Assessment of endpoint definitions in recurrent and metastatic mucosal head and neck squamous cell carcinoma trials: Head and Neck Cancer International Group consensus recommendations.

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.

Phase III randomized trial comparing palliative systemic therapy to best supportive care in advanced esophageal/GEJ cancer.

No study has unequivocally proven that chemotherapy prolongs overall survival (OS) in advanced esophageal cancer. We conducted a Phase III randomized study in first-line advanced unresectable/metastatic esophageal/GEJ cancer. Patients aged 18-70 years, with performance status 0-2, were randomized to best supportive care (BSC) alone, or BSC with weekly paclitaxel 80 mg/m2. BSC comprised, as indicated, education, counselling, radiation, stenting, feeding tube placement, nutritional supplementation, medications like analgesics, and referral to a support group and palliative care. The primary endpoint was OS; secondary endpoints included progression free survival (PFS), response, toxicity, and QoL. Between May 2016-December 2020, we recruited 281 patients: 143 to chemotherapy and 138 to BSC. Histopathology was squamous in 269 (95.7%) patients. Median number of paclitaxel doses was 12 (IQR, 7-23). Median OS was 4.2 months (95% CI, 3.42-5.32) in BSC, and 9.2 months (95% CI, 8.02-10.48) in chemotherapy; HR, 0.49 (95% CI, 0.39-0.64); p < .001. As compared to BSC, chemotherapy increased response (2.9% to 39%), median PFS (2.1 to 4.2 months), 1-year OS (11% to 32%), 2-year OS (0 to 9%), median dysphagia-free survival (2.9 to 14.8 months), and global and esophagus-specific QoL, without significantly increasing all-grade or grade ≥3 toxicities. Using ESMO clinical benefit scale and ASCO Value Framework, palliative chemotherapy scored as having "substantial value." Our study provides the first level 1 evidence that chemotherapy prolongs survival in advanced esophageal/GEJ carcinoma. BSC alone is no longer appropriate. Weekly paclitaxel is an attractive option, especially in LMICs with limited access to immunotherapy.

Evaluation of quantitative imaging parameters in head and neck squamous cell carcinoma.

BACKGROUND: Functional imaging such as 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT), 18F-fluoro-misonidazole (F-MISO)-PET/CT, and diffusion-weighted magnetic resonance imaging (DW-MRI) can assess complex biological phenomena in tumors reflecting underlying disease biology. The aim of this prospective observational study was to correlate quantitative imaging parameters derived from pretreatment biological imaging such as FDG-PET/CT, F-MISO-PET/CT, and DW-MRI with each other and with clinical outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with definitive radio(chemo)therapy. METHODS: Twenty patients with pharyngo-laryngeal cancers underwent pretreatment biological imaging. Gross tumor volume (GTV) was delineated on axial planning CT (GTVCT). Quantitative FDG-PET/CT parameters included maximum, mean, minimum standardized uptake values (SUVmax-FDG, SUVmean-FDG, SUVmin-FDG); metabolic tumor volume (MTV); and total lesion glycolysis (TLG). F-MISO-PET/CT parameters included hypoxic tumor volume (HTV); maximum, mean, minimum SUV; and fractional hypoxic volume (FHV). Mean apparent diffusion coefficient (ADCmean) was derived from DW-MRI. RESULTS: There was moderately strong positive correlation (r=0.616, P=0.005) between GTVCT and MTV. HTV derived from F-MISO-PET/CT at 3-hours (HTV3hrs-F-MISO) showed strong positive correlation with GTVCT (r=0.753, P<0.0001) and MTV (r=0.796, P<0.0001) respectively. ADCmean showed strong positive correlations with SUVmean-5hrs-F-MISO (r=0.713, P=0.021) and SUVmin-5hrs-F-MISO (r=0.731, P=0.016) respectively. A moderate negative correlation (r=-0.500, P=0.049) was observed between ADCmean and MTV. At a median follow up of 44 months, the 5-year Kaplan-Meier estimates of loco-regional control, disease-free survival, and overall survival were 53%, 43%, and 40% respectively. Larger volume of primary tumor (GTVCT>22cc and MTV>7.9cc) and increasing hypoxia (HTV3hr-F-MSO>4.9cc) were associated with worse outcomes. CONCLUSIONS: Functional imaging represents an attractive and non-invasive modality to assess complex biological phenomena in solid tumors. Larger tumor volume and increasing hypoxia emerged as putative prognostic imaging biomarkers in HNSCC.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Concurrent chemoradiotherapy for locally advanced unresectable adenoid cystic carcinoma of head and neck: experience from a single institute.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Radical concurrent chemoradiotherapy is a promising treatment option in locally advanced unresectable ACC with acceptable toxicity.

