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.

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.

The role of PET-CT in the management of patients with advanced cancer of the head and neck.

The development of functional imaging using positron emission tomography (PET) has been a major advancement in clinical oncology. In addition, the integration of functional imaging with CT anatomical imaging (PET-CT) has dramatically increased the clinical applicability of PET. This review discusses the current role of PET-CT in head and neck cancer, focusing on its role in staging, detection of unknown primaries, radiotherapy planning, assessment of treatment response, and biological characterization of disease. We also demonstrate why PET-CT should be an integral part of modern management of head and neck cancer.

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).

Intensity-modulated radiotherapy for nasopharyngeal carcinoma: clinical correlation of dose to the pharyngo-esophageal axis and dysphagia.

PURPOSE: The aim of this study was to quantify the dose delivered to the pharyngo-esophageal axis using different intensity-modulated radiation therapy (IMRT) techniques for treatment of nasopharyngeal carcinoma and to correlate this with acute swallowing toxicity. METHODS AND MATERIALS: The study population consisted of 28 patients treated with IMRT between February 2002 and August 2005: 20 with whole field IMRT (WF-IMRT) and 8 with IMRT fields junctioned with an anterior neck field with central shielding (j-IMRT). Dose to the pharyngo-esophageal axis was measured using dose-volume histograms. Acute swallowing toxicity was assessed by review of dysphagia grade during treatment and enteral feeding requirements. RESULTS: The mean pharyngo-esophageal dose was 55.2 Gy in the WF-IMRT group and 27.2 Gy in the j-IMRT group, p < 0.001. Ninety-five percent (19/20) of the WF-IMRT group developed Grade 3 dysphagia compared with 62.5% (5/8) of the j-IMRT group, p = 0.06. Feeding tube duration was a median of 38 days for the WF-IMRT group compared with 6 days for the j-IMRT group, p = 0.04. CONCLUSIONS: Clinical vigilance must be maintained when introducing new technology to ensure that unanticipated adverse effects do not result. Although newer planning systems can reduce the dose to the pharyngo-esophageal axis with WF-IMRT, the j-IMRT technique is preferred at least in patients with no gross disease in the lower neck.

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.

Relapse patterns in WHO 2/3 nasopharyngeal cancer: is there a difference between ethnic Asian vs. non-Asian patients?

PURPOSE: The purpose of this study was to assess whether ethnicity is an independent prognostic factor in patients with World Health Organization (WHO) type 2 or 3 nasopharyngeal carcinoma (NPC). Specifically, we examined the patterns of relapse observed in patients classified as "Asian" (born in southern China or southeast Asia) or "non-Asian" (born in Australia, Europe, the Middle East, or the Pacific Islands). METHODS AND MATERIALS: All patients planned for radical treatment at the Peter MacCallum Cancer Centre from April 1985 to December 1999 were included in this study. Pathology was reviewed to confirm WHO type 2 or 3 NPC. Patients were staged using the 1997 International Union Against Cancer (UICC) criteria. Mean potential follow-up time was 9.6 years (range, 1.0-18.5 years) RESULTS: There were 158 patients: 86 Asian and 72 non-Asian. Stage groupings were: I--12 patients; II--32 patients; III--59 patients; and IV--55 patients. A staging computerized tomography was performed in 121 patients, and 53 (34%) also had a staging magnetic resonance imaging (MRI). The Asian patients had significantly more women, more patients aged <45, and more with performance status 0 than the non-Asians. Other putative prognostic factors were not significantly different between the groups. The 5-year rates for freedom from local recurrence (FLR), failure-free survival (FFS), and overall survival (OS) for Asian and non-Asian patients were 74% vs. 82%, 61% vs. 55%, and 75% vs. 63%, respectively. Corresponding 10-year figures were: 62% vs. 82%, 43% vs. 48%, and 58% vs. 49%, respectively. Multifactor analysis showed stage and the use of MRI for staging to be significant prognostic factors for all three endpoints. Age was also significant for FFS and OS. There were no significant differences in FFS or OS between Asian and non-Asian patients. However, the FLR interval was significantly worse in the Asian group (hazard ratio [HR], 2.37; 95% confidence interval [CI], 1.11-5.06), whereas duration of freedom from distant metastasis tended to be better (HR, 0.71; 95% CI, 0.33-1.53). CONCLUSIONS: Although this study provides no evidence that race is an independent prognostic factor for overall survival in patients with WHO 2/3 NPC, it does suggest that relapse patterns may vary, with a higher rate of late primary failures (offset by a lower rate of distant failure) in the Asian population. Further confirmatory studies with larger patient cohorts are indicated.

