Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial Comparing Conventional IMRT to Adaptive IMRT in Head and Neck Squamous Cell Carcinomas.

BACKGROUND: The utility of Adaptive Radiotherapy (ART) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains to be ascertained. While multiple retrospective and single-arm prospective studies have demonstrated its efficacy in decreasing parotid doses and reducing xerostomia, adequate randomized evidence is lacking. METHODS AND ANALYSIS: ReSTART (Reducing Salivary Toxicity with Adaptive Radiotherapy) is an ongoing phase III randomized trial of patients with previously untreated, locally advanced HNSCC of the oropharynx, larynx, and hypopharynx. Patients are randomized in a 1:1 ratio to the standard Intensity Modulated Radiotherapy (IMRT) arm {Planning Target Volume (PTV) margin 5 mm} vs. Adaptive Radiotherapy arm (standard IMRT with a PTV margin 3 mm, two planned adaptive planning at 10th and 20th fractions). The stratification factors include the primary site and nodal stage. The RT dose prescribed is 66Gy in 30 fractions for high-risk PTV and 54Gy in 30 fractions for low-risk PTV over six weeks, along with concurrent chemotherapy. The primary endpoint is to compare salivary toxicity between arms using salivary scintigraphy 12 months' post-radiation. To detect a 25% improvement in the primary endpoint at 12 months in the ART arm with a two-sided 5% alpha value and a power of 80% (and 10% attrition ratio), a sample size of 130 patients is required (65 patients in each arm). The secondary endpoints include acute and late toxicities, locoregional control, disease-free survival, overall survival, quality of life, and xerostomia scores between the two arms. DISCUSSION: The ReSTART trial aims to answer an important question in Radiation Therapy for HNSCC, particularly in a resource-limited setting. The uniqueness of this trial, compared to other ongoing randomized trials, includes the PTV margins and the xerostomia assessment by scintigraphy at 12 months as the primary endpoint.

Contralateral Nodal Relapse in Well-lateralised Oral Cavity Cancers Treated Uniformly with Ipsilateral Surgery and Adjuvant Radiotherapy With or Without Concurrent Chemotherapy: a Retrospective Study.

AIMS: To evaluate the incidence and pattern of contralateral nodal relapse (CLNR), contralateral nodal relapse-free survival (CLNRFS) and risk factors predicting CLNR in well-lateralised oral cavity cancers (OCC) treated with unilateral surgery and adjuvant ipsilateral radiotherapy with or without concurrent chemotherapy. MATERIALS AND METHODS: Consecutive patients of well-lateralised OCC treated between 2012 and 2017 were included. The primary endpoint was incidence of CLNR and CLNRFS. Univariable and multivariable analyses were carried out to identify potential factors predicting CLNR. RESULTS: Of the 208 eligible patients, 21 (10%) developed isolated CLNR at a median follow-up of 45 months. The incidence of CLNR was 21.3% in node-positive patients. CLNR was most common at level IB (61.9%) followed by level II. The 5-year CLNRFS and overall survival were 82.5% and 57.7%, respectively. Any positive ipsilateral lymph node (P = 0.001), two or more positive lymph nodes (P < 0.001), involvement of ipsilateral level IB (P = 0.002) or level II lymph node (P < 0.001), presence of extranodal extension (P < 0.001), lymphatic invasion (P = 0.015) and perineural invasion (P = 0.021) were significant factors for CLNR on univariable analysis. The presence of two or more positive lymph nodes (P < 0.001) was an independent prognostic factor for CLNR on multivariable analysis. CLNR increased significantly with each increasing lymph node number beyond two compared with node-negative patients. CONCLUSION: The overall incidence of isolated CLNR is low in well-lateralised OCC. Patients with two or more positive lymph nodes have a higher risk of CLNR and may be considered for elective treatment of contralateral neck.

Outcomes of surgical versus non-surgical treatment of resectable T4a laryngeal and hypopharyngeal carcinoma.