Poorly differentiated thyroid carcinoma (PDTC) characteristics and the efficacy of radioactive iodine (RAI) therapy as an adjuvant treatment in a tertiary cancer care center.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is biologically more aggressive. Surgery remains the mainstay of treatment. The utility of radioactive iodine (RAI) after surgery is unclear. METHODS: In this retrospective study, patients treated between Jan 2012 and Dec 2017 were included. The demographic, clinical and treatment-related details, including RAI ablation, were recorded and their survival analyzed. RESULTS: Thirty-five patients fulfilled the eligibility criteria. Majority was treatment naïve at presentation. All patients underwent surgery followed by RAI ablation, with a cumulative median dose of 220 mCi (range 40-1140). Sixteen patients received more than one radioiodine treatment for distant metastases. Incomplete resection, age > 45 years and the presence of distant metastasis influenced survival the most. The 3-year PFS of patients with PDTC was 69%. CONCLUSION: All patients in our series showed uptake and responded to treatment. Further use of molecular markers and functional molecular imaging would better our understanding of this entity.

A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.

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.

Impact of age on elderly patients with oral cancer.

INTRODUCTION: In this study we have tried to analyze the impact of age on various clinico-pathological parameters, treatment completion and subsequent survival in older patients. MATERIALS AND METHODS: This is a retrospective analysis of 140 elderly (> 65 years) patients of oral cancer operated between January 2012 and December 2013. The patients were divided into two groups based upon their age that ≤ 70 years and > 70 years.Association of distribution of various clinico-pathological factors between different groups was assessed by using Chi-square test. Survival analysis was done using Kaplan Meir analysis. Univariate and multivariate analysis were performed. RESULTS: The two groups had similar distribution of various clinico-pathological factors. Disease free survival for the group ≤ 70 and > 70 years was 37.6 months and 36.4 months (p < 0.594). 13.5% and 7.8% patients > 70 years and ≤ 70 years were either advised or received sub-optimal adjuvant therapy (p < 0.002). CONCLUSION: There is no difference distribution of various clinico-pathological factors and survival in patients of oral cancer ≤ 70 and > 70 years of age. Age did not affect survival. Majority of patients could complete the adjuvant therapy advised. Still, significantly more number of patients > 70 years could not receive/complete appropriate adjuvant therapy. Thus treatment needs to be tailored keeping in mind the individual's performance status and the co-morbidities.

Outcome of patients following neo-adjuvant chemotherapy for unresectable cervical nodes in head and neck squamous cell carcinomas.

BACKGROUND: This study was undertaken to assess the effects of neo-adjuvant chemotherapy (NACT) on patients with head and neck squamous cell carcinoma (HNSCC) having advanced unresectable cervical nodal metastasis. METHODOLOGY: A retrospective cohort study was conducted to assess the response of unresectable nodes to NACT in a pragmatic manner. Patients were grouped according to the response noted and the treatment offered after chemotherapy. The median survival amongst the patients in these groups was compared. RESULTS: The study included 51 patients. Oral cavity was the commonest site (67.2%). Favourable nodal response was seen in 64.7% of the patients. Up to 87.9% of the nodal responders were amenable to curative intent therapy. The overall survival of patients undergoing surgery, definitive chemoradiotherapy, palliative chemotherapy and palliative radiotherapy was 24, 13, 10 and 9 months, respectively. CONCLUSION: NACT may be utilized in HNSCC with advanced inoperable nodal disease to make them amenable to definitive therapy.

Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer.

BACKGROUND: Whether patients with early-stage oral cancers should be treated with elective neck dissection at the time of the primary surgery or with therapeutic neck dissection after nodal relapse has been a matter of debate. METHODS: In this prospective, randomized, controlled trial, we evaluated the effect on survival of elective node dissection (ipsilateral neck dissection at the time of the primary surgery) versus therapeutic node dissection (watchful waiting followed by neck dissection for nodal relapse) in patients with lateralized stage T1 or T2 oral squamous-cell carcinomas. Primary and secondary end points were overall survival and disease-free survival, respectively. RESULTS: Between 2004 and 2014, a total of 596 patients were enrolled. As prespecified by the data and safety monitoring committee, this report summarizes results for the first 500 patients (245 in the elective-surgery group and 255 in the therapeutic-surgery group), with a median follow-up of 39 months. There were 81 recurrences and 50 deaths in the elective-surgery group and 146 recurrences and 79 deaths in the therapeutic-surgery group. At 3 years, elective node dissection resulted in an improved rate of overall survival (80.0%; 95% confidence interval [CI], 74.1 to 85.8), as compared with therapeutic dissection (67.5%; 95% CI, 61.0 to 73.9), for a hazard ratio for death of 0.64 in the elective-surgery group (95% CI, 0.45 to 0.92; P=0.01 by the log-rank test). At that time, patients in the elective-surgery group also had a higher rate of disease-free survival than those in the therapeutic-surgery group (69.5% vs. 45.9%, P<0.001). Elective node dissection was superior in most subgroups without significant interactions. Rates of adverse events were 6.6% and 3.6% in the elective-surgery group and the therapeutic-surgery group, respectively. CONCLUSIONS: Among patients with early-stage oral squamous-cell cancer, elective neck dissection resulted in higher rates of overall and disease-free survival than did therapeutic neck dissection. (Funded by the Tata Memorial Centre; ClinicalTrials.gov number, NCT00193765.).

Asymptomatic Cardiac Metastasis in a Diagnosed Case of Squamous Cell Carcinoma of the Middle Third of Esophagus.

A lady walks in with complaints of dysphagia mostly to solids to begin with and gradually progressive to liquids requiring naso-gastric tube feeding, with history of vomiting after taking food and weight loss of 20kilograms over 2months. Upper gastrointestinal endoscopy showed an ulceroproliferative growth starting at 28cms from the central incisor and extending upto 36 cms with luminal compromise. Biopsy from the lesion was found to be moderately differentiated squamous cell carcinoma. As part of metastatic work-up a PET-CT (Figure 1 shows lesion in the left ventricle) was done which revealed a metabolically active lesion involving the lower third of esophagus and a metabolically active lesion in the wall of the left ventricle which was the only site of metastatic diseae(Figure 2. Maximum intensity projection). Further investigations were done for characterisation of the cardiac lesion. 2-D Echo cardiography was done and was normal with an ejection fraction of 60%. A cardiac MRI was done which showed a soft tissue mass in the wall of the left ventricle which was isointense with normal myocardium and hyperintense on double inversion recovery sequence which measured 3.2 x 3 cms with post contrast enhancement. She was planned for palliative radiotherapy. A total dose of 30Gy in 10 fractions over 2 weeks was delivered. She tolerated the treatment well with Grade I mucositis (as per RTOG grading) and on follow-up after 4 weeks she had 40% relief in dysphagia and could take semi-solid food with little difficulty.

Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis.

BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8). INTERPRETATION: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. FUNDING: Institut National du Cancer; and Ligue Nationale Contre le Cancer.

Thyroid Mass: Metastasis from Nasopharyngeal Cancer - An Unusual Presentation.

Thyroid gland is an uncommon site of metastasis, and metastasis to the gland secondary to nasopharyngeal carcinoma is seldom seen. We were only able to identify eight reported cases in the literature. A 61-year-old man, diagnosed case of nasopharyngeal cancer-second primary ( first primary-oropharynx), was found to have a thyroid nodule on routine follow-up positron emission tomography-computed tomography (PET-CT) scan. There was no evidence of metastases at any other sites. The thyroid nodule was confirmed as metastatic carcinoma by fine needle aspiration cytology. He was treated with multimodal treatment comprising of surgery followed by reirradiation with concurrent chemotherapy. Subsequently, at the first follow-up (2 months after completion of all treatment), the patient remained asymptomatic, but the response assessment with PET-CT scan was suggestive of lung metastases with no evidence of locoregional disease. Although thyroid parenchymal metastasis is an uncommon occurrence and signifies a poor prognosis, in appropriately selected patients, aggressive therapy with reirradiation and chemotherapy may improve local control and quality of life.

Adjuvant therapy for intermediate risk factors in oral cancer: Can we reach a consensus?

Oral carcinoma is a common disease that poses challenges in treatment management, especially for advanced cases. Adjuvant therapies, such as radiation and chemoradiation therapy, are typically used for advanced oral cancer patients. However, there is uncertainty regarding the use of adjuvant therapy for early-stage patients with certain soft histological parameters. The UICC manual of clinical oncology suggests that adjuvant therapy for such parameters is desirable but not essential. These parameters include perineural invasion, lymphovascular invasion, single nodal positivity, and patterns of invasion, which complicate the decision-making process for including adjuvant therapy. This review aims to provide evidence-based literature for effectively managing this patient group and developing treatment protocols based on current evidence.

Long-term outcomes of neo-adjuvant chemotherapy on borderline resectable oral cavity cancers: Real-world data of 3266 patients and implications for clinical practice.

BACKGROUND: Neo-adjuvant chemotherapy (NACT) followed by response assessment is the standard treatment algorithm for locally advanced oral cavity squamous cell carcinomas (OCSCC) in the Indian subcontinent. The 3-drug NACT regimen (Docetaxel-Cisplatin-5-FU) has shown improvement in overall survival over 2-drug regimen (Docetaxel-Cisplatin) in a phase-3 randomised study. We have analysed the 10-year outcomes with this treatment algorithm. METHODS: This was an institutional review board approved retrospective analysis of a prospectively collected dataset of borderline resectable OCSCC patients who underwent NACT. Patients who became resectable after NACT underwent surgery followed by appropriate adjuvant therapy. Patients who were unresectable received definitive chemoradiation (CTRT), palliative chemotherapy, radiotherapy or best supportive care based on general condition. RESULTS: A total of 3266 patients were included. The most common subsite was buccal mucosa and the most frequent indication was peri-tumoral edema upto zygoma. More than 2-drugs NACT was offered to 32.9% patients. Overall, 32.5% patients had a response to NACT. A total of 1358 patients were offered curative treatment, of which 929 (32%) underwent surgery and the rest underwent definitive chemo-radiation (14.8%). Patients who received more than 2-drugs NACT versus those who received 2-drugs had a 10-years OS of 21% vs 5.1% (p < 0.001). Patients who underwent surgery versus those who did not had a 10-year OS of 21.8% vs 4.1% (p < 0.001). Patients who achieved pCR had a 5-year OS of 45.3% vs 13.3% for those who did not (p < 0.001). CONCLUSION: NACT leads to long term survival benefit in patients of borderline resectable oral cavity cancer.

Volumetric and geometric changes in the parotid glands and target volume during image-guided radiotherapy for locally advanced oropharyngeal cancers.

