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The aim of this TROG 12.01 substudy was to report longitudinal variations in patient- (PRO) and clinician-reported outcomes based on receipt of unilateral (URT) or bilateral radiation therapy (BRT).Patients with lateralized T1-2 N1-2b human papillomavirus-associated tonsillar carcinoma (AJCC7) enrolled on TROG 12.01 were eligible. The primary endpoint was patient-reported radiation symptom severity score (MDASI-RSS) at 2 years, a composite of 9 MDASI-Head and Neck (HN) symptom items. Secondary endpoints included patient-reported symptom burden and interference (MDASI-HN), quality of life (FACT-HN), emotional distress (HADS), return to work (RTW), clinician-reported performance status scale (PSS-HN), and late adverse events (CTCAE). Mean MDASI-RSS, symptom severity (MDASI-SS), symptom interference (MDASI-SI) and selected single items were compared 1 week, 3 months, and 2 years post-RT.Seventy-four patients were eligible for analysis (26 URT, 48 BRT). Median follow-up was 3.7 years (1.8-5.2 years). Sociodemographic, staging, and treatment variables were mostly balanced, with larger primaries observed in the BRT group. Four regional failures were reported (3 URT, 1 BRT), including one isolated contralateral regional failure in the URT cohort. Mean MDASI-RSS scores did not differ at 2 years (URT vs BRT, 1.1 vs 1.3; difference 0.1 [95% CI: -0.7 to 0.9], P = .75) or at any other time points for the MDASI-RSS, MDASI-SS, and MDASI-SI scores, except for worse MDASI-SI 1 week after treatment in the BRT group (4.7 vs 5.6). Fatigue (6.6 vs 5.4) at 1 week and dry mouth (3.5 vs 2.0) at 2 years were also worse in the BRT group. FACT-HN, HADS, RTW, PSS-HN, and CTCAE results were similar across the follow-up period.In this favorable-risk cohort, treatment laterality resulted in fewer differences than anticipated in patient-reported or clinician-reported outcomes. Two years after treatment patients treated with BRT reported significantly worse dry mouth. Longer follow-up is needed to determine the impact of treatment laterality on late effects.

Radiotherapy treatment (RT) irradiates a patient's tumour volume while minimising damage to healthy tissue and surrounding critical organs at risk (OAR). In the conventional RT planning process, the RT planner has to iteratively adjust either the planning objectives (tumour or OAR dose levels) or the weights of the planning objectives until an acceptable plan is obtained that satisfies the minimum requirements. At the end of this iterative process, it remains unknown whether this plan is the best that can be obtained for the patient. The oncologist reviews each plan and decides to either treat using this plan or request further plan development, which may or may not lead to an actual improvement of the reviewed plan. We describe how Data Envelopment Analysis (DEA) is used as a real-time decision support tool to assess quality of RT plans for head and neck cancer patients by applying a knowledge-based comparison of each new plan to a library of previous clinically approved plans. This library allows benchmarking, which gives planners and oncologists a better idea of the relative quality of their plan and its improvement potential, resulting in improved use of resources and better quality treatments for patients. Our DEA-based approach provides a novel way of capturing multiple measures of plan quality as well as anatomical differences between patients in the benchmarking process. We present the developed DEA model and results for a set of benchmark instances. Initial results of integrating DEA-based quality feedback into the RT planning process are presented showing that operations research can contribute significantly to planning quality in this setting.

Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.

Purpose The excellent prognosis of patients with low-risk human papillomavirus (HPV)- associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiation therapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an epidermal growth factor receptor targeting antibody, when combined with radiation therapy would result in a decrease in symptom burden and toxicity with similar efficacy compared with weekly cisplatin. Methods and Materials TROG12.01, a randomized, multicenter trial involving 15 sites in Australia and New Zealand enrolled patients with HPV-associated oropharyngeal squamous cell carcinoma, American Joint Committee on Cancer 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomized (1:1) to receive radiation therapy (70 Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40 mg/m2, or cetuximab, loading dose of 400 mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks postcompletion of radiation therapy using the area under the curve. Trial was registered on ClinicalTrials.gov: NCT01855451. Results Between June 17, 2013, and June 7, 2018, 189 patients were enrolled, with 92 in cisplatin arm and 90 in cetuximab included in the main analysis. There was no difference in the primary endpoint of symptom severity; difference in area under the curve cetuximab-cisplatin was 0.05 (95% confidence interval [CI], –0.19, 0.30), P = .66. The T-score (mean number of ≥grade 3 acute adverse events) was 4.35 (standard deviation 2.48) in the cisplatin arm and 3.82 (standard deviation 1.8) in the cetuximab arm, P = .108. The 3-year failure-free survival rates were 93% (95% CI, 86%-97%) in the cisplatin arm and 80% (95% CI, 70%-87%) in the cetuximab arm (hazard ratio = 3.0 [95% CI, 1.2-7.7]); P = .015. Conclusions For patients with low-risk HPV-associated oropharyngeal cancer, radiation therapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared with radiation therapy and weekly cisplatin. Radiation therapy and cisplatin remain the standard of care.

