Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy.

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.

Liver Metastasis Irradiation Can Restore Immunotherapeutic Responsiveness.

Allogeneic liver transplants tolerize the immune system, preventing organ rejection from the same donor. A recent article by Yu et al. shows that liver metastases can likewise prevent tumor rejection in immunotherapy-treated murine and human hosts. Furthermore, radiation can reprogram the liver microenvironment to restore systemic tumor rejection.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Cellular senescence in the response of HR+ breast cancer to radiotherapy and CDK4/6 inhibitors.

BACKGROUND: Preclinical evidence from us and others demonstrates that the anticancer effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can be enhanced with focal radiation therapy (RT), but only when RT is delivered prior to (rather than after) CDK4/6 inhibition. Depending on tumor model, cellular senescence (an irreversible proliferative arrest that is associated with the secretion of numerous bioactive factors) has been attributed beneficial or detrimental effects on response to treatment. As both RT and CDK4/6 inhibitors elicit cellular senescence, we hypothesized that a differential accumulation of senescent cells in the tumor microenvironment could explain such an observation, i.e., the inferiority of CDK4/6 inhibition with palbociclib (P) followed by RT (P→RT) as compared to RT followed by palbociclib (RT→P). METHODS: The impact of cellular senescence on the interaction between RT and P was assessed by harnessing female INK-ATTAC mice, which express a dimerizable form of caspase 8 (CASP8) under the promoter of cyclin dependent kinase inhibitor 2A (Cdkn2a, coding for p16Ink4), as host for endogenous mammary tumors induced by the subcutaneous implantation of medroxyprogesterone acetate (MPA, M) pellets combined with the subsequent oral administration of 7,12-dimethylbenz[a]anthracene (DMBA, D). This endogenous mouse model of HR+ mammary carcinogenesis recapitulates key immunobiological aspects of human HR+ breast cancer. Mice bearing M/D-driven tumors were allocated to RT, P or their combination in the optional presence of the CASP8 dimerizer AP20187, and monitored for tumor growth, progression-free survival and overall survival. In parallel, induction of senescence in vitro, in cultured human mammary hormone receptor (HR)+ adenocarcinoma MCF7 cells, triple negative breast carcinoma MDA-MB-231 cells and mouse HR+ mammary carcinoma TS/A cells treated with RT, P or their combination, was determined by colorimetric assessment of senescence-associated ß-galactosidase activity after 3 or 7 days of treatment. RESULTS: In vivo depletion of p16Ink4-expressing (senescent) cells ameliorated the efficacy of P→RT (but not that of RT→P) in the M/D-driven model of HR+ mammary carcinogenesis. Accordingly, P→RT induced higher levels of cellular senescence than R→TP in cultured human and mouse breast cancer cell lines. CONCLUSIONS: Pending validation in other experimental systems, these findings suggest that a program of cellular senescence in malignant cells may explain (at least partially) the inferiority of P→RT versus RT→P in preclinical models of HR+ breast cancer.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.

BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. METHODS: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. FUNDING: AstraZeneca.

Perspectives in immunotherapy: meeting report from the immunotherapy bridge (December 2nd-3rd, 2020, Italy).

Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd-3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.

Dual Transforming Growth Factor-ß and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

Tumors that elude infiltration by CD8+ T lymphocytes are particularly resistant to multiple forms of treatment, including immune checkpoint blockade. Stromal transforming growth factor (TGF)-ß appears to play a key role in this process, potentially constituting a target for novel combinatorial regimens tackling immune-excluded neoplasms.

Estimating child mortality associated with maternal mortality from breast and cervical cancer.

BACKGROUND: Large-scale population studies demonstrate an association between mothers' deaths and child mortality in both lower and higher income countries. The authors estimated children's deaths in association with mothers' deaths from breast or cervical cancer, 2 common cancers in low-income and middle-income countries affecting women of reproductive age, to develop a comprehensive assessment of the death burden of these cancers. METHODS: A Monte Carlo simulation model was devised whereby women were at risk of dying from breast cancer, cervical cancer, or another cause. Compared with children who have living mothers, children of women who die before they reached age 10 years have an elevated risk of death from all causes. Therefore, simulations were conducted, and the impact of mothers' deaths from cervical and breast cancer on associated child mortality was quantified for Bangladesh, Burkina Faso, and Denmark (benchmark analysis), then the analyses were extended to all African countries. RESULTS: Benchmark estimates of child deaths associated with mothers' deaths from breast and cervical cancer resulted in an increment in cancer-related mortality of approximately 2% in Bangladesh, 14% in Burkina Faso, and less than 1% in Denmark. The model predicted an increment in comprehensive cancer deaths when including child death estimates by as high as 30% in certain African countries. CONCLUSIONS: To the authors' knowledge, this is the first study to estimate the impact of a mother's death from cancer on child mortality. The model's estimates call for further investigation into this correlation and underscore the relevance of adequate access to prevention and treatment among women of childbearing age.

Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 2: Existing Experience and Considerations for Future Trials.

The brain has long been considered an immunologically privileged site, and the role of immunotherapy in treating intracranial disease has only recently been revived-with preclinical evidence showing that the systemic immune system responds to immunotherapy for intracranial disease, and with clinical evidence demonstrating improved locoregional control and survival compared with historical outcomes when immune-directed therapies are combined with radiation. Pharmaceutical industry-supported multi-institutional drug efficacy studies routinely exclude patients with brain metastases, so current evidence for treatment of brain metastases using stereotactic radiosurgery combined with immunotherapy comes from single-institution studies. Many studies of combinations of immune checkpoint blockade (with anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed death 1 antibodies) with stereotactic radiosurgery have demonstrated promising improvements in intracranial control and survival. In addition to evaluating the optimal combination of these therapies, future studies will likely search for predictive biomarkers to better select patients whose disease is most appropriately managed with this combined-modality approach.

Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 1: Principles of Combined Treatment.

The role of systemic therapy in the treatment of intracranial metastases has traditionally been limited by the blood-brain barrier, and radiation therapy-either with whole-brain treatment or stereotactic radiosurgery-has remained a primary treatment modality. Recent evidence has demonstrated that antigens released in the brain can inform the systemic immune system, and systemic antibodies can traverse into the brain. This has led to a renewed interest in investigating novel immunotherapy agents to treat both systemic and intracranial disease. Currently, several trials of immunotherapy, with or without sequential or concurrent radiation, have been performed in patients with brain metastases to evaluate the safety and efficacy of combined treatment. Combined use of stereotactic radiosurgery and checkpoint inhibitors appears safe and effective in the treatment of various brain metastases. Future studies will evaluate the optimal sequencing of radiosurgery and immunotherapy and assess the radiation doses and fractionations that will provide the best tumor response.

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.

BACKGROUND: Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. METHODS: We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8-34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34-0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1-8·6] vs 2·1 months [1·6-2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30-0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1-10·4] vs 2·0 months [1·8-2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36-0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5-18·9] vs 5·3 months [2·7-7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36-0·96], p=0·034; median overall survival 11·6 months [95% CI 6·5-20·5] vs 5·3 months [3·0-8·5]). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). INTERPRETATION: Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. FUNDING: US National Institutes of Health.

Future perspectives in melanoma research "Melanoma Bridge", Napoli, November 30th-3rd December 2016.

Major advances have been made in the treatment of cancer with targeted therapy and immunotherapy; several FDA-approved agents with associated improvement of 1-year survival rates became available for stage IV melanoma patients. Before 2010, the 1-year survival were quite low, at 30%; in 2011, the rise to nearly 50% in the setting of treatment with Ipilimumab, and rise to 70% with BRAF inhibitor monotherapy in 2013 was observed. Even more impressive are 1-year survival rates considering combination strategies with both targeted therapy and immunotherapy, now exceeding 80%. Can we improve response rates even further, and bring these therapies to more patients? In fact, despite these advances, responses are heterogeneous and are not always durable. There is a critical need to better understand who will benefit from therapy, as well as proper timing, sequence and combination of different therapeutic agents. How can we better understand responses to therapy and optimize treatment regimens? The key to better understanding therapy and to optimizing responses is with insights gained from responses to targeted therapy and immunotherapy through translational research in human samples. Combination therapies including chemotherapy, radiotherapy, targeted therapy, electrochemotherapy with immunotherapy agents such as Immune Checkpoint Blockers are under investigation but there is much room for improvement. Adoptive T cell therapy including tumor infiltrating lymphocytes and chimeric antigen receptor modified T cells therapy is also efficacious in metastatic melanoma and outcome enhancement seem likely by improved homing capacity of chemokine receptor transduced T cells. Tumor infiltrating lymphocytes therapy is also efficacious in metastatic melanoma and outcome enhancement seem likely by improved homing capacity of chemokine receptor transduced T cells. Understanding the mechanisms behind the development of acquired resistance and tests for biomarkers for treatment decisions are also under study and will offer new opportunities for more efficient combination therapies. Knowledge of immunologic features of the tumor microenvironment associated with response and resistance will improve the identification of patients who will derive the most benefit from monotherapy and might reveal additional immunologic determinants that could be targeted in combination with checkpoint blockade. The future of advanced melanoma needs to involve education and trials, biobanks with a focus on primary tumors, bioinformatics and empowerment of patients and clinicians.

