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.
Abstract Aims: Emerging evidence in viral-associated oro- and naso-pharynx cancers supports the concept of radiotherapy (RT) dose de-intensification in these radiosensitive tumours. This notion is particularly relevant in the background that a majority of head and neck cancer patients develop severe late toxicities despite modern precision RT. A reasonable strategy could thus entail stratifying patients at risk of late toxicities to dose de-intensification. Here, we investigated the utility of a lymphocyte apoptosis (RILA) assay to predict for late toxicities in EBV-positive nasopharynx cancer patients. We also test if a multi-modal approach incorporating DNA damage induction and repair improves the prediction of clinical radiosensitivity. Methods: Assays were assessed retrospectively among survivors of a randomised controlled trial (NCC-0902), where patients were assigned to weekly cisplatin-RT with or without neoadjuvant gemcitabine, carboplatin, and paclitaxel. Late toxicities were assessed by CTCAE v.2 at the following intervals - 2-mo year 1, 4-mo year 2, 6-mo years 3-5, and annually thereafter; and considered severe if CTCAE v.2 ≥Grade 2. RILA was based on a fluorogenic inhibitor of caspases assay (48 h post-8 Gy). DNA damage induction and repair were assessed by semi-automated scoring of ϒH2AX foci at 30 min post-1 Gy and 24 h post-4 Gy, respectively. Results: Median follow-up of patients was 5.7 (range 4.6-7.4) years. Clinical and treatment indices, including assigned study arm and RT dosimetry to normal tissue structures, were balanced between patients with and without late toxicities (p >0.05). We observed a trend between decreasing RILA scores and increased risks of late toxicities; odds ratio (OR) 1.27 (95% CI = 0.92-1.72) for lowest quartile cut-off, corresponding to an AUC of 0.608 for prediction accuracy (p = 0.049). A multi-modal approach incorporating DNA damage induction and repair did not improve upon the predictive accuracy of RILA for clinical radiosensitivity. Independently, DNA damage induction and repair were not associated with risks of late toxicities; OR 1.03 (95% CI = 0.69-1.53, p = 0.901) and 1.04 (95% CI = 0.73-1.49, p = 0.829), respectively. Interestingly, onset of late toxicities was correlated to an improved disease-free survival in our cohort (5-y DFS = 94.1% vs 73.3%, no late toxicity, p = 0.003), which suggests a common mechanism underlying tumour and normal tissue radiosensitivity in EBV-positive nasopharynx cancer. Conclusions: Herein, we report on the potential utility of a RILA assay in stratifying for patients at risk of late RT-induced toxicities. The clinical implication of this assay is further exemplified by the observation of a superior survival in these sensitive individuals, which supports the approach of selecting this subgroup for treatment de-intensification. Citation Format: Kevin L.M. Chua, Shihabuddeen Waseem Ahamed, Ma Than Than Shwe, Li-lian Kwok, Joseph T.S. Wee, Terence W.K. Tan, Prakash M. Hande, Kai Rothkamm, Melvin L.K. Chua. Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer [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 1794. doi:10.1158/1538-7445.AM2017-1794
Abstract 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.
Comprehensive molecular characterisation of muscle-invasive urothelial carcinoma and variant histological subtypes has led to the identification of recurrent driver mutations that are distinct in these aggressive subgroups of bladder cancer. While distant metastasis dominates as a pattern of relapse following radical cystectomy or chemoradiotherapy, loco-regional control rates are also suboptimal with single modality local treatment, and likewise, harbour equivocal implications on the long-term prognosis of patients. The role of adjuvant radiotherapy for optimising disease control within the pelvis is controversial, with limited evidence to support its efficacy. Herein, we present a stepwise review on adjuvant radiotherapy post-cystectomy; first, discussing the evidence to date supporting the concept that adjuvant radiotherapy is effective in targeting occult metastases within the pelvis, and adds to the benefits of adjuvant chemotherapy. Next, we outlined the principles underlying the definition of radiotherapy target volumes. To conclude, we addressed the need for appropriate patient stratification for treatment intensification, based on existing clinical models and novel molecular indices of aggression in muscle-invasive urothelial cancers and variant histological subtypes.
Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB.Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N=10). All patients received ablative RT (8-50Gy/1-5fr) for oligoprogression and/ or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools.Results: Median follow-up of the overall cohort was 18mo; median duration of ICB received in the ICB-RT-ICB arm was 15mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/ effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P<0.01). This clinical phenomenon corresponded to an increased %Ki67high CD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P<0.01). Deeper immunophenotyping of the Ki67high subsets revealed associated high expression of GranzymeB and Eomes.Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB.Citation Format: Kevin L. Chua, Michael Fehlings, Pek Lim Chu, Xiao-Tian Lin, Eugenia Yeo, Kar Perng Low, Dennis Poon, Enya Ong, Wai Yee Woo, Joseph Wee, Alessandra Nardin, Gopalakrishna Iyer, Daniel S. Tan, Kee Chee Soo, Evan Newell, Melvin Chua. High-dimensional profiling of the systemic immune response informs on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 527.