Objectives: The aim of this study was to assess the outcome of treating glottic dysplasia and early squamous cell carcinoma (SCC) with potassium titanyl phosphate (KTP) photoangiolytic laser ablation. Methods: Patient demographics, comorbidities, and tumor characteristics were recorded. Perceptual, patient-reported, and objective voice outcomes were assessed. Use of treatment modalities in addition to the KTP laser, development of locoregional or metastatic SCC, and overall survival were recorded. Results: There were 23 patients with glottic dysplasia and 18 patients with glottic SCC. Mean age at treatment was 69 years. Most patients (95%) were male. Posttreatment fundamental frequency fell from 132 ± 35 to 116 ± 24 Hz ( P = .03). Overall, 61% of patients achieved a normal voice. There was a learning-curve, and most treatment failures occurred in the first half of the series. Five-year KTP-only disease-control rates were 87.1% and 53.5% for dysplasia and malignancy, respectively. Five-year overall survival was 56%, with no laryngectomies or deaths due to SCC. Conclusions: Ablating dysplasia and early glottic cancer using a KTP laser is a viable treatment option. It has a learning curve and a failure rate but, in this series, no ultimate loss of oncologic control. Its introduction into clinical practice should be managed carefully in the context of multidisciplinary cancer care. Level of Evidence: 4.

Purpose Follicular lymphoma (FL) is curable by involved-field radiotherapy (IFRT) in < 50% of patients with stage I to II disease. We hypothesized that adding systemic therapy to IFRT would improve long-term progression-free survival (PFS). Patients and Methods A multicenter randomized controlled trial enrolled patients with stage I to II low-grade FL after staging computed tomography scans and bone marrow biopsies. 18F-labeled fluorodeoxyglucose–positron emission tomography (PET) was not mandatory. Patients were randomly assigned to either arm A (30 Gy IFRT alone) or arm B (IFRT plus six cycles of cyclophosphamide, vincristine, and prednisolone [CVP]). From 2006, rituximab was added to arm B (R-CVP). Results Between 2000 and 2012, 150 patients were enrolled, 75 per arm. In arm B, 44 patients were allocated to receive CVP and 31 were allocated to receive R-CVP. At randomization, 75% had stage I, the median age was 57 years, 52% were male, and 48% were PET staged. With a median follow-up of 9.6 years (range, 3.1 to 15.8 years), PFS was superior in arm B (hazard ratio, 0.57; 95% CI, 0.34 to 0.95; P = .033). Ten-year PFS rates were 59% (95% CI, 46% to 74%) and 41% (95% CI, 30% to 57%) for arms B and A, respectively. Patients in arm B who received R-CVP had markedly superior PFS compared with contemporaneous patients in arm A (hazard ratio, 0.26; 95% CI, 0.07 to 0.97; P = .045). Fewer involved regions ( P = .047) and PET staging ( P = .056) were associated with better PFS. Histologic transformation occurred in four and 10 patients in arms B and A, respectively ( P = .1). Ten deaths occurred in arm A versus five in arm B, but overall survival was not significantly different ( P = .40; 87% and 95% at 10 years, respectively). Conclusion Systemic therapy with R-CVP after IFRT reduced relapse outside radiation fields and significantly improved PFS. IFRT followed by immunochemotherapy is more effective than IFRT in early-stage FL.

