Locally advanced cervical cancer is treated with chemoradiotherapy. The treatment-related morbidity is high. Tumor hypoxia has prognostic impact and represents a valid, interventional target. This phase II study investigated efficacy of the antidiabetic drug metformin to modify hypoxia according to established biomarkers. Preliminary results including tolerability, safety and feasibility are reported here.

Patients were included in a 1:1 randomized, open-label design, comparing standard chemoradiotherapy ± metformin. Metformin 850 mg twice daily was administered 1 week before and during chemoradiotherapy. Magnetic resonance images (MRI) and tumor biopsies were collected at baseline, after 1 week of metformin treatment, and at brachytherapy for biomarker assessments. Tolerability and safety were determined by treatment completion rates and frequency of adverse events (AEs). Safety was further evaluated by possible increase in MRI-based hypoxia during the first week of metformin. Feasibility was determined by proportion of completed study interventions and imaging and biopsy procedures.

In total, 18 and 23 patients were allocated to the intervention and control arm, respectively. Eighteen and 15 patients completed metformin treatment for 1 and 5 weeks. Frequency of AEs ≥ grade 3 was not significantly different between study arms. Most AEs were gastrointestinal toxicities. Tumors with increase in hypoxia during the first week were all below the defined safety limit. A total of 98% of scheduled MR series and biopsies were collected with satisfactory quality.

Addition of metformin to chemoradiotherapy is tolerable and safe. Serial sampling of MRI and tumor biopsies for hypoxia biomarker assessment is feasible.

Intratumour hypoxia is a feature of all heterogenous solid tumours. Increased levels or subregions of tumour hypoxia are associated with an adverse clinical prognosis, particularly when this co-occurs with genomic instability. Experimental evidence points to the acquisition of DNA and chromosomal alterations in proliferating hypoxic cells secondary to inhibition of DNA repair pathways such as homologous recombination, base excision repair and mismatch repair. Cell adaptation and selection in repair-deficient cells give rise to a model whereby novel single-nucleotide mutations, structural variants and copy number alterations coexist with altered mitotic control to drive chromosomal instability and aneuploidy. Whole-genome sequencing studies support the concept that hypoxia is a critical microenvironmental cofactor alongside the driver mutations in MYC, BCL2, TP53 and PTEN in determining clonal and subclonal evolution in multiple tumour types. We propose that the hypoxic tumour microenvironment selects for unstable tumour clones which survive, propagate and metastasize under reduced immune surveillance. These aggressive features of hypoxic tumour cells underpin resistance to local and systemic therapies and unfavourable outcomes for patients with cancer. Possible ways to counter the effects of hypoxia to block tumour evolution and improve treatment outcomes are described.

Men with high-risk prostate cancer (PCa) are treated with androgen deprivation therapy (ADT) and radiation therapy, but the disease reoccurs in 30% of patients. Biochemical recurrence of PCa after treatment is influenced by tumor hypoxia. Tumors with high levels of hypoxia are aggressive, resistant to treatment, and have increased metastatic capacity. Gene expression signatures derived from diagnostic biopsies can predict tumor hypoxia and radiosensitivity, but none are in routine clinical use, due to concerns about the applicability of these biomarkers to new patient cohorts. There has been no or limited testing in cohorts of high-risk PCa.

We generated transcriptomic data for cohorts of patients with high-risk PCa. Patients were treated with ADT followed by external beam radiation therapy with or without a brachytherapy boost. Biomarkers curated from the literature were calculated from pretreatment biopsy gene expression data. The primary endpoint for survival analyses was biochemical recurrence-free survival and the secondary endpoints were distant metastasis-free survival and overall survival.

The performance of the selected biomarkers was poor, with none achieving prognostic significance for biochemical recurrence-free survival or distant metastasis-free survival in any cohort. The brachytherapy boost cohort received shorter durations of ADT than the conventionally fractionated or hypofractionated cohorts (Wilcoxon rank sum test, P = 2.1 × 10-18 and 2.3 × 10-10, respectively) and had increased risk of distant metastasis (log-rank test, P = 8 × 10-4). There were no consistent relationships between biomarker score and outcome for any of the endpoints.

Hypoxia and radiosensitivity biomarkers were not prognostic in patients with high-risk PCa treated with ADT plus radiation therapy. We speculate that the lack of prognostic capability could be caused by the variable hypoxia-modifying effects of the ADT that these high-risk patients received before and during definitive treatment with radiation therapy. A deeper understanding of biomarker construction, performance, and inter-cohort transferability in relation to patient characteristics, sample handling, and treatment modalities is required before hypoxia biomarkers can be recommended for routine clinical use in the pretreatment setting.