Emotional Intelligence and Burnout in Academic Radiation Oncology Chairs.

EXECUTIVE SUMMARY: The importance of emotional intelligence (EI) in physicians has attracted attention as researchers begin to focus on the relationship of EI to retention, promotion, and productivity among academic physicians. However, to date, no formal evaluation of EI has been conducted among current department chairs. The objectives of this study were to assess the EI of current chairs of academic radiation oncology departments and to correlate EI with a self-reported assessment of burnout.The authors invited 95 chairs of academic radiation oncology departments to participate in a survey, approved by an institutional review board, consisting of the Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF) and the abbreviated Maslach Burnout Inventory (a-MBI). TEIQue-SF scores were evaluated for correlation with respondents' demographics and self-reported burnout scores on the a-MBI. Sixty chairs responded to the survey, for a response rate of 63.2%. The median (interquartile range) TEIQue-SF for the responding cohort was 172 (155-182) out of a maximum possible score of 210. The a-MBI emotional exhaustion and depersonalization subscores were low, with median (interquartile range) scores of 4 (2.25-6.75) and 1 (0-2.75) out of maximum possible scores of 18 and 30, respectively. Higher TEIQue-SF global scores were weakly correlated with decreased burnout. The study results show that academic radiation oncology chairs had a high EI and low rates of self-reported burnout. EI may be of increasing importance with respect to recruitment and retention of academic medical leaders.

Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial.

BACKGROUND: An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS: Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 µg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simon's optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS: From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simon's two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION: The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING: New York University School of Medicine's Department of Radiation Oncology and Cancer Institute.

Chemoradiation therapy versus chemotherapy alone for gastric cancer after R0 surgical resection: a meta-analysis of randomized trials.

OBJECTIVE: Current national guidelines include category 1 recommendations for perioperative chemotherapy or adjuvant chemoradiation with surgical resection for patients with stage IB-IIIB gastric cancer. We conducted a meta-analysis of randomized trials in which chemotherapy was prospectively tested against chemoradiation with surgical resection. METHODS: We electronically searched PubMed and EMBASE for randomized, controlled clinical trials involving patients with gastric adenocarcinoma, status post-R0 resection. The interventions compared were adjuvant chemotherapy versus chemoradiation, with any chemotherapy regimen. The primary outcomes of interest were disease-free survival and overall survival. The Mantel-Haenszel random-effects model was used to calculate effect sizes. RESULTS: Six trials that included 1,171 patients were evaluated; 599 were randomized to adjuvant chemoradiation and 572 to chemotherapy alone. Chemoradiation was associated with a significant increase in disease-free survival (odds ratio 1.48, 95% confidence interval 1.08-2.03) when compared to chemotherapy alone. However, there was no significant difference in overall survival (odds ratio 1.27, 95% confidence interval 0.95-1.71). Five trials found no statistically significant differences in toxicities between the two groups. CONCLUSION: In patients with gastric cancer status post-R0 resection, adjuvant chemoradiation was associated with higher disease-free survival when compared to chemotherapy alone. It remains appropriate to design trials testing new systemic agents with radiotherapy.

Taxanes as radiosensitizers.

In parallel with the discovery of the taxanes, our understanding of the molecular underpinnings that comprise the classic biologic principles of fractionated radiotherapy has rapidly evolved over the past half century. Early studies have implicated DNA as the primary target for radiation-induced lethality. More recently, however, the molecular biology involved in radiosensitization of tumor cells has been unveiled. Specifically, factors associated with DNA damage and cell killing, collectively known as the 'four Rs' of radiobiology, including (r)eassortment of tumor cells into the radiosensitive phases of the cell cycle (G2/M), (r)eoxygenation of hypoxic areas within a tumor, (r)epair of sublethal DNA damage, and (r)epopulation of surviving tumor cells, have been elucidated, and upon manipulation of each factor or a combination of factors a significant impact on radiation-associated tumor control probabilities was found. Not only does spatial cooperation have a theoretical benefit in patients with undetectable micrometastatic disease at presentation, but the manipulation of either of the 'four Rs' using taxanes provokes further local radiation-associated tumor cell killing with an associated improvement in clinical responses. Numerous studies have shown that taxanes radiosensitize tumor cells directly and/or indirectly by perturbing the tumor microenvironment in a time-dependent and dose-dependent manner. Herein, the impact of taxanes on radiobiological tenets as a mode of radiosensitizing tumor cells and their clinical implications are reviewed.