Tumour hypoxia is a marker of poor prognosis and failure of chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC), providing a strategy for therapeutic intervention in this setting. To evaluate the utility of the hypoxia-activated prodrug evofosfamide (TH-302) in HNSCC, we established ten early passage patient-derived xenograft (PDX) models of HNSCC that were characterised by their histopathology, hypoxia status, gene expression, and sensitivity to evofosfamide. All PDX models closely resembled the histology of the patient tumours they were derived from. Pimonidazole-positive tumour hypoxic fractions ranged from 1.7&ndash, 7.9% in line with reported HNSCC clinical values, while mRNA expression of the Toustrup hypoxia gene signature showed close correlations between PDX and matched patient tumours, together suggesting the PDX models may accurately model clinical tumour hypoxia. Evofosfamide as a single agent (50 mg/kg IP, qd &times, 5 for three weeks) demonstrated antitumour efficacy that was variable across the PDX models, ranging from complete regressions in one p16-positive PDX model to lack of significant activity in the three most resistant models. Despite all PDX models showing evidence of tumour hypoxia, and hypoxia being essential for activation of evofosfamide, the antitumour activity of evofosfamide only weakly correlated with tumour hypoxia status determined by pimonidazole immunohistochemistry. Other candidate evofosfamide sensitivity genes&mdash, MKI67, POR, and SLFN11&mdash, did not strongly influence evofosfamide sensitivity in univariate analyses, although a weak significant relationship with MKI67 was observed, while SLFN11 expression was lost in PDX tumours. Overall, these data confirm that evofosfamide has antitumour activity in clinically-relevant PDX tumour models of HNSCC and support further clinical evaluation of this drug in HNSCC patients. Further research is required to identify those factors that, alongside hypoxia, can influence sensitivity to evofosfamide and could act as predictive biomarkers to support its use in precision medicine therapy of HNSCC.

6012 Background: The excellent prognosis of patients with low risk HPV associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiotherapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an EGFR targeting antibody, when combined with radiotherapy would result in a decrease in symptom burden and toxicity with similar efficacy when compared to weekly cisplatin. Methods: TROG 12.01, a randomised, multicentre trial involving 15 sites in Australia and New Zealand enrolled patients with HPV associated oropharyngeal squamous cell carcinoma, AJCC 7th edition Stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomised (1:1) to receive radiotherapy (70Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40mg/m2 or cetuximab, loading dose of 400mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks post completion of radiotherapy using the area under the time-severity curve (AUC). Sample size was 170 evaluable patients to provide at least 90% power to detect an effect size of 0.5, using a 2-sided test at 0.05 level of significance. Trial was registered on ClinicalTrials.gov: NCT01855451. Results: Between 17th June 2013 and 7th June 2018, 189 patients were enrolled and 182 were evaluable, with 92 on cisplatin arm and 90 on cetuximab included in the main analysis. The median follow-up was 4.1 years (0.4 - 5.3). Analyses were performed in all eligible randomised patients that commenced treatment (modified intention-to-treat population). There was no difference in the primary endpoint of symptom severity; difference in AUC cetuximab – cisplatin was 0.05 (95%CI: -0.19, 0.30), p= 0.66. The T-score (mean number of > grade 3 acute adverse events) was 4.35 (SD 2.48) in the cisplatin arm and 3.82 (SD 1.8) in the cetuximab arm, p= 0.108. The 3 -year failure-free survival rates were 93% (95% CI: 86-97%) in the cisplatin arm and 80% (95% CI: 70-87%) in the cetuximab arm (hazard ratio = 3.0 (95% CI: 1.2-7.7); p=0.015. The increase in failures in the cetuximab arm was evenly split between distant and locoregional failures. Conclusions: For patients with low risk HPV associated oropharyngeal cancer, radiotherapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared to radiotherapy and weekly cisplatin. Radiotherapy and cisplatin remains the standard of care. Clinical trial information: NCT01855451.

Aim To determine the completeness of reporting of patient-reported outcomes (PROs) of head and neck cancer (HNC) and thyroid cancer randomised-controlled trials (RCTs) and identify PRO measures used. Methods A systematic literature search was conducted for HNC and thyroid cancer RCTs with PRO end-points (January 2004–June 2015). Two investigators independently extracted data, assessed adherence to the International Society for Quality of Life Research (ISOQOL) PRO reporting standards and concordance between hypotheses and PRO measures used. Data were entered into the Patient-Reported Outcomes Measurements Over Time in Oncology (PROMOTION) Registry. Results Sixty-six RCTs were included, 56 (85%) HNC and 10 (15%) thyroid cancer. Twenty-two (33%) included a primary and 44 (67%) included a secondary PRO end-point. A total of 40 unique PRO measures were used. Adherence to the ISOQOL PRO reporting standards was higher for RCTs with primary PRO end-points than for secondary PRO end-points: (mean adherence of 43% and 29% respectively). Completeness of PRO reporting did not improve with time: r = .13, p = .31. ISOQOL checklist items poorly reported included: PRO hypothesis (reported for eight RCTs, 12%), justification chosen of PRO measures (n = 16, 24%), rates of missing PRO data (n = 19, 29%), and generalisability of results (n = 12, 18%). Encouragingly, PROs were identified in 55 RCT abstracts (83%) and PRO results interpreted for 30 RCTs (45%). Conclusions Reporting of PRO end-points was more comprehensive in RCTs with primary rather than secondary PRO end-points. Improvement is needed in the transparent reporting of PRO studies, particularly regarding data collection, analyses and generalisability of PRO results.

