International Recommendations on Reirradiation by Intensity Modulated Radiation Therapy for Locally Recurrent Nasopharyngeal Carcinoma.

PURPOSE: Reirradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging because prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking because available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions. METHODS AND MATERIALS: A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the whole panel for review and reconsideration. The current guideline was based on majority voting after repeated iteration for final agreement. RESULTS: The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of reirradiation (including patient selection, targets contouring, dose prescription, and constraints). CONCLUSION: This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of reirradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's condition, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications.

International Guideline on Dose Prioritization and Acceptance Criteria in Radiation Therapy Planning for Nasopharyngeal Carcinoma.

PURPOSE: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference. METHODS AND MATERIALS: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement. RESULTS: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed. CONCLUSIONS: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk.

International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma.

PURPOSE: Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome. METHOD: A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies. RESULTS: Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration. CONCLUSION: Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients' factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery).

Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy and Pathologic Risk Groups in Patients With Head and Neck Cancer.

PURPOSE: To present the long-term and final report of a phase 3 trial designed to assess dose-response relationship for postoperative radiation therapy (PORT) and pathologic risk groups in head and neck cancer. METHODS AND MATERIALS: Patients who underwent primary surgery for American Joint Committee on Cancer stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and who required PORT were eligible. Patients' primary sites and involved necks were independently assigned to higher- or lower-risk categories based on a cumulative point score representing increasing risk of recurrence. The sites in the lower-risk group were randomized to receive 57.6 or 63 Gy and those in the higher-risk group were randomized to receive 63 or 68.4 Gy, all at 1.8 Gy per fraction. RESULTS: A total of 264 patients were included. The actuarial 5-year locoregional control rate was 67%. A second primary cancer was documented in 27% of patients. The 5- and 10-year freedom-from-distant metastasis rates were 64% and 60%, respectively, whereas the 5- and 10-year overall survival rates were 32% and 20%, respectively. There was no statistically significant difference in tumor control between different dose levels in both the lower- and higher-risk groups. On multivariate analysis, nonwhite race (P=.0003), positive surgical margins (P=.009), extracapsular extension (ECE, P=.01), and treatment package time (TPT) ≥85 days (P=.002) were independent correlates of worse locoregional control, whereas age ≥57 years (P<.0001), positive surgical margins (P=.01), ECE (P=.026), and TPT ≥85 days (P=.003) were independently associated with worse overall survival. CONCLUSIONS: This long-term report of PORT delivered at 1.8 Gy/d to total doses of 57.6 to 68.4 Gy without chemotherapy for head and neck squamous cell carcinoma demonstrated that increasing dose did not significantly improve tumor control. On multivariate analysis, the only significant treatment variable was TPT. The results confirm that positive surgical margins and/or nodal ECE remains the most significant predictive pathologic factors.

Weekly cisplatin and radiotherapy for low risk, locoregionally advanced human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus-positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009. METHODS: Data from patients with low-risk HPV(+) oropharyngeal SCC treated with weekly cisplatin (40 mg/m(2) ) and 70 Gy radiotherapy were collected. Low risk was defined as stage III to IV oropharyngeal SCC excluding T1-2N1, T4 or N3 disease, or N2b to N2c disease in patients with >10 pack-year smoking history. RESULTS: Of 31 patients, the median age was 56 years (range, 41-69 years). All patients completed 70 Gy radiotherapy within 51 days and 84% completed at least 5 cycles of cisplatin. Grade 3 mucositis occurred in 22 patients (71%) and grade 3 febrile neutropenia in 6 patients (19%). No patients required enteral feeding at 12 months. The median follow-up was 30 months (range, 21-57 months) with no recurrences or deaths. CONCLUSION: Concurrent weekly cisplatin is relatively well-tolerated and associated with excellent disease control in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1117-E1121, 2016.

Outcome impact and cost-effectiveness of quality assurance for radiotherapy planned for the EORTC 22071-24071 prospective study for head and neck cancer.

INTRODUCTION: One of the goals of Quality Assurance in Radiotherapy (QART) is to reduce the variability and uncertainties related to treatment planning and beam delivery. The purpose of this study was to assess the outcome impact and cost-effectiveness (CE) of various QART levels for a head and neck (H&N) cancer study. MATERIALS AND METHODS: QART levels were defined as: basic QART with a dummy run (level 2), level 2 plus prospective Individual Case Reviews (ICRs) for 15% of patients (level 3) and level 2 plus prospective ICRs for all patients (level 4). The follow-up of patients was modeled using a multi-state model with parameters derived from EORTC, TROG and RTOG prospective studies. Individual patient data, linking QART results with outcome, were retrieved from the TROG database. Results for each QART level were expressed as percentage of mortality and local failure at 5 years. RESULTS: Quality-of-life-adjusted and recurrence-free survival increased with increasing QART levels. The increase of all these metrics was more sizeable with an increased QART level from 2 or 3 to 4. The estimated quality-adjusted-life-years (QALYs) for an increase of QART levels of 3-4 and 2-4 were 0.09 and 0.15, respectively. The incremental CE ratio was €5525 and €3659 Euros per QALY for these QART levels. Compared to QART level 2 or 3, level 4 was cost-effective. CONCLUSIONS: Increasing QART levels resulted in better patient outcome in this simulated study. The increased complexity of the QART program was also cost-effective.

Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer.

INTRODUCTION: We investigated the relationship between hypoxia, human papillomavirus (HPV) status and outcome in head and neck squamous cell carcinoma. METHODS: Patients with stage III and IV head and neck squamous cell carcinoma treated on phase I and II chemoradiation trials with 70-Gy radiation combined with tirapazamine/cisplatin or cisplatin/fluorouracil (5FU), hypoxic imaging using [18F]-misonidazole positron emission tomography and known HPV status (by p16 immunohistochemistry) were included in this sub-study. Separate analyses were conducted to consider the impact of tirapazamine on HPV-negative tumours in the phase II trial. RESULTS: Both p16-positive oropharyngeal tumours and p16-negative head and neck squamous cell carcinoma tumours had a high prevalence of tumour hypoxia; 14/19 (74%) and 35/44 (80%), respectively. The distribution of hypoxia (primary, nodal) was similar. On phase II, trial patients with p16-negative hypoxic tumours had worse loco-regional control with cisplatin and 5FU compared with tirapazamine and cisplatin (P < 0.001) and worse failure-free survival (hazard ratio = 5.18; 95% confidence interval, 1.98-13.55; P = 0.001). Only 1 out of 14 p16-positive patients on the phase II trial experienced loco-regional failure. CONCLUSION: Hypoxia, as assessed by [18F]-misonidazole positron emission tomography, is frequently present in both p16-positive and negative head and neck cancer. Further research is required to determine whether hypoxic imaging can be used to predict benefit from hypoxia-targeting therapies in patients with p16-negative tumours.

Tonsillar cancer: the Peter MacCallum experience with unilateral and bilateral irradiation.

BACKGROUND: The primary purpose of this study was to review the efficacy of unilateral treatment of lateralized tonsil primaries, in particular whether laterality of the primary is a more powerful determinant of contralateral neck failure than advanced ipsilateral nodal classification. METHODS: A retrospective study of all patients with tonsillar cancer treated with curative intent between January 1990 and December 2002 was performed. RESULTS: There were 167 patients, 76% men, median age 58 years, 86% current or ex-smokers. The majority of patients (58%) had stage IV disease. Five-year local, nodal, locoregional, and distant failure rates were 14%, 4%, 18%, and 8%, respectively. Of the 58 patients treated unilaterally, 33% had N2a, N2b, or N3 nodal disease. There were no contralateral nodal failures in the unilaterally treated group. CONCLUSION: These results support the potential use of unilateral radiation therapy (RT) for lateralized tonsil primaries even with advanced ipsilateral nodal disease.

Relationship between epidermal growth factor receptor status, p16(INK4A), and outcome in head and neck squamous cell carcinoma.

BACKGROUND: Human papilloma virus (HPV) infection is a powerful prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). Increased epidermal growth factor receptor (EGFR) gene copy number and protein expression have been reported to be negative predictors of outcome. This study examined the relationship between HPV status, EGFR gene copy number, EGFR protein expression, and clinical outcome in HNSCC patients treated with chemoradiation. METHODS: HPV status was determined using p16(INK4A) immunohistochemistry (IHC), EGFR gene copy number was evaluated with FISH, and EGFR protein expression by IHC in 212 subjects. RESULTS: EGFR FISH was positive in 41 of 204 (20%) patients and was negatively correlated with failure-free survival (FFS; HR = 1.84, P = 0.027) and overall survival (OS; HR = 1.78, P = 0.082). For p16(INK4A), 85 of 200 (42.5%) patients were found to be p16 positive, including 75 of 131 (57%) with oropharyngeal cancer. Patients with p16-positive oropharyngeal cancer had significantly improved FFS (HR = 0.28, P < 0.001) and OS (HR = 0.31, P = 0.002). Only 2 of 126 (1.6%) oropharyngeal cancer patients were found to be p16+/EGFR FISH+. EGFR IHC was positive in 81 of 93 (87%) of patients and was associated with poorer FFS (HR = 1.98, P = 0.35) and OS (HR = 2.52, P = 0.22). CONCLUSIONS: Increased EGFR gene copy number is largely restricted to p16(INK4A)-negative oropharyngeal cancer. Although p16(INK4A) and EGFR FISH are both predictive of outcome in univariate analyses, only p16(INK4A) remains independently predictive. IMPACT: Knowledge of HPV and EGFR status can have implications for treatment options and prognosis in HNSCC.