OBJECTIVE: Surgery is the recommended treatment for resectable T4a laryngeal and hypopharyngeal carcinoma. Non-surgical treatment is an option in a select few patients. METHOD: This retrospective study was undertaken to assess the treatment outcomes in patients with resectable T4a carcinoma of the larynx and hypopharynx who received either surgical or non-surgical treatment at our institute and to assess factors influencing these outcomes. RESULTS: A total of 120 patients were included in the study. They were divided into groups A, B and C based on the presence of extralaryngeal spread through laryngeal membrane, cartilage or both. The overall survival was better among patients who received surgery than those who received non-surgical treatment in the three groups. The factor influencing overall survival was the treatment given in the form of surgical versus non-surgical treatment. CONCLUSION: Surgery is the preferred treatment for T4a laryngeal and hypopharyngeal carcinoma, even in patients with extralaryngeal spread without cartilage erosion.

Salvage radiotherapy for postoperative locoregional failure in esophageal cancer: a systematic review and meta-analysis.

Locoregional recurrences following surgery for esophageal cancers represent a significant clinical problem with no standard recommendations for management. We conducted this systematic review and meta-analysis with the objective of studying safety and efficacy of salvage radiotherapy in this setting. All prospective and retrospective cohort studies, which studied patients who developed locoregional recurrence following initial radical surgery for esophageal cancer and subsequently received salvage radiation therapy (RT)/chemoradiation with all relevant information regarding survival outcome and toxicity available, were included. The quality of eligible individual studies was assessed using the Newcastle-Ottawa Scale score for risk of bias. R package MetaSurv was used to obtain a summary survival curve from survival probabilities and numbers of at-risk patients collected at various time points and to test the overall heterogeneity using the I2 statistic. Thirty studies (27 retrospective, 3 prospective) published from 1995 to 2020 with 1553 patients were included. The median interval between surgery and disease recurrence was 12.5 months. The median radiation dose used was 60 Gy and 57% received concurrent chemotherapy. The overall incidence of acute grade 3/4 mucositis and dermatitis were 8 and 4%, respectively; grade 3/4 acute pneumonitis was reported in 5%. The overall median follow-up of all studies included was 27 months. The 1-, 2- and 3-year overall survival (OS) probabilities were 67.9, 35.9 and 30.6%, respectively. Factors which predicted better survival on multivariate analysis were good PS, lower group stage, node negativity at index surgery, longer disease-free interval, nodal recurrence (as compared to anastomotic site recurrence), smaller disease volume, single site of recurrence, RT dose >50 Gy, conformal RT, use of concomitant chemotherapy and good radiological response after radiotherapy. Salvage radiotherapy with or without concomitant chemotherapy for locoregional recurrences after surgery for esophageal cancer is safe and effective. Modern radiotherapy techniques may improve outcomes and reduce treatment-related morbidity.

Taxane-based Induction Chemotherapy Plus Concurrent Chemoradiotherapy in Nasopharyngeal Carcinoma: Prospective Results from a Non-endemic Cohort.

AIMS: To report the outcomes of induction chemotherapy (ICT) followed by chemoradiotherapy (CTRT) for a large cohort of locoregionally advanced nasopharyngeal cancer (LA-NPC) from a non-endemic region. MATERIALS AND METHODS: Between January 2008 and July 2015, 201 patients with histologically proven, non-metastatic NPC were treated with ICT followed by CTRT at our institute. All the patients received two to three cycles of a taxane-based ICT regimen. Radiotherapy was delivered using an intensity-modulated radiotherapy (IMRT) technique in all patients. RESULTS: After a median follow-up of 37 months (range: 7-110 months), the 3-year disease-free survival (DFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival of the entire cohort was 72, 85, 83 and 87.4%, respectively. On multivariate analysis, histology was an independent predictor of DFS, LRFS and overall survival, with keratinising squamous cell carcinoma histologies predicting a worse outcome. The nodal stage was an independent predictor of DFS, DMFS and overall survival. Age, gender, ethnicity, tumour stage and response to ICT did not significantly affect any of the outcomes. Grade 2 or worse subcutaneous fibrosis was seen in 19% of patients at last follow-up and grade 2 or worse xerostomia was seen in 24% of patients. Thirty-nine per cent of patients developed clinical hypothyroidism at last follow-up. CONCLUSION: ICT followed by concurrent CTRT in the IMRT era provides excellent locoregional control, distant control and overall survival rates in patients with LA-NPC. However, distant failure continues to be a problem and may require further systemic intensification.

