliferation and apoptosis arises the question of whether p53 family proteins status influences the efficacy of EGFR inhibitors, investigating its ability to reduce cell growth, to induce apoptosis and to modulate cell cycle and various EGFR pathwayrelated targets in head and neck cancer. Because, recently improved understanding of the pathogenesis of human head and neck squamous cell carcinoma has led to the development of new, molecular based therapeutic strategies, one of the most promising is the utilization of tyrosine kinase (TK) inhibitors, targeting EGFR. The comparison between the targets analysed and gefitinib effectiveness evidenced the absence of a clear relationship, exluding them as predictive factors for gefitinib efficacy. Our results confirmed the in vitro efficacy of an anti-EGFR approach, but other targets than those analysed here should be characterized in order to identify valid predictive factors for gefitinib utilization in head and neck cancer. We have also performed chemoresistance analysis in our invitro model of HNSCC cell lilnes and found that p53 family network has less predictive role in HNSCC chemoresistance but ABCG2, a multidrug resistance protein, has over-expressed in HNSCC.

Strategies to promote translational research within the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group: a report from the Translational Research Subcommittee

Objective To evaluate the application effect of carnation-11 red light therapy by photon therapeutic apparatus for radiation dermatitis induced by radiation therapy in patients with head and neck cancer. Methods 60 patients with head and neck cancer hospitalized first time were randomly divided into an experimental group and a control group, 30 cases for each group. The control group received routine nursing care during the period of radiotherapy (health education, skin care, skin protective agent, etc.); in addition of routine daily care, the experimental group got red light therapy by photon therapeutic apparatus, twice a day, 10 min per time, until the end of radiotherapy. The pain and skin conditions were evaluated daily. The skin pain and dermatitis degree were compared between these two groups. Results All the patients completed radiotherapy. There was statistical difference in the degree of radiation dermatitis reaction between these two groups (U=4.79, P=0.000). The experimental group mainly got 0-2 grade radioactive dermatitis and the control group 2-3.Chi square test showed that there were statistical differences in the incidences of oral pain week 2, 3, and 4 between these two groups (χ2=65.083, 27.091, P < 0.05), indicating that the occurrence of pain increased with time. Conclusions Photon therapeutic apparatus can significantly improve the radiation dermatitis in head and neck cancer patients, shorten healing time, increase clinical efficacy, and reduce the patients’ economic burden and pain. Key words: Photon therapeutic apparatus; Red light therapy; Head and neck cancer; Radiation dermatitis

Patients with head and neck cancer (HNC) experience painful, debilitating symptoms and functional limitations that can interrupt cancer treatment, and decrease their health-related quality of life (HRQoL). The Electronic Patient Visit Assessment (ePVA) for head and neck is a web-based mHealth patient-reported measure that asks questions about 21 categories of symptoms and functional limitations common to HNC. This article presents the development and usefulness of the ePVA as a clinical support tool for real-time interventions for patient-reported symptoms and functional limitations in HNC. Between January 2018 and August 2019, 75 participants were enrolled in a clinical usefulness study of the ePVA. Upon signing informed consent, participants completed the ePVA and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) general (C30) questionnaire v3.0 (scores range from 0 to 100 with 100 representing best HRQoL). Clinical usefulness of the ePVA was defined as demonstration of reliability, convergent validity with HRQoL, and acceptability of the ePVA (i.e., >70% of eligible participants complete the ePVA at two or more visits and >70% of ePVA reports are read by providers). Formal focus group discussions with the interdisciplinary team that cared for patients with HNC guided the development of the ePVA as a clinical support tool. Qualitative and quantitative methods were used throughout the study. Descriptive statistics consisting of means and frequencies, Pearson correlation coefficient, and Student's t-tests were calculated using SAS 9.4 and STATA. The participants were primarily male (71%), White (76%), diagnosed with oropharyngeal or oral cavity cancers (53%), and undergoing treatment for HNC (69%). Data analyses supported the reliability (alpha =0.85), convergent validity with HRQoL scores, and acceptability of the ePVA. Participants with the highest number of symptoms and functional limitations reported significantly worse HRQoL (sum of symptoms: r=-0.50, P<0.0001; sum of function limitations: r=-0.56, P<0.0001). Ninety-two percent of participants (59 of 64) who had follow-up visits within the 6-month study period completed the ePVA at two or more visits and providers read 89% (169 of 189) of automated ePVA reports. The use of the ePVA as a clinical support tool for real-time interventions for symptoms and functional limitations reported by patients is described in a clinical exemplar. This research indicates that the ePVA may be a useful mHealth tool as a clinical support tool for real-time interventions for patient-reported symptoms and functional limitations in HNC. The study findings support future translational research to enhance the usefulness of the ePVA in real world settings for early interventions that decrease symptom burden and improve the QoL of patients with HNC.

