Long term survival in patients with human papillomavirus-positive oropharyngeal cancer and equivocal response on 12-week PET-CT is not compromised by the omission of neck dissection.

BACKGROUND AND AIM: The aim of this study was to evaluate the long-term safety of the omission of immediate neck dissections (IND) in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) achieving a less than complete nodal response on 12-week FDG PET-CT. MATERIAL AND METHODS: Patients with HPV-positive, node-positive HNSCC that were treated with radical (chemo) radiotherapy (RT) between January 2013 and September 2019 were identified. PET-CT responses were classified as complete (CR), incomplete (ICR) or equivocal (EQR) nodal responses. Clinical outcomes were obtained. RESULTS: 347 patients were identified. Median follow-up was 43.9 (IQR, 30.8-61.2) months. 62.8% (218/347) achieved a CR, 23.4% (81/347) EQR and 13.8% (48/347) ICR nodal response. 70 of 81 (86.4%) patients with an EQR and 25 of 48 (52.1%) with an ICR had no residual disease during follow up (a pathologically negative ND if surgery undertaken or no subsequent neck or distant relapse clinically/radiologically). Median survival of the EQR and CR groups were not reached, and despite the omission of IND in 95% of the EQR group there was no statistically significant differences in overall survival (OS) between the groups, p = 1.0. Median survival of ICR was not reached. However, OS for ICR group was significantly worse than that of CR, and EQR, both p < 0.001. CONCLUSION: The omission of IND in those achieving an EQR nodal response does not compromise long-term survival. This supports the safety of extended surveillance in patients with HPV-positive disease and an EQR on 12-week FDG PET-CT.

Comparative cohort study of volumetric modulated arc therapy for squamous cell cancer of unknown primary in the head and neck-Involved neck only versus mucosal irradiation.

OBJECTIVES: Target volumes for irradiation remain ill-defined for squamous cell cancer of unknown primary in the head and neck (SCCUP). The aim of this study was to compare involved neck only (INO) radiotherapy (RT) with irradiating involved neck plus potential mucosal primary sites and contralateral neck (MUC) in patients diagnosed and treated with modern diagnostics and techniques. DESIGN: This is a retrospective cohort study. Patients with a diagnosis of SCCUP with unilateral neck disease were included. RESULTS: Thirty patients were identified. All underwent FDG PET-CT. 47% of patients had HPV-positive SCC. 20 patients received RT to INO, 10 patients to MUC, all with volumetric modulated arc therapy (VMAT). A significantly lower dose for each organ at risk was delivered in INO-treated patients, with mean dose to contralateral parotid gland 57% less. The proportion of patients with late grade 2 or worse xerostomia was higher in MUC patients. The incidence of grade 2-3 mucositis (89% vs 45%) and grade 3 or worse dysphagia (50% vs 10%) was higher in MUC patients. Median follow-up was 31 months. No mucosal primaries emerged. Progression-free survival at 2 years was 74.7% for INO patients, 70% in the MUC group. Overall survival at 2 years was 79.7% in the INO group and 70% in the MUC patients. CONCLUSION: INO radiotherapy for patients with SCCUP of the head and neck is a safe treatment strategy resulting in clinically significant lower RT doses to OARS. Acute and late toxicities are reduced without detriment to patient survival.

Dosimetric impact of organ at risk daily variation during prostate stereotactic ablative radiotherapy.

OBJECTIVE: Prostate stereotactic ablative radiotherapy (SABR) delivers large doses using a fast dose rate. This amplifies the effect geometric uncertainties have on normal tissue dose. The aim of this study was to determine whether the treatment dose-volume histogram (DVH) agrees with the planned dose to organs at risk (OAR). METHODS: 41 low-intermediate risk prostate cancer patients were treated with SABR using a linac based technique. Dose prescribed was 35 Gy in five fractions delivered on alternate days, planned using volumetric modulated arc therapy (VMAT) with 10X flattening filter free (FFF). On treatment, prostate was matched to fiducial markers on cone beam CT (CBCT). OAR were retrospectively delineated on 205 pre-treatment CBCT images. Daily CBCT contours were overlaid on the planning CT for dosimetric analysis. Verification plan used to evaluate the daily DVH for each structure. The daily doses received by OAR were recorded using the D%. RESULTS: The median rectum and bladder volumes at planning were 67.1 cm3 (interquartile range 56.4-78.2) and 164.4 cm3 (interquartile range 120.3-213.4) respectively. There was no statistically significant difference in median rectal volume at each of the five treatment scans compared to the planning scan (p = 0.99). This was also the case for median bladder volume (p = 0.79). The median dose received by rectum and bladder at each fraction was higher than planned, at the majority of dose levels. For rectum the increase ranged from 0.78-1.64Gy and for bladder 0.14-1.07Gy. The percentage of patients failing for rectum D35% < 18 Gy (p = 0.016), D10% < 28 Gy (p = 0.004), D5% < 32 Gy (p = 0.0001), D1% < 35 Gy (p = 0.0001) and bladder D1% < 35 Gy (p = 0.001) at treatment were all statistically significant. CONCLUSION: In this cohort of prostate SABR patients, we estimate the OAR treatment DVH was higher than planned. This was due to rectal and bladder organ variation. ADVANCES IN KNOWLEDGE: OAR variation in prostate SABR using a FFF technique, may cause the treatment DVH to be higher than planned.

