Metastasis.

Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively treat it is still emerging. Metastasis requires the acquisition of a succession of traits to disseminate, variably enter and exit dormancy, and colonize distant organs. The success of these events is driven by clonal selection, the potential of metastatic cells to dynamically transition into distinct states, and their ability to co-opt the immune environment. Here, we review the main principles of metastasis and highlight emerging opportunities to develop more effective therapies for metastatic cancer.

Recent trends of characteristics and treatments in adults with newly diagnosed brain metastases.

OBJECTIVE: We aimed to evaluate recent trends in characteristics and treatments among patients with brain metastases in clinical practice. METHODS: All newly diagnosed patients with brain metastases during 2016-2021 at a single cancer center were enrolled. We collected the detailed features of each patient and estimated the number of candidates considered to meet the following criteria used in common clinical trials: Karnofsky performance status ≥ 70 and mutated non-small cell lung cancer, breast cancer or melanoma. The brain metastases treatments were classified as follows: (i) stereotactic radiosurgery, (ii) stereotactic radiosurgery and systemic therapy, (iii) whole-brain radiotherapy, (iv) whole-brain radiotherapy and systemic therapy, (v) surgery, (vi) immune checkpoint inhibitor or targeted therapy, (vii) cytotoxic agents and (ix) palliative care. Overall survival and intracranial progression-free survival were estimated from brain metastases diagnosis to death or intracranial progression. RESULTS: A total of 800 brain metastases patients were analyzed; 597 (74.6%) underwent radiotherapy, and 422 (52.7%) underwent systemic therapy. In addition, 250 (31.3%) patients were considered candidates for common clinical trials. Compared to 2016, the later years tended to shift from whole-brain radiotherapy to stereotactic radiosurgery (whole-brain radiotherapy: 35.7-29.1% and stereotactic radiosurgery: 33.4-42.8%) and from cytotoxic agents to immune checkpoint inhibitor/targeted therapy (cytotoxic agents: 10.1-5.0 and immune checkpoint inhibitor/targeted therapy: 7.8-10.9%). There was also an increase in the proportion of systemic therapy combined with radiation therapy (from 26.4 to 36.5%). The median overall survival and progression-free survival were 12.7 and 5.3 months, respectively. CONCLUSIONS: This study revealed the diversity of brain metastases patient characteristics, recent changes in treatment selection and the percentage of candidates in clinical trials.

Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.

Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.

Intervencionismo para el control del dolor por metástasis óseas / Interventionism for pain control due bone metastases

Objetivo: El dolor óseo por cáncer óseo o metástasis es un dolor de difícil manejo asociado a dolor incidental. Hay distintas estrategias quirúrgicas para su tratamiento, sin embargo, no todos los pacientes con metástasis óseas pueden beneficiarse de un tratamiento quirúrgico. La presente revisión bibliográfica tiene como objetivo identificar terapias intervencionales mínimamente invasivas para el control del dolor por metástasis óseas. Métodos: Revisión bibliográfica acerca de terapias intervencionales para el control del dolor por metástasis óseas utilizando la base de datos PubMed (www.pubmed.gov) y el motor de búsqueda Google (www.google.cl). Tipos de participantes: Pacientes con metástasis óseas dolorosas de cualquier tumor primario. Tipos de intervenciones: Bloqueos anestésicos, bloqueos neurolíticos, terapias ablativas, cementoplastías. Resultados: Se obtuvieron 384 resultados que incluyeron revisiones sistemáticas, revisiones bibliográficas, ensayos clínicos controlados, series de casos y reporte de casos. Todos los artículos relevantes en inglés y español se incluyeron para su análisis. Conclusión: Las metástasis óseas son un evento común en los pacientes con cáncer, y el dolor óseo es un dolor de difícil manejo asociado a dolor incidental. Se han desarrollado terapias intervencionales no invasivas o mínimamente invasivas para tratar el dolor, mejorar la calidad de vida y la funcionalidad, disminuir el consumo de fármacos, y reducir el tamaño del tumor. La gran mayoría ha demostrado ser terapias seguras y eficaces, con pocos eventos adversos y de rápida resolución, y que si son combinadas mejoran los resultados.

Objective: Bone pain from bone cancer or metastasis is a pain that is difficult to manage associated with incidental pain. There are different surgical strategies for its treatment, however, not all patients with bone metastases can benefit from a surgical treatment. This literature review aims to identify minimally invasive interventional therapies for the control of pain due to bone metastasis. Methods: Literature review of interventional therapies for the control of pain due to bone metastases was done using the PubMed database (www.pubmed.gov) and the Google search engine (www.google.cl). Types of participants: Patients with painful bone metastases from any primary tumor. Types of interventions: Anesthetic blocks, neurolytic blocks, ablative therapies, cementoplasties. Results: We obtained 384 results that included systematic reviews, literature reviews, controlled clinical trials, case series and case reports. All relevant articles in English and Spanish were included for analysis. Conclusion: Bone metastases are a common event in cancer patients, and bone pain is a difficult-to-manage pain associated with incidental pain. Non-invasive or minimally invasive interventional therapies have been developed to treat pain, improve quality of life and functionality, decrease drug use, and reduce tumor size. The vast majority therapies have been shown to be safe and effective ones, with few adverse events and rapid resolution, and that if combined they improve the outcomes.