Photoactivatable metal complexes offer the prospect of novel drugs with low side effects and new mechanisms of action to combat resistance to current therapy. We highlight recent progress in the design of platinum, ruthenium, iridium, gold and other transition metal complexes, especially for applications as anticancer and anti-infective agents. In particular, understanding excited state chemistry related to identification of the bioactive species (excited state metallomics/pharmacophores) is important. Photoactivatable metallodrugs are classified here as photocatalysts, photorelease agents and ligand-activated agents. Their activation wavelengths, cellular mechanisms of action, experimental and theoretical metallomics of excited states and photoproducts are discussed to explore new strategies for the design and investigation of photoactivatable metallodrugs. These photoactivatable metallodrugs have potential in clinical applications of Photodynamic Therapy (PDT), Photoactivated Chemotherapy (PACT) and Photothermal Therapy (PTT).

Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT).

NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m2 daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level.

Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P = .35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P = .88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P < .05).

Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival.

Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxia-inducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having anti-tumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials.

Breast cancer has overtaken lung cancer to rank as the top malignant tumor in terms of incidence. Herein, a gold nanostar (denoted as AuNS) is used for loading disulfide-coupled camptothecin-fluorophore prodrugs (denoted as CPT-SS-FL) to form a nanocomposite of AuNS@CPT-SS-FL (denoted as AS), which, in turn, is further encapsulated with hyaluronic acid (HA) to give the final nanoplatform of AuNS@CPT-SS-FL@HA (denoted as ASH). ASH effectively carries the prodrug and targets the CD44 receptor on the surface of tumor cells. The endogenously overexpressed glutathione (GSH) in tumor cells breaks the disulfide bond to activate the prodrug and release the radiosensitizer drug camptothecin (CPT) and the fluorescence imaging reagent rhodamine derivative as a fluorophore (FL). The released FL can track the precise release position of the radiosensitizer camptothecin in tumor cells in real time. The AuNS has strong X-ray absorption and deposition ability due to the high atomic coefficient of elemental Au (Z = 79). At the same time, the AuNS can alleviate the tumor microenvironment (TME) hypoxia through its mild photothermal therapy (PTT). Therefore, through the multiple radiosensitizing effects of GSH depletion, the high atomic coefficient of Au, and hypoxia alleviation, accompanied by the radiosensitizer camptothecin, the designed ASH nanoplatform can effectively induce strong immunogenic cell death (ICD) at the tumor site via radiosensitizing therapy combined with PTT. This work provides a new way of constructing a structurally compact and highly functionalized hierarchical system toward efficient breast cancer treatment through ameliorating the TME with multiple modalities.

Though growing evidence has been collected in support of the concept of dose escalation based on the molecular level images indicating hypoxic tumor sub-volumes that could be radio-resistant, validation of the concept is still a work in progress. Molecular imaging of tumor hypoxia using radiopharmaceuticals is expected to provide the required input to plan dose escalation through Image Guided Radiation Therapy (IGRT) to kill/control the radio-resistant hypoxic tumor cells. The success of the IGRT, therefore, is heavily dependent on the quality of images obtained using the radiopharmaceutical and the extent to which the image represents the true hypoxic status of the tumor in spite of the heterogeneous nature of tumor hypoxia. Available literature on radiopharmaceuticals for imaging hypoxia is highly skewed in favor of nitroimidazole as the pharmacophore given their ability to undergo oxygen dependent reduction in hypoxic cells. In this context, present review on nitroimidazole radiopharmaceuticals would be immensely helpful to the researchers to obtain a birds-eye view on what has been achieved so far and what can be tried differently to obtain a better hypoxia imaging agent. The review also covers various methods of radiolabeling that could be utilized for developing radiotracers for hypoxia targeting applications.

Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia.

A DNA-methylome-based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression-based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)-negative patients with HNSCC treated with primary radiochemotherapy (RCHT).

Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status.

Our findings highlight an unexplored avenue for DNA methylation-based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors. See related commentary by Heft Neal and Brenner, p. 2954.

Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system.

MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems.

Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems.

