Treatment response biomarkers: working towards personalised radiotherapy for lung cancer.

Due to major advances in the field of radiation oncology, patients with lung cancer (LC) can now receive technically individualised radiotherapy treatments. However, in the era of precision oncology, radiotherapy-based treatment selection needs to be improved as many patients do not benefit or are not offered optimum therapies. Cost-effective robust biomarkers can address this knowledge gap and lead to individuals being offered more bespoke treatments leading to improved outcome. This narrative review discusses some of the current achievements and challenges in the realisation of personalised radiotherapy delivery in patients with LC.

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol.

BACKGROUND: Recent evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as this results in better neurocognitive preservation compared to whole brain radiotherapy. However, there is often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, delivers a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrated boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes. This technique is abbreviated to HA-SIB-WBRT or HA-WBRT+SIB. METHODS: We hypothesise that the SIB in HA-SIB-WBRT (experimental arm) will result in better tumour control compared to HA-WBRT (control arm). This may also lead to better intracranial disease control as well as functional and survival outcomes. We aim to conduct a prospective randomised phase II trial in patients who have good performance status, multiple brain metastases (4-25 lesions) and a reasonable life expectancy (> 6 months). These patients will be stratified according to the number of brain metastases and randomised between the 2 arms. We aim for a recruitment of 100 patients from a single centre over a period of 2 years. Our primary endpoint is target lesion control. These patients will be followed up over the following year and data on imaging, toxicity, quality of life, activities of daily living and cognitive measurements will be collected at set time points. The results will then be compared across the 2 arms and analysed. DISCUSSION: Patients with brain metastases are living longer. Maintaining functional independence and intracranial disease control is thus increasingly important. Improving radiotherapy treatment techniques could provide better control and survival outcomes whilst maintaining quality of life, cognition and functional capacity. This trial will assess the benefits and possible toxicities of giving a SIB to HA-WBRT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04452084 . Date of registration 30th June 2020.

Which patients benefit most from stereotactic body radiotherapy or surgery in medically operable non-small cell lung cancer? An in-depth look at patient characteristics on both sides of the debate.

The role of stereotactic body radiotherapy (SBRT) in early stage medically operable non-small cell lung cancer is currently under debate. SBRT's advantage is its ability to provide high radiotherapy doses to a tumor in a short timeframe, without the risk of postoperative complications and mortality. Currently, in part due to limited prospective data comparing both treatments, international guidelines continue to recommend surgical resection as the gold standard for medically operable patients. However, not all patients possess uniform characteristics, and there is some evidence that certain subgroups of patients would benefit more from one form of treatment - SBRT or surgery - than the other. The aim of this review is to provide a brief summary of the evidence comparing SBRT to surgery, followed by a deeper discussion of the subgroups of patients who would benefit most from surgery: those with large tumors, centrally located tumors, increased risk of occult nodal metastases, increased risk of toxicity from radiotherapy and radioresistant histological tumor subtypes. Meanwhile, patients who could benefit most from SBRT might include elderly patients, those with reduced lung function or cardiac comorbidities, those with synchronous lung nodules, and those with specific tumor mutational status. We hope that this review will aid in the clinical decision-making process regarding patient selection for either treatment.

Are heart doses associated with survival in patients with non-small cell lung cancer who received post-operative thoracic radiotherapy?: A national population-based study.

The aim of this retrospective national cohort study is to assess the association between various radiation heart dosimetric parameters (RHDPs), acute myocardial infarct (AMI) and overall survival (OS) outcomes in non-small cell lung cancer (NSCLC) patients treated with post-operative thoracic radiotherapy (PORT) using contemporary radiation techniques.We identified patients with stage I to III NSCLC treated with PORT at the 2 national cancer institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. Univariable Cox regression was performed to assess the association between various RHDPs, AMI, and OS.We included 43 eligible patients with median follow-up of 36.6 months. Median age was 64 years. Majority of the patients had pathological stage III disease (72%). Median prescription dose was 60Gy. Median mean heart dose (MHD) was 9.4Gy. There were no AMI events. The 5-year OS was 34%. Univariable Cox regression showed that age was significantly associated with OS (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P = .008). Radiation heart doses, including MHD, volume of heart receiving at least 5, 25, 30, 40, 50Gy and dose to 30% of heart volume, were not significantly associated with OS.There is insufficient evidence to conclude that RHDPs are associated with OS for patients with NSCLC treated with PORT in this study. Studies with larger sample size and longer term follow-up are needed to assess AMI outcome.