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.

Results of treatment intensification for progressive locoregional disease in head-and-neck cancer patients undergoing postoperative radiotherapy.

PURPOSE: Patients who develop progressive locoregional disease during radical surgery and postoperative radiotherapy for squamous cell carcinoma of the head and neck represent a management dilemma. We present our experience using treatment intensification for such patients. METHODS AND MATERIALS: A prospective record of eligible patients was kept between May 1998 and December 2001. The study included 15 patients, 11 men and 4 women (median age, 60 years); 67% had Stage III-IV disease. The sites of progression were primary in 3, nodes/scar in 10, and both primary and nodes in 2. Relative to the initial plan, treatment intensification was achieved by an increased radiation dose in 7 (using accelerated fractionation in 5), an increased radiation dose and the addition of concomitant chemotherapy in 7, and the addition of concomitant chemotherapy alone in 1 patient. RESULTS: The median follow-up was 40 months. Eight patients had a complete response to intensified treatment. At the closeout date, 6 patients were alive with no evidence of disease. Eight patients had died with locoregional disease; two also had distant metastases. One patient was lost to follow-up after achieving a complete response. The median failure-free survival for all patients was 6 months, but for those with a complete response, it was 37 months. The median overall survival time was 28 months. The 2-year and 3-year overall survival rate was 50% and 42%, respectively. Acute mucosal and skin toxicity was increased relative to standard postoperative radiotherapy but was not dissimilar to that expected after radical definitive chemoradiotherapy. CONCLUSION: Intensification of treatment in patients who develop progressive locoregional disease is warranted, because it can lead to long-term disease control in a subset of patients with significant but acceptable toxicity.

The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer.

BACKGROUND AND PURPOSE: The primary objective of this study was to estimate the rate of tumour response to a cyclical hypofractionated palliative radiotherapy regimen (QUAD SHOT) in previously untreated patients with incurable squamous cell carcinoma of the head and neck. Secondary objectives were to prospectively evaluate toxicity, quality of life (QoL) and survival in these patients. PATIENTS AND METHODS: The QUAD SHOT consisted of 14 Gy in four fractions, given twice a day and at least 6h apart, for 2 consecutive days. This regimen was repeated at 4 weekly intervals for a further two courses if there was no tumour progression. The QoL tool used was an abbreviation of the EORTC QLQ-C30. RESULTS: Thirty eligible patients (29 Stage IV, 20 performance status 2-3) had at least one treatment and 16 patients completed all three cycles. Sixteen patients (53%) had an objective response (2CR, 14PR) and a further seven had stable disease. Median overall survival was 5.7 months, median progression free survival was 3.1 months. The treatment was very well tolerated, with improved QoL in 11 of 25 evaluable patients (44%). CONCLUSION: The QUAD SHOT regimen is an effective palliative treatment with minimal toxicity and a good response rate, which impacts positively on patients' QoL.

Postoperative chemoradiotherapy for high-risk head-and-neck squamous cell carcinoma.

