Identification of dose constraints and evaluation of optimal planning technique for radical thoracic re-irradiation for non-small cell lung cancer

Background There are approximately 48,000 new diagnoses of lung cancer in the United Kingdom. It is one of the most lethal cancers, with a 10% chance of survival at 10 years. A third of patients receive radiotherapy a part of the primary treatment for lung cancer. However, there is an approximately 30% local recurrence rate after radical radiotherapy for non-small cell lung cancer, and there is a 14% risk at 10 years of developing a second lung cancer. There are no treatment guidelines for patients who are diagnosed with intra-thoracic relapsed disease. Radical thoracic re-irradiation for non-small cell lung cancer has been performed in selected patients from the 1970s with promising efficacy. However, re-irradiation is associated with increased risk of toxicity compared to de novo radiotherapy. Re-irradiation is being delivered more frequently due to the advances in radiotherapy technology and better detection of recurrent disease, despite the lack of evidence in how to deliver re-irradiation safely, or any recent prospective studies that demonstrate efficacy. Aim of thesis The aim of this thesis is to investigate how to optimise the safety of radical thoracic re-irradiation, in preparation for a future prospective clinical trial. Methods (i) An international Delphi consensus process with thoracic oncologists was performed to identify current practice in thoracic re-irradiation, patient selection, develop dose constraints and radiotherapy planning strategies. (ii) A retrospective review of 39 patients who underwent re-irradiation in the Beatson West of Scotland cancer centre was conducted. Clinical outcomes and cumulative dosimetric information were analysed. Image and dose registration strategies were developed to account for the previous dose delivered from initial radiotherapy with the re-irradiation dose. (iii) A literature review was performed to collect information (including toxicity, cumulative dose, interval between treatments and use of chemotherapy) about thoracic re-irradiation. This was divided into five datasets for the organs at risk in the chest (spinal cord, oesophagus, lungs, proximal bronchial tree, and aorta) and logistic regression modelling was performed to determine cumulative dose constraints. (iv) A literature review was performed to collect information (including cumulative dose, local control, and overall survival rates) from thoracic re-irradiation for non-small cell lung cancer. Logistic regression modelling was performed to determine the dose required for 50% rates of 2-year local control and overall survival. (v) A radiotherapy planning study using the 39 Beatson patients was conducted using volumetric arc therapy (VMAT) and multi-criteria optimisation (MCO). Patients were re planned to the cumulative dose constraints and the models developed in sections (iii) and (iv) were applied to assess if the re-planned re-irradiation was safer. (vi) Patients who had completed a course of radical lung radiotherapy were recruited into a qualitative interview study to explore patients’ perspectives on re-irradiation. The interviews were transcribed and underwent thematic analysis. Results (i) Fifteen lung oncologists participated in the Delphi process. Patients being considered for radical re-irradiation should be PS 0-2, and radical resection should be discussed. Staging with PET-CT and brain imaging was endorsed. Consensus dose constraints based on clinician expertise were agreed upon for the oesophagus, spinal cord, brachial plexus and aorta. There was no consensus for lung and proximal bronchial tree doses. (ii) Clinical outcomes and cumulative dose of 39 patients from the Beatson were analysed and divided into patients with local recurrence and second primary lung cancers. The 2-year OS rate was 38.5% in the local recurrence group, and 69.2% in the SPLC group. Sixteen patients (41%) experienced grade 3 toxicities and one patient (2.6%) had fatal haemoptysis. A reproducible process to accumulate dose was developed, which identified that using the whole lung for image registration was the optimal strategy. (iii) The literature search identified 55 studies with the cumulative dose and toxicity required for modelling. Dose/toxicity models were developed using logistic regression for the spinal cord, oesophagus, the mean lung dose, the lung V20Gy, the proximal bronchial tree and aorta. There was insufficient data to model the heart, chest wall and brachial plexus dose. For the spinal cord, oesophagus, proximal bronchial tree and aorta, the maximum likelihood 5% risk of grade 3 toxicity was seen at 77.2Gy, 94.3Gy, 157.5Gy and 142.5Gy respectively (all doses in equivalent dose in 2-Gray fractions, median values used if other variables were included in the model). The mean lung dose and V20Gy associated with 20% grade 3 toxicity were 19.3Gy and 28.4% respectively. These models were validated on the Beatson data, and dose constraints developed. (iv) The literature search identified 21 studies with 2-year local control or overall survival data and cumulative dose to the tumour. Dose/outcome models were developed using logistic regression modelling. The modelling predicted a 50% 2-year local control rate at 67.8Gy using a median planning target volume of 112cc. The predicted dose to the tumour for a 50% 2-year overall survival rate was 76.5Gy. A sub-study to assess if 13 locally recurrent patients from the Beatson cohort could have dose escalation identified six patients where their re-irradiation dose could potentially be increased. (v) The planning study identified 15 patients from the 39 patients in the Beatson cohort that breached the re-irradiation dose constraints. These patients mostly had locally recurrent disease. Seven patients were replanned using VMAT and MCO and met the dose constraints. The remaining eight patients required alternate strategies (such as a change in dose fractionation or modification of the planning target volume) to meet the constraints. Six patients were able to be safely replanned with these alternate strategies. The combination of VMAT and MCO was superior to VMAT alone when planning re-irradiation for sparing the serial organs at risk in the chest. (vi) Eight patients participated in a qualitative interview exploring their perspectives on radical re-irradiation. Thematic analysis identified two main themes from the interviews: fear and control. The key finding was that all patients would consider re-irradiation. A common reason given was they were not afraid of it having experienced radiotherapy before. Each patient had a very different attitude to risk, with some patients stating that they would accept high risk treatment if the outcomes were better, whereas others preferred to prioritise avoiding toxicity. Conclusions The research detailed in this thesis contributes to the delivery of safe re-irradiation in several ways. The consensus statements provided guidance for the selection and staging of patients to be considered for radical re-irradiation, ensuring that only suitable patients proceed with high-risk treatment. The dose constraints developed from the dose/toxicity can be used to limit severe re-irradiation toxicity and allows patients to be better counselled prior to treatment. The dose/outcome study identified that recurrent disease required higher doses for disease control, and that dose escalation may be possible in selected patients. The planning study identified that the optimal planning technique is VMAT with MCO. The qualitative study demonstrated that patients may consider re-irradiation and require individual counselling regarding their acceptance of risk. This research provides insights to the inclusion criteria, dose constraints, radiotherapy planning technique and the patient and public involvement necessary for a prospective clinical study of re-irradiation

