Rising cancer incidence combined with improvements in systemic and local therapies extending life expectancy are translating into more patients with spinal metastases. This makes the ...multidisciplinary management of spinal metastases and development of new therapies increasingly important. Spinal metastases may cause significant pain and reduced quality of life and lead to permanent neurological disability if compression of the spinal cord and/or nerve root occurs. Until recently, treatments for spinal metastases were not optimal and provided temporary local control and pain relief. Spinal stereotactic ablative radiotherapy (SABR) is an effective approach associated with an improved therapeutic ratio, with evolving clinical application.
To review the literature of spinal SABR for spinal metastases, discuss a multidisciplinary approach to appropriate patient selection and technical considerations, and summarize current efforts to combine spinal SABR with systemic therapies.
The MEDLINE database was searched to identify articles reporting on spinal SABR to September 30, 2018. Articles including clinical trials, prospective and retrospective studies, systematic reviews, and consensus recommendations were selected for relevance to multidisciplinary management of spinal metastases.
Fifty-nine unique publications with 5655 patients who underwent SABR for spinal metastases were included. Four comprehensive frameworks for patient selection were discussed. Spinal SABR was associated with 1-year local control rates of approximately 80% to 90% in the de novo setting, greater than 80% in the postoperative setting, and greater than 65% in the reirradiation setting. The most commonly discussed adverse effect was development of a vertebral compression fracture with variable rates, most commonly reported as approximately 10% to 15%. High-level data on the combination of SABR with modern therapies are still lacking. At present, 19 clinical trials are ongoing, mainly focusing on combined modality therapies, radiotherapy prescription dose, and oligometastic disease.
These findings suggest that spinal SABR may be an effective treatment option for well-selected patients with spinal metastases, achieving high rates of local tumor control with moderate rates of adverse effects. Optimal management should include review by a multidisciplinary care team.
Despite the rapidly evolving treatment landscape in advanced non-small-cell lung cancer (NSCLC), developments in neoadjuvant and adjuvant treatments have been nascent by comparison. Establishing ...overall survival benefit in the early-stage setting has been challenging because of the need for large trials and long-term survival data. Encouraged by improved treatment outcomes with a biomarker-driven approach in advanced NSCLC, and recognising the need to improve survival outcomes in early-stage NSCLC, there has been renewed interest in revisiting neoadjuvant strategies. Multiple neoadjuvant trials with targeted therapy and immunotherapy, either alone or in combination with chemotherapy, have yielded unique insights into traditional response parameters, such as the discordance between RECIST response and pathological response, and expanded opportunities for biomarker discovery. With further standardisation of trial endpoints across studies, coupled with the implementation of novel technologies including radiomics and digital pathology, individual risk-stratified neoadjuvant treatment approaches are poised to make a striking impact on the outcomes of early-stage NSCLC.
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•We reported our efficacy and safety results of apatinib for rmNPC.•Apatinib yielded 31.4% ORR and 74.3% DCR, which was comparable to other VEGFR TKIs.•We observed long-term ...responders among patients with low EBV DNA pre-apatinib.•G3 toxicities were low, although dose modification was required in 43% of patients.
There is no standard-of-care for recurrent, metastatic nasopharyngeal carcinoma (rmNPC) after first-line chemotherapy. Here, we report the efficacy and safety data of apatinib in rmNPC patients.
Thirty-five biopsy-proven rmNPC patients received apatinib at 500 mg/day under a compassionate access programme. Primary end-point was objective response rate (ORR; RECIST v1.1). Kaplan-meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Toxicity was assessed by CTCAE v4.0.
82.9% (29 of 35) of patients had poly-metastatic rmNPC. All patients, except five, were platinum-refractory; 37.1% (13 of 35) received ≥ 2 lines. Median number of apatinib cycles was 4.0 (IQR: 2.0–8.0). ORR was 31.4% (11 of 35 95% CI: 16.9–49.3) and disease control rate was 74.3% (26 of 35 95% CI: 56.7–87.5); 11 (31.4%) and 4 (11.4%) patients demonstrated response for ≥ 6 and ≥ 12 months, respectively. Median PFS and OS was 3.9 (95% CI: 3.1–5.5) months and 5.8 (95% CI: 4.5–8.0) months, respectively. Among the ≥ 12-month responders, all patients had pre-apatinib EBV DNA titer of <700 (range: 353–622) copies/ml; this was consistent with the association of PFS with pre-apatinib EBV DNA titer (adjusted HR 3.364 95% CI: 1.428–7.923 for ≥ 4000 copies/ml, P = 0.006). 42.9% (15 of 35) of patients required dose reduction. Nonetheless, only five (14.3%) patients suffered from G3 toxicities (two haematological, one hypertension, one hand-foot syndrome and one elevated aminotransferases).
Our data suggests potential efficacy of apatinib in rmNPC patients. Although incidence of severe toxicities was low, dose modification was required in 42.9% of patients.
