Abstract Purpose/objective: To analyse outcome and toxicity of stereotactic body radiotherapy (SBRT) in pancreatic cancer (PDAC). Material/methods: We systematically reviewed full reports on outcome ...and toxicity transforming prescription doses to equivalent doses of 2 Gy (EQD2) and biological equivalent doses (BED). Pearson product-moment correlation coefficient, regression analysis and Lyman–Kutcher–Burman modelling were used. Results: Sixteen trials (572 patients) were identified. Local control correlated with dose. Additionally 4 upper gastrointestinal-SBRT trials (149 patients) were included for toxicity analysis. Acute toxicity was mild but late toxicity ⩾G2 was substantial and predominantly gastrointestinal. Late toxicity ⩾G2 and ⩾G3 correlated highly with EQD2/BED after linear ( R2 = 0.85 and 0.77, respectively) and Lyman–Kutcher–Burman modelling. Linear regression lines indicated ⩾G2 and ⩾G3 toxicity frequencies of 5% at 65 Gy and 80 Gy EQD2-α/β = 3, respectively. A comparison of toxicity with dose constraints for duodenum revealed partly inadequate dose constraints. Conclusion: Results from multiple fraction regimens could be successfully interpreted to estimate toxicity according to EQD2/BED prescription doses, and dose constraints for the duodenum were derived, whereas local control appeared to be less dose-dependent. This analysis may be useful to plan clinical trials for SBRT and hypofractionated radiotherapy in pancreatic cancer.
Cisplatin is increasingly used in chemoimmunotherapy and may enhance the T cell-dependent radiation-induced abscopal effect, but how it promotes antitumor immunity is poorly understood. We ...investigated whether and why cisplatin is immunogenic, and the implications for the cisplatin-enhanced abscopal effect.
Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce type I IFN (IFN-I) and extracellular ATP, danger signals of ICD. The hypothetical role of necroptosis and associated damage-associated molecular patterns for cisplatin-induced ICD was investigated by inhibitors and knockout cells in vitro and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed.
Cisplatin enhanced the abscopal effect more strongly than oxaliplatin or carboplatin. This correlated with higher induction of IFN-I and extracellular ATP by cisplatin, in a necroptosis-dependent manner. Cisplatin triggered receptor-interacting protein kinase 3 (RIPK3)-dependent tumor cell necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and IFN-I secretion promoting T-cell cross-priming by dendritic cells (DC). Accordingly, tumor cell RIPK3 or mtDNA deficiency and loss of IFN-I or ATP signaling diminished the cisplatin-enhanced abscopal effect. Cisplatin-treated tumor cells were immunogenic in vaccination experiments, depending on RIPK3 and mtDNA. In human tumor transcriptome analysis, necroptotic features correlated with abundant CD8+ T cells/DCs, sparse immunosuppressive cells, and immunotherapy response.
Cisplatin induces antitumor immunity through necroptosis-mediated ICD. Our findings may help explain the benefits of cisplatin in chemo(radio)immunotherapies and develop clinical trials to investigate whether cisplatin enhances the abscopal effect in patients.
Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre‐activated NK cells. In our retrospective study the expression ...of Hsp70 was determined in relation to tumor‐infiltrating CD56+ NK cells in formalin‐fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin‐based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3–4) showed significantly decreased overall survival (OS; p = 0.008), local progression‐free survival (LPFS; p = 0.034) and distant metastases‐free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0–2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16‐ (p = 0.001), p53‐ (p = 0.0003) and HPV16 DNA‐negative (p = 0.001) tumors. The absence or low numbers of tumor‐infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor‐infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor‐infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers.
What's new?
It's difficult to predict how a patient with squamous‐cell carcinoma of the head and neck (SCCHN) will respond to treatment, because every tumor is different. In this study, the authors identified two pre‐treatment measures that were associated with poor prognosis following surgery and RCT: high levels of staining for a protein called Hsp70 in tumor cells, and low numbers of tumor‐infiltrating NK lymphocytes. These measures may thus serve as useful prognostic biomarkers for predicting the response of SCCHN to therapy.
Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting ...CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8
T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8
T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8
T cells increase. Consistent with the surge in tumor-specific CD8
T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8
T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers.
We examined the prognostic role of PD‐1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD‐L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery ...and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD‐1, CD8 and PD‐L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression‐free survival (LPFS) and distant metastases free‐survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow‐up was 48 months (range: 4–100). The 2‐year‐OS was 84.1% for the entire cohort. High PD‐1 and PD‐L1 expression were more common in patients with positive HPV16 DNA (p < 0.001 and p = 0.008, respectively) and high infiltration by CD8+ TILs (p < 0.001 for both markers). High PD‐L1 expression correlated with superior OS (p = 0.025), LPFS (p = 0.047) and DMFS (p = 0.048) in multivariable analysis, whereas no significance could be demonstrated for PD‐1. Patients with CD8high/PD‐L1high expression had favorable outcome (p < 0.001 for all endpoints) compared to other groups. We validated the superior OS data on CD8high/PD‐L1high using the Cancer Genome Atlas TCGA dataset (n = 518; p = 0.032). High PD‐L1 expression was a favorable prognostic marker in HPV16‐negative but not HPV16‐positive patients. In conclusion, HPV‐positive tumors showed higher expression of immune markers. PD‐L1 expression constitutes an independent prognostic marker in SCCHN patients post‐adjuvant CRT. In conjunction with CD8 status, these data provide an important insight on the immune contexture of SCCHN and are directly relevant for future treatment stratification with PD‐1/PD‐L1 immune checkpoint inhibitors to complement CRT.
What's new?
Human papillomavirus (HPV)–positivity in squamous cell carcinoma of the head and neck (SCCHN) has been associated with improved response and superior survival rates after radiotherapy and chemoradiotherapy (CRT) compared to patients with HPV‐negative tumors. However, the impact of immune checkpoint contexture in SCCHN treated with adjuvant CRT remains unclear. Here, the authors show that PD‐L1 constitutes an independent prognostic marker. The immune phenotype I (CD8high/PD‐L1high) is more common in HPV16‐positive tumors and associated with favorable patient outcome. The findings provide a rationale for examining the therapeutic potential of using PD‐1/PD‐L1 immune checkpoint inhibitors in combination with CRT in SCCHN.
Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's ...lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied.
Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT.
With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy.
Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.
We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote ...γ-irradiationγIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote γIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 µM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted γIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in γ-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes γIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, γIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death.
Oncological outcomes for head-and-neck squamous cell carcinoma (HNSCC) patients are still unsatisfactory, especially for advanced tumor stages. Besides the moderate survival rates, the prevalence of ...severe treatment-induced normal tissue toxicities is high after multimodal cancer treatments, both causing significant morbidity and decreasing quality of life of surviving patients. Therefore, risk-adapted and individualized treatment approaches are urgently needed for HNSCC patients to optimize the therapeutic gain. It has been a well-known fact that especially HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients exhibit an excellent prognosis and may therefore be subject to overtreatment, resulting in long-term treatment-related toxicities. Regarding the superior prognosis of HPV-positive OSCC patients, treatment de-escalation strategies are currently investigated in several clinical trials, and HPV-positive OSCC may potentially serve as a model for treatment de-escalation also for other types of HNSCC. We performed a literature search for both published and ongoing clinical trials and critically discussed the presented concepts and results. Radiotherapy dose or volume reduction, omission or modification of concomitant chemotherapy, and usage of induction chemotherapy are common treatment de-escalation strategies that are pursued in clinical trials for biologically selected subgroups of HNSCC patients. While promising data have been reported from various Phase II trials, evidence from Phase III de-escalation trials is either lacking or has failed to demonstrate comparable outcomes for de-escalated treatments. Therefore, further data and a refinement of biological HNSCC stratification are required before deescalated radiation treatments can be recommended outside of clinical trials.
Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function ...(NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).
This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter.
This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases.
The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).
PDF
