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.

Effect of p16 Status on the Quality-of-Life Experience During Chemoradiation for Locally Advanced Oropharyngeal Cancer: A Substudy of Randomized Trial Trans-Tasman Radiation Oncology Group (TROG) 02.02 (HeadSTART).

PURPOSE: Human papillomavirus-associated oropharyngeal cancer (OPC) has a favorable prognosis. Current research de-escalates treatment, aiming to improve quality of life (QOL). Understanding the QOL experience with current standard treatment (chemoradiation therapy) provides context for emerging data. We report the impact of p16 status on QOL for patients with stage III or IV OPC undergoing chemoradiation therapy in an international phase 3 trial (TROG 02.02 [HeadSTART]). METHODS AND MATERIALS: A subgroup analysis by p16 status was conducted in patients with OPC treated in a phase 3 randomized trial. The study subset with OPC and known p16 status was mainly from Australasia, Western Europe, and North America. Of 861 participants, 200 had OPC, known p16 status, and baseline QOL data; 82 were p16 negative and 118 were p16 positive. Radiation therapy (70 Gy over a period of 7 weeks) was given concurrently with 3 cycles of either cisplatin (100 mg/m2) or cisplatin (75 mg/m2) plus tirapazamine. QOL was measured with the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) questionnaire at baseline and 2, 6, 12, 23, and 38 months. Because no significant difference in QOL score was observed between arms, results by p16 status are reported with arms combined. RESULTS: The p16-positive patients were younger, had a better Eastern Cooperative Oncology Group performance status, and were less often current smokers. Our primary hypothesis that the change in FACT-H&N score from baseline to 6 months would be more favorable in the p16-positive cohort was not met (p16 positive, -6.3; p16 negative, -1.8; P=.14). The mean baseline FACT-H&N score was statistically and clinically significantly better in p16-positive patients (111 vs 102, P<.001); at 2 months, scores declined in both groups but more dramatically for p16-positive patients. By 12 months, p16-positive patients again had superior scores. A higher baseline FACT-H&N score and p16-positive status were independent predictors of overall survival. CONCLUSIONS: Patients with p16-positive OPC exhibited better baseline QOL but showed a more dramatic QOL drop with concurrent chemoradiation. Given the favorable prognosis of p16-positive OPC, efforts to reduce the QOL burden of treatment are warranted.

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.

Quantitative and qualitative analysis of [(18)F]FDG and [(18)F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome.

PURPOSE: While methods for imaging tumor hypoxia with positron emission tomography (PET) have been developed, optimal methods for interpreting and utilizing these datasets in the clinic remain unclear. In this study, we analyzed hypoxia PET images of head and neck cancer patients and compared imaging metrics with human papilloma virus (HPV) status and clinical outcome. METHODS: Forty-one patients treated as part of a phase III trial of the hypoxic cytotoxin tirapazamine (TROG 02.02) were imaged with PET using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA). FDG and FAZA PET images were interpreted qualitatively and quantitatively, and compared with tumor T stage, HPV status, and treatment outcome using multivariate statistics. RESULTS: PET signals in the tumor and lymph nodes exhibited significant intra- and inter-patient variability. The FAZA hypoxic volume demonstrated a significant correlation with tumor T stage. PET-hypoxic tumors treated with cisplatin exhibited significantly worse treatment outcomes relative to PET-oxic tumors or PET-hypoxic tumors treated with tirapazamine. CONCLUSION: Quantitative analysis of FAZA PET yielded metrics that correlated with clinical T stage and were capable of stratifying patient outcome. These results encourage further development of this technology, with particular emphasis on establishment of robust quantitative methods.

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.

Treatment response in the neck: p16+ versus p16- oropharyngeal cancer.

INTRODUCTION: To compare nodal response rates following chemoradiotherapy in patients with p16+ and p16- oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Patients with node-positive OPSCC treated at Peter MacCallum Cancer Centre on the published phase I-III tirapazamine trials were identified. All patients had conventional assessment (clinical examination (CA), CT and/or MRI) and positron emission tomography (PET) at both baseline and 2-4 months post-treatment. RESULTS: There were 30 p16+ and 18 p16- patients, the former group having significantly higher stage nodal disease (P = 0.016). The mean overall reduction in nodal size at post-treatment assessment was similar in p16+ and p16- patients (78% vs. 75%), and no statistically significant difference in nodal complete response (CR) rates was detected by either CA (50% vs. 39%, P = 0.35) or PET/PET-CT (93% vs. 83%, P = 0.19). PET was significantly more accurate in determining the true nodal CR rate in both groups, with a negative predictive value of 96%. CONCLUSION: Nodal response rates following chemoradiotherapy appear to be similar in p16+ and p16- patients when assessed by either CA or PET/PET-CT. However, higher nodal CR was seen in PET/PET-CT compared with CA in both groups. Metabolic imaging is more accurate than CA in assessing nodal response post-treatment.

A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma.

OBJECTIVES: To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m(2) day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m(2)/day for 5 days of weeks 1, 4 and 7. RESULTS: 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5-98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6-96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. CONCLUSION: The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.

Larynx preservation for patients with locally advanced laryngeal cancer.

A 53-year-old man presented with a 6-month history of mild hoarseness, with no associated pain, dysphagia, or stridor. At nasoendoscopy, a lesion was detected involving the whole length of the left vocal cord, with abnormal mucosa also seen in the right ventricle (Fig 1). The left vocal cord movement was impaired. There were no palpable neck nodes. Biopsy under anesthesia revealed moderately differentiated squamous cell carcinoma. He was a current smoker of 30 cigarettes per day (45 pack-year smoking history), and he consumed four standard drinks of alcohol per day. His Eastern Cooperative Oncology Group performance status was 1, and he had no significant comorbidities. Radiologic review of his outside computed tomography scan noted that it was of poor quality, and a magnetic resonance imaging scan was recommended, which showed low-volume T4a disease based on focal thyroid cartilage penetration (Fig 2). A positron emission tomography (PET) scan revealed no evidence of nodal or distant metastasis.

Prognostic and predictive significance of plasma HGF and IL-8 in a phase III trial of chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer.

PURPOSE: Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin. EXPERIMENTAL DESIGN: Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16(INK4A) staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with (18)F-fluoroazomycin arabinoside ((18)FAZA)-positron emission tomography. RESULTS: Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16(INK4A)-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with (18)FAZA tumor standard uptake value. CONCLUSIONS: IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients.