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The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative imaging parameters derived from 18F-fluoro-misonidazole (F-MISO) and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) and clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Tumor-tissue blocks of HNSCC patients with pretreatment F-MISO-PET/CT and FDG-PET/CT were de-archived for expression of hypoxia-inducible factor-1 alpha (HIF-1α) subunit, carbonic anhydrase-IX (CA-IX), and glucose transporter subunit-1 (GLUT-1) using immunohistochemistry (IHC). The intensity of staining was graded and correlated with quantitative imaging parameters and with disease-related outcomes. Tissue blocks were analyzed for 14 of 20 patients. On IHC, median H-scores for HIF-1α, CA-IX, and GLUT-1 were 130, 0, and 95, respectively. No significant correlation of tissue biomarkers of hypoxia with quantitative imaging parameters was found. However, borderline significant correlation was seen for H-scores of CA-IX with hypoxic tumor volume (HTV) (r = 0.873, P = 0.054) and fractional hypoxic volume (r = 0.824, P = 0.086) derived from F-MISO-PET/CT. At a median follow-up of 43 months, 5-year Kaplan–Meier estimates of locoregional control, disease-free survival, and overall survival were 53%, 43%, and 40%, respectively. Increased expression of HIF-1α or GLUT-1 (dichotomized by median H-scores) was not individually associated with disease-related outcomes. However, a combination of high HTV (>4.89cc) with above median H-scores of either HIF-1α (>130) and/or GLUT-1 (>95) was associated with worse clinical outcomes. None of the three patients with such “adverse hypoxic profile” were long-term survivors. There is no significant correlation of endogenous tissue biomarkers of hypoxia (HIF-1α, CA-IX, and GLUT-1) with quantitative imaging parameters (on F-MISO-PET/CT and FDG-PET/CT) or long-term outcomes in HNSCC. However, a combination of both can identify a subgroup of patients with adverse outcomes.

To analyze the outcome of locally advanced unresectable adenoid cystic carcinoma (ACC) of head and neck treated with radical concurrent chemoradiotherapy (CRT) at a single tertiary care centre. Between 2011 and 2018, 23 patients with locally advanced unresectable ACC of head and neck treated with non-surgical radical treatment with concurrent chemoradiotherapy were evaluated for outcome and toxicity. All but one patient received cisplatin-based concurrent chemotherapy and 74% of patients were treated with intensity-modulated radiotherapy. Median follow-up was 53 months (range 3–115 months). Following treatment, 11 patients achieved complete response (47.8%) and of the 12 patients with residual disease, 7 patients additionally had disease stabilization without local progression. Overall 15 patients had disease progression. Median time to progression was 28 months (range 6–67 months). The 3-year and 5-year overall survival, local progression-free survival (LPFS) and distant progression-free survival (DPFS) were 78%, 79.7%, 67.4% and 63%, 50.9%, 48.6%, respectively. Acute grade 3 mucositis was observed in three patients, and one patient additionally developed grade 4 neutropenia with subsequent complete recovery. No grade 3 or higher late toxicity was observed. Radical concurrent chemoradiotherapy is a promising treatment option in locally advanced unresectable ACC with acceptable toxicity.

Background To identify clinicoradiological factors that determine functional outcomes in laryngopharyngeal cancers treated with chemoradiotherapy. Methods One hundred patients of locally advanced laryngopharyngeal cancers who were treated with chemoradiotherapy were accrued in this prospective study. The coprimary endpoint of the study was local control (LC) and functional larynx preservation survival (FLPS). Results The median follow-up was 39 months. Thirty-nine patients had a local failure of which 17 underwent a salvage laryngectomy. A dysfunctional larynx with clinic-radiologically disease was seen in only 1 patient. Factors significant for LC were thyroid cartilage erosion/lysis and cricoarytenoid joint involvement. Within the T4a subset, patients with exolaryngeal disease through the soft tissue framework had significantly better LC and FLPS than those with cartilage erosion/lysis. Conclusions Patients with limited exolaryngeal disease through the soft-tissue framework can be considered for functional organ preservation, while those with thyroid cartilage involvement and cricoarytenoid joint involvement are not suitable.

Purpose Brachytherapy (BT) forms major treatment modality in squamous cell carcinoma of head and neck cancers (HNC). However, there is a dearth of literature and guidelines for the use in various indications. High-dose-rate brachytherapy (HDR-BT) in Indian scenario is an important treatment modality, and the recommendations in this guidelines aim to provide the necessary recommendations for the use of HDR-BT for uniform application across the country in patients with HNC. Material and methods A panel consisting of members of the Indian Brachytherapy Society (IBS), based on their clinical experience was invited. The process involved defining important steps, precautions, target volumes and indications, thorough literature review, and discussion with fellow members. The guidelines were established and formulated the recommendations for HDR-BT based on available evidences and individual experience for sites, relevant to Indian settings. Results The IBS recommends the use of HDR brachytherapy as a part of treatment of head and neck tumors. The scope of these guidelines and recommendations included practical suggestions, ensuring efficient use of brachytherapy treatment as radical with external beam radiotherapy (EBRT) boost, palliative and adjuvant as definitive, or re-radiation as salvage for HNC in India. The IBS has made specific site-wise recommendations for previously untreated and recurrent HNC patients on their selection criteria, implant techniques, target volume definition, and HDR treatment parameters, such as time, dose rate, total dose, and fractionation schedules. Limited experience exists with HDR-BT in patients with head and neck cancers in India and across the globe. Conclusions IBS provided a consensus statement and guidelines for the head and neck brachytherapy and believed that these recommendations will overcome the fear of practicing radiation oncologists. This should generate interest amongst students and will help radiation oncologists all across the country to use the art of brachytherapy carefully in HNC patients, with better curative and salvage options.

// Vanita Noronha 1 , * , Vijay Maruti Patil 1 , * , Amit Joshi 1 , Manoj Mahimkar 2 , Usha Patel 2 , Manish Kumar Pandey 2 , Arun Chandrasekharan 1 , Hollis Dsouza 1 , Atanu Bhattacharjee 3 , Abhishek Mahajan 1 , Nilesh Sabale 1 , Jai Prakash Agarwal 4 , Sarbani Ghosh-Laskar 4 , Ashwini Budrukkar 4 , Anil K. D’Cruz 5 , Pankaj Chaturvedi 5 , Prathamesh S. Pai 5 , Devendra Chaukar 5 , Sudhir Nair 5 , Shivakumar Thiagarajan 5 , Shripad Banavali 1 and Kumar Prabhash 1 1 Department of Medical Oncology, Tata Memorial Hospital, HBNI, Mumbai, India 2 Mahimkar Laboratory, Cancer Research Institute (CRI), Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), HBNI, Navi Mumbai, India 3 Section of Biostatistics, Department of Epidemiology, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India 4 Department of Radiation Oncology, Tata Memorial Hospital, HBNI, Mumbai, India 5 Department of Head and Neck Surgery, Tata Memorial Hospital, HBNI, Mumbai, India * These authors contributed equally to this work Correspondence to: Kumar Prabhash, email: kumarprabhashtmh@gmail.com Keywords: HPV negative; oropharynx; nimotuzumab; weekly; cisplatin Received: September 03, 2019 Accepted: December 21, 2019 Published: January 28, 2020 ABSTRACT Background: Addition of nimotuzumab to weekly cisplatin and radiation improves outcomes in head and neck cancer. HPV negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. We wanted to determine whether the addition of nimotuzumab to cisplatin-radiation could improve outcomes in these poor-risk tumors. Methods: This was a subgroup analysis of a phase 3 randomized study. In this study, locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin (30 mg/m2 IV)- radiation (66–70 Gy) {CRT arm} or nimotuzumab (200 mg weekly) -weekly cisplatin (30 mg/m2)-radiation (66–70 Gy) {NCRT arm}. The data of HPV negative oropharyngeal cancer was extracted from the database of this study for the analysis. HPV testing was done with p16 immunohistochemistry (IHC) staining and reported according to the CAP criteria. The outcomes assessed were progression-free survival (PFS), disease-free survival (DFS), locoregional control, and overall survival (OS). Interaction test was performed between the study arms and HPV status prior to doing any HPV specific analysis for each of the studied outcomes. Kaplan Meier estimates for 2 year OS with 95%CI was calculated. The hazard ratio was obtained using COX regression analysis. Results: We had 187 HPV negative oropharyngeal cancers, 91 in the CRT arm and 96 in NCRT arm. The interaction test was significant for PFS ( p = 0.000), locoregional control ( p = 0.007) and overall survival ( p = 0.002) but not for DFS ( p = 0.072). The 2- year PFS was 31.5% (95%CI 21.5–42) in CRT arm versus 57.2% (95%CI 45.8–67.1) in NCRT arm (HR -0.54; 95%CI 0.36–0.79, p = 0.002). The 2-year LRC was 41.4% (95%CI 29.8–52.6) in the CRT arm versus in 60.4% (95%CI 48.7–70.2) in the NCRT arm (HR -0.61; 95%CI 0.4–0.94, p = 0.024). The addition of nimotuzumab also lead to an improvement in 2-year OS from 39.0% (95%CI 28.4–49.6) to 57.6% (95%CI 46.3–67.4) (HR-0.63, 95%CI 0.43–0.92, p = 0.018). Conclusions: The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.