PURPOSE: To describe the use of postoperative concurrent chemoradiotherapy, with either weekly cisplatin or carboplatin, for high-risk head-and-neck squamous cell carcinoma (HNSCC) in a single institutional setting. METHODS AND MATERIALS: Between July 1999 and January 2003, 47 patients were treated with postoperative chemoradiotherapy. RESULTS: Of the 47 patients, 41 (87%) had Stage III-IV disease. The predominant primary site was the oral cavity in 24 patients (51%), 27 had nodal disease with extracapsular extension, and 26 had positive or close mucosal margins (<5 mm). Ten patients had undergone resection of recurrent disease after previous surgery. Twenty-seven (57%) were treated with cisplatin, and the remaining patients received carboplatin because of contraindications to cisplatin. The median radiotherapy dose was 60 Gy (range, 50-66 Gy). Of the 47 patients, 45 (96%) completed at least four of the six planned doses of chemotherapy and 45 (96%) completed the planned course of radiotherapy. Nineteen patients (40%) had confluent mucositis, eight (17%) had Grade 3-4 hematologic toxicity, and four (9%) had febrile neutropenia. No treatment-related deaths occurred. The estimated 2-year locoregional control, progression-free survival, and overall survival rate was 73%, 56%, and 62%, respectively. Excluding the 10 patients with recurrence after previous surgery, the locoregional control, progression-free survival, and overall survival rate was 81%, 64%, and 71%, respectively. Five cases of Grade 3-4 late treatment-related sequelae developed. CONCLUSION: Treatment with postoperative concurrent weekly cisplatin or carboplatin and radiotherapy was reasonably well tolerated. Acute and late toxicity was acceptable. The overall results achieved are comparable with the preliminary results of recent randomized trials. Patients treated after resection of recurrent disease (after previous surgery alone) fared worse than those treated at the initial resection.

Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation.

PURPOSE: To investigate the relationship between positron emission tomography (PET) detected inflammatory changes in irradiated normal tissues and metabolic response at tumor sites in patients receiving radical radiotherapy for non-small-cell lung cancer. The prognostic significance of these changes was also studied. METHODS: In 73 consecutive patients, (18)F-fluorodeoxyglucose (FDG) PET was performed at a median of 70 days after completion of radical radiotherapy. Radiation-induced inflammatory change was scored for normal tissues within the radiation treatment volume using a 0-3 grading scale. Metabolic tumor response was assessed using a pattern-recognition algorithm comparing pre- and posttreatment scans. Prognostic significance of inflammatory changes was tested using the Cox proportional hazards regression model. RESULTS: Increased FDG uptake in normal tissues (radiotoxicity) was associated with a greater likelihood of complete or partial tumor response on both PET (p = 0.0044) and computed tomography (p = 0.029). Prognostic stratification provided by PET response was both significant and of a similar magnitude in patients with low- and high-grade radiotoxicity. CONCLUSION: Postradiotherapy inflammatory changes detected by FDG-PET are positively correlated with tumor response, suggesting that tumor radioresponsiveness and normal tissue radiosensitivity may be linked. Prognostic stratification provided by PET is not compromised by inflammatory changes if a meticulous visual response assessment technique is used.

Factors affecting risk of symptomatic temporal lobe necrosis: significance of fractional dose and treatment time.

PURPOSE: To study the factors affecting the risk of symptomatic temporal lobe necrosis after different fractionation schedules. METHODS AND MATERIALS: One thousand thirty-two patients with T1-2 nasopharyngeal carcinoma treated with radical radiotherapy in Hong Kong during 1990-1995 were studied. They were treated at four different centers with similar techniques but different fractionation schedules: 984 patients were given 1 fraction daily throughout (q.d.), and 48 patients were irradiated twice daily (b.i.d.) for part of the course. The median total dose was 62.5 Gy (range 50.4-71.2), dose per fraction was 2.5 Gy (range 1.6-4.2), and overall treatment time (OTT) was 44 days (range 29-70). In addition, 500 patients received supplementary doses for parapharyngeal extension, 113 received booster doses by brachytherapy, and 114 received sequential chemotherapy using cisplatin-based regimes. RESULTS: Altogether, 24 patients developed symptomatic temporal lobe necrosis: 18 from the q.d. group and 6 from the b.i.d. group. The 5-year actuarial incidence ranged from 0% (after 66 Gy in 33 fractions within 44 days) to 14% (after 71.2 Gy in 40 fractions within 35 days). Multivariate analyses showed that the risk was significantly affected by the fractional effect of the product of total dose and dose per fraction (hazard ratio [HR] = 1.04, 95% confidence interval [CI] 1.02-1.05), OTT (HR 0.88, 95% CI 0.80-0.97), and b.i.d. scheduling (HR 13, 95% CI 3-54). Repeating the analyses for patients treated with the q.d. schedules confirmed the independent significance of OTT in addition to the product of total dose and dose per fraction. CONCLUSION: The tentative results suggest that in addition to fractional dose, the OTT also had significant impact on the risk of temporal lobe necrosis, and b.i.d. scheduling increased the hazard further.