The utility of PET/CT in staging and assessment of treatment response of nasopharyngeal cancer.

INTRODUCTION: The aim of this study was to evaluate the impact of positron emission tomography/computerised tomography (PET/CT) as an adjunct to conventional imaging (CI) in the management of nasopharyngeal cancer (NPC) both for initial staging and assessment of post-treatment response. METHODS: All NPC cases referred to the Peter MacCallum Centre for Metabolic Imaging between January 2002 and December 2007 were identified. In patients undergoing initial staging, any differences between the pre-PET/CT management plan based on CI and that following performance of the PET/CT scan were noted. Clinical impact was scored using the Centre's published criteria: 'high' if PET/CT changed the primary treatment modality or intent, 'medium' if treatment modality was unchanged but the radiotherapy technique or dose was altered, and 'low' if there was no change in treatment modality or intent. Patients undergoing PET/CT following definitive treatment were scored according to whether or not they achieved a complete metabolic response. RESULTS: Forty-eight patients underwent a staging PET/CT. The clinical impact was high in 8%, medium in 25% and low in 66% of patients. Twenty-one patients were scanned for post-treatment response. PET/CT was less frequently equivocal than MRI (3 vs 8/21). A complete metabolic response on PET/CT was associated with a 93% negative predictive value for subsequent recurrence. CONCLUSION: PET/CT is a valuable staging tool for the detection of occult metastatic disease and defining the extent of neck nodal disease. Post-treatment, a complete metabolic response on PET/CT has a very high negative predictive value with fewer equivocal results than MRI.

Larynx preservation with primary non-surgical treatment for loco-regionally advanced larynx cancer.

INTRODUCTION: The objective of this paper was to review the results of primary non-surgical treatment with the aim of larynx preservation for loco-regionally advanced larynx cancer (LALC). METHODS: All patients with LALC presenting between January 2002 and December 2006 who were selected for primary non-surgical treatment were included in this study. RESULTS: There were 60 patients, 48% with stage III and 52% with stage IV disease. The median follow-up of living patients was 41 months. Larynx preservation with local disease control was achieved in 83% and 77% of patients at 3 and 5 years, respectively. Failure-free survival at 3 and 5 years was 66% and 59%, respectively, and overall survival was 67% and 45%, respectively. All patients with larynx preservation had a functional voice. Two patients became feeding tube dependant. Thirty-nine percent of all deaths were unrelated to LALC. CONCLUSIONS: Primary non-surgical treatment achieves high rates of larynx preservation with a low rate of severe complications but overall survival remains disappointing.

Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial.

PURPOSE: To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial. PATIENTS AND METHODS: Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction. RESULTS: Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P = .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P = .13). CONCLUSION: HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02.

PURPOSE: To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer. PATIENTS AND METHODS: The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality. RESULTS: At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively. CONCLUSION: These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.

Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group.

PURPOSE: Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial. PATIENTS AND METHODS: Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m(2)) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m(2)) plus TPZ (290 mg/m(2)/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69). RESULTS: Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS--CIS: 95% CI, -5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck. CONCLUSIONS: We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.

Optimising the therapeutic ratio in head and neck cancer.

The intensity of contemporary treatment for locally advanced head and neck cancer is at the upper limit of human tolerance of acute toxicities. While impressive gains in locoregional control have been achieved, improvements in overall survival have been more modest. We hypothesise that unrecognised sequelae of highly toxic contemporary treatments substantially contribute to patient mortality. This possibility provides motivation to investigate reducing treatment intensity in selected patients with locally advanced head and neck cancer. With the demonstration of a good prognosis among subgroups of patients with head and neck cancer, major improvements in the technical delivery of radiotherapy, and further research into relevant factors in survivorship, we may be able to improve overall survival of patients with locally advanced disease without further increasing, and possibly reducing, treatment intensity.

Prospective trial to evaluate staged neck dissection or elective neck radiotherapy in patients with CT-staged T1-2 N0 squamous cell carcinoma of the oral tongue.

BACKGROUND: A prospective study was undertaken to evaluate a policy of selective, single-modality elective neck treatment in T1-2, node-negative oral tongue squamous cell carcinoma. METHODS: Where the primary tumor showed 1 of the 4 key pathological criteria (greater than 7 mm of muscle invasion, less than 5 mm of resection margin, perineural or lymphovascular invasion), radiotherapy was delivered to the primary site and the at-risk undissected neck. Otherwise patients underwent ipsilateral neck dissection within 4 weeks of initial resection. Prospective quality of life assessments were performed. RESULTS: The study was closed after accrual of 25 patients, because the high locoregional recurrence rate met early stopping criteria. With a median follow-up of 3.4 years, the locoregional recurrence rate was 23%. The 4-year overall and disease-free survival rates were 71% and 64%, respectively. CONCLUSION: The poor disease-free survival reflects the need for better prognostic markers and more aggressive treatment in these patients.