BackgroundThe impact of modern high-precision conformal techniques on rare but highly morbid late complications of head and neck radiotherapy, such as necrosis of the bone, cartilage or soft-tissues, is not well described.MethodMedical records of head and neck cancer patients treated in prospective clinical trials of definitive high-precision radiotherapy were reviewed retrospectively to identify patients with necrosis.ResultsTwelve of 290 patients (4.1 per cent) developed radiotherapy necrosis at a median interval of 4.5 months. There was no significant difference in baseline demographic (age, gender), disease (primary site, stage) and treatment characteristics (radiotherapy technique, total dose, fractionation) of patients developing radiotherapy necrosis versus those without necrosis. Initial management included antibiotics or anti-inflammatory agents, tissue debridement and tracheostomy as appropriate followed by hyperbaric oxygen therapy and resective surgery for persistent symptoms in selected patients.ConclusionMultidisciplinary management is essential for the prevention, early diagnosis and successful treatment of radiotherapy necrosis of bone, cartilage or cervical soft tissues.

Background To assess the efficacy of intensity-modulated radiation therapy (IMRT) for tumors of the nasal cavity and paranasal sinus (PNS) region. Materials and methods Two hundred fourteen patients with tumors of the nasal cavity and PNS region treated with curative intent IMRT between 2007 and 2019 were included in this retrospective analysis. Results Fifty-one (24.1%) received definitive RT/CTRT and 163 (75.9%) received adjuvant RT. Most common histology was squamous cell carcinoma (26.1%) followed by adenoid cystic carcinoma (21.5%). The median follow-up was 43.5 months. The 5-year local control (LC), event-free survival (EFS), and overall survival (OS) for the entire cohort was 66.9%, 59%, and 73.9%, respectively. On univariate analysis treatment with nonsurgical modality, T classification and undifferentiated/poorly differentiated histology were associated with inferior 5-year LC, EFS, and OS. Four patients had late Grade 3/Grade 4 ocular toxicity. Conclusions IMRT should be the standard of care for tumors of PNS region across all histologies and treatment setting.

OBJECTIVE/HYPOTHESIS To estimate the prevalence of baseline clinically significant distress (distress score ≥ 4) in head and neck cancer patients planned and treated with radical intent radiotherapy using the National Comprehensive Cancer Network Distress Thermometer (DT) and assess factors predictive of distress. STUDY DESIGN Cross-sectional study. METHODS This was a cross-sectional study evaluating distress in 600 head and neck cancer patients undergoing radiation therapy. The DT was used to screen patients for distress at baseline before radiotherapy. RESULTS The median distress score of the entire cohort was 4 interquartile range (IQR) (IQR: 3-5), and 340 patients (56.7%) had clinically significant distress. On univariate analysis, the causal factors predictive of distress were low socioeconomic status (P = .04), presence of proliferative growth at presentation (P = .008), site of the tumor (oral cavity, P = .02), comorbidity (P = .04), and presence of Ryle's tube or tracheostomy tube at baseline (P = .01). Low socioeconomic status was significant (P = .04) on multivariate analysis for high levels of distress. CONCLUSIONS Among head and neck cancer patients, 56% of patients had clinically significant baseline distress, and patients with low socioeconomic status had high distress. There is a need for interventions to mitigate distress. LEVEL OF EVIDENCE 4 Laryngoscope, 131:2023-2029, 2021.

PurposeTo compare long-term disease-related outcomes and late radiation morbidity between intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in head and neck squamous cell carcinoma (HNSCC) in the setting of a prospective randomized controlled trial.MethodsPreviously untreated patients with early to moderately advanced non-metastatic squamous carcinoma of the oropharynx, larynx, or hypopharynx (T1-T3, N0-N2b, M0) planned for comprehensive irradiation of primary site and bilateral neck nodes were randomly assigned to either IMRT or 3D-CRT after written informed consent. Patients were treated with 6MV photons to a total dose of 70Gy/35 fractions over 7 weeks (3D-CRT) or 66Gy/30 fractions over 6 weeks (IMRT). A sample size of 60 patients was estimated to demonstrate 35% absolute difference in the incidence of ≥grade 2 acute xerostomia between the two arms. All time-to-event outcomes were calculated from date of randomization until the defined event using the Kaplan-Meier method.ResultsAt a median follow-up of 140 months for surviving patients, 10-year Kaplan-Meier estimates of loco-regional control (LRC); progression-free survival (PFS); and overall survival (OS) with 95% confidence interval (95%CI) were 73.6% (95%CI: 61.2–86%); 45.2% (95%CI: 32–58.4%); and 50.3% (95%CI: 37.1–63.5%) respectively. There were no significant differences in 10-year disease-related outcomes between 3D-CRT and IMRT for LRC [79.2% (95%CI: 62.2–96.2%) vs 68.7% (95%CI: 51.1–86.3%),p = 0.39]; PFS [41.3% (95%CI: 22.3–60.3%) vs 48.6% (95%CI: 30.6–66.6%),p = 0.59]; or OS [44.9% (95%CI: 25.7–64.1%) vs 55.0% (95%CI: 37–73%),p = 0.49]. Significantly lesser proportion of patients in the IMRT arm experienced ≥grade 2 late xerostomia and subcutaneous fibrosis at all time-points. However, at longer follow-up, fewer patients remained evaluable for late radiation toxicity reducing statistical power and precision.ConclusionsIMRT provides a clinically meaningful and sustained reduction in the incidence of moderate to severe xerostomia and subcutaneous fibrosis compared to 3D-CRT without compromising disease-related outcomes in long-term survivors of non-nasopharyngeal HNSCC.

Objective:To study if pre-treatment CT texture features in locally advanced squamous cell carcinoma of laryngo-pharynx can predict long-term local control and laryngectomy free survival (LFS).Methods:Image texture features of 60 patients treated with chemoradiation (CTRT) within an ethically approved study were studied on contrast-enhanced images using a texture analysis research software (TexRad, UK). A filtration-histogram technique was used where the filtration step extracted and enhanced features of different sizes and intensity variations corresponding to a particular spatial scale filter (SSF): SSF = 0 (without filtration), SSF = 2 mm (fine texture), SSF = 3–5 mm (medium texture) and SSF = 6 mm (coarse texture). Quantification by statistical and histogram technique comprised mean intensity, standard-deviation, entropy, mean positive pixels, skewness and kurtosis. The ability of texture analysis to predict LFS or local control was determined using Kaplan–Meier analysis and multivariate cox model.Results:Median follow-up of patients was 24 months (95% CI:20–28). 39 (65%) patients were locally controlled at last follow-up. 10 (16%) had undergone salvage laryngectomy after CTRT. For both local control & LFS, threshold optimal cut-off values of texture features were analyzed. Medium filtered-texture feature that were associated with poorer laryngectomy free survival were entropy ≥4.54, (p = 0.006), kurtosis ≥4.18; p = 0.019, skewness ≤−0.59, p = 0.001, and standard deviation ≥43.18; p = 0.009). Inferior local control was associated with medium filtered features entropy ≥4.54; p 0.01 and skewness ≤ – 0.12; p = 0.02. Using fine filters, entropy ≥4.29 and kurtosis ≥−0.27 were also associated with inferior local control (p = 0.01 for both parameters). Multivariate analysis showed medium filter entropy as an independent predictor for LFS and local control (p < 0.001 & p = 0.001).Conclusion:Medium texture entropy is a predictor for inferior local control and laryngectomy free survival in locally advanced laryngo-pharyngeal cancer and this can complement clinico-radiological factors in predicting prognosticating these tumors.Advances in knowledge:Texture features play an important role as a surrogate imaging biomarker for predicting local control and laryngectomy free survival in locally advanced laryngo-pharyngeal tumors treated with definitive chemoradiation.