149 Background: Curative treatment for unresectable LA NSCLC comprises chemoradiotherapy (CRT) and immunotherapy (IO). However, this uniform approach does not take into account the intrinsic heterogeneity of NSCLC and nearly half of all pts relapse within the first year. This highlights the need to define distinct molecular and phenotypic subgroups of LA NSCLC so that we can interrogate the divergent responses to CRT-IO and identify biomarkers that can guide pt specific strategies. Methods: Consecutive pts treated with CRT +/- IO from May 2010 and recruited to an observational study were retrospectively analysed (N = 336). All pts with adenocarcinoma (ADC) were subject to reflex molecular profiling including NGS and FISH testing for ALK, ROS1, MET and RET. Of note, tracking of bespoke circulating tumour DNA (ctDNA) levels was performed for 25 pts. Plasma samples were collected at longitudinal timepoints pre, during and post CRT (N = 118; median 5 samples/ pt). WES of biopsies and matched normal DNA was used to design tumour informed ctDNA assays to track 16 single nucleotide variants in plasma samples. ctDNA levels were then quantified as mean tumour molecule per mL (MTM/mL). Primary endpoint was progression free survival (PFS). Results: Median age was 61 (IQR 48, 74). Of 336 pts, 74% were male; 32% never smokers; 54% were ADC, 33% squamous cell carcinoma (SCC); 18% had EGFR mutations (EGFRm), 37%EGFR wild type (EGFRw), 40% unknown EGFR status (EGFRu), 5% ALK rearranged, 1% ROS1 rearranged. At median follow-up of 44 months (m), median PFS for the entire cohort was 16.2m. Pts who received consolidation IO had longer PFS [IO, not reached vs no IO, 14.9m; P = 0.05]. Median PFS was shorter for pts with EGFRm [EGFRm, 13m vs EGFRw, 22.5m vs EGFRu, 15.8m]. Patterns of failure were analysed according to local in-field, regional out-field and distant. EGFRm pts were less likely to fail locally in-field [EGFRm, 12% vs EGFRw,18% vs EGFRu, 28%] and significantly more likely to develop distant metastases as first site of failure post CRT [EGFRm, 51% vs EGFRw, 28% vs EGFRu, 19%; P = 0.01]. For the 25 pts with ctDNA analysed, 24 pts had evaluable ctDNA post CRT. Significant heterogeneity was noted at baseline pre CRT [EGFRm, 6.45 vs EGFRw, 7.49 vs SCC, 37.67 MTM/mL; P = 0.05]. No difference was noted in PFS between pts with high vs low baseline ctDNA. Of note, 14 of 24 (58%) pts achieved undetectable ctDNA post CRT and had significantly longer PFS [undetectable, 24.1m vs detectable, 3.5m; P = 0.02]. Conclusions: Here, we demonstrate distinct phenotypic responses to CRT based on molecular subtypes of NSCLC. Crucially, we demonstrate clinical feasibility of deploying tumour-informed ctDNA assays in LA NSCLC with detection of ctDNA post CRT serving as a potential actionable biomarker to guide intensification strategies, providing a window into developing patient-specific combinatorial approaches.
Abstract Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET , and fusions involving ALK and RET . We term these “non-smoking-related oncogenes” (NSROs). In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers, and the clonal architecture and genomic landscape of these tumors remain unknown. We investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. NSRO-driven NSCLCs in smokers and non-smokers have similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle, suggesting that smoking still affects tumor phenotype independently of genomic alterations. Statement of significance This study highlights the lack of genomic scars caused by smoking in NSCLCs driven by non-smoking-related oncogenes regardless of smoking history. The impact of smoking on these tumors is mainly non-genomic. The transcriptomic features of NSCLCs associated with smoking may help in the development of therapeutic approaches.
Abstract: Intracranial hemangiopericytomas (HPC) are chemotherapy- and radiotherapy (RT)-resistant. Here, we report on a novel stereotactic radiosurgery (SRS) technique—“Cor Occidere” (Latin), as a potential strategy of overcoming radioresistance of HPC. A 36-year old female presented to our clinic for consideration of a 3rd-course of RT for her recurrent cavernous sinus HPC, following previous cranial RT at 13 and 5 years prior, and a failed 9 months trial of bevacizumab/temozolomide. The tumor-adjacent brain stem and carotid artery risked substantial damage given the cumulative RT doses to these organs. We therefore designed an SRS plan targeting only the tumor core with 16 Gy single-fraction. Despite underdosing the tumor margin, we achieved stable disease over 25 months, contrasting her responses to systemic therapies. Achieving tumor control despite a suboptimal treatment that utilized high dose ablation of the tumor core suggests novel biological mechanisms to overcome radioresistance of HPC.
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