Radiotherapy resources in Latin America and the Caribbean: a review of current and projected needs based on International Atomic Energy Agency data.

The inequitable access to radiotherapy globally is a complex undertaking that will require sustained work identifying gaps and mobilising efforts to resolve. The purpose of this review is to identify gaps and needs in radiotherapy in Latin America and the Caribbean. Data from 41 countries in Latin America and the Caribbean on teletherapy megavoltage units and brachytherapy resources were extracted from the International Atomic Energy Agency (IAEA) Directory of Radiotherapy Centers. These data were then matched to open-source data from GLOBOCAN and World Bank Data which included data on population size, gross national income per capita, cancer incidence, and mortality. These data were matched to current and projected cancer incidence and mortality (as estimated by the Global Cancer Observatory in 2020) to calculate current and projected gaps in external beam radiotherapy facilities. For brachytherapy, the analysis was focused on cervical cancer and included high dose rate and low dose rate machines. As of Oct 22, 2022, external beam radiotherapy was available in 32 (78%) of 41 countries, representing 742 radiotherapy centres and 1122 megavoltage units. Average coverage was 63%. LINACs accounted for 85% (955 of 1122) of megavoltage units and Cobalt-60 capacity decreased to 12% compared with in 2018. Median megavoltage units per 1000 cancer cases were 0·8 (IQR 0·54-1·03). Most countries clustered in the same range of gross national income per capita for teletherapy units per 1000 cases at a median of US$9380. The current deficit in megavoltage units is estimated at 668 units and is projected to be 2455 units by 2030. 28 (68%) of 41 countries had 279 installed brachytherapy services, both high dose rate and low dose rate, which could treat 108 420 patients with cervical cancer per year and meet the current needs, albeit with inequitable distribution of resources. Overall, this review indicated a 15% improvement in the current external beam radiotherapy capacity in Latin America and the Caribbean compared with 2018. However, there is still a current shortage of at least 668 extra units. By 2030, the need for megavoltage units will be double the current capacity. There is inequitable distribution of brachytherapy resources across the region primarily in the Caribbean. Adoption of hypofractionation can help overcome machine shortage; however, it will present technical challenges that need to be taken into account. Rays of Hope, is a novel IAEA initiative that is designed to mobilise global efforts to address radiotherapy gaps while ensuring the highest return on investment.

Cultivating Cultural Humility to Address the Healthcare Burnout Epidemic-Why It Matters.

Physician burnout is a major problem that has long been facing our healthcare system. The COVID-19 pandemic has unfortunately deepened this problem and shed the light on the multiple structural shortcomings of our healthcare system that need immediate attention. Demoralization is one of the core features of "physician burnout," which results from a breakdown of genuine physician-patient interaction. A healthcare system that embraces cultural humility, where we find ourselves rewarded for supporting, uplifting, and respecting our patients' diverse voices could pave the way for battling burnout. Unlike cultural competency, which suggests that one should know everything about another's culture (an unfeasible task), cultural humility is a continuum of self-reflection and critique that aims to foster a deep connection between the physician and patient; a connection that sits at the core of the humanistic and multicultural experience of medicine.

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy.

In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ''one size fits all'' paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.

Impact of Lung Parenchymal-Only Failure on Overall Survival in Early-Stage Lung Cancer Patients Treated With Stereotactic Ablative Radiotherapy.

INTRODUCTION: The impact of lung parenchymal-only failure on patient survival after stereotactic ablative body radiotherapy (SABR) for early-stage non-small-cell lung cancer (NSCLC) remains unclear. PATIENTS AND METHODS: The study population included 481 patients with early-stage NSCLC who were treated with 3- to 5-fraction SABR between 2000 and 2016. The primary study objective was to assess the impact of out-of-field lung parenchymal-only failure (OLPF) on overall survival (OS). RESULTS: At a median follow-up of 5.9 years, the median OS was 2.7 years for all patients. Patients with OLPF did not have a significantly different OS compared to patients without failure (P = .0952, median OS 4.1 years with failure vs. 2.6 years never failure). Analysis in a 1:1 propensity score-matched cohort for Karnofsky performance status, comorbidity score, and smoking status showed no differences in OS between patients without failure and those with OLPF (P = .8). In subgroup analyses exploring the impact of time of failure on OS, patients with OLPF 6 months or more after diagnosis did not have significantly different OS compared to those without failure, when accounting for immortal time bias (P = .3, median OS 4.3 years vs. 3.5 years never failure). Only 7 patients in our data set experienced failure within 6 months of treatment, of which only 4 were confirmed to be true failures; therefore, limited data are available in our cohort on the impact of OLPF for ≤ 6 months on OS. CONCLUSION: OLPF after SABR for early-stage NSCLC does not appear to adversely affect OS, especially if occurring at least 6 months after SABR. More studies are needed to understand if OLPF within 6 months of SABR is associated with adverse OS. These data are useful when discussing prognosis of lung parenchymal failures after initial SABR.