Objective Accurate determination of human papilloma virus (HPV) status is critical when identifying patients with oropharyngeal squamous cell carcinoma (OPSCC) who may be candidates for de-escalation trials. In this study we investigated whether local p16 screening, by immunohistochemistry (IHC), has high positive predictive value (PPV) for HPV status in a good prognosis HPV positive OPSCC (HPVOPSCC) population treated on a clinical trial. Methods and materials Patients enrolled on the TROG 12.01 randomised trial for good prognosis HPVOPSCC were randomised based on local p16 IHC testing but subsequently had central p16 IHC and HPV RNA in situ hybridisation (HPV RNA ISH) testing. Correlations between the local and central p16 and central HPV RNA ISH were studied. The main outcome was the positive predictive value (PPV) of local pathology laboratory testing of p16. Results 176/182 patients had samples available for central testing. 172/176 were evaluable for central testing of p16, and all were confirmed to be p16 positive (172/172, 100%, 95% CI = [97.9%, 100%]). Similarly, 100% of those evaluable for HPV RNA ISH (155/155, 100%, 95% CI = [97.6%, 100%]) were confirmed HPV positive, indicating p16 overexpression driven by transcriptionally active HPV and a PPV of 100% for local p16 testing. Conclusions Our results validate the suitability of local pathology laboratory p16 testing alone, in populations with a high attributable fraction of OPSCC due to HPV, to screen and enrol low risk HPVOPSCC patients onto de-intensification trials. This obviates the need for upfront more complex and expensive HPV assays and/or central laboratory testing.

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

Background. The aim of this study was to deter- mine the incidence of isolated nodal failure in patients with N2/3 disease who achieved a complete clinical and radiological response (CR) at 12 weeks postchemoradiation, when no planned neck dissection was performed. Methods. We analyzed the nodal response and subsequent neck control of 102 patients with initial N2/3 disease treated on the Trans Tasman Radiation Oncology Group 98.02 study. Results. With a median 4.3 years follow-up, the patterns of first failure in the CR patients were local 4%, local and nodal 2%, distant 28%, and locoregional plus distant (within 1 month) 6%.There were no patients who had only neck failure. Conclusion. Patients in this trial with N2/3 disease who obtained a clinical and radiological complete response to che- moradiation had a zero incidence of isolated neck failure without a planned neck dissection. The continued use of planned neck dissections in this patient subset cannot be justified. V C 2008

Purpose To evaluate the effect of radiotherapy on the severe pulmonary toxicity observed in the pilot study of BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's lymphoma. Methods and Materials Patients with Stage III or IV Hodgkin's lymphoma or Stage IIB with risk factors participated in this single-arm, multicenter pilot study. Results Twenty-seven patients were enrolled on the study before its premature closure as a result of the development of serious pulmonary toxicity in 8 patients. The pulmonary toxicity occurred either during or immediately after the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early fatality but resolved in the other 7 patients after cessation of gemcitabine and bleomycin, allowing continuation of therapy. Fifteen patients received consolidative radiotherapy, including 4 who previously had pulmonary toxicity. There were no reported cases of radiation pneumonitis and no exacerbation of pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity. Conclusions The severe pulmonary toxicity observed in this study has been attributed to an interaction between gemcitabine and bleomycin. Gemcitabine (when administered without bleomycin) remains of interest in Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's Lymphoma Study Group protocol that also includes consolidative radiotherapy. This study supports the concept of the integration of radiotherapy in gemcitabine-containing regimens in Hodgkin's lymphoma if there is an interval of at least 4 weeks between the two modalities and with a schedule whereby radiotherapy follows the chemotherapy.