The abnormal regulation of long noncoding RNA(lncRNA) plays an important role in the development and progression of tumor. HOT transcript antisense RNA(HOTAIR) is the first discovered lncRNA with trans-regulatory effect. A number of studies have shown that HOTAIR is up-regulated in head and neck cancers and regulates the signaling pathways of Wnt, Akt and p53 by mobilizing PCR2 or LSD1 proteincomplex, and its abnormal regulation finally affects the cell cycle, apoptosis, angiogenesis, invasion, metastasis and other processes of head and neck cancers.This study will discuss the clinical application prospect of lncRNA HOTAIR in the diagnosis, prognosis and treatment of head and neck cancers in combination with the molecular mechanism of HOTAIR and its latest research progress in head and neck cancers. Key words: Head and Neck Neoplasms; long noncoding RNA; HOTAIR

Objective To validate the gross tumor volume (GTV) delineation in head and neck cancer based on magnetic resonance imaging (MRI) or computed tomography (CT) by cross-sectional autopsy,and to provide a basis for clinical evaluation of the two imaging methods.Methods Ten New Zealand rabbits were selected for transplantation of VX2 carcinoma cells,and a head and neck cancer model was successfully established in six rabbits.Each rabbit was fixed and received MRI scan and CT scan in the same body position.Then,they were sacrificed and fixed in gelatin solution (-70℃) for 72 h; all cryopreserved rabbits underwent cross-sectional autopsy using a jig saw,with the same position and sectional thickness as in MRI scan and CT scan,and cross-sectional autopsy images were obtained using a digital single-lens reflex camera.GTVs were separately delineated based on CT,MRI,and cross-sectional autopsy images.The GTVMRI,GTVCT,GTVSA,and volume difference ratios (VDRs) were calculated;two-way classification ANOVA and paired t-test were used for difference analyses.Results The mean values of GTVMRI,GTVCT,and GTVSA were 8.20 ± 2.56,8.40 ± 2.20,and 8.11 ± 2.88 cm3,respectively,without significant differences among them (F =0.06,P =0.943).The mean values of VDRMRI-SA and VDRCT-SA were 0.180 ± 0.060 and 0.309 ± 0.091,respectively,with a significant difference between them (t =7.49,P =0.001).Conclusion The GTV delineation based on MRI is more accurate than that based on CT in head and neck cancer. Key words: Head and neck neoplasms; Gross tumor volume; Dosimetry