The effect of anaemia on efficacy and normal tissue toxicity following radiotherapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: The aims of this analysis were to determine the effect of anaemia on loco-regional control, relapse-free survival, cause-specific survival, overall survival, and acute and late radiation therapy toxicity in patients with Stage III and IV squamous cell carcinoma of the head and neck treated with radiotherapy. PATIENTS AND METHODS: Between 1991 and 1998, 350 patients were randomly assigned to either conventional radiotherapy, (70 Gy in 35 fractions in 49 days) or to accelerated radiotherapy (59.4 Gy in 33 fractions in 24 days). Patients were divided into two groups according to their haemoglobin level: a normal haemoglobin group (>/=13 g/dl in males, >/=12 g/dl in females) and a low haemoglobin group (<13 g/dl in males, <12 g/dl in females). The influence of anaemia on cause-specific survival and the development of confluent mucositis independent of other variables was tested using Cox proportional hazards model. RESULTS: Of 350 patients recruited to the trial, 238 had haemoglobin measurements and were eligible for inclusion in this secondary analysis. One hundred and ninety-three were considered to have normal haemoglobin, and 45 patients were considered to be anaemic. There were significant differences between the groups in loco-regional control, relapse-free survival, cause-specific survival and overall survival, with hazards ratios of 0.56 (95% confidence interval (CI) 0.34-0.94), 0.57 (95% CI 0.35-0.92), 0.49 (95% CI 0.29-0.85) and 0.43 (95% CI 0.26-0.70) in favour of the normal haemoglobin group. Using Cox proportional hazards modelling, haemoglobin level was a significant predictor of cause-specific survival in addition to disease site, stage, and Eastern Cooperative Oncology Group status. There were no statistically significant differences between the groups in the development of acute or late reactions. CONCLUSION: Significant reductions in loco-regional control, disease-free survival, cause-specific survival and overall survival occur in the presence of anaemia. No significant differences in normal tissue toxicity have been identified in this analysis.

Outcomes in sinonasal mucosal melanoma.

BACKGROUND: The present paper assesses treatment outcomes in a series of 20 patients with sinonasal mucosal melanoma (SNMM) over 11 years. METHODS: All patients who presented to a single institution between 1991 and 2002 with a diagnosis of SNMM had their treatment reviewed and outcomes determined. RESULTS: Twenty patients presented to our institution with SNMM over the study period. No cervical node or metastatic involvement was detected at presentation. The most common site of involvement was the nasal cavity (17/20). The majority of patients received initial surgery followed by radiotherapy (15/20). At the completion of treatment 14 patients had no disease evident. The median time to failure in these patients was 12 months. Of these patients 10 relapsed, including six who had metastatic failure only. Fifteen patients died due to disease. Median overall survival was 17 months, with a 2-year overall survival of 23%. In univariate analysis, patients with advanced tumours (T3-4) had a 4.3 times greater risk of dying than patients with early tumours (T1-2). CONCLUSIONS: Patients with SNMM have poor outcomes with conventional therapy. Full staging prior to treatment is recommended. Aggressive treatment carrying significant morbidity is justified only for patients with early stage disease.

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.

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.