We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

The success of inhibitor-based therapeutics is largely constrained by the acquisition of therapeutic resistance, which is partially driven by the undruggable proteome. The emergence of proteolysis targeting chimera (PROTAC) technology, designed for degrading proteins involved in specific biological processes, might provide a novel framework for solving the above constraint. A heterobifunctional PROTAC molecule could structurally connect an E3 ubiquitin ligase ligand with a protein of interest (POI)-binding ligand by chemical linkers. Such technology would result in the degradation of the targeted protein via the ubiquitin-proteasome system (UPS), opening up a novel way of selectively inhibiting undruggable proteins. Herein, we will highlight the advantages of PROTAC technology and summarize the current understanding of the potential mechanisms involved in biotherapeutics, with a particular focus on its application and development where therapeutic benefits over classical small-molecule inhibitors have been achieved. Finally, we discuss how this technology can contribute to developing biotherapeutic drugs, such as antivirals against infectious diseases, for use in clinical practices.

Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification.

Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts.

Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P < .05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015).

We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.

Owing to advances in radiotherapy, the physical properties of radiation can be optimized to enable individualized treatment; however, optimization is rarely based on biological properties and, therefore, treatments are generally planned with the assumption that all tumours respond similarly to radiation. Radiation affects multiple cellular pathways, including DNA damage, hypoxia, proliferation, stem cell phenotype and immune response. In this Review, we summarize the effect of these pathways on tumour responses to radiotherapy and the current state of research on genomic classifiers designed to exploit these variations to inform treatment decisions. We also discuss whether advances in genomics have generated evidence that could be practice changing and whether advances in genomics are now ready to be used to guide the delivery of radiotherapy alone or in combination.

The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy. The hTME impairs the delivery of a range of anti-cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia-Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme-DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by co-addressing the therapeutic challenge presented by the hTME.

Hypoxia is a common feature of solid tumors that contributes to angiogenesis, invasiveness, metastasis, altered metabolism and genomic instability. As hypoxia is a major actor in tumor progression and resistance to radiotherapy, chemotherapy and immunotherapy, multiple approaches have emerged to target tumor hypoxia. It includes among others pharmacological interventions designed to alleviate tumor hypoxia at the time of radiation therapy, prodrugs that are selectively activated in hypoxic cells or inhibitors of molecular targets involved in hypoxic cell survival (i.e., hypoxia inducible factors HIFs, PI3K/AKT/mTOR pathway, unfolded protein response). While numerous strategies were successful in pre-clinical models, their translation in the clinical practice has been disappointing so far. This therapeutic failure often results from the absence of appropriate stratification of patients that could benefit from targeted interventions. Companion diagnostics may help at different levels of the research and development, and in matching a patient to a specific intervention targeting hypoxia. In this review, we discuss the relative merits of the existing hypoxia biomarkers, their current status and the challenges for their future validation as companion diagnostics adapted to the nature of the intervention.

Radiotherapy is recognized globally as a mainstay of treatment in most solid tumors and is essential in both curative and palliative settings. Ionizing radiation is frequently combined with surgery, either preoperatively or postoperatively, and with systemic chemotherapy. Recent advances in imaging have enabled precise targeting of solid lesions yet substantial intratumoral heterogeneity means that treatment planning and monitoring remains a clinical challenge as therapy response can take weeks to manifest on conventional imaging and early indications of progression can be misleading. Photoacoustic imaging (PAI) is an emerging modality for molecular imaging of cancer, enabling non-invasive assessment of endogenous tissue chromophores with optical contrast at unprecedented spatio-temporal resolution. Preclinical studies in mouse models have shown that PAI could be used to assess response to radiotherapy and chemoradiotherapy based on changes in the tumor vascular architecture and blood oxygen saturation, which are closely linked to tumor hypoxia. Given the strong relationship between hypoxia and radio-resistance, PAI assessment of the tumor microenvironment has the potential to be applied longitudinally during radiotherapy to detect resistance at much earlier time-points than currently achieved by size measurements and tailor treatments based on tumor oxygen availability and vascular heterogeneity. Here, we review the current state-of-the-art in PAI in the context of radiotherapy research. Based on these studies, we identify promising applications of PAI in radiation oncology and discuss the future potential and outstanding challenges in the development of translational PAI biomarkers of early response to radiotherapy.