Baseline Karnofsky performance status is independently predictive of death within 30 days of intracranial radiation therapy completion for metastatic disease.

INTRODUCTION: For patients with brain metastases, palliative radiation therapy (RT) has long been a standard of care for improving quality of life and optimizing intracranial disease control. The duration of time between completion of palliative RT and patient death has rarely been evaluated. METHODS: A compilation of two prospective institutional databases encompassing April 2015 through December 2018 was used to identify patients who received palliative intracranial radiation therapy. A multivariate logistic regression model characterized patients adjusting for age, sex, admission status (inpatient versus outpatient), Karnofsky Performance Status (KPS), and radiation therapy indication. RESULTS: 136 consecutive patients received intracranial palliative radiation therapy. Patients with baseline KPS <70 (OR = 2.2; 95%CI = 1.6-3.1; p < 0.0001) were significantly more likely to die within 30 days of treatment. Intracranial palliative radiation therapy was most commonly delivered to provide local control (66% of patients) or alleviate neurologic symptoms (32% of patients), and was most commonly delivered via whole brain radiation therapy in 10 fractions to 30 Gy (38% of patients). Of the 42 patients who died within 30 days of RT, 31 (74%) received at least 10 fractions. CONCLUSIONS: Our findings indicate that baseline KPS <70 is independently predictive of death within 30 days of palliative intracranial RT, and that a large majority of patients who died within 30 days received at least 10 fractions. These results indicate that for poor performance status patients requiring palliative intracranial radiation, hypofractionated RT courses should be strongly considered.

Correction: Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma.

Receptor tyrosine kinase inhibitors have shown clinical benefit in clear cell renal cell carcinoma (ccRCC), but novel therapeutic strategies are needed. The angiopoietin/Tie2 and MET pathways have been implicated in tumor angiogenesis, metastases, and macrophage infiltration. In our study, we used trebananib, an angiopoietin 1/2 inhibitor, and a novel small-molecule MET kinase inhibitor in patient-derived xenograft (PDX) models of ccRCC. Our goal was to assess the ability of these compounds to alter the status of tumor-infiltrating macrophages, inhibit tumor growth and metastases, and prolong survival. Seven-week-old SCID mice were implanted subcutaneously or orthotopically with human ccRCC models. One month postimplantation, mice were treated with angiopoietin 1/2 inhibitor trebananib (AMG 386), MET kinase inhibitor, or combination. In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone, and in combination with a MET kinase inhibitor, significantly reduced lung metastases and M2 macrophage infiltration (P = 0.0075 and P = 0.0205, respectively). Survival studies revealed that treatment of the orthotopically implanted RP-R-02LM tumors yielded a significant increase in survival in both trebananib and combination groups. In addition, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared with vehicle and both single-agent groups. Our results show that the combination of trebananib with a MET kinase inhibitor significantly inhibits the spread of metastases, reduces infiltrating M2-type macrophages, and prolongs survival in our highly metastatic ccRCC PDX model, suggesting a potential use for this combination therapy in treating patients with ccRCC.

Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer.

Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.

Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.

Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such dependency are poorly understood. Here, we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss of the CDKI p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.

Dietary Protein Restriction Reprograms Tumor-Associated Macrophages and Enhances Immunotherapy.

PURPOSE: Diet and healthy weight are established means of reducing cancer incidence and mortality. However, the impact of diet modifications on the tumor microenvironment and antitumor immunity is not well defined. Immunosuppressive tumor-associated macrophages (TAMs) are associated with poor clinical outcomes and are potentially modifiable through dietary interventions. We tested the hypothesis that dietary protein restriction modifies macrophage function toward antitumor phenotypes. EXPERIMENTAL DESIGN: Macrophage functional status under different tissue culture conditions and in vivo was assessed by Western blot, immunofluorescence, qRT-PCR, and cytokine array analyses. Tumor growth in the context of protein or amino acid (AA) restriction and immunotherapy, namely, a survivin peptide-based vaccine or a PD-1 inhibitor, was examined in animal models of prostate (RP-B6Myc) and renal (RENCA) cell carcinoma. All tests were two-sided. RESULTS: Protein or AA-restricted macrophages exhibited enhanced tumoricidal, proinflammatory phenotypes, and in two syngeneic tumor models, protein or AA-restricted diets elicited reduced TAM infiltration, tumor growth, and increased response to immunotherapies. Further, we identified a distinct molecular mechanism by which AA-restriction reprograms macrophage function via a ROS/mTOR-centric cascade. CONCLUSIONS: Dietary protein restriction alters TAM activity and enhances the tumoricidal capacity of this critical innate immune cell type, providing the rationale for clinical testing of this supportive tool in patients receiving cancer immunotherapies.

Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma.

PURPOSE: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that are not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. EXPERIMENTAL DESIGN: We have established and characterized a tRCC patient-derived xenograft, RP-R07, as a novel preclinical model for drug development by using next-generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway using in vitro and in vivo models. RESULTS: The presence of a SFPQ-TFE3 fusion [t(X;1) (p11.2; p34)] with chromosomal break-points was identified by RNA-seq and validated by RT-PCR. TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway. Consistently, miRNA microarray analysis also identified PI3K/AKT/mTOR as a highly enriched pathway in RP-R07. Upregulation of PI3/AKT/mTOR pathway in additional TFE3-tRCC models was confirmed by significantly higher expression of phospho-S6 (P < 0.0001) and phospho-4EBP1 (P < 0.0001) in established tRCC cell lines compared with clear cell RCC cells. Simultaneous vertical targeting of both PI3K/AKT and mTOR axis provided a greater antiproliferative effect both in vitro (P < 0.0001) and in vivo (P < 0.01) compared with single-node inhibition. Knockdown of TFE3 in RP-R07 resulted in decreased expression of IRS-1 and inhibited cell proliferation. CONCLUSIONS: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3-tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for patients with TFE3-tRCC.

EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming.

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle-regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651-66. ©2017 AACR.

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts.

PURPOSE: Effective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response. EXPERIMENTAL DESIGN: We performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference. RESULTS: We identified a number of somatic mutations, mostly shared by the primary tumors and PDX. In particular, BLCAb001, which is less responsive to cisplatin than BLCAb002, carried non-sense mutations in several genes associated with cisplatin resistance, including MLH1, BRCA2, and CASP8. Furthermore, RNA-Seq analysis revealed the overexpression of cisplatin resistance associated genes such as SLC7A11, TLE4, and IL1A in BLCAb001. Two different PIK3CA mutations, E542K and E545K, were identified in BLCAb001 and BLCAb002, respectively. Thus, we tested whether the genomic profiling was predictive of response to a dual PI3K/mTOR targeting agent, LY3023414. Despite harboring similar PIK3CA mutations, BLCAb001 and BLCAb002 exhibited differential response, both in vitro and in vivo. Sustained target modulation was observed in the sensitive model BLCAb002 but not in BLCAb001, as well as decreased autophagy. Interestingly, computational modelling of mutant structures and affinity binding to PI3K revealed that E542K mutation was associated with weaker drug binding than E545K. CONCLUSIONS: Our results suggest that the presence of activating PIK3CA mutations may not necessarily predict in vivo treatment response to PI3K targeted therapies, while specific gene alterations may be predictive for cisplatin response in bladder cancer models and, potentially, in patients as well.

Alternative approaches to prevent androgen action in prostate cancer: are we there yet?

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men in the U.S. Prostate cancer deaths are due to failure of androgen deprivation therapy (ADT). ADT is the standard of care for non-organ confined prostate cancer and inhibits action of androgen receptor (AR), which is necessary for the growth of prostate cancer. ADT blocks AR activity by preventing either production of its ligands or interaction between AR and its ligands. Following an initial remission, almost all patients experience prostate cancer recurrence during ADT. Remarkably, prostate cancer that reemerges remains dependent on AR. This recognition has led to the recent development of novel treatment strategies that focus on alternative means to target ligand production and availability for AR. These therapies induce remission and offer moderate survival benefits but none are curative while all are associated with significant side effects. We propose that an alternative tactic to achieve the beneficial effects of ADT could be explored by targeting a different step in the AR signaling cascade, namely the biological consequences of AR activation. Insights in molecular regulation of AR function and genome-wide AR action could be used to develop therapeutic interventions that focus on eliminating only distinct AR-dependent biological processes responsible for aggressive prostate cancer cell behavior. Such selective forms of ADT could be used alone or in combination with existing therapies to improve prostate cancer therapeutic outcome in a stage-specific and personalized manner.