PURPOSE: This study aimed to evaluate the volumetric and geometric changes in the parotid glands and target volume during image-guided radiotherapy (IGRT) for locally advanced oropharyngeal cancers. MATERIALS AND METHODS: Twenty patients receiving radiotherapy using IGRT at a dose of 70 Gy/35 fractions/7 weeks for locally advanced oropharyngeal cancers were accrued. Radiotherapy planning computed tomography (CT) scans were performed at pre-radiotherapy (RT), 20, 40, and 60 Gy for each patient. Volume changes in target and parotids along with shifts of parotids were assessed with respect to pre-RT scan after co-registration. In study scans, GTVp and GTVn were recontoured as per particular CT. CTV and PTV were copied from planning CT to study CT. CTV was edited from anatomical barriers, and PTV was edited only from the skin in the study CT. The parotids were recontoured on each study scan. The center of mass (COM) of C2 vertebral body was considered as the reference to evaluate its shifts. RESULTS: There was a statistically significant percentage regression of ipsilateral and contralateral parotid mean volumes at the rate of 0.85%/0.207 cc and 0.98%/0.26 cc per day, respectively. We observed the mean medial shift of center of mass of ipsilateral parotid of 2.23 mm (p = 0.011) and contralateral parotid of 2.67 mm (p = 0.069) at the end of 60 Gy. GTVp (mean) reduced from 41.87 cc at 0 Gy to 31.13 cc (25.65%) at 60 Gy (p = 0.003), while GTVn (mean) reduced from 19.98 cc at 0 Gy to 10.79 cc (45.99%) at 60 Gy (p = 0.003). There was a statistically significant reduction in CTV and PTV volumes at 60 Gy. CONCLUSION: Statistically significant volumetric and geometric changes occurred during intensity-modulated radiation (IMRT), which were most prominent after 40 Gy and were maximum at 60 Gy. There was a medial shift of parotid glands toward the high-dose region. This study can be useful to devise an adaptive radiotherapy strategy.

Intensity-Modulated Radiation Therapy Alone Versus Intensity-Modulated Radiation Therapy and Brachytherapy for Early-Stage Oropharyngeal Cancers: Results From a Randomized Controlled Trial.

PURPOSE: The objective of this study was to compare clinical outcomes of intensity-modulated radiation therapy (IMRT) alone versus IMRT + brachytherapy (BT) in patients with T1-T2N0M0 oropharyngeal squamous cell cancers (OPSCC). METHODS AND MATERIALS: This open-label randomized controlled trial was conducted at Tata Memorial Hospital, Mumbai, India. Patients with stage I and II OPSCC were considered for IMRT to a dose of 50 Gy/25 fractions/5 weeks in phase I followed by randomization (1:1) to further treatment with IMRT (20 Gy/10 fractions/2 weeks) or BT (192Ir high dose rate, 21 Gy/7 fractions/2 fractions per day). The primary endpoint of the trial was the reduction in xerostomia at 6 months evaluated using 99mTc salivary scintigraphy. Severe salivary toxicity (xerostomia) was defined as posttreatment salivary excretion fraction ratio <45%. Secondary endpoints were local control, disease-free survival, and overall survival. RESULTS: Between November 2010 and February 2020, 90 patients were randomized to IMRT (n = 46) alone or IMRT + BT (n = 44). Eleven patients (8 residual/recurrent disease, 2 lost to follow-up, 1 second primary) in the IMRT arm and 9 patients (8 residual/recurrence, 1 lost to follow-up) in the BT arm were not evaluable at 6 months for the primary endpoint. At 6 months, xerostomia rates using salivary scintigraphy were 14% (5/35: 95% CI, 5%-30%) in the BT arm while it was seen in 44% (14/32: 95% CI, 26%-62%) in the IMRT arm (P = .008). Physician-rated Radiation Therapy Oncology Group grade ≥2 xerostomia at any time point was observed in 30% of patients (9/30) in the IMRT arm and 6.7% (2/30) in the BT arm (P = .02). At a median follow-up of 42.5 months, the 3-year local control in the IMRT arm was 56.4% (95% CI, 43%-73%) while it was 66.2% (95% CI, 53%-82%) in the BT arm (P = .24). CONCLUSIONS: The addition of BT to IMRT for T1-T2N0M0 OPSCC results in a significant reduction in xerostomia. This strongly supports the addition of BT to IMRT in suitable cases.