Hypoxia is common in non-small cell lung cancer (NSCLC) and an attractive therapeutic target. As hypoxia-targeting treatments are effective in patients with the most hypoxic tumours, we aimed to develop a lung adenocarcinoma (LUAD) hypoxia-related gene expression signature. RNAseq was used to identify genes significantly differentially expressed under hypoxia (1% O2) in four LUAD cell lines. Identified genes were used for unsupervised clustering of a TCGA-LUAD training dataset (n = 252) and in a machine learning approach to build a hypoxia-related signature. Thirty-five genes were upregulated in common in three of the four lines and reduced in the training cohort to a 28-gene signature. The signature was prognostic in the TCGA training (HR 2.12, 95% CI 1.34-3.37, p = 0.0011) and test (n = 250; HR 2.13, 95% CI 1.32-3.45, p = 0.0016) datasets. The signature was prognostic for overall survival in a meta-analysis of nine other datasets (n = 1257; HR 2.08, 95% CI 1.60-2.70, p < 0.0001). The 28-gene LUAD hypoxia related signature can be taken forward for further validation using a suitable gene expression platform.

Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.

Head and neck squamous cancers are a heterogeneous group of cancers that arise from the upper aerodigestive tract. Etiologically, these tumors are linked to alcohol/tobacco abuse and infections with high-risk human papillomavirus (HPV). HPV-positive HNSCCs are characterized by a different biology and also demonstrate better therapy response and survival compared to alcohol/tobacco-related HNSCCs. Despite this advantageous therapy response and the clear biological differences, all locally advanced HNSCCs are treated with the same chemo-radiotherapy schedules. Although we have a better understanding of the biology of both groups of HNSCC, the biological factors associated with the increased radiotherapy response are still unclear. Hypoxia, i.e., low oxygen levels because of an imbalance between oxygen demand and supply, is an important biological factor associated with radiotherapy response and has been linked with HPV infections. In this review, we discuss the effects of hypoxia on radiotherapy response, on the tumor biology, and the tumor microenvironment of HPV-positive and HPV-negative HNSCCs by pointing out the differences between these two tumor types. In addition, we provide an overview of the current strategies to detect and target hypoxia.

In this experimental study, the effect of dose-dense systemic application of propolis on oral mucosity, histological changes in papilla, and inflammatory and hypoxic markers in rats exposed to radiation was investigated.

Seven rats were in the control and 30 rats in the experimental group. Three experimental groups were formed. In Group 1 RT (15 Gy) was delivered only to the head and neck region. In Group 2, RT (15 Gy) and systemic administration of 100 mg/kg/ml propolis, in Group 3, RT (15 Gy) and systemic administration of 200 mg/kg/ml propolis were applied. Oral mucositis index (OMI) was scored in control and experimental groups. Proinflammatory markers [interleukin-6 (IL-6), myeloperoxidase (MPO), tumor-necrosis factor-α (TNF-α)] hypoxia markers [glucose transporter-1 (GLUT-1), hypoxia-inducible factor 1α (HIF-1α)] were studied histomorphologically.

The significantly highest OMI score was observed in the G1. OMI score was statistically significantly decreased in experimental groups receiving systemic propolis, especially in G3. Proinflammatory markers increased significantly only in the experimental RT group, G1. Serum levels of MPO and TNF-α significantly decreased in the dose-dense systemic propolis arm. The highest levels of hypoxia markers (HIF-1α and GLUT-1) were detected in the RT group, then in G2, G3, and control groups in order of decreasing frequency. However, the difference between the groups did not reach the level of statistical significance.

Systemic propolis can be reduced acute mucositis with its anti-inflammatory effect without developing resistance to RT (tumor protection). However, greater number of clinical studies should be designed to arrive at definitive conclusions.

One third of patients with bladder cancer present with muscle invasive bladder cancer (MIBC) which has a poor prognosis. International guidelines for the management of MIBC recommend radical cystectomy or bladder-preserving treatment based on radical radiotherapy with a form of radiosensitisation. In the UK, both conventional fractionation with 64 Gy in 32 fractions and hypofractionation with 55 Gy in 20 fractions are standard of care options with the choice varying between centres. A meta-analysis of individual patients with locally advanced bladder cancer from two UK multicentre phase 3 trials was published recently. This study evaluated the non-inferiority of a hypofractionated schedule compared to a conventional regime. This analysis confirmed the non-inferiority of the hypofractionated regimen, and noted superior locoregional control. We discuss the relevance of these findings to current practice while considering the radiobiology of hypofractionation, the role of systemic therapies and radiosensitisation, as well as the socioeconomic benefits.