The aim of this paper is the retrospective comparison of accelerated/hypofractionated radiotherapy regimen (AHFX) with standard fractionation regimen (SFX) for patients with early glottic carcinoma. One hundred and forty-five patients with T(1)-T(2) glottic cancer between 1986 and 1998 were eligible. Before 1992, patients received 60-66 Gy in 30-33 fractions over 6-6.5 weeks (SFX) with (60)Co and 6-MV beams. After 1992, patients received 52.5-55 Gy in 20 fractions over 4 weeks (AHFX) using 6-MV beams. The end-points were overall survival, laryngectomy-free survival (LFS), loco-regional control and toxicity. One hundred and two were stage T(1)N(0); 43 were stage T(2)N(0). Median follow up was 4.9 years. The 5-year overall survival was 78%. Five-year loco-regional control in T(1)N(0) patients was higher in AHFX than in SFX group (95 vs 75%, P = 0.002). Loco-regional control in T(2)N(0) patients was similar for AHFX and SFX (81 vs 80%, P = 0.813). Overall LFS was 88%. T(1)N(0) AHFX patients had 5-year LFS of 95% compared with 75% for SFX (P = 0.003). For T(2)N(0) AHFX patients, overall LFS was 92% compared with 80% for the SFX group (P = 0.291). No grade 4 or 5 late toxicity occurred. One AHFX patient developed grade 3 toxicity; two of 51 SFX patients developed grade 2 toxicity versus five of 94 AHFX patients. AHFX using 6-MV beams for treatment of early glottic cancer resulted in equivalent LFS and toxicity when compared with SFX.

Tumor hypoxia is prevalent in head and neck squamous cell carcinoma (HNSCC), where it limits radiotherapy outcomes. Hypoxia-activated prodrugs (HAPs) have been developed to target hypoxic regions of tumors. These agents undergo oxygen-sensitive reductive activation, thereby delivering cytotoxic species within hypoxic cells. This study investigated the efficacy and sensitivity determinants of the clinical-stage HAP evofosfamide (TH-302) using molecularly-characterized models of HNSCC. We deployed a collection of 27 HPV-negative HNSCC cell lines derived from lesions of varying TNM stages and primary, nodal or recurrent sites. The collection was characterized for gene expression by RNA-seq, from which somatic variants were also called. Their transcriptomic features were investigated in the context of pan-cancer TCGA data by hierarchical clustering. The potency and hypoxic selectivity of 3 HAPs - evofosfamide, PR-104A and SN30000 - were assessed by antiproliferative assay in 22 lines and compared to bromo-isophosphoramide mustard (Br-IPM), cisplatin and 5-FU. The antitumor activity of evofosfamide (50 mg/kg qdx5 for 2-3 cycles with or without a single 10 Gy dose of radiation on day 5 of cycle 1) was evaluated in HNSCC xenografts in addition to a PDX isolated from an SCC of the glottic larynx. The hypoxic fraction at baseline and after 5 days of treatment was quantified by pimonidazole staining. Genetic modifiers of sensitivity to evofosfamide and its cytotoxic metabolite Br-IPM were explored through whole-genome CRISPR-Cas9 screens using the GeCKO v2 library. High-throughput screens with a custom shRNA pool were performed in one HNSCC and two pancreatic ductal adenocarcinoma cell lines to identify reductases responsible for the activation of evofosfamide in hypoxic cells. Evofosfamide was more potent and more selective for hypoxic HNSCC cells in vitro than PR-104A or SN30000. Cell line sensitivity to evofosfamide was correlated with Br-IPM and cisplatin but not with PR-104A, SN30000 or 5-FU, indicating distinct sensitivity determinants. Evidence of antitumor activity with evofosfamide was observed in vivo. CRISPR screens identified potential evofosfamide sensitivity genes that were reproducibly enriched following drug exposure. Reductase-focused RNA interference screens defined a cluster of sensitivity genes that mapped to mitochondrial electron transport, whereas shRNA’s targeted against presumed activating enzymes such as POR were not enriched. Concentration-dependent oxidation of cytochrome a and decreased respiration was observed in cells exposed to evofosfamide, suggesting reduction by mitochondrial complexes. This study provides a rationale for the clinical evaluation of evofosfamide with radiotherapy in genetically defined subsets of HNSCC patients. Citation Format: Francis W. Hunter, Avik Shome, Dan Li, Way W. Wong, Peter Tsai, Nooriyah Poonawala, Purvi M. Kakadiya, Troy M. Ketelä, Maria K. Kondratyev, Courtney R. Lynch, Tet-Woo Lee, Khanh B. Tran, Jules B. Devaux, Rachel Zussman, Cho R. Hong, Dennis Kee, Andrew M. Macann, Anthony J. Hickey, Stefan K. Bohlander, Cristin G. Print, William R. Wilson, Bradly G. Wouters, Stephen M. Jamieson. Preclinical efficacy and sensitivity determinants of evofosfamide in molecularly defined models of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 169. doi:10.1158/1538-7445.AM2017-169