N0 neck trial: Does intensification of follow-up (Ultrasound + Physical Examination) influence outcomes in early-stage oral cancer?

AIM OF THE STUDY: We previously reported a survival benefit of elective neck dissection (END) over therapeutic neck dissection (TND) in patients with clinically node-negative early-stage oral cancer. We now report the results of the second question in the same study addressing the impact of adding neck ultrasound to physical examination during follow-up on outcomes. METHODS: Patients with lateralized T1/T2 oral squamous cell carcinoma (SCC) were randomized to END or TND and to follow-up with physical-examination plus neck ultrasound (PE+US) versus physical-examination (PE). The primary endpoint was overall survival (OS). RESULTS: Between January 2004 and June 2014, 596 patients were enrolled. This is an intention to treat analysis of 592 analysable patients, of whom 295 were allocated to PE+US and 297 to PE with a median follow-up of 77.47 months (interquartile range (IQR) 54.51-126.48). There was no significant difference (unadjusted hazard ratio [HR], 0.92, 95% CI, 0.71-1.20, p = 0.54) in 5-year OS between PE+US (70.8%, 95% CI, 65.51-76.09) and PE (67.3%, 95% CI, 61.81-72.79). Among 131 patients with neck node relapse as the first event, the median time to relapse detection was 4.85 (IQR 2.33-9.60) and 7.62 (IQR 3.22-9.86) months in PE+US and PE arms, respectively. The N stage in the PE+US arm was N1 33.8%, N2a 7.4%, N2b/c 44.1% and N3 14.7% while in PE was N1 28.6%, N2a 9.5%, N2b/c 39.7%, N3 20.6% and unknown 1.6%. CONCLUSION: Adding neck ultrasound to physical examination during follow-up detects nodal relapses earlier but does not improve overall survival.

Development and Validation of Single-Optimization Knowledge-Based Volumetric Modulated Arc Therapy Model Plan in Nasopharyngeal Carcinomas.

Purpose: Knowledge-based planning (KBP) has evolved to standardize and expedite the complex process of radiation therapy planning for nasopharyngeal cancer (NPC). Herein, we aim to develop and validate the suitability of a single-optimization KBP for NPC. Methods and Materials: Volumetric modulated arc therapy plans of 103 patients with NPC treated between 2016 and 2020 were reviewed and used to generate a KBP model. A validation set of 15 patients was employed to compare the quality of single optimization KBP and clinical plans using the paired t test and the Wilcoxon signed rank test. The time required for either planning was also analyzed. Results: Most patients (86.7%) were of locally advanced stage (III/IV). The median dose received by 95% of the high-risk planning target volume was significantly higher for the KBP (97.1% vs 96.4%; P = .017). The median homogeneity (0.09 vs 0.1) and conformity (0.98 vs 0.97) indices for high-risk planning target volume and sparing of the normal tissues like optic structures, spinal cord, and uninvolved dysphagia and aspiration-related structures were better with the KBP (P < .05). In the blinded evaluation, the physician preferred the KBP plan in 13 out of 15 patients. The median time required to generate the KBP and manual plans was 53 and 77 minutes, respectively. Conclusions: KBP with a single optimization is an efficient and time saving alternative for manual planning in NPC.

Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. METHODS: In this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. RESULTS: 495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8-23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637-0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5-59.1) and 5% (95%CI 2.9-8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). CONCLUSION: NACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.