12 week PET-CT has low positive predictive value for nodal residual disease in human papillomavirus-positive oropharyngeal cancers.

OBJECTIVES: Surveillance PET-CT scans at 12 weeks post-radiotherapy for head and neck cancer can be used to omit neck dissections with no detriment in overall survival. Human Papillomavirus (HPV) driven tumours behave differently on conventional imaging after radiotherapy but it is unknown if this effect is seen on PET-CT and if HPV status affects the accuracy of PET-CT. We aimed to determine the negative and positive predictive values (NPV and PPV) of 12 week surveillance PET-CT in HPV positive and negative tumours, and investigate predictors of relapse in equivocal responders. MATERIALS AND METHODS: A retrospective cohort study in a UK tertiary level oncology hospital, between 2013 and 2016 included adults with oropharyngeal squamous cell carcinoma, or HPV positive head and neck squamous cell cancers of unknown primary, treated with radiotherapy. RESULTS: The PPVs of 12 week PET-CT in HPV positive and negative disease are 30% and 81.8% respectively (p < 0.01). The NPVs of 12 week PET-CT in HPV positive and negative disease are 92.9% and 55.6% respectively (p < 0.01). 67% of HPV positive patients with equivocal responses on 12 week PET-CT achieved complete response by 24 weeks. Equivocal responses in HPV positive disease had statistically similar survival to patients with complete responses. Comparing disease and imaging characteristics, there were no predictors of residual tumour. CONCLUSIONS: HPV positive tumours have a poor PPV of 30% on 12 week surveillance PET-CTs and take longer to achieve complete response. A period of further surveillance can be considered instead of an immediate neck dissection in this group of patients.

Safety and feasibility of prostate stereotactic ablative radiotherapy using multimodality imaging and flattening filter free.

OBJECTIVE: To investigate feasibility and safety of stereotactic ablative radiotherapy in the management of prostate cancer while employing MR/CT fusion for delineation, fiducial marker seeds for positioning and Varian RapidArc with flattening filter free (FFF) delivery. METHODS: 41 patients were treated for low-intermediate risk prostate cancer with initial prostate-specific antigen of ≤20 ng ml-1, Gleason score 6-7. Patients had MR/CT fusion for delineation of prostate ±seminal vesicles. CT/MR fusion images were used for delineation and planned using flattening filter free modality. Verification on treatment was cone beam CT imaging with fiducial markers for matching. Patients had Radiation Therapy Oncology Group scoring for genitourinary and gastointestinal symptoms at baseline, week 4, 10 and 18. RESULTS: Clinically acceptable plans were achieved for all patients, all plans achieved the objective clinical target volume D99% ≥ 95%, and for planning target volume D95% ≥ 95%. Rectum dose constraints were met for 95.1% for V18 Gy ≤ 35%, 80% V28 Gy ≤ 10%. A total of 32 (78.0%) plans achieved all rectum dose constraints. Grade 1 acute genitourinary symptoms were 53.7% of patients at baseline, 90.2% [95% CI (76.8-97.3%)] (p = 0.0005) at treatment 5, falling to 78.0% (62.4-89.4%) at week 4, and 75.0% (58.8-87.3%) by week 10 and 52.5% (36.1-68.5%) (p = 1.00) at week 18. Acute gastrointestinal symptoms were 5% at baseline, 46.3% [95% CI (30.7-62.6%)] at treatment 5, week 4 43.9% [95% CI (28.5-60.3%)], week 10 25.0% (11.1-42.3%), and declined slightly by week 18 [-20.095% CI (12.7-41.2)] p = 0.039. Overall 75.6% (31/41) of patients experienced Grade 1-2 toxicity during or after treatment. CONCLUSION: This planning and delivery technique is feasible, safe and efficient. A homogeneous dose can be delivered to prostate with confidence, whilst limiting high dose to nearby structures. The use of this technology can be applied safely within further randomized study protocols. Advances in knowledge: Multimodality imaging for delineation and linac-based image-guided RT with FFF for the treatment of prostate stereotactic ablative radiotherapy.