Effect of Electronic Symptom Monitoring on Patient-Reported Outcomes Among Patients With Metastatic Cancer: A Randomized Clinical Trial.

Importance: Electronic systems that facilitate patient-reported outcome (PRO) surveys for patients with cancer may detect symptoms early and prompt clinicians to intervene. Objective: To evaluate whether electronic symptom monitoring during cancer treatment confers benefits on quality-of-life outcomes. Design, Setting, and Participants: Report of secondary outcomes from the PRO-TECT (Alliance AFT-39) cluster randomized trial in 52 US community oncology practices randomized to electronic symptom monitoring with PRO surveys or usual care. Between October 2017 and March 2020, 1191 adults being treated for metastatic cancer were enrolled, with last follow-up on May 17, 2021. Interventions: In the PRO group, participants (n = 593) were asked to complete weekly surveys via an internet-based or automated telephone system for up to 1 year. Severe or worsening symptoms triggered care team alerts. The control group (n = 598) received usual care. Main Outcomes and Measures: The 3 prespecified secondary outcomes were physical function, symptom control, and health-related quality of life (HRQOL) at 3 months, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference [MCID], 2-7 for physical function; no MCID defined for symptom control or HRQOL). Results on the primary outcome, overall survival, are not yet available. Results: Among 52 practices, 1191 patients were included (mean age, 62.2 years; 694 [58.3%] women); 1066 (89.5%) completed 3-month follow-up. Compared with usual care, mean changes on the QLQ-C30 from baseline to 3 months were significantly improved in the PRO group for physical function (PRO, from 74.27 to 75.81 points; control, from 73.54 to 72.61 points; mean difference, 2.47 [95% CI, 0.41-4.53]; P = .02), symptom control (PRO, from 77.67 to 80.03 points; control, from 76.75 to 76.55 points; mean difference, 2.56 [95% CI, 0.95-4.17]; P = .002), and HRQOL (PRO, from 78.11 to 80.03 points; control, from 77.00 to 76.50 points; mean difference, 2.43 [95% CI, 0.90-3.96]; P = .002). Patients in the PRO group had significantly greater odds of experiencing clinically meaningful benefits vs usual care for physical function (7.7% more with improvements of ≥5 points and 6.1% fewer with worsening of ≥5 points; odds ratio [OR], 1.35 [95% CI, 1.08-1.70]; P = .009), symptom control (8.6% and 7.5%, respectively; OR, 1.50 [95% CI, 1.15-1.95]; P = .003), and HRQOL (8.5% and 4.9%, respectively; OR, 1.41 [95% CI, 1.10-1.81]; P = .006). Conclusions and Relevance: In this report of secondary outcomes from a randomized clinical trial of adults receiving cancer treatment, use of weekly electronic PRO surveys to monitor symptoms, compared with usual care, resulted in statistically significant improvements in physical function, symptom control, and HRQOL at 3 months, with mean improvements of approximately 2.5 points on a 0- to 100-point scale. These findings should be interpreted provisionally pending results of the primary outcome of overall survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03249090.

Treatment of Metastasis in the Appendicular Skeleton / Tratamento das metástases no esqueleto apendicular

Abstract Bone metastases may evolve with events (pain, fractures and compression) that the orthopedic surgeon will encounter regardless of his subspecialty. Accumulated surgical knowledge is predictive for the prevention of impending fractures, as well as of pathological fractures. We will present a guide to properly evaluate and conduct a patient with bone implant for surgeons who are not specialists in this area.

Resumo As metástases ósseas podem evoluir com eventos (dor, fraturas e compressão) com os quais o cirurgião ortopédico irá se depararar independentemente da sua subespecialidade. Os conhecimentos cirúrgicos acumulados são predicativos para a prevenção de fraturas iminentes, assim como de fraturas patológicas. Apresentaremos um guia para avaliar e conduzir de forma adequada um paciente com implante ósseo para cirurgiões que não sejam especialistas na área.

Complementary Medicine Use Amongst Patients with Metastatic Cancer Enrolled in Phase III Clinical Trials.

BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer.