Purpose The purpose of this study is to evaluate long-term clinical outcomes of women treated with accelerated partial breast irradiation (APBI) using multicatheter interstitial brachytherapy (MIB-APBI) with risk groups defined by Groupe Europeen de Curie-therapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO), American Society for Radiation Oncology (ASTRO), updated ASTRO, and American Brachytherapy Society (ABS) guidelines and to elucidate the most appropriate guideline that could differentiate outcomes among its risk groups. Methods and Materials Two hundred forty women underwent MIB-APBI during July 2000 to March 2013. Comparisons of long-term clinical outcomes (local control [LC], disease-free survival [DFS], cause-specific survival [CSS], and overall survival [OAS]) stratified by the risk groups proposed by the aforementioned patient selection guidelines were carried out on a prospectively maintained database. Results At a median follow-up of 114 months, 10-year LC, DFS, and OAS were 90%, 81%, and 83.5%, respectively, for the entire group. There was no statistically significant difference in the LC rates for risk groups by ESTRO, ASTRO, updated ASTRO and ABS guidelines. The 10-year DFS and OAS for GEC-ESTRO low-, intermediate-, and high-risk group was 75%, 88%, and 60% (p = 0.02) and 86%, 93%, and 62% (p = 0.001), respectively. Ten-year DFS and OAS in the ABS 2018–acceptable and ABS 2018–unacceptable group were 78% and 67% (p = 0.01) and 88% and 69% (p = 0.001), respectively. No significant difference in any of the outcomes was observed with risk groups suggested by ASTRO or updated ASTRO consensus guidelines. Conclusions None of the current patient selection guidelines for APBI could differentiate LC (main APBI endpoint) among its risk groups, whereas GEC-ESTRO and ABS guideline could differentiate DFS and OAS.

Bilateral breast cancer (BBC) is an uncommon presentation. The characteristics and outcomes of synchronous and metachronous BBC were compared within an Indian cohort.This was a retrospective audit of 193 BBC patients treated at a tertiary hospital in India over a period of 10 years from January 2004 to December 2014. The demographic, tumor and treatment characteristics were compared between synchronous (n = 131 patients) and metachronous tumors (n = 62 patients) using descriptive analysis. The survival outcomes were assessed using Kaplan-Meier survival curves and compared using the log rank test. Univariate and multivariate analysis was done using a Cox proportional hazards model to assess the effect of the prognostic factors on survival.The mean age of presentation in synchronous BBC (SBBC) and metachronous BBC (MBBC) was 55 years (SD, 12.5) and 51 years (SD, 9.5), respectively. The median time to contralateral presentation in MBBC was 3.8 years. Mean tumor size was larger in SBBC (P = .01). Breast Cancer gene mutation was positive in 13 of 38 evaluated patients (of whom 12 had MBBC). The concordance rates for the estrogen receptor (ER) and progesterone receptor negativity and triple-negative receptor status were higher in MBBC compared with SBBC (P .001). Grade III tumor was more frequently seen in MBBC (P = .03). The median follow-up of the entire cohort was 42 months (range, 30-60 months): 45 months for SBBC and 35 months for MBBC. The 3-year rates of overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) for SBBC and MBBC was 88% and 90%, 74% and 64% and 90% and 84%, respectively. There was no difference in overall OS, DFS, and LRC between SBBC and MBBC.BBC is an uncommon presentation. Synchronous presentation was more common. Metachronous tumors differ from synchronous with higher Grade of presentation and less expression of ER. There was no difference in outcome between patients with synchronous and metachronous tumors.

Purpose Chemoradiation with cisplatin 100 mg/m2 given once every 3 weeks is the standard of care in locally advanced head and neck squamous cell cancer (LAHNSCC). Increasingly, low-dose once-a-week cisplatin is substituted because of perceived lower toxicity and convenience. However, there is no level 1 evidence of comparable efficacy to cisplatin once every 3 weeks. Patients and Methods In this phase III randomized trial, we assessed the noninferiority of cisplatin 30 mg/m2 given once a week compared with cisplatin 100 mg/m2 given once every 3 weeks, both administered concurrently with curative intent radiotherapy in patients with LAHNSCC. The primary end point was locoregional control (LRC); secondary end points included toxicity, compliance, response, progression-free survival, and overall survival. Results Between 2013 and 2017, we randomly assigned 300 patients, 150 to each arm. Two hundred seventy-nine patients (93%) received chemoradiotherapy in the adjuvant setting. At a median follow-up of 22 months, the estimated cumulative 2-year LRC rate was 58.5% in the once-a-week arm and 73.1% in the once-every-3-weeks arm, leading to an absolute difference of 14.6% (95% CI, 5.7% to 23.5%); P = .014; hazard ratio (HR), 1.76 (95% CI, 1.11 to 2.79). Acute toxicities of grade 3 or higher occurred in 71.6% of patients in the once-a-week arm and in 84.6% of patients in the once-every-3-weeks arm ( P = .006). Estimated median progression-free survival in the once-a-week arm was 17.7 months (95% CI, 0.42 to 35.05 months) and in the once-every-3-weeks arm, 28.6 months (95% CI, 15.90 to 41.30 months); HR, 1.24 (95% CI, 0.89 to 1.73); P = .21. Estimated median overall survival in the once-a-week arm was 39.5 months and was not reached in the once-every-3-weeks arm (HR, 1.14 [95% CI, 0.79 to 1.65]; P = .48). Conclusion Once-every-3-weeks cisplatin at 100 mg/m2 resulted in superior LRC, albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m2, and should remain the preferred chemoradiotherapy regimen for LAHNSCC in the adjuvant setting.

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [1%] vs seven [1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (1%) of 4851 patients died while on trial treatment (13 [1%] of 2417 patients in the intermittent letrozole group vs ten [1%] of 2411 in the continuous letrozole group).In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.Novartis and the International Breast Cancer Study Group.

Purpose: Clinical data collecting is expensive in terms of time and human resources. Data can be collected in different ways; therefore, performing multicentric research based on previously stored data is often difficult. The primary objective of the ENT COBRA (COnsortium for BRachytherapy data Analysis) ontology is to define a specific terminological system to standardized data collection for head and neck (H&N) cancer patients treated with interventional radiotherapy. Material and methods: ENT-COBRA is a consortium for standardized data collection for H&N patients treated with interventional radiotherapy. It is linked to H&N and Skin GEC-ESTRO Working Group and includes 11 centers from 6 countries. Its ontology was firstly defined by a multicentric working group, then evaluated by the consortium followed by a multi-professional technical commission involving a mathematician, an engineer, a physician with experience in data storage, a programmer, and a software expert. Results: Two hundred and forty variables were defined on 13 input forms. There are 3 levels, each offering a specific type of analysis: 1. Registry level (epidemiology analysis); 2. Procedures level (standard oncology analysis); 3. Research level radiomics analysis). The ontology was approved by the consortium and technical commission; an ad-hoc software architecture (“broker”) remaps the data present in already existing storage systems of the various centers according to the shared terminology system. The first data sharing was successfully performed using COBRA software and the ENT COBRA Ontology, automatically collecting data directly from 3 different hospital databases (Lübeck, Navarra, and Rome) in November 2017. Conclusions: The COBRA Ontology is a good response to the multi-dimensional criticalities of data collection, retrieval, and usability. It allows to create a software for large multicentric databases with implementation of specific remapping functions wherever necessary. This approach is well-received by all involved parties, primarily because it does not change a single center’s storing technologies, procedures, and habits.

Purpose To investigate the change of clinical target volume (CTV) and its dosimetric impact during the course of accelerated partial breast irradiation (APBI) using intraoperative multicatheter interstitial brachytherapy after open cavity surgery. Methods and Materials Twenty-two patients of APBI with intraoperative placement of catheters underwent computed tomography scans for the treatment planning before the first (CT1) and the last (CT2) treatment fraction. Delineation of lumpectomy cavity and CTV was done consistently on both CT data sets by one of the coauthors. Optimum plan (P CT1 ) was made on CT1. P CT1 was manually reproduced in CT2 which yielded plan P CT2 . Plans were compared using coverage index (CI), dose homogeneity index (DHI), external volume index (EI), overdose volume index (OI) and conformal index (COIN). Results The mean ± SD volume of lumpectomy cavity and CTV was 78.5 ± 40.7 cm 3 , 156.4 ± 69.0 cm 3 for P CT1 , and 84.7 ± 50.1 cm 3 ( p = 0.11), 165.7 ± 82.8 cm 3 ( p = 0.15) for P CT2 , respectively. CTV volume increase by ≥ 10% was observed in 9 cases however decrease of ≥10% was observed in 5 cases. Mean (SD) of absolute pairwise difference in CTV volume was found to be 13.2 (6.7) %. For cases with increase in CTV volume, significant ( p p = 0.004) increase of 45% in EI was observed, whereas COIN reduced significantly ( p = 0.001) by 13.5%. Overall 22 cases showed significant decrease of 5.8% and 8.1% in mean CI and COIN, respectively. Conclusions The change of CTV during the course of APBI using intraoperative multicatheter interstitial brachytherapy after open cavity surgery was found patient specific and showed a significant impact on coverage and conformity.