Intra-patient and inter-patient comparisons of DNA damage response biomarkers in Nasopharynx Cancer (NPC): analysis of NCC0901 randomised controlled trial of induction chemotherapy in locally advanced NPC.

BACKGROUND: Inter-patient heterogeneity in radiation-induced DNA damage responses is proposed to reflect intrinsic variations in tumour and normal tissue radiation sensitivity, but the prediction of phenotype by a molecular biomarker is influenced by clinical confounders and assay reproducibility. Here, we characterised the intrapatient and inter-patient heterogeneity in biomarkers of DNA damage and repair and radiation-induced apoptosis. METHODS: We enrolled 85 of 172 patients with locally advanced nasopharynx cancer from a randomised controlled phase II/III trial of induction chemotherapy added to chemo-radiotherapy. G0 blood lymphocytes were harvested from these patients, and irradiated with 1, 4, and 8 Gy ex vivo. DNA damage induction (1 Gy 0.5 h) and repair (4 Gy 24 h) were assessed by duplicate γH2AX foci assays in 50-100 cells. Duplicate FLICA assays performed at 48 h post-8 Gy were employed as surrogate of radiation-induced apoptosis; %FLICA-positive cells were quantified by flow cytometry. RESULTS: We observed limited intrapatient variation in γH2AX foci and %FLICA readouts; median difference of duplicate foci scores was - 0.37 (IQR = - 1.256-0.800) for 1 Gy 0.5 h and 0.09 (IQR = - 0.685-0.792) for 4 Gy 24 h; ICC of ≥0.80 was observed for duplicate %FLICA0Gy and %FLICA8Gy assays of CD4+ and CD8+ T lymphocytes. As expected, we observed wide inter-patient heterogeneity in both assays that was independent of intrapatient variation and clinical covariates, with the exception of age, which was inversely correlated with %FLICAbackground-corrected (Spearman R = - 0.406, P < 0.001 [CD4+]; R = - 0.220, P = 0.04 [CD8+]). Lastly, an exploratory case-control analysis indicates increased levels of γH2AX foci at 4 Gy 24 h in patients with severe late radiotherapy-induced xerostomia (P = 0.05). CONCLUSION: Here, we confirmed the technical reproducibility of DNA damage response assays for clinical implementation as biomarkers of clinical radiosensitivity in nasopharynx cancer patients.

Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE) radiotherapy improved tumor control and survival in GBM patients. METHODS: We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction) and conventional doses (60 Gy), respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ) were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. RESULTS: Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS) of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0-18.6), while median OS of the latter cohort was 18.4 months (95% CI =12.5-31.4, P=0.253). Univariate analyses of clinical and dosimetric parameters among the DE cohort demonstrated a trend of longer progression-free survival, but not OS, with incremental radiation doses to the ipsilateral SVZ (hazard ratio [HR] =0.95, 95% CI =0.90-1.00, P=0.052) and proportion of ipsilateral SVZ receiving 50 Gy (HR =0.98, 95% CI =0.97-1.00, P=0.017). CONCLUSION: DE radiotherapy did not improve survival in patients with GBM. Incorporation of ipsilateral SVZ as a radiotherapy target volume for patients with GBM requires prospective validation.

The diverse and complex roles of radiation on cancer treatment: therapeutic target and genome maintenance.

Cancer is a genetic disease, grows exponentially with the development of intrinsic and acquired treatment resistance. Past decade has witnessed a considerable progress towards the treatment and understanding of proposed hallmarks of cancer and together with advances in early detection and various treatment modalities. Radiation therapy is an integral part of cancer treatment armamentarium. In developed countries more than half of all cancer patients receive radiation therapy during their course of illness. Although radiation damages both cancer and normal cells, the goal of radiation therapy is to maximize the radiation dose to abnormal cancer cells while minimizing exposure to normal cells, which is adjacent to cancer cells or in the path of radiation. In recent years, life expectancy increases among cancer patients and this increase is due to the results of early diagnosis, screening efforts, improved treatments and with less late effects mostly secondary cancer development. Therefore, cancer survivorship issues have been gaining prominence in the area of radiation oncology research. Understanding the tradeoff between the expected decreases in normal tissue toxicity resulting from an improved radiation dose distribution to the targeted site is an increasingly pertinent, yet needed attention and research in the area of radiation oncology. In recent years, a number of potential molecular targets that involve either with radiation increased tumor cell killing or protecting normal cells have been identified. For clinical benefits, translating these findings to maximize the toxicity of radiation on tumor cells while safeguarding early or late normal cell toxicities using molecular targeted radioprotectors will be useful in radiation treatment.