6008 Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node > 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute & late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- & 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- & 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- & 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.

Purpose To assess the impact of domicile-based humidification on symptom burden during radiation therapy (RT) for head-and-neck (H&N) cancer. Methods and Materials From June 2007 through June 2011, 210 patients with H&N cancer receiving RT were randomized to either a control arm or to receive humidification using the Fisher & Paykel Healthcare MR880 humidifier. Humidification commenced on day 1 of RT and continued until Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, clinical mucositis (CMuc) grade ≤1 occurred. Forty-three patients (42%) met a defined benchmark for humidification compliance and contributed to per protocol (PP) analysis. Acute toxicities, hospitalizations, and feeding tube events were recorded prospectively. The McMaster University Head and Neck Radiotherapy Questionnaire (HNRQ) was used for patient-reported outcomes. The primary endpoint was area under the curve (AUC) for CMuc grade ≥2. Results There were no significant differences in AUC for CMuc ≥2 between the 2 arms. Humidification patients had significantly fewer days in hospital ( P =.017). In compliant PP patients, the AUC for CTCAE functional mucositis score (FMuc) ≥2 was significantly reduced ( P =.009), and the proportion who never required a feeding tube was significantly greater ( P =.04). HNRQ PP analysis estimates also in the direction favoring humidification with less symptom severity, although differences at most time points did not reach significance. Conclusions TROG 07.03 has provided efficacy signals consistent with a role for humidification in reducing symptom burden from mucositis, but the influence of humidification compliance on the results moderates recommendations regarding its practical utility.

Oropharyngeal mucositis is a frequent, severe complication of local irradiation for tumours in the head and neck. We postulated that heated humidification of inspired air via a nasal interface may palliate symptoms of mucositis by reducing the discomfort associated with dry, sticky secretions. We sought to review the effect of home-based humidification on hospital admissions and the patient reported experience of that humidification.This study was a retrospective review. A historical (control) group of patients did not receive home humidification at any stage (n = 55) and a study group (n = 53) received home humidification at or after the onset of grade 3 mucositis. A questionnaire was sent to study group patients to obtain information about their experience of using the humidifier at home.There were no demographic differences between the study and control groups, but the study group had significantly more advanced cancer (stage IV; p = .0307) and significantly higher total fractions and days treated (p.01). Group comparison showed no difference in subsequent overall hospital admissions (p = .9269), but 7 of the 55 control group patients (12.7%) were admitted for supportive care within 2 months of completing radiotherapy, whereas none of the 53 patients who used home humidification were admitted after starting that use (p.01). Almost all (95%) of the study group patients reported that humidification was of benefit, and 81% stated that it relieved mouth or throat pain.Humidification of inspired gas offers a simple, drug-free option for managing a number of the adverse mucosal effects of radiation and chemoradiation in head and neck cancer patients.

Purpose To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma (SCC) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial. Patients and Methods One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (75 mg/m2) plus tirapazamine (290 mg/m2/d) on day 2 of weeks 1, 4, and 7, and tirapazamine alone (160 mg/m2/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS), or cisplatin (50 mg/m2) on day 1 and infusional fluorouracil (360 mg/m2/d) on days 1 through 5 of weeks 6 and 7 (chemoboost). Results Three-year failure-free survival rates were 55% with TPZ/CIS (95% CI, 39% to 70%) and 44% with chemoboost (95% CI, 30% to 60%; log-rank P = .16). Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm (95% CI, 71% to 92%) and 66% in the chemoboost arm (95% CI, 51% to 79%; P = .069). More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS, while acute skin radiation reaction was more severe and prolonged with chemoboost. Compliance with protocol treatment was satisfactory on both arms. Conclusion Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting. Based on the promising efficacy seen in this trial, TPZ/CIS is being evaluated in a large phase III trial.