Purpose: The main objective of this study was to evaluate appropriate doses for elective nodal irradiation (ENI) in head and neck squamous cell carcinoma (HNSCC) patients to optimize the therapeutic ratio. Methods and materials: A matched pair analysis of 2 similar cohorts of HNSCC treated with intensity modulated radiation therapy with different dose prescriptions to the elective nodal regions was conducted. One group received 60 Gy, whereas the other received 50 Gy (ENI60 and ENI50 groups, respectively). Isolated regional recurrences (IRR) and locoregional control were evaluated. Doses received by the parotid and thyroid glands were compared among both groups and were clinically correlated with the trend of salivary function recovery and incidence of hypothyroidism. Results: Of the 110 patients studied, 97 were eligible for analysis after matching based on propensity scores. The 3-year locoregional control rate was similar in ENI60 and ENI50 (78.7% and 77%, respectively; P = .93). There were no IRR in ENI regions in either group. The mean ipsilateral parotid dose in ENI60 was significantly higher compared with ENI50 (42 vs 35.7 Gy, P = .03). There was no significant difference in the mean contralateral parotid doses (32.5 vs 31.7 Gy, P = .6). The mean thyroid doses were high in ENI60 compared with ENI50 (54.7 vs 43.3 Gy, P < .001). A significant difference in ipsilateral parotid salivary excretory fraction ratio at 1 year (P = .03) was observed with quicker recovery of salivary function. The salivary excretory fractions were poorer in the ENI60 group with higher mean parotid doses (P = .009). At 2 years, 26 patients (54%) in the ENI60 group and 13 patients (26.5%) in the ENI50 group developed biochemical hypothyroidism (P = .007). Conclusions: Doses of 50 Gy equivalent are sufficient to sterilize the uninvolved nodal regions because the rates of IRR are extremely low. Using ENI50 results in clinically meaningful reduction in salivary and thyroid toxicity in HNSCC.

BACKGROUND The rates and factors associated with the return to work of head and neck cancer survivors from low- and middle-income countries, such as India, are largely unknown. METHODS We conducted a preliminary cross-sectional survey of 250 consecutive eligible head and neck cancer survivors (age

Purpose: To investigate the interobserver variations in delineation of lumpectomy cavity (LC) and clinical target volume (CTV), and its impact on irradiated volume in accelerated partial breast irradiation using intraoperative multicatheter brachytherapy. Material and methods : Delineation of LC and CTV was done by five radiation oncologists on planning computed tomography (CT) scans of 20 patients with intraoperative interstitial breast implant. Cavity visualization index (CVI), four-point index ranging from (0 = poor) to (3 = excellent) was created and assigned by observers for each patient. In total, 200 contours for all observers and 100 treatment plans were evaluated. Spatial concordance (conformity index, CI common , and CIgen), average shift in the center of mass (COM), and ratio of maximum and minimum volumes (V max /V min ) of LC and CTV were quantified among all observers and statistically analyzed. Variation in active dwell positions (0.5 cm step) for each catheter, total reference air kerma (TRAK), volume enclosed by prescription isodose (V100%) among observers and its spatial concordance were analyzed. Results : The mean ± SD CI common of LC and CTV was 0.54 ± 0.09, and 0.58 ± 0.08, respectively. Conformity index tends to increase, shift in COM and V max /V min decrease significantly (p < 0.05), as CVI increased. Out of total 309 catheters, 29.8% catheters had no change, 29.8% and 17.5% catheters had variations of 1 and 2 dwell positions (0.5 cm and 1 cm), respectively. 9.3% catheters shown variations ≥ 10 dwell positions (5 cm). The mean ± SD CI common of V100% was 0.75 ± 0.11. The mean observed V max /V min of prescription isodose and TRAK was 1.18 (range, 1.03 to 1.56) and 1.11 (range, 1.03 to 1.35), respectively. Conclusions : Interobserver variability in delineation of target volume was found to be significantly related to CVI. Smaller variability was observed with excellent visualization of LC. Interobserver variations showed dosimetric impact on irradiation of breast tissue volume with prescription dose.

Purpose : The literature and experience of high-dose-rate (HDR) surface mould brachytherapy (SMB) in head and neck cancer is sparse. We report our institutional experience of SMB for such tumours. Material and methods: Thirty-five patients with malignant localized early T1/T2, N0 (21 intra-oral and 14 skin) tumours treated with SMB during 2008-2014 were analyzed. Treatment was delivered using HDR 192Ir source to a median dose of 49 Gy (range, 38.5-52.5 Gy) as radical brachytherapy and 18 Gy (range, 15.5-30 Gy) as boost with 3-4 Gy/fraction twice daily using customized surface mould. Results : Median follow-up was 52 months (range, 6 to 98 months). Local control (LC) for skin tumours and intra-oral malignancies at 5 years were 92% and 76%, respectively. Five-year cause specific survival was 92%. For T1 and T2 tumours, 5 year LC was 94.2% and 68.2%, respectively. T stage (p < 0.04) and dose/fractions (p < 0.003) were the only significant prognostic factors for LC on univariate analysis. Conclusions : Surface mould brachytherapy results in excellent LC rates for skin tumours and T1 intraoral tumours when considered as radical treatment, and preferable to consider it as a boost for T2 intraoral tumours. Surface mould brachytherapy results in excellent organ and function preservation.

Objective To evaluate the survival outcomes for a cohort of nasopharyngeal cancer with intracranial extension (ICE) treated with induction chemotherapy (ICT) followed by chemo-intensity-modulated radiotherapy (CTRT) at a tertiary cancer center. Methods We retrospectively analyzed 45 patients with histologically proven, non-metastatic NPC with ICE treated at our institute between October 2008 and October 2016. Patients were classified as minor ICE or major ICE, based on the extent of ICE. All the patients received 2–3 cycles of a taxane-based ICT regimen followed by CTRT. Radiotherapy was delivered with “risk-adapted” intensity-modulated radiotherapy (IMRT) technique in all patients. Results After a median follow up of 45 months (range: 8–113 months), the estimated 5-year DFS, LRFS, DMFS, and OS of the entire cohort was 58%, 82%, 67% and 74% respectively. On multivariate analysis, histological subtype was an independent predictor of LRFS, and age was an independent predictor of DFS. The extent of ICE showed only a trend towards worse DFS (P = 0.06). None of the factors significantly predicted for DMFS or OS. Gender, N-stage, and response to ICT did not significantly affect any of the outcomes. Grade 2 or worse subcutaneous fibrosis was seen in 22% of patients and grade 2 or worse xerostomia was seen in 24% of patients at last follow up. Thirty-three percent of the patients developed clinical hypothyroidism at last follow up. None of the patients experienced any neurological or vascular complications. Conclusions Taxane-based induction chemotherapy followed by chemo-intensity modulated radiotherapy resulted in excellent locoregional control and survival with acceptable toxicities in patients of nasopharyngeal cancer with intracranial extension. Distant metastasis continues to be the predominant problem in these patients.

Background Because the addition of nimotuzumab to chemoradiation in patients with locally advanced head and neck cancer improved outcomes in a phase 2 study, the authors conducted a phase 3 study to confirm these findings. Methods This open-label, investigator-initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with locally advanced head and neck cancer who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66-70 grays) with concurrent weekly cisplatin (30 mg/m2 ) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT).The primary endpoint was progression-free survival (PFS); key secondary endpoints were disease-free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). An intent-to-treat analysis also was performed. Results In total, 536 patients were allocated equally to both treatment arms. The median follow-up was 39.13 months. The addition of nimotuzumab improved PFS (hazard ratio [HR], 0.69; 95% CI, 0.53-0.89; P = .004), LRC (HR, 0.67; 95% CI, 0.50-0.89; P = .006), and DFS (HR, 0.71; 95% CI, 0.55-0.92; P = .008) and had a trend toward improved OS (HR, 0.84; 95% CI, 0.65-1.08; P = .163). Grade 3 through 5 adverse events were similar between the 2 arms, except for a higher incidence of mucositis in the NCRT arm (66.7% vs 55.8%; P = .01). Conclusions The addition of nimotuzumab to concurrent weekly CRT improves PFS, LRC, and DFS. This combination provides a novel alternative therapeutic option to a 3-weekly schedule of 100 mg/m2 cisplatin in patients with locally advanced head and neck cancer who are treated with radical-intent CRT.