Stage III NSCLC represents a heterogeneous disease for which optimal treatment continues to pose a clinical challenge. Recent changes in the American Joint Commission on Cancer staging to the eighth ...edition has led to a shift in TNM stage grouping and redefined the subcategories (IIIA–C) in stage III NSCLC for better prognostication. Although concurrent chemoradiotherapy has remained standard-of-care for stage III NSCLC for almost 2 decades, contemporary considerations include the impact of different molecular subsets of NSCLC, and the roles of tyrosine kinase inhibitors post-definitive therapy and of immune checkpoint inhibitors following chemoradiotherapy. With rapid evolution of diagnostic algorithms and expanding treatment options, the need for interdisciplinary input involving multiple specialists (medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists and thoracic surgeons) has become increasingly important. The unique demographics of Asian NSCLC pose further challenges when applying clinical trial data into clinical practice. This includes differences in smoking rates, prevalence of oncogenic driver mutations, and access to health care resources including molecular testing, prompting the need for critical review of existing data and identification of current gaps. In this expert consensus statement by the Asian Thoracic Oncology Research Group, an interdisciplinary group of experts representing Hong Kong, Korea, Japan, Taiwan, Singapore, Thailand, Malaysia, and Mainland China was convened. Standard clinical practices for stage III NSCLC across different Asian countries were discussed from initial diagnosis and staging through to multi-modality approaches including surgery, chemotherapy, radiation, targeted therapies, and immunotherapy.
Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host ...systemic immune system has not been elucidated.
In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry–based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses.
Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype.
Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies.
Traditional endpoints such as progression-free survival and overall survival do not fully capture the pharmacologic and pharmacodynamic effects of a therapeutic intervention. Incorporating ...mechanism-driven biomarkers and validated surrogate proximal endpoints can provide orthogonal readouts of anti-tumor activity and delineate the relative contribution of treatment components on an individual level, highlighting the limitation of solely relying on aggregated readouts from clinical trials to facilitate go/no-go decisions for precision therapies.
•We present here consensus guidelines on the diagnosis and management of radiation pneumonitis (RP).•These consensus guidelines serve as a practical guide for clinicians in assessing RP risk in ...individual patients.•These guidelines represent areas of agreement amongst radiation oncology and pulmonary experts from a Delphi consensus study.•Future work should clarify the relationship between radiation- and drug-induced pneumonitis and optimal management strategies.
Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study.
In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3.
Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease.
This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.
Background
In early‐stage non–small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for ...recurrence after curative intent therapy. This study aimed to risk stratify patients with early‐stage NSCLC via a personalized, tumor‐informed multiplex polymerase chain reaction (mPCR) next‐generation sequencing assay.
Methods
This retrospective cohort study included patients with stage I–III NSCLC. Recruited patients received standard‐of‐care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole‐exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient‐specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single‐nucleotide variants in plasma samples.
Results
The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence‐free survival (RFS; hazard ratio HR, 3.54; 95% confidence interval CI, 1.00–12.62; p = .009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0–12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63–158.9; p < .0001).
Conclusions
ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early‐stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.
Circulating tumor DNA (ctDNA) detection before surgical resection was strongly associated with a high risk of relapse in early‐stage non–small cell lung cancer in a large unique Asian cohort. In addition, ctDNA detection longitudinally after surgery identified patients who recurred, with ctDNA positivity preceding radiological findings.
•Vandetanib enhanced PDT-mediated cytotoxicity through the impairment of NHEJ repair of DNA double strand breaks.•Vandetanib inhibits PDT-induced EGFR-mediated DNA-PKcs activation.•Vandetanib + PDT ...modulates tumour microenvironment through vasculature shutdown, coupled with inhibition of EGFR signalling.•MAPK-ERK1/2 pathway is a potential target to overcome the eventual tumour regrowth post-vandetanib + PDT treatment in HNSCC.
Epidermal growth factor receptor (EGFR) overexpression is characteristic in head and neck cancers and is associated with tumour regrowth following photodynamic therapy (PDT).
We investigated vandetanib, which selectively blocks EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2), to enhance the efficacy of PDT.
We assessed the in vitro therapeutic efficacy of: 1) vandetanib; 2) PDT with the photosensitizer Chlorin e6 (Fotolon®); and 3) combined PDT + vadetanib treatment in CAL-27 oral squamous cell carcinoma (OSCC) cell line by cell viability, γH2AX foci immunostaining, cell cycle arrest and western blot. We also performed in vivo tumour regression study and immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) regressed and regrown tumour tissues.
First, we observed significantly higher cytotoxicity and residual DNA damage in vandetanib + PDT-treated CAL-27 OSCC cells than tumour cells treated with PDT alone. This is due to impaired DNA DSB repair caused by downregulation of EGFR-mediated DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activation. Next, combined vandetanib and PDT resulted in significant tumour growth delay in vivo that is linked to reduction of PDT-induced EGFR phosphorylation and cellular proliferation, along with loss of tumour vasculature. In particular, we observed significant revascularisation of the microenvironment that is associated with upregulated ERK1/2 phosphorylation in regrown tumours post-vandetanib + PDT, thereby corroborating the importance of microenvironmental modification for the observed drug-PDT synergistic interaction.
Taken together, our data suggests that vandetanib enhances the efficacy of PDT through both direct and indirect effects on the cellular DNA repair machinery and tumour microenvironment, respectively.
The application of radiosurgery dose escalation extra-cranially in a moving target, surrounded by critical normal tissue, presents unique dosimetric and clinical challenges. Building on a strong ...foundation of robust technological advancements and well-planned clinical studies, lung stereotactic body radiotherapy (SBRT) has firmly established its place in the management of early stage non-small cell lung cancer (NSCLC). Nevertheless, favourable outcomes and long-term survival still evade a substantial proportion of patients, especially for central and larger peripheral lung tumours. In this review, we will document the historical developments of lung SBRT over the past decades, highlighting key studies, which have shaped current clinical practice. At the same time, we will address some of the recent advancements in radiation technology, molecular profiling and immunotherapy, and discuss how these important developments can lead to combinatorial strategies, which we hope will form the backbone of new clinical trials and drive better cure rates.
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