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.

Heterogeneous Tumor-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient.

We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8+ and CD4+ T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8+ T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy. VIDEO ABSTRACT.

Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade.

Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms.

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.

Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.

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.

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.

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.

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.

Exercise Training Decreases Hepatic Injury and Metastases Through Changes in Immune Response to Liver Ischemia/Reperfusion in Mice.

BACKGROUND AND AIMS: Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown. APPROACH AND RESULTS: Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment. CONCLUSIONS: ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.

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.

Therapeutic Targeting of Vasculature in the Premetastatic and Metastatic Niches Reduces Lung Metastasis.

In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1ß and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic Listeria monocytogenes-based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.

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.

Does surgery benefit patients with oligometastatic or metastatic prostate cancer? - A retrospective cohort study and meta-analysis.

BACKGROUND: To evaluate long-term oncological outcomes of radical prostatectomy (RP) plus androgen deprivation therapy (ADT) in oligometastatic prostate cancer (PCa) patients. METHODS: Our study included oligometastatic PCa patients hospitalized between January 1, 2010 and December 31, 2015, who received ADT with or without RP. We evaluated survival by employing Kaplan-Meier methods, with log-rank tests and univariate and multivariate Cox regression analyses. A meta-analysis of previously published studies was additionally performed. RESULTS: The median follow-up times of both groups were 68.4 months (interquartile range = 56.5-85.0). In this cohort study, significant statistical difference in preoperative total prostate-specific antigen (tPSA; p = .121), clinical T stage (p = .115), and N stage (p = .394) were not found between the two groups. Meanwhile, the difference in overall survival (OS) between the two groups did not reach statistical significance (p = .649). A significant difference was not observed in castration-resistant prostate cancer (CRPC)-free survival between two groups as well (p = .183). Numbers of metastases might be an independent prognosis factor (p = .05) for OS, and postoperative tPSA is a risk predictor for CRPC-free survival (p = .032). A meta-analysis of four relevant studies demonstrated significant statistical difference in clinical improvement with RP plus ADT over ADT alone in OS survival (p < .001; hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.38-0.69) instead of CRPC-free survival (p = .42; HR = 0.86; 95% CI = 0.59-1.24). CONCLUSION: The addition of RP to ADT for the treatment of oligometastatic PCa was associated with an improved OS instead of CRPC-free survival.

CT-based assessment of body composition following neoadjuvant chemohormonal therapy in patients with castration-naïve oligometastatic prostate cancer.

BACKGROUND: The purpose of this study is to assess the body composition changes in men with recently diagnosed oligometastatic prostate cancer following neoadjuvant chemohormonal therapy. Further, we evaluated whether CT-based body composition parameters are associated with biochemical recurrence or imaging progression. MATERIAL AND METHODS: Recently diagnosed castration-naïve oligometastatic prostate cancer patients who received neoadjuvant docetaxel chemotherapy and androgen deprivation treatment (ADT) before prostatectomy and consolidation of local and oligometastatic disease (total eradication therapy), as part of a phase-II prospective clinical trial were included. Body composition parameters including cross-sectional areas of the psoas muscle, total, visceral, and subcutaneous adipose tissue were measured on serial CT scans obtained before and following completion of neoadjuvant treatment. RESULTS: A total of 22 prostate cancer patients were included (median age 58 years, median Gleason score 8). The median time intervals between commencement of neoadjuvant chemohormonal therapy and first and second follow-up CTs were 3 and 12 months, respectively. Compared to the baseline scan, there were significant declines in psoas muscle cross-sectional areas with estimated percentage declines of -13.9% (IQR: 7.6%-16.5%, p < .001) and -13.2% (IQR: 6%-11.2%, p < .001) on first and second follow-up CTs. There were significant increases in subcutaneous adipose tissue following neoadjuvant chemohormonal therapy with percentage increases of +8.9% (IQR: 5.1%-21.5%, p = .002) and +18.9% (IQR: 6.1%-33.8%, p < .001), respectively. The median follow-up was 34.5 months. The estimated 2-year prostate-specific antigen progression-free and radiologic progression-free survival were 95.5%. No significant association between baseline or percentage change in body composition parameters and disease progression were identified. CONCLUSIONS: Our findings showed a significant reduction in muscle mass and an increase in subcutaneous adiposity in men treated with neoadjuvant docetaxel and ADT, more pronounced on the first follow-up scan after completion of neoadjuvant treatment. Body composition parameters were not found to be significant predictors of disease progression in our cohort.