This study attempted to review the impact of extent of squamous differentiation in 56 infiltrating duct carcinomas (IDC) with squamous differentiation (metaplastic squamous carcinomas [MSC]). Tumors showing 100% squamous elements were labeled as primary squamous carcinomas (PSC; n = 28) and compared with 28 MSC showing lesser squamous components. A clinicopathological comparison revealed that lymphovascular emboli were never seen in any PSC but were noted in 7/28 of other MSC, while perineural invasion was seen only in PSC and not in MSC. Nodal metastasis was significantly more in other MSC as opposed to PSC. Most MSC presented with 2- to 5-cm sized tumors while PSC were 5 to 10 cm in size. PSC showed cystic change while MSC did not. Disease free survival (DFS) for MSC versus PSC was 64% versus 39.8%, while overall survival (OAS) was 72.7% in MSC versus 66.7% in PSC. Tumor stage affected DFS in MSC while none of the factors affected DFS/OAS in PSC. The extent of squamous differentiation affected DFS with best behavior for metaplastic carcinomas showing 90% squamous component ( P = .024). PSC of breast is an aggressive disease and show distinct clinicopathological features from other MSC, and though the current definition of MSC does not advocate quantifying the squamous element, clearly this affects prognosis.

Background: Adjuvant trastuzumab has improved overall survival in women with HER2 receptor positive breast cancer. However, only a small fraction (4%) of eligible patients in resource constrained settings have access to this drug. A patient assistance program of 12 weeks of adjuvant or neoadjuvant trastuzumab was thus started for those who did not have any access to trastuzumab due to financial constraints. We undertook a retrospective analysis of outcomes in women who were enrolled between January 2011 to December 2012 in this patient assistance program. Methods: Patients received four cycles of anthracycline based chemotherapy (AC/CAF/ EC/CEF) and 12 doses of weekly paclitaxel (80mg/m2) with trastuzumab (4mg/kg loading followed by 2mg/kg) in the neoadjuvant or adjuvant setting in either sequence (anthracycline followed by taxane trastuzumab or taxane trastuzumab followed by anthracycline). Patients received adjuvant hormonal therapy depending on the hormone receptor status. The primary endpoint of this analysis was disease free survival (DFS). Results: A total of 103 patients with HER2 receptor positive breast cancer were analysed. The median age was 46 (24-65) years, 50% were premenopausal, 60.7% had stage III disease (86.8% had node positive disease) and 37% patients had ER and or PR positive disease. Forty patients (38.8%) had breast conserving surgery while the rest had modified radical mastectomy. At a median follow-up of 34 (7-46) months the 3-year DFS and overall survival was 77.2% and 82.7% respectively. Among patients who developed recurrence one had only local recurrence, 4 had both local and distant recurrence and 11 had distant metastasis alone. Of the 15 patients who developed distant metastasis 7 had brain involvement . Symptomatic cardiac dysfunction developed in four patients, two of whom died while in the other 2 ejection fraction recovered. The results are summarised in the table. Patient Characteristic and outcome with 12 weks of adjuvant or neoadjuvant TrastuzumabNumber of PatientsNode Positive (%)Hormone Positive (%)DFS at 3 yearsOS at 3 yearsBrain Mets(%)Grade 3/4 Cardiac Toxicity(%)10386.83777.282.76.83.9 Conclusions: These results suggest that 12 weeks of neoadjuvant or adjuvant trastuzumab is an acceptable alternative in patients who lack access to full 1 year of trastuzumab. Citation Format: Ghosh J, Joy Phillip DS, Ghosh J, Gupta S, Bajpai J, Gulia S, Parmar V, Nair N, Budrukkar AN, Jalali R, Desai SB, Sawant S, Dhir AA, Kembhavi S, Hawaldar R, Banavali SD, Badwe RA. Outcome with use of 12 weeks of adjuvant or neoadjuvant trastuzumab in a resource constrained setting. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-07.

Background: Positron emission tomography-computed tomography (PET-CT) is an emerging modality for staging and response evaluation in carcinoma nasopharynx. This study was conducted to evaluate the impact of PET-CT in assessing response and outcomes in carcinoma nasopharynx. Materials and Methods: Forty-five patients of nonmetastatic carcinoma nasopharynx who underwent PET-CT for response evaluation at 10-12 weeks posttherapy between 2004 and 2009 were evaluated. Patients were classified as responders (Group A) if there was a complete response on PET-CT or as nonresponders (Group B) if there was any uptake above the background activity. Data regarding demographics, treatment, and outcomes were collected from their records and compared across the Groups A and B. Results: The median age was 41 years. 42 out of 45 (93.3%) patients had WHO Grade 2B disease (undifferentiated squamous carcinoma). 24.4%, 31.1%, 15.6, and 28.8% patients were in American Joint Committee on Cancer Stage IIb, III, Iva, and IVb. All patients were treated with neoadjuvant chemotherapy followed by concomitant chemoradiotherapy. Forty-five patients, 28 (62.2%) were classified as responders, whereas 17 (37.8%) were classified as nonresponders. There was no significant difference in the age, sex, WHO grade, and stage distribution between the groups. Compliance to treatment was comparable across both groups. The median follow-up was 25.3 months (759 days). The disease-free survival (DFS) of the group was 57.3% at 3 years. The DFS at 3 years was 87.3% and 19.7% for Group A and B, respectively (log-rank test, P < 0.001). Univariate and multivariate analysis revealed Groups to be the only significant factor predicting DFS (P value 0.002 and < 0.001, respectively). In Group B, the most common site of disease failure was distant (9, 53%). Conclusion: PET-CT can be used to evaluate response and as a tool to identify patients at higher risk of distant failure. Further, this could be exploited to identify patients who may need treatment intensification. This needs to be validated prospectively.

Background The purpose of this study was to explore urinary Epstein–Barr virus (EBV)-DNA as a potential biomarker in patients with nasopharyngeal carcinoma (NPC). Methods EBV-DNA copies were estimated in plasma/urine of patients with NPC (n = 76) by real-time polymerase chain reaction (PCR) at baseline, during therapy, and at follow-up. Their correlation with EBV-RNA expression in tissues (n = 53) was used to assess sensitivity and specificity of plasma/urine EBV-DNA. Correlation of urine and plasma EBV-DNA with each other and with radiological response was evaluated. Results This study demonstrated that urine EBV-DNA has high sensitivity (96%) at diagnosis and it correlates well with plasma EBV-DNA at baseline and after neoadjuvant chemotherapy. The EBV-DNA copies reduced significantly with therapy (plasma: p < .001; urine: p = .011). Patients with low EBV-DNA copies demonstrated improved survival (plasma: p = .023; urine: p = .083). Conclusion Plasma EBV-DNA is a good prognostic marker, whereas further study on a larger cohort may help in developing urine EBV-DNA as a surrogate prognostic marker for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Objective/hypothesis Extranodal extension (ENE) is an independent prognosticator in head-neck Squamous cell carcinoma (SCC). All patients with ENE, however, do not behave the same, and there is a need for further risk stratification. This study evaluates the prognostic significance of various grades of ENE and the number of nodes with ENE on overall survival (OS) in oral cavity SCC (OCSCC). Study design Retrospective cohort study. Methods Ninety-four patients with node-positive OCSCC treated with primary surgery and appropriate adjuvant therapy during the year 2011 were evaluated. Surgical histopathology slides of all patients were reviewed, and ENE was graded according to the grading system proposed by Lewis Jr et al. RESULTS: On univariate analysis, lymph node density (LND) greater than or equal to 0.12 (P = 0.013), the presence of ENE in more than two nodes (P = 0.006), and ENE grade 3 through 4 (P = 0.035) were associated with worse (OS). Conventional prognostic factors such as tumor (T) stage, nodal (N) stage, stage grouping, depth of invasion, and pattern of invasion did not have a significant impact on OS. On multivariate analysis, the presence of ENE in more than two nodes (P = 0.018) independently predicted a worse OS. Extranodal extension grade 3 through 4 showed a trend toward significance (P = 0.08). A combination of LND greater than or equal to 0.12, ENE grade 3 through 4, and ENE in more than two lymph nodes conferred the poorest prognosis (3-year OS: 18%; P = 0.000). Conclusion In patients with ENE and advanced nodal disease, T stage, N stage, stage group, depth, and pattern of invasion lose their impact on OS. In patients with ENE, nodal characteristics such as LND, the number of nodes with ENE, and grade of ENE serve as important prognosticators and aid in further risk stratification. Level of evidence 4 Laryngoscope, 129:1130-1136, 2019.

