Radiographic and serologic response in patients with unresectable hepatocellular carcinoma receiving systemic antineoplastic treatments: A trial-level analysis.

BACKGROUND: In a disease like unresectable hepatocellular carcinoma, overall survival is an inadequate outcome measure for evaluating the effectiveness of treatments given the high risk of death from liver failure. There is an unmet need for reliable alternative end points for clinical trials and daily clinical practice. To evaluate treatment response in patients with unresectable or metastatic hepatocellular carcinoma (mHCC), imaging-related end points are often used, whereas serologic end points have been developed for patients with serum alpha-fetoprotein levels >20 ng/mL. The objective of this study was to evaluate clinical trials that report concomitant assessment of radiographic and serologic response in patients with mHCC. METHODS: After a systematic review, studies that evaluated response according to radiographic and serologic criteria were selected. A correlation between progression-free survival (PFS) and overall survival (OS) was performed, and a linear regression of each response-related outcome measure with OS was reported. Finally, the effect of eight baseline variables on OS and response-related measures was evaluated. RESULTS: Twenty-six studies were included, including 16 first-line studies and 10 second-line studies. PFS and response rates demonstrated a significant relationship with OS, whereas disease control rates did not. The responses were correlated with OS, particularly in the first-line setting, after targeted therapy, and whenever assessment was early. Among the baseline variables, only performance status had a prognostic role, whereas hepatitis B virus-related liver disease was associated with higher radiographic response rates. CONCLUSIONS: PFS and radiographic and serologic response rates appear to be reliable intermediate end points in patients with mHCC who are undergoing systemic antineoplastic therapy. However, the serologic response is available earlier.

Reduction of derived neutrophil-to-lymphocyte ratio after four weeks predicts the outcome of patients receiving second-line chemotherapy for metastatic colorectal cancer.

Systemic inflammation response (SIR) plays a role in predicting prognosis of patients with metastatic colorectal cancer (mCRC). Chemotherapy-induced neutropenia has been suggested as another evaluable prognostic and predictive factor. This is a retrospective analysis of derived neutrophil-to-lymphocyte ratio (dNLR) and its reduction > 10% after the first cycle of chemotherapy (R10) in a monoinstitutional series of patients with mCRC receiving a first-line and a second-line cytotoxic chemotherapy. The effects of the neutrophil-related variables on overall survival (OS) and on chemotherapy activity were analyzed. One hundred twenty-eight patients were selected. A relationship of dNLR with OS was evident at both time points, but disappeared after multivariate analysis, whereas R10 was independent prognostic factor only after second-line chemotherapy in multivariate analysis. A dNLR reduction > 10% before the second cycle predicts OS and disease control from second-line chemotherapy in patients with mCRC, in particular among patients with right-sided tumors and synchronous metastases.

Systemic Inflammation Scores Predict the Activity of First-Line Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma.

BACKGROUND: Systemic inflammation response (SIR)-related variables are controversial as predictive variables. METHODS: Patients with metastatic pancreatic adenocarcinoma (mPDAC) receiving chemotherapy were identified, three SIR-related variables and the relationships between each of them with overall survival (OS) were analysed. RESULTS: Of 129 patients receiving chemotherapy, 97 had metastases. A significant relationship between SIR and OS has been documented. Each of the SIR-related variables retained its independent prognostic role after multivariate analysis, whereas tri-linear peripheric blood-cell score (TRIS) appeared as the most reliable predictive parameter. CONCLUSIONS: Among patients with mPDAC receiving chemotherapy, SIR is prognostic and could predict the effectiveness of chemotherapy.

Leukocyte kinetics during the first cycle of chemotherapy predicts the outcome of patients with metastatic colorectal cancer and previous resection of the primary tumor.

BACKGROUND: Many reports suggest more activity of cytotoxic chemotherapy among patients with metastatic colorectal cancer (mCRC) who experience neutropenia, but it is not clear whether this finding is related to drug effect alone. The aim of the study is to identify the characteristics of patients whose peripheral blood cell kinetics (PBCK) is related to the outcome. METHODS: The study is a retrospective analysis of patients with mCRC who had received first-line chemotherapy at Sanremo hospital from 2010 to 2015, evaluating seventeen baseline variables, six related to systemic inflammatory response activation (SIRA), and six to peripheral blood cell kinetics after one cycle. The relationship of peripheral blood cell kinetics variables was evaluated by tumor location, SIRA, and timing of metastases. RESULTS: Among 203 eligible patients, only four variables were able to independently predict survival (age, CA 19-9, number of drugs, chemotherapy-induced leukopenia after the first cycle or CIL-1). After stratification by tumor location or by SIRA, no relationship of PBCK variables with prognosis was