Emerging immunotherapies for metastasis.

Major advances in cancer immunotherapy have dramatically expanded the potential to manipulate immune cells in cancer patients with metastatic disease to counteract cancer spread and extend patient lifespan. One of the most successful types of immunotherapy is the immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, that keep anti-tumour T cells active. However, not every patient with metastatic disease benefits from this class of drugs and patients often develop resistance to these therapies over time. Tremendous research effort is now underway to uncover new immunotherapeutic targets that can be used in patients who are refractory to anti-CTLA-4 or anti-PD-1 treatment. Here, we discuss results from experimental model systems demonstrating that modulating the immune response can negatively affect metastasis formation. We focus on molecules that boost anti-tumour immune cells and opportunities to block immunosuppression, as well as cell-based therapies with enhanced tumour recognition properties for solid tumours. We also present a list of challenges in treating metastatic disease with immunotherapy that must be considered in order to move laboratory observations into clinical practice and maximise patient benefit.

A mathematical model of the metastatic bottleneck predicts patient outcome and response to cancer treatment.

Metastases are the main reason for cancer-related deaths. Initiation of metastases, where newly seeded tumor cells expand into colonies, presents a tremendous bottleneck to metastasis formation. Despite its importance, a quantitative description of metastasis initiation and its clinical implications is lacking. Here, we set theoretical grounds for the metastatic bottleneck with a simple stochastic model. The model assumes that the proliferation-to-death rate ratio for the initiating metastatic cells increases when they are surrounded by more of their kind. For a total of 159,191 patients across 13 cancer types, we found that a single cell has an extremely low median probability of successful seeding of the order of 10-8. With increasing colony size, a sharp transition from very unlikely to very likely successful metastasis initiation occurs. The median metastatic bottleneck, defined as the critical colony size that marks this transition, was between 10 and 21 cells. We derived the probability of metastasis occurrence and patient outcome based on primary tumor size at diagnosis and tumor type. The model predicts that the efficacy of patient treatment depends on the primary tumor size but even more so on the severity of the metastatic bottleneck, which is estimated to largely vary between patients. We find that medical interventions aiming at tightening the bottleneck, such as immunotherapy, can be much more efficient than therapies that decrease overall tumor burden, such as chemotherapy.

Synchronous Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Liver and Peritoneal Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Synchronous liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases have traditionally been contraindicated. More recent clinical practice has begun to promote this aggressive treatment in select patients. OBJECTIVE: This study aimed to investigate the perioperative and oncological outcomes of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, with and without liver resection, in the management of metastatic colorectal cancer. DATA SOURCES: Medline, Embase, and Cochrane Library databases were searched up to July 2020. STUDY SELECTION: Cohort studies comparing outcomes following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with and without liver resection for metastatic colorectal cancer were reviewed. No randomized controlled trials were available. INTERVENTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with or without synchronous liver resection were compared. MAIN OUTCOME MEASURES: The primary outcome measures were perioperative mortality and major morbidity. Secondary outcomes included 3- and 5-year overall survival and 1- and 3-year disease-free survival. RESULTS: Fourteen studies fitted the inclusion criteria, with 8 studies included in the meta-analysis. On pooled analysis, there was no significant difference in perioperative morbidity and mortality between the two groups. Patients that underwent concomitant liver resection had worse 1- and 3-year disease-free survival and 3- and 5-year overall survival. LIMITATIONS: Only a limited number of studies were available, with a moderate degree of heterogeneity. CONCLUSIONS: The addition of synchronous liver resection to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of resectable metastatic colorectal cancer was not associated with increased perioperative major morbidity and mortality in comparison with cytoreduction and hyperthermic intraperitoneal chemotherapy alone. However, the presence of liver metastases was associated with inferior disease-free and overall survival. These data support the continued practice of liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy in the management of select patients with such stage IV disease.

Clinical Benefit of Therapeutic Drug Monitoring in Colorectal Cancer Patients Who Received Fluorouracil-Based Chemotherapy.

BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.