Objective To investigate how much the patient setup accuracy for irradiation of head and neck cancer can be improved by online setup verification and offline setup verification using cone-beam computed tomography(CBCT), and the feasibility of image-guided adaptive correction procedure to reduce the PIN margin.Methods 16 patients of head-and-neck cancer treated with three-dimensional conformal radiotherapy (3D-CRT)or intensity modulated radiotherapy(IMRT)were investigated. The first online kV CBCT scan, rigid image registration, setup correction were performed before radiotherapy. The second kV CBCT scan were acquired immediately after treatment and analysis was performed as above. CBCT scans were acquired at two or three fractions weekly during the entire course of radiotherapy and CBCT online-guided correction data were recorded. The data was used to calculate the population-based CTV-PTV margins under the condition of non-correction, correction every fraction and compensation of the systematic setup error respectively. The number of initial images required to predict systematic setup error was evaluated with the permission of 0.5 mm residue error. Results Total of 320 sets of CBCT images were analyzed for 16 patients. Under the condition of non-correction, the margins required to account for total error are 5.7 mm,5.6 mm,and 7.3 mm in the left-right(X axis),cranio-eaudal(Y axis), and anterior-posterior (Z axis)directions respectively, when the tumor was corrected every fraction, the margins required to account for intrafraetion error are 1.7 mm,1.7 mm,and 2.3 mm in X, Y,and Z axis.To correct the systematic setup error,8 sets of CBCT images are adequate. After compensation for the effect of the systematic setup error, 2.7 mm,2.5 mm, and 3.6 mm PTV margins are necessary in X, Y, and Z axis respectively. Conclusions There exists some extent of setup error in head and neck 3D-CRT or IMRT.The on-line CBCT correction and the approach based on off-line adaptive correction both can be used to reduce the impact of setup error obviously, the required margins for the PTV was reduced accordingly. Key words: Head and neck cancer; Planning target volume; Adaptive radiotherapy; Image-guided radiotherapy ; Cone-beam CT

Prognostication of head and neck cancer (HNCC) involves molecular identification of residual tumor cells, prediction of recurrence, distant metastases or secondary tumors and prediction of the sensitvity to therapy. Biomarkers of HNCC are mutations of p53, p16 and amplification of Cyclin D and E2F4. One hundred and fifty-two HNCC cases have been evaluated for p53, hMLH1, Cyclin D and p16 gene alterations using PCR-SSCP and Western blot analysis. P53 mutations of HNCC have been found in 37.5% of cases. However, 11% of the cases showed p53 mutations in the normal peritumoral mucosa suggesting "field cancerization" process. Mismatch-repair gene mutations (MMR: hMHL1 and hMSH2) occurred with 17 and 8.6% frequency, respectively, while E2F4 mutations were even more frequent (21.4%) in HNCC. Our data suggest that E2F4 overexpression can be caused by the inactivation of the p16 gene in HNCC, while its mutations are most probably associated to the mutations of the MMR genes. These molecular informations can help to predict the biological potential of HNCC as well as the probability of the development of secondary HNCCs.

Objective To determine the planning target volume margins of head and neck cancers treated by image guided radiotherapy (IGRT).Methods 464 sets cone beam computed tomography (CBCT) images before setup correction and 126 sets CBCT images after correction were obtained from 51 head and neck cancer patients treated by IGRT in our department.The systematic and random errors were evaluated by either online or offline correction through registering the CBCT images to the planning CT.The data was divided into 3 groups according to the online correction times.Results The isocenter shift were 0.37 mm±2.37 mm, -0.43 mm±2.30 mm and 0.47 mm±2.65 mm in right-left (RL), anterior-posterior (AP) and superior-inferior (SI) directions respectively before correction, and it reduced to 0.08 mm±0.68 mm, -0.03 mm±0.74 mm and 0.03 mm±0.80 mm when evaluated by 126 sets corrected CBCT images.The planning target volume (PTV) margin from clinical target volume (CTV) before correction were:6.41 mm,6.15 mm and 7.10 mm based on two parameter model, and it reduced to 1.78 mm,1.80 mm and 1.97 mm after correction.The PTV margins were 3.8 mm,3.8 mm,4.0 mm;4.0 mm,4.0 mm,5.0 mm and 5.4 mm,5.2 mm,6.1 mm in RL, AP and SI respectively when online-correction times were more than 15 times, 11-15 times,5-10 times.Conclusions CBCT-based on online correction reduce the PTV margin for head and neck cancers treated by IGRT and ensure more precise dose delivery and less normal tissue complications. Key words: Intensity modulated radiotherapy; Image guided radiotherapy; Setup error; Treatment margin