BACKGROUND High prevalence of comorbidity in head and neck squamous cell carcinoma (HNSCC) often lead to suboptimal treatment. The presence study aims to evaluate the presence of comorbidity, its impact on therapeutic decision making, treatment compliance, and overall survival in HNSCC. METHODS Five hundred eighteen patients with nonmetastatic HNSCC, elder than 18 years of age, without any prior history of cancer or anticancer treatment in the last 5 years were evaluated using Adult Comorbidity Evaluation 27 (ACE 27) index. RESULTS Two hundred ninety three (56.6%) patients had comorbidity, and 20.6% had deviation from the ideal treatment plan. Higher grade of comorbidity led to less likely completion of guideline-concordant therapy (moderate ACE 27 vs none: odds ratio [OR] 0.46, 95% confidence interval [CI] 0.26-0.82, P

Summary Background The role of locoregional treatment in women with metastatic breast cancer at first presentation is unclear. Preclinical evidence suggests that such treatment might help the growth of metastatic disease, whereas many retrospective analyses in clinical cohorts have suggested a favourable effect of locoregional treatment in these patients. We aimed to compare the effect of locoregional treatment with no treatment on outcome in women with metastatic breast cancer at initial presentation. Methods In this open-label, randomised controlled trial, we recruited previously untreated patients (≤65 years of age with an estimated remaining life expectancy of at least 1 year) presenting with de-novo metastatic breast cancer from Tata Memorial Centre, Mumbai, India. Patients were randomly assigned (1:1) to receive locoregional treatment directed at their primary breast tumour and axillary lymph nodes, or no locoregional treatment, by a computer-generated block randomisation sequence (block size of four). Randomisation was stratified by site of distant metastases, number of metastatic lesions, and hormone receptor status. Patients with resectable primary tumour in the breast that could be treated with endocrine therapy were randomly assigned upfront, whereas those with an unresectable primary tumour were planned for chemotherapy before randomisation. Of the patients who had chemotherapy before randomisation, we randomly assigned patients who had an objective tumour response after six to eight cycles of chemotherapy. The primary endpoint was overall survival analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT00193778. Findings Between Feb 7, 2005, and Jan 18, 2013, of the 716 women presenting with de-novo metastatic breast cancer, we randomly assigned 350 patients: 173 to locoregional treatment and 177 to no locoregional treatment. At data cut-off of Nov 1, 2013, median follow-up was 23 months (IQR 12·2–38·7) with 235 deaths (locoregional treatment n=118, no locoregional treatment n=117). Median overall survival was 19·2 months (95% CI 15·98–22·46) in the locoregional treatment group and 20·5 months (16·96–23·98) in the no-locoregional treatment group (HR 1·04, 95% CI 0·81–1·34; p=0·79), and the corresponding 2-year overall survival was 41·9% (95% CI 33·9–49·7) in the locoregional treatment group and 43·0% (35·2–50·8) in the no locoregional treatment group. The only adverse event noted was wound infection related to surgery in one patient in the locoregional treatment group. Interpretation There is no evidence to suggest that locoregional treatment of the primary tumour affects overall survival in patients with metastatic breast cancer at initial presentation who have responded to front-line chemotherapy, and this procedure should not be part of routine practice. Funding Department of Atomic Energy, Government of India.

INTRODUCTION: The treatment of nasopharyngeal carcinoma (NPC) has come a long way from treatment with conventional radiotherapy (RT) alone for the use of concurrent chemoradiotherapy (CCRT) and sequential chemotherapy (CT). We report the outcomes of patients treated with combined modality at a tertiary cancer center in India over a period of 10 years. MATERIALS AND METHODS: A total of 206 patients with NPC between 1994 and 2004, who completed planned treatment, were retrospectively analyzed. Demographic features, disease, and treatment-related factors were analyzed for their impact on loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS). RESULTS: Most patients had Stage III or IV (70.8%) disease. Twenty-six percent received RT alone, 37% received neoadjuvant chemotherapy (NACT) followed by RT alone, 29% received NACT + CCRT, and 8% received CCRT alone. Median RT dose was 64 Gy with 84% receiving RT doses of ≥60 Gy. At a median follow-up of 29 months, 112 (54.4%) patients were alive and disease free. Three-year DFS and OS were 64% and 82.3%, respectively. LRC at 3 years was 71.1%. Independent factors for significantly better LRC and DFS were younger age at presentation, RT dose of more than 64 Gy, and immediate response to RT. The use of CCRT in advanced nodal stages (N2–N3) resulted in significantly better LRC and DFS on multivariate analysis. CONCLUSIONS: Combined modality treatment in advanced stage NPC results in favorable outcomes. RT doses of more than 64 Gy should be considered in all patients, respecting normal tissue tolerances. The role of NACT remains debatable.

Purpose To evaluate the impact of timing of adjuvant chemotherapy on wound healing and cosmetic outcome in women treated with accelerated partial breast irradiation (APBI). Methods and Materials Between August 2000 to December 2011, 224 women were treated with APBI using multicatheter interstitial high-dose-rate brachytherapy. Patients were treated to a dose of 34 Gy/10#/5–7 days with bid regimen. Systemic chemotherapy was administered as per the standard guidelines. Results Multicatheter interstitial brachytherapy technique was open cavity in 136 (60%) and closed cavity in 88 (40%). Adjuvant chemotherapy was given in 117 (52%). Wound complications (WCs) were observed in 24 patients (11%), which included wound infections (WIs) in 20 and wound dehiscence in 14. The median gap between chemotherapy and APBI was 13 days in women who developed WCs, 20 days for prechemo, and 32 days for postchemo APBI in its absence. On multivariate analysis, gap between APBI and chemotherapy of ≤3 weeks was the only significant factor (p = 0.03) affecting WCs. Acute WI (p = 0.01) and two-dimensional planning (p = 0.04) had significant impact on cosmesis resulting in fair to poor cosmetic outcome. Conclusions Gap of ≤3 weeks between APBI and chemotherapy resulted in increased WCs. WI and two-dimensional planning resulted in poorer cosmetic outcome. We recommend gap of at least 3 weeks for optimal outcome.

BACKGROUND: Limited data are available on the prevalence and prognostic significance of human papillomavirus (HPV) in squamous cell carcinoma of head and neck (SCCHN) in the Indian population. AIM: The present study aimed to determine the prevalence of HPV and p16 in an Indian cohort of SCCHN and assess their correlation and influence of tobacco use on patient outcomes. MATERIALS AND METHODS: The p16 and HPV status of 170 patients of SCCHN treated with curative chemoradiotherapy was determined using immunohistochemistry and polymerase chain reaction, respectively, and further correlated with their demographic characteristics. In addition, genotyping of HPV-positive samples was performed. Survival outcomes were analyzed and compared for both p16 positive (p16 +ve) and p16 negative (p16 −ve) population. The influence of tobacco use on outcomes was assessed. RESULTS: p16 expression was observed in 20% (34/170) cases whereas HPV positivity was detected in 39.4% (67/170) of SCCHN patients with HPV16 being the most common (91%) subtype. About 73.5% patients were p16 +ve among the tobacco users in this cohort (83.5%). Interestingly, p16 positivity was significantly associated with nonusers of tobacco ( P = 0.02) and younger females ( P = 0.06). The p16 +ve and p16 −ve groups did not exhibit a significant difference in the 5-year cause-specific survival (CSS) (79% vs. 72.2%), disease-free survival (DFS) (78.3% vs. 68.3%, P = 0.5), and locoregional control (LRC) (82.2% vs. 71.5%, P = 0.4). However, the outcome analyses in tobacco nonusers revealed a definite large improvement in CSS ( P = 0.08) and a trend toward improvement in DFS ( P = 0.15) and LRC ( P = 0.11) in the p16 +ve versus the p16 −ve groups. CONCLUSION: The low prevalence of p16 positivity (20%) and dual HPV and p16 positivity (38.8%) in the studied Indian cohort indicates the low utility of p16 as a surrogate for HPV in the background of high tobacco burden. The outcomes are largely improved in a small subset of SCCHN cases comprising p16 +ve tobacco nonusers.