C.H.E. Det Optimisme, disiplin dan wawasan

Optimisme, disiplin dan wawasan. Tiga perkataan ini cukup untuk menggambarkan kualiti beliau. Optimisme – kepercayaan teguh beliau bahawa cita-cita yang diisi akan menatijahkan kejayaan, dan tanpa pengisian, cita-cita tersebut sekadar tinggal angan-angan. Disiplin – tunjang prinsip beliau bahawa usaha ke arah kecemerlangan menuntut sikap dan watak yang khusus, dan tanpa disiplin, kegagalan pasti menanti. Wawasan – pandangan jauh beliau bahawa kejayaan sebenar terletak kepada keupayaan untuk melestarikan pencapaian di atas garis masa yang panjang. 87 tahun usia yang bakal dilewati tanggal 20 Disember kelak, dan tiga kualiti ini – DISIPLIN, OPTIMISME dan WAWASAN terus segar mendasari penyandang keempat jawatan Perdana Menteri Malaysia, Tun Dr. Mahathir Mohamad

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. Subjects/patients and Methods: Patients in the West of Scotland Cancer Network (WoSCAN) with newly diagnosed mPC were identified from the regional multidisciplinary team (MDT) 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: Out of 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 (HR 2.03, 95% 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 p=0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine times greater if chemotherapy was started within three 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 3 weeks or more after androgen deprivation

Radiotherapy-induced xerostomia: a randomised, double-blind, controlled trial of Visco-ease™ oral spray compared with placebo in patients with cancer of the head and neck

Radiotherapy-induced xerostomia (RIX) is a common and untreatable side effect of radiotherapy to the head and neck. Visco-ease™ mouth spray (Lamellar Biomedical Ltd), a new product that is made from lamellar body mimetics, reduces the viscosity of saliva ex vivo. The purpose of this study was to evaluate its safety and effectiveness in the treatment of RIX in 43 patients with cancer of the head and neck. They were randomised into the Visco-ease™ or placebo groups, and asked to complete the Groningen radiotherapy-induced xerostomia (GRIX) questionnaire each week. The primary endpoint was a change in GRIX score from baseline to end of treatment. There was no difference in scores between the two groups, and none of the patients had device-related serious adverse events. Visco-ease™ oral spray was safe and tolerable but no better than placebo in reducing RIX in this group of patients

Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours

Background: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. Methods: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). Results: Seventy-three patients received BAL101553 at doses of 15–80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. Conclusions: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties. Clinical trial registration: EudraCT: 2010-024237-23

An international expert survey on the indications and practice of radical thoracic reirradiation for non-small cell lung cancer

Purpose: Thoracic re-irradiation for non-small cell lung cancer (NSCLC) with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating NSCLC with radiotherapy in the setting of prior thoracic irradiation. Methods and materials: Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined over four rounds on the definition of re-irradiation, appropriate patients and pre-treatment assessments, planning of radiotherapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents’ comments and re-presented in subsequent rounds. Results: Fifteen radiation oncologists participated in the four surveys between September 2019 and March 2020. The first three rounds had a 100% response rate, and the final round was completed by 93% of participants. 33 out of 77 statements across all rounds achieved consensus. Key recommendations are: (1) appropriate patients should have a good performance status, can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude re-irradiation; (2) a full diagnostic work-up should be performed in patients with suspected local recurrence and; (3) any re-irradiation should be delivered using optimal image-guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described. Conclusion: These consensus statements provide practical guidance on appropriate patient selection for re-irradiation, appropriate radiotherapy techniques, and cumulative dose constraints

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

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. 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. 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. 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