Simple SummaryQuality of life (QoL) scores and frailty status are becoming increasingly important criterion with implications on both how patients are treated and survival in head and neck cancer (HNC). Despite this, physicians lack tools to identify patients who are at risk of suffering declines in QoL and becoming frail following treatment. Therefore, we investigated whether functional decline, as measured by a series of physical tests called the Short Physical Performance Battery (SPPB), correlated with a reduction in QoL and increased risk of frailty. In the current study, patients who experienced a decline in SPPB scores were significantly more likely to have changes in physical functioning QoL measures as well as transition to frail status following treatment. In conclusion, the SPPB may be a useful tool to identify patients who may benefit from additional rehabilitation in future studies.Patient-reported quality of life (QoL) metrics, frailty status, and physical functioning are emerging concepts in head and neck cancer (HNC) with implications on both treatment decision-making and prognosis. The impact of treatment-related functional decline on QoL and frailty has not been well-characterized in HNC and was the focus of this investigation. Methods: Patients who underwent radiation therapy for HNC from 2018 to 2020 were evaluated as a prospective observational cohort. Functional decline, QoL, and the frailty phenotype were measured via the Short Physical Performance Battery (SPPB), European Organization for Research and Treatment of Cancer (EORTC) qlq-C30, and Fried Frailty index, respectively. Results: A total of 106 HNC patients were included, 75 of which received concurrent chemoradiation therapy (CCRT) and 31 received radiation alone, both with and without surgery. There was a decrease in SPPB overall (p < 0.001) from the beginning to the end of treatment in the CCRT group but not the radiation group (p = 0.43). Change in overall SPPB points following treatment correlated with the decline in physical QoL for both groups (p < 0.05) as well as transition frail status in the CCRT group (p < 0.001) with a trend in the radiation group (p = 0.08). Conclusions: Change in SPPB correlates with QoL and transition to frailty status in patients undergoing definitive CCRT for HNC with similar trends in those receiving radiation alone. Decline in SPPB could potentially be useful in identification of those who may benefit from rehabilitation in future studies.

Patients with head and neck cancers (HNCs) are at an increased risk of developing functional symptoms associated with eating, speaking, and breathing along with symptoms caused by a fungating tumour (e.g., cosmetic change, malodor, and bleeding). These may substantially reduce their physical functioning and quality of life (QoL). This observational study aimed to find out the QoL in patients with HNC in a tertiary care oncology centre. A prospective observational study was conducted in adult patients diagnosed with HNC. The patients were divided depending upon their disease extent into early, advanced, and very advanced local disease. The physical, cognitive, emotional, financial and social domains were assessed using a validated Hindi version of the European Organisation for Research and Treatment of cancer (EORTC)- QoL 30 and EORTC H&N 35 at baseline and 3 months. A total of 100 patients were assessed with a mean age of 49.3 ± 12.4 years. Most of the patients had carcinoma buccal mucosa (42%) followed by carcinoma tongue (17%). The patients experienced difficulties with physical functioning and deterioration in emotional functioning. Pain and fatigue were the major problematic symptoms especially in advanced disease patients resulting in poor QoL. There was a significant improvement in various domains of QoL at 3 months follow-up in those with advanced disease. The fatigue scores at baseline and follow-up showed a positive correlation with other symptoms. Patients with HNC have a high symptom burden that leads to poor QoL. Appropriate palliative care interventions help to decrease symptom burden and prevent deterioration of their QoL in patients with HNC.