Oropharyngeal Cancers in the East and the West - Implications of Aetiopathogenesis on Prognosis and Research.

There has been a surge in human papillomavirus (HPV)-positive oropharyngeal cancers (OPCs) in the West. Although the prognosis of HPV-positive OPC is good, de-escalation strategies have so far not been able to confirm comparable cancer control. We examine the strategies implemented across the globe to safely reduce toxicities in HPV-positive disease. HPV-negative OPC has a poorer prognosis and is more prevalent in Eastern countries. We outline the intensification strategies currently used in HPV-negative cancers, with an aim to better prognosis. With recent improvements in clinical trial frameworks in Eastern countries such as India, we discuss areas where joint collaborative research between Western and Eastern countries could further improve outcomes in OPC.

Oral Cavity Cancer in the Indian Subcontinent - Challenges and Opportunities.

Oral cavity cancer (OCC) poses a global challenge that plagues both the Orient and the Occident, accounting for an estimated 350 000 new cases and 177 000 deaths in 2018. OCC is a major public health problem in the Indian subcontinent, where it ranks among the top three cancer types in both incidence and mortality. Major risk factors are the use of tobacco, betel quid and alcohol consumption. OCC is a heterogeneous group of multiple histologies that affects multiple subsites. The oral cavity includes the lips, buccal mucosa, teeth, gingiva, anterior two-thirds of the tongue, floor of the mouth and hard palate. OCC is defined as cancer of lips, mouth and tongue as defined by the International Classification of Diseases coding scheme. The epidemiology, aetio-pathogenesis and treatment philosophy are similar within this group. Although salivary gland malignancies, sarcomas, mucosal melanomas and lymphomas can also arise within the oral cavity, this review will focus on squamous cell cancer, which is the predominant histology in OCC. We review and contrast data from developing and developed countries. We also highlight the unique regional challenges that countries in the East face; citing India as an example, we elaborate on the opportunities and scope for improvement in the management of OCC.

Twice-weekly palliative radiotherapy for locally very advanced head and neck cancers.

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.

Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma.

AIMS: Treatment intensification either by using concurrent chemoradiotherapy (CCRT) or altered fractionation radiotherapy (AFRT) improves outcomes of locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The superiority of one approach over the other, however, remains to be firmly established. The aim of the present study was to compare outcomes of CCRT versus AFRT in the definitive non-surgical management of locoregionally advanced HNSCC for evidence-based decision making. MATERIALS AND METHODS: An electronic search of Medline via PubMed was conducted with no language, year, or publication status restrictions. The Cochrane Central Register of Controlled Trials (CENTRAL) and Database of Abstracts of Reviews of Effectiveness (DARE) were also searched electronically. Only randomised controlled trials assigning HNSCC patients randomly to conventionally fractionated CCRT or AFRT alone were included. Data were extracted independently by two reviewers and pooled using the Cochrane methodology for meta-analysis and expressed as a hazard ratio with 95% confidence intervals. Overall survival was the primary outcome of interest, whereas disease-free survival, locoregional control and toxicity were secondary end points. RESULTS: Five randomised controlled trials (involving 1117 patients and 627 deaths) directly comparing conventionally fractionated CCRT with AFRT alone were included. The risk of bias in included studies was low for efficacy outcomes, but high for toxicity outcomes. The overall pooled hazard ratio of death was 0.73 (95% confidence interval = 0.62-0.86), which significantly favoured conventionally fractionated CCRT over AFRT alone (P < 0.0001). Similarly, disease-free survival (hazard ratio = 0.79, 95% confidence interval = 0.68-0.92; P = 0.002) and locoregional control (hazard ratio = 0.71, 95% confidence interval = 0.59-0.84; P < 0.0001) were significantly improved with CCRT. There were no significant differences in the incidence of severe acute toxicity (dermatitis and mucositis) between the two approaches of treatment intensification. Late xerostomia was significantly increased with CCRT. Significant haematological toxicity and nephrotoxicity were seen exclusively with chemotherapy. CONCLUSION: There is moderate quality evidence that conventionally fractionated CCRT improves survival outcomes compared with AFRT alone in the definitive radiotherapeutic management of locoregionally advanced HNSCC. No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy.