Background The purpose of this study was to determine the incidence of hypothyroidism after chemoradiation in head and neck squamous cell cancer (HNSCC). Methods One hundred twenty-two patients treated with 3-dimensional conformal radiotherapy (3DCRT; 70 Gy/35#) or intensity-modulated radiation therapy (IMRT; 66 Gy/30#) in 2 identical simultaneous randomized trials were studied. Thyroid function was assessed at baseline and every 3 to 6 monthly thereafter. Development of subclinical (thyroid-stimulating hormone [TSH] >4.67 μIU/mL) or biochemical (T4

Background Brain metastases (BM) is a commonly encountered clinical scenario in patients with HER2 positive breast cancer (BC). We report here the clinical profile and outcome of patients with HER2 positive breast cancer with brain metastasis (BCBM) who were treated with HER2 targeted therapy at a single institution. Methods Clinical and outcome data of patients with HER2 positive BCBM treated with HER2 targeted agents were retrospectively collected. Efficacy variables were progression-free survival (PFS, time from diagnosis of BM to first progression or death due to any cause, whichever was earlier) and overall survival (OS). Results Between 2013 and 2017, 102 HER2 positive BCBM patients with median age 52 (IQR 45-57) years were treated with HER2 targeted therapy. Of these, 40 (39.2%) had ER positive disease, 98 (96.1%) were symptomatic at diagnosis of BM, 69 (67.6%) had received ≥2 lines of chemotherapy before BM, 22 (25.3%) had solitary brain lesion, 22 (25.3%) had 2-5 lesions and 43 (49.4%) had > 5 lesions. After BM diagnosis, whole brain radiotherapy (WBRT) was administered in 93 (91.2%) patients, stereotactic radiosurgery (SRS) in 4 (4.0%), WBRT and SRS in 4 (4%), and 9 (8.9%) patients underwent surgical resection of BM. The first HER2 targeted therapy after BM diagnosis was lapatinib in 70 (68.6%), trastuzumab in 19 (18.6%), lapatinib and trastuzumab in 3 (2.9%), trastuzumab emtansine in 4 (3.9%) and intrathecal trastuzumab in 5 (4.9%), patients. After diagnosis of BM, 17 (16.7%) patients received ≥3 lines of therapy. At a median follow-up of 13.5 months, there were 91 PFS events and 80 deaths. The median PFS after BM was 8 [95% confidence interval (CI), 6.2-9.8] months and median OS was 14 (95%CI, 10.8-17.2) months with a 2-year OS of 25% (95% CI, 16.7-34.4%). Median PFS in patients who received lapatinib-capecitabine regimen (n = 62) was 9.0 (95%CI, 7.3-10.7) months. Conclusions The median OS in patients with HER2 positive BCBM, treated with HER2 targeted therapy, is good and exceeds that reported in metastatic triple negative breast cancer. The difference between median PFS and OS suggests that continued treatment after first or subsequent progression may be therapeutically beneficial in some patients. Legal entity responsible for the study Sudeep Gupta. Funding Has not received any funding. Disclosure J. Bajpai: Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Samsung Bioepis; Research grant / Funding (institution): Sun Pharma. S. Gupta: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Johnson & Johnson; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Celltrion; Advisory / Consultancy, Research grant / Funding (institution): Oncosten; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Intas; Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Biocon; Advisory / Consultancy: Dr. Reddy’s Laboratories; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Core Diagnostics. All other authors have declared no conflicts of interest.

Background Addition of nimotuzumab to weekly cisplatin and radiation improves outcomes in head and neck cancer. HPV-negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. Hence we wanted to determine whether the addition of nimotuzumab to cisplatin-radiation can improve outcomes in these subsets of poor-risk tumors. Methods This was a subgroup analysis of a phase 3 randomized study. In this study locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin (30 mg/m2 IV )- radiation (66-70 Gy) {CRT arm} or nimotuzumab (200 mg weekly) -weekly cisplatin (30 mg/m2)-radiation (66-70 Gy) {NCRT arm}. The data for HPV-negative oropharyngeal cancer was extracted from the database of this study for the current analysis. HPV testing was done with p16 IHC staining and reported according to the CAP criteria. The outcomes assessed were progression-free survival (PFS), disease-free survival (DFS), locoregional control (LRC), and overall survival (OS). Interaction test was performed between the study arms and HPV status prior to doing any HPV-specific analysis for each of the studied outcomes. Kaplan Meier estimates for 2-year OS with 95% CI is provided. The hazard ratio was calculated using Cox regression analysis. Results We had 187-HPV negative oropharyngeal cancers, 91-CRT arm and 96 in NCRT arm. The interaction test was significant for PFS (p = 0.000), locoregional control (p = 0.007) and overall survival (p = 0.002) but not for DFS (p = 0.072). The 2-year PFS was 31.5% (95%CI 21.5-42) in CRT arm versus 57.2% (95%CI 45.8-67.1) in NCRT arm (HR -0.54;95%CI 0.36-0.79, p = 0.002). While the 2-year LRC was 41.4 % (95%CI 29.8-52.6) in CRT arm versus in 60.4% (95%CI 48.7-70.2) in NCRT arm (HR -0.61;95%CI 0.4-0.94, p = 0.024). The addition of nimotuzumab also led to an improvement in OS from 39.0% (95%CI 28.4-49.6) to 57.6% (95%CI 46.3-67.4) (HR-0.63, 95%CI 0.43-0.92, p = 0.018). Conclusions The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV-negative oropharyngeal cancers. Clinical trial identification CTRI/2014/09/004980. Legal entity responsible for the study The authors. Funding Biocon Ltd, TRAC. Disclosure K. Prabhash: Research grant / Funding (institution): Dr. Reddy’s Laboratories Inc; Research grant / Funding (institution): Fresenius Kabi India Pvt Ltd; Research grant / Funding (institution): Alkem Laboratories; Research grant / Funding (institution): Natco Pharma Ltd; Research grant / Funding (institution): BDR Pharmaceutics Intl Pvt Ltd; Research grant / Funding (institution): Roche Holding AG. V. Noronha: Research grant / Funding (institution): Dr. Reddy’s Laboratories Inc; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Sanofi Aventis. All other authors have declared no conflicts of interest.

Objective: The objective of this study is to evaluate the diagnostic and prognostic ability of fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan in patients with squamous cell carcinoma of the head and neck treated with chemoradiotherapy or radiotherapy only. Materials and Methods: Fifty-nine patients with HNSCC planned for radical nonsurgical treatment were randomized to receive either three-dimensional conformal radiotherapy or intensity-modulated radiation therapy. In addition to routine clinical examination and staging investigations, patients had a FDG PET-CT scan at baseline and on the first follow-up for response assessment. No evidence of clinicopathological disease for at least 6 months after the completion of treatment was considered confirmation of complete response. The presence or absence of disease during the follow-up period was used to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET-CT for the primary site and node. Results: At a median follow-up of 52.5 months, 55.6% of patients were alive and disease free. Response assessment PET-CT was done at a median of 9 weeks (range: 5–18 weeks). PET-CT assessment of the primary had sensitivity, specificity, PPV, and NPV of 81.8%, 93%, 75%, and 95.2%, respectively; the corresponding figures at the node were 44.4%, 95.6%, 66.7%, and 89.6%. The median baseline maximum standardized uptake value (SUVmax) at primary and node was 14.9 and 8.1, respectively. When PET-CT was done after 10 weeks, no false-positive or false-negative findings were seen. Patients with negative PET at the first follow-up had a significantly better progression-free and overall survival. Conclusions: Disease evaluation using PET-CT has an overall accuracy of 80%. High baseline SUVmax correlates with worse clinical outcomes. Negative PET-CT at the first follow-up is a predictor for survival.