The cGAS-STING pathway serves a critical role in anticancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance. Here, we used combined expression data from 2,307 tumors from five cancer types from The Cancer Genome Atlas to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy-treated cohort, patients with low cGAS-STING expression showed limited response to treatment, while patients with high expression showed improved response and prognosis, particularly among patients with high CIN and more neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this suggests a potential role of cGAS-STING activity as a predictive biomarker for the application of immunotherapy. Significance: The cGAS-STING pathway is induced by CIN, triggers inflammation and is often deficient in cancer. We provide a tool to evaluate cGAS-STING activity and demonstrate clinical significance in immunotherapy response.

Prognostic role of 11C-choline PET/CT scan in patients with metastatic castrate resistant prostate cancer undergoing primary docetaxel chemotherapy.

BACKGROUND: We sought to assess the prognostic utility of 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with metastatic castrate resistant prostate cancer (mCRPC) undergoing primary docetaxel chemotherapy. METHODS: We performed a single institution retrospective analysis of 77 mCRPC patients who were treated with 6 cycles of docetaxel chemotherapy, and who also underwent 11C-choline PET/CT scans at baseline (before chemotherapy), mid-course (after 3 cycles), and posttherapy (after 6 cycles). We evaluated treatment response based on percent change in blood pool-corrected maximum standardized uptake value (SUVmax) of the target lesion on PET/CT, as well as percent change in serum prostate specific antigen (PSA). Logistic regression analysis was used to identify factors associated with complete treatment response. Progression free survival (PFS) analysis was performed using log-rank test and shown on Kaplan-Meier plot. RESULTS: Percent change in blood pool-corrected SUVmax on mid-course scan was a significant predictor of complete response (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-0.99, p = .0003), whereas percent change in PSA was not (OR: 0.99, 95% CI: 0.99-1.01, p = .6025). 57 of 77 patients (74%) achieved ≥20% reduction in blood pool-corrected SUVmax on mid-course; these patients were 3.6 times more likely to achieve complete response after full 6 cycles of docetaxel chemotherapy, compared to patients with <20% reduction in blood pool-corrected SUVmax (OR: 3.56, 95% CI: 1.04-16.52, p = .0420). Median PFS in the complete response group was 35.1 months (95% CI: 26.0-52.7 months), compared to 9.4 months (95% CI: 6.9-13.0 months) in the incomplete response group (p = .0005). CONCLUSIONS: Our study showed that mid-course and posttherapy 11C-choline PET/CT evaluation for mCRPC patients undergoing primary docetaxel chemotherapy can predict full course treatment response and PFS, respectively. 11C-choline PET/CT imaging may provide valuable prognostic information to guide treatment choices for patients with mCRPC.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Systematic Review.

BACKGROUND: Combined treatment modality of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is emerging as an alternative option for colorectal peritoneal metastases, but there is ambiguity regarding patient selection, treatment protocols, and efficacy. OBJECTIVE: To elaborate on the patient characteristics, hyperthermic intraperitoneal chemotherapy protocol and health outcomes in colorectal peritoneal metastases patients undergoing a combination of hyperthermic intraperitoneal chemotherapy and cytoreductive surgery and provide guidance for future studies. DATA SOURCES: A Medline search for English language studies published between 2004 and 2019. STUDY SELECTION: Medical subject headings and key terms, including: hyperthermic intraperitoneal chemotherapy, colorectal peritoneal metastases, colorectal cancer and combinations thereof as per guidelines. MAIN OUTCOME MEASURES: Overall survival, disease-free survival, and morbidity and mortality rates. RESULTS: Of the 26 included studies, 42% were published between 2016 and 2019. More than half of the studies were retrospective in nature and conducted in tertiary specialized centers outside of the United States. The median age range was 44 to 62 years. Mitomycin C-based therapy was seen in 50% of studies. Mean weighted median disease-free survival for 11 studies was 15 months (9 to 36 months). Median OS ranged from 12 to 63 months, with an average of 33.6 months among 20 studies. Overall morbidity varied from 11% to 56%, with a weighted mean of 29% in 18 studies. Mortality ranged from 0 to 34%, with a weighted mean of 4% in 15 studies. LIMITATIONS: Despite careful study selection, variability in methodology of the included studies can limit review findings. CONCLUSION: Due to study heterogeneity, and a recent large, randomized trial showing no overall benefit, use of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in colorectal peritoneal metastases patients is highly controversial. Further standardized controlled studies can help uniformly define and build consensus among the medical community on patient eligibility and the optimal hyperthermic intraperitoneal chemotherapy techniques. PROSPERO: Registered on March 3, 2020, CRD42020146942.

Overall and progression-free survival of Afro-Caribbean men with metastatic castration-resistant prostate cancer (mCRPC).