Factors predicting 'time to distant metastasis' in radically treated head and neck cancer.

Context: Various studies have shown the important risk factors for distant metastasis in head and neck cancer (HNC) which are present in most of the patients in developing countries. Identification of factors on the basis of time to distant metastasis (TDM) can help in future trials targeting smaller subgroups. Aims and Objectives: To identify the factors that predict TDM in radically treated HNC patients. Settings and Design: Retrospective audit. Materials and Methods: Retrospective audit of the prospectively maintained electronic database of a single HNC radiotherapy clinic from 1990 to 2010 was done to identify radically treated patients of HNC who developed distant metastasis. Univariate and multivariate analysis were done to identify baseline (demographic, clinical, pathological, and treatment) factors which could predict TDM, early time to metastasis (ETM; <12 months), intermediate time to metastasis (ITM; 12-24 months), and late time to metastasis (LTM; >2 years) using Kaplan Meier and Cox regression analysis, respectively. Results: One hundred patients with distant metastasis were identified with a median TDM of 7.4 months; 66 had ETM, 17 had ITM, and 17 had LTM. On multivariate analysis, the nodal stage 2-3 (N2/3) was the only baseline factor independently predicting TDM, ETM, and ITM, whereas none of the baseline factors predicted LTM. Conclusions: Higher nodal burden (N2/3) is associated with both ETM and ITM, and calls for aggressive screening, systemic therapy options, and surveillance. It is difficult to predict patients who are at a risk of developing LTM with baseline factors alone and evaluation of biological data is needed.

Radical radiotherapy in head and neck squamous cell carcinoma: an analysis of prognostic and therapeutic factors.

AIMS: Head and neck squamous cell carcinoma (HNSCC) continues to be a leading cancer in developing countries. Definitive radiation therapy either primary or as postoperative adjuvant is offered to most patients. We aimed to identify prognostic and therapeutic factors that affect locoregional control and survival in patients undergoing radical radiotherapy for head and neck squamous cell cancers. MATERIALS AND METHODS: A retrospective analysis of 568 previously untreated patients with squamous head and neck cancers, who received radical radiotherapy between 1990 and 1996, using local control, locoregional control and disease-free survival (DFS) as outcome measures. RESULTS: With a median follow-up of 18 months for living patients, the 5-year local control, locoregional control and DFS for all 568 patients were 53%, 45% and 41%, respectively, for all stages combined. The 5-year local control, locoregional control and DFS as per the American Joint Committee on Cancer stage grouping were 78%, 70% and 70%; 64%, 59% and 57%; 51%, 42% and 37%; and 40%, 27% and 22% from stages I to IV, respectively, with highly significant P values. Patients receiving higher doses (> or = 66 Gy) had a significantly better outcome compared with lower doses. The 5-year local control (59% vs 48%, P = 0.0015), locoregional control (47% vs 41%; P = 0.0043) and DFS (44% vs 37%; P = 0.0099) were significantly better in patients receiving > or = 66 Gy. Site of primary also affected outcome significantly, with oral cavity lesions faring badly. CONCLUSION: Tumour stage remains the most important factor affecting outcome in radical radiotherapy of HNSCC. A definite dose-response relationship exists with higher total doses, leading to better local control, locoregional control and DFS in all stages. Site of primary affects outcome too, with laryngeal primaries doing well and oral cavity cancers faring the worst.