Real-world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer.

OBJECTIVES: To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone-naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial. PATIENTS AND METHODS: Patients in the West of Scotland Cancer Network with newly diagnosed mPC were identified from the regional multidisciplinary team meetings and their treatment details were collected from electronic patient records. The rate of febrile neutropenia, hospitalisations, time to progression, and overall survival were compared between those patients who received docetaxel and androgen-deprivation therapy (ADT), or ADT alone using survival analysis. RESULTS: Of the 270 eligible patients, 103 received docetaxel (38.1%). 35 patients (34%) were hospitalised and there were 17 episodes of febrile neutropenia (16.5%). Two patients (1.9%) died within 30 days of chemotherapy. Patients who received ADT alone had an increased risk of progression (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.27-3.25; log-rank test, P = 0.002) and had an increased risk of death (HR 5.88, 95% CI: 2.52-13.72; log-rank test, P = 0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine-times greater if chemotherapy was started within 3 weeks of ADT initiation (95% CI: 1.22-77.72; P = 0.032). CONCLUSION: Docetaxel chemotherapy in hormone-naïve mPC has significant toxicities, but has a similar effect on time to progression and overall survival as seen in randomised trials. Chemotherapy should be started at ≥3 weeks after ADT.

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss.

BACKGROUND: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. METHODS: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. RESULTS: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. CONCLUSIONS: Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.

An assessment of cone beam CT in the adaptive radiotherapy planning process for non-small-cell lung cancer patients.

OBJECTIVE: To investigate the potential use of cone beam CT (CBCT) in adaptive radiotherapy (ART) planning process for non-small-cell lung cancer (NSCLC). METHODS: 17 retrospective patients with NSCLC Stage T1-T4, who had completed a course of radiotherapy with weekly CBCT imaging were selected for the study. The patients had been delineated and planned for three-dimensional (3D) conformal treatment (prescription: 55 Gy in 20 fractions) based on free-breathing four-dimensional CT data. Of these initial 17 patients, 12 had full quantitative data on gross tumour volume (GTV) position and volume throughout treatment. GTV delineation was carried out on weekly CBCT by a clinical oncologist. For each patient, mean percentage change in GTV and centre of mass (COM) displacement (based on 3D vectors) were calculated throughout treatment. Volume overlap between GTVs was calculated. Correlation of the COM displacement and planning GTV (pGTV) was assessed. A linear mixed model with patients as random effects was fitted to the data to assess potential benefit from using ART for these patients. RESULTS: Comparison of CBCT-based GTV acquired prior to Fraction 1 (cbctGTV1) to pGTV showed mean 20 ± 19% volume increase using a related sample Wilcoxon signed rank test p = 0.04. Correlation was identified between volume reductions and dose delivered (beta = -0.003, p < 0.001)-a highly statistically significant association. Compared with cbctGTV1, the mean ratios ± standard deviation were cbctGTV2, 0.93 ± 0.08; cbctGTV3, 0.84 ± 0.12; and cbctGTV4, 0.75 ± 0.14. The dice similarity coefficient was 0.81 ± 0.14, 0.78 ± 0.17, 0.73 ± 0.19, respectively. The COM was consistent throughout treatment (mean 0.35 ± 0.24 cm). A fitted model predicts that a mean change of 30% volume relative to cbctGTV1 occurs at a dose of approximately 50 Gy. CONCLUSION: Using a 30% reduction in volume, ART would not be of benefit for all radiotherapy-alone-treated patients with NSCLC assessed in this study. For individual patients and patients with atelectasis, CBCT imaging was able to identify volume change. ADVANCES IN KNOWLEDGE: For patients treated with 55 Gy in 20 fractions, target volume changes throughout treatment have been demonstrated using CBCT and can be used to highlight patients who may benefit from ART.