INTRODUCTION: Several studies in the Caucasian population have shown the benefit of using docetaxel, abiraterone, or enzalutamide for patients with metastatic prostate cancer at the castration-resistant stage (mCRPC). However, there are no strong data for men of African ancestry. The objective of this study was to estimate the overall and progression-free survival of patients according to these treatments at the mCRPC stage. PATIENTS AND METHODS: This was a monocentric retrospective study that consecutively included 211 men with mCRPC between June 1, 2009 and August 31, 2020. The primary end point was overall survival (OS). The secondary end point was progression-free survival. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS: The present study included 180 patients for analyses. There was no difference in OS (log-rank test = 0.73), with a median follow-up of 20.7 months, regardless of the treatment administered in the first line. Men with mCRPC who received hormonotherapy (abiraterone or enzalutamide) showed better progression-free survival than those who received docetaxel (log-rank test = 0.004), with a particular interest for abiraterone hazard ratio (HR) = 0.51 (95% confidence interval: 0.39-0.67). The patient characteristics were similar, except for bone lesions, irrespective of the treatment administered in the first line. After univariate then multivariate analysis, only World Health Organization status and metastases at diagnosis were significantly associated with progression. CONCLUSION: Our results suggest the use of hormonotherapy (abiraterone or enzalutamide) with a tendency for abiraterone in first line for men with African ancestry at the mCRPC stage.

Impact of Tumor Growth Speed of Primary Lesions on the Clinical Outcomes of Appendicular Skeletal Metastases.

BACKGROUND/AIM: This study aimed to investigate the clinical influence of the growth speed of primary lesions on appendicular skeletal metastases to provide an optimal treatment strategy for the metastases. PATIENTS AND METHODS: Fifty-seven patients who underwent surgery for appendicular skeletal metastases between 2008 and 2020 were included. According to the growth speed of primary lesions, the patients were divided into the S group (slow-to-moderate, n=34) and the R group (rapid, n=23), and the outcomes were investigated. RESULTS: The period from diagnosis of skeletal metastases to pathological fracture (PF) was shorter in the R group than in the S group (p=0.24). The overall survival of the S group was significantly better than that of the R group (p=0.02). CONCLUSION: The appendicular skeletal metastases of the primary tumor with rapid growth speed have a high risk of PFs developed early from the diagnosis of skeletal metastases, and the prognosis may be poor.

Evolutionary game theory and oligometastatic patient: considering the role of interventional oncology.

The possible role of evolutionary game theory (EGT), to pursue a tailored therapeutic strategy, has recently gained widespread interest within the clinical setting of oncological patients. The potentially revolutionary shift of paradigm suggested by EGT points to the fact that, for metastatic patients, the optimal therapeutic strategy should be aimed at reducing the survival fitness of tumor cells compared with normal cells, thus allowing natural selection to help control the overall tumor burden, instead of trying to kill all tumor cells. A specific subset of metastatic patients, the so-called oligometastatic patients, has not been adequately considered so far in the light of EGT theoretical approach. A modern and comprehensive definition of oligometastatic patient should consider at least three main parameters: the total number of lesions, the timing of their appearance and their biological heterogeneity. A valid therapeutic option for oligometastatic patients could be to integrate together both systemic and local therapies, such as interventional oncology. The potential advantage of implementing interventional oncology in the clinical practice, for example in oligorecurrent or oligoprogressive patients, could be to delay or even to avoid unnecessary shifts in systemic therapies. Another important point to consider is the potential role that the treatment of a single metastatic site may have in terms of immune system activation towards other untreated metastatic sites; such phenomenon is known as abscopal effect.

Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis.

Bone marrow is a preferred metastatic site for multiple solid tumours and is associated with poor prognosis and significant morbidity. Accumulating evidence indicates that cancer cells colonise specialised niches within the bone marrow to support their long-term propagation, but the precise location and mechanisms that mediate niche interactions are unknown. Using breast cancer as a model of solid tumour metastasis to the bone marrow, we applied large-scale quantitative three-dimensional imaging to characterise temporal changes in the bone marrow microenvironment during disease progression. We show that mouse mammary tumour cells preferentially home to a pre-existing metaphyseal domain enriched for type H vessels. Metastatic lesion outgrowth rapidly remodelled the local vasculature through extensive sprouting to establish a tumour-supportive microenvironment. The evolution of this tumour microenvironment reflects direct remodelling of the vascular endothelium through tumour-derived granulocyte-colony stimulating factor (G-CSF) in a hematopoietic cell-independent manner. Therapeutic targeting of the metastatic niche by blocking G-CSF receptor inhibited pathological blood vessel remodelling and reduced bone metastasis burden. These findings elucidate a mechanism of 'host' microenvironment hijacking by mammary tumour cells to subvert the local microvasculature to form a specialised, pro-tumorigenic niche.

Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo.

Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.