IntroductionSinonasal cancers have variable biological behavior and outcomes. The physical proximity of several critical structures renders radiotherapy challenging for these cancers.PurposeTo report our early experience of helical tomotherapy (HT)-based image-guided intensity-modulated radiation therapy (IMRT) in midline sinonasal cancers.Materials and methodsPatients with midline sinonasal cancers were accrued on a prospective generic protocol of HT-based IMRT. HT plans were evaluated using standardized indices. All patients were followed up clinicoradiologically. Local control was defined as absence of failure (recurrence/ progression) in the tumor bed, whereas distant disease control was defined as absence of distant metastases. All time-to-event data was analyzed using Kaplan-Meier methods.ResultsTen patients with a median age of 42 years (range: 29-62 years) were included. HT was able to achieve excellent target volume coverage, good high-dose conformality with exquisite sparing of organs at risk. The acute toxicity of HT was generally mild and self-limiting. Seven patients experienced acute grade I-II ocular toxicity that responded to topical steroids, while one patient developed grade III conjunctivitis. The same patient later developed bilateral cataract necessitating extraction (late grade III ocular toxicity). No patient experienced dry-eye syndrome, corneal opacity or blindness. With a median follow-up of 27 months (interquartile range: 13-35 months), the 3-year Kaplan-Meier estimate of local progression-free survival, distant metastases-free survival, disease-free survival and overall survival was 59.3, 90, 53.3 and 90% respectively.ConclusionHT-based image-guided IMRT for midline sinonasal cancers achieves good high-dose conformality and is associated with mild, self-limiting acute ocular toxicity, minimal late morbidity with acceptable disease control.How to cite this articleGupta T, Wadasadawala T, Phurailatpam R, Paul SN, Murthy V, Budrukkar A, Ghosh-Laskar S, Nair D, Pai P, Chaturvedi P, Agarwal JP. Early Clinical Outcomes in Midline Sinonasal Cancers treated with Helical Tomotherapy-based Image-guided Intensity-modulated Radiation Therapy. Int J Head and Neck Surg 2013;4(1): 6-12.

Aims To determine the influence of dose and fractionation on tumour characteristics, toxicity, disease control and survival outcomes in T1 glottic carcinoma. Materials and methods Between 1975 and 2000, treatment charts of 652 patients with T1 glottic carcinoma who received curative radiation with four hypofractionated schedules (50 Gy/15 fractions [3.3 Gy/fraction] or 55 Gy/16 fractions [3.43 Gy/fraction] or 60 Gy/24 fractions or 62.5 Gy/25 fractions [2.5 Gy/fraction]) were analysed. The patients were divided into two groups based on fraction size 3 Gy. Local control and overall survival were calculated. Patient- and tumour-related factors affecting local control were analysed using univariate and multivariate analysis. Factors affecting late toxicity were also analysed. Results The local control and overall survival at 10 years were 84 and 86.1%, respectively, for T1 glottic carcinoma. The response to radiation had a significant effect on local control with univariate analysis ( P = 0.001). Other factors, such as beam energy, anterior commissure involvement and fractionation, did not affect local control. Persistent radiation oedema was seen in 123 patients (23.4%) and was significantly worse in patients who received radiation with a larger field size (>36 cm 2 ) on a telecobalt machine ( P Conclusions Radical radiotherapy schedules incorporating a higher dose per fraction yield acceptable local control rates and late toxicity. Telecobalt therapy for early glottic cancer is a safe alternative to treatment with 6 MV photons on a linear accelerator in terms of local control and late toxicity as long as field sizes smaller than 36 cm 2 are used.

The Head and Neck Working Group of the GEC-ESTRO (Groupe Europeen de Curietherapie - European Society for Therapeutic Radiology and Oncology) published in 2009 the consensus recommendations for low-dose rate, pulsed-dose rate and high-dose rate brachytherapy in head & neck cancers. The use of brachytherapy in combination with external beam radiotherapy and/or surgery was also covered as well as the use of brachytherapy in previously irradiated patients. Given the developments in the field, these recommendations needed to be updated to reflect up-to-date knowledge. The present update does not repeat basic knowledge which was published in the first recommendation but covers in a general part developments in (1) dose and fractionation, (2) aspects of treatment selection for brachytherapy alone versus combined BT+EBRT and (3) quality assurance issues. Detailed expert committee opinion intends to help the clinical practice in lip-, oral cavity-, oropharynx-, nasopharynx-, and superficial cancers. Different aspects of adjuvant treatment techniques and their results are discussed, as well the possibilities of salvage brachytherapy applications.

To assess interobserver variability (IOV) in the delineation of structures during intensity-modulated radiation therapy for head and neck squamous cell carcinoma and the impact of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) on such variability at the primary site.Three experienced head-neck radiation oncologists, blinded to each other, delineated the primary site gross tumour volume (GTV) and specified organs-at-risk (OARs) viz parotid gland, spinal cord, and cochlea in 10 patients with pharyngolaryngeal cancers suited for definitive intensity-modulated radiation therapy. IOV was assessed by concordance index (CI), Dice similarity coefficient (DSC), and Fleiss' kappa. Subsequently, the observers refined their corresponding GTVs incorporating information from FDG-PET/CT. The impact of FDG-PET/CT on variability of GTV was assessed by comparing the overlap indices with and without FDG-PET/CT using paired 't' test.There was moderate IOV in the delineation of GTV as evidenced by mean CI, DSC, and Fleiss' kappa of 0.41, 0.57, and 0.56, respectively. The use of FDG-PET/CT improved consistency of target volume delineation with resultant improvement in the overlap indices (mean CI, DSC, and Fleiss' kappa of 0.54, 0.69, and 0.69, respectively) that was statistically significant (P.001). There was good agreement between the three observers for delineation of spinal cord and parotid glands. Concordance was worst for the cochlea.This study demonstrates the presence of moderate IOV between three experienced head and neck radiation oncologists in an academic institutional setting for the delineation of GTV. The use of FDG-PET/CT for target volume delineation results in significant reduction of such variability.

Purpose : Aim of the COBRA (Consortium for Brachytherapy Data Analysis) project is to create a multicenter group (consortium) and a web-based system for standardized data collection. Material and methods: GEC-ESTRO (Groupe Européen de Curiethérapie – European Society for Radiotherapy & Oncology) Head and Neck (H&N) Working Group participated in the project and in the implementation of the consortium agreement, the ontology (data-set) and the necessary COBRA software services as well as the peer reviewing of the general anatomic site-specific COBRA protocol. The ontology was defined by a multicenter task-group. Results : Eleven centers from 6 countries signed an agreement and the consortium approved the ontology. We identified 3 tiers for the data set: Registry (epidemiology analysis), Procedures (prediction models and DSS), and Research (radiomics). The COBRA-Storage System (C-SS) is not time-consuming as, thanks to the use of “brokers”, data can be extracted directly from the single center’s storage systems through a connection with “structured query language database” (SQL-DB), Microsoft Access®, FileMaker Pro®, or Microsoft Excel®. The system is also structured to perform automatic archiving directly from the treatment planning system or afterloading machine. The architecture is based on the concept of “on-purpose data projection”. The C-SS architecture is privacy protecting because it will never make visible data that could identify an individual patient. This C-SS can also benefit from the so called “distributed learning” approaches, in which data never leave the collecting institution, while learning algorithms and proposed predictive models are commonly shared. Conclusions : Setting up a consortium is a feasible and practicable tool in the creation of an international and multi-system data sharing system. COBRA C-SS seems to be well accepted by all involved parties, primarily because it does not influence the center’s own data storing technologies, procedures, and habits. Furthermore, the method preserves the privacy of all patients.

Purpose: The purpose of the following study is to evaluate the efficacy of a twice-weekly hypofractionated palliative radiotherapy schedule in locally very advanced head and neck cancers. Materials and Methods: Patients with locally very advanced, head and neck cancers were prospectively evaluated after twice-weekly palliative radiotherapy regimen of 32 Gy in 8 fractions. Median age was 55.5 years and the predominant primary site was oral cavity (46%). Majority (70.6%) had Stage IV B disease. Disease related distressing symptoms such as pain, bleeding, skin fungation, respiratory symptoms due to tumor burden, were prospectively assessed before the start of treatment, at conclusion and at 6-12 weeks of completion of treatment. Results: A total of 126 patients were enrolled in the study. Ninety three (73.8%) patients who completed the planned treatment of 32 Gy in 8 fractions were included in the symptom analysis. Overall response rates were 42% at primary disease and 55% at nodal disease. At conclusion of radiotherapy 76.3% of the patients reported improvement in pain scores (P = 0.001) and 42.8% patients reported improvement in anxiety and depression levels (P = 0.001). At first follow-up after 6-12 weeks significant improvement in pain scores (P = 0.001) and anxiety/depression levels (P = 0.001) persisted. The median survival of the patients was 5.5 months. Acute grade III mucositis was seen in one patient (1.2%) while none had grade III skin reactions. Conclusion: The proposed radiotherapy regimen is effective for sustained symptom palliation with low acute toxicity in locally very advanced head and neck cancers. It delivers a moderately high dose while being logistically simpler for the patient.