Background: Head and neck cancers (HNCs) are the 6th most common cancer worldwide and account for 4% of malignancies. Recent studies implied that tumor volumes play a useful prognostic role in HNC. This meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the relationship between tumor volume and prognosis of HNC. Methods: A comprehensive search strategy was used to search relevant literature in PubMed, EBSCO and ISI Web of Science. The correlation between tumor volume and HNC prognosis was analyzed. This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and using STATA Version 12.0. Results: Finally, fifteen eligible studies consisting of 2,447 participants were included. We found that HNC with a primary gross tumor volume (GTVp) larger than the cut-off value were associated with an increased risk of local control failure (pooled HR =1.34; 95% CI =1.22–1.47). For the longtime survival, a larger GTVp was significantly associated with disease free survival (DFS) (pooled HR =1.34; 95% CI =1.23–1.46) and overall survival (OS) (pooled HR =1.27; 95% CI =1.17–1.37). On PET-CT, the primary tumor metabolic tumor volume (MTVp) was associated with local control (pooled HR =3.51; 95% CI =1.87–6.59), DFS (pooled HR =5.70; 95% CI =4.30–7.5) and OS (pooled HR =4.13; 95% CI =2.63–6.47). Conclusions: The GTVp and MTVp were highly significant in evaluating local control, OS and DFS of patients with HNC and might be a useful adjuvant and complementary index for a new T staging system in HNC.

MicroRNAs (miRNAs) regulate target genes expression in the post-transcriptional levels.There are many kinds of differential expressions of miRNA in head and neck cancer,and the miRNA participate in a series of important biological processes such as cell development,proliferation,differentiation,apoptosis and etc.miRNAs is expected to become an effective means for the diagnosis and treatment of head and neck cancer. Key words: MicroRNAs ; Head and neck neoplasms ; Gene expression regulation ;

Objective To perform a systematic review and Meta-analysis on volumetric and dosimetric changes in target volumes and organs at risk (OARs) in adaptive radiotherapy (ART) for patients with head and neck cancer (HNC), and to investigate the role of ART in the treatment of HNC. Methods Literature retrieval was performed to include related studies, and the parameters of primary tumor, GTV-T and GTV-N, parotid volume, D95 and Dmean of target volumes, Dmean of ipsilateral and contralateral parotid volume (I-PG and C-PG), and Dmax of the spinal cord and brainstem. Results A total of 17 studies involving 336 patients were included in the meta-analysis. Primary tumor and parotid volume changed significantly. The volumes of GTV-T, GTV-N, and I-PG were significantly reduced during the 15-20th radiotherapy and after the 20th radiotherapy (P<0.05), and the C-PG was significantly reduced after the 20th radiotherapy (P=0.004). The analysis of actual dose showed that the D95 and Dmean of primary tumor showed no significant differences, and during the 15-20th radiotherapy, the Dmax of the spinal cord was increased by 2.26 Gy (P=0.000), while the Dmax of the brainstem showed no significant changes before the 20th radiotherapy and was increased by 1.78 Gy after the 25th radiotherapy (P=0.020). In addition, the Dmean of I-PG was increased by 2 Gy during the 20-25th radiotherapy (P=0.0001), and the Dmean of C-PG was increased before the 20th radiotherapy and showed no significant changes after the 25th radiotherapy (P=0.110). The dosimetric analysis of ART showed that the Dmax of the spinal cord and brainstem was reduced significantly (spinal cord: MD=-2.15, 95% CI-3.12 to -1.18, P=0.000; brainstem: MD=-2.20, 95% CI-3.32 to -1.09, P=0.000). The Dmean of I-PG was reduced by about 3.5 Gy, and the sensitivity analysis revealed that the results of Dmean of C-PG were unstable. Conclusions The volumes of primary tumors and parotid glands change significantly, and the actual doses of OARs (Dmax of the spinal cord and brainstem and Dmean of the parotid glands) significantly increase, while the doses of GTV-T and GTV-N show no significant changes. ART can effectively protect the OARs, and patients with locally advanced HNC who receive concurrent chemoradiotherapy can obtain good dose gains from ART plan performed during the 15-20th radiotherapy and at about the 25th radiotherapy. Key words: Head and neck cancer; Adaptive radiotherapy; Volumetric and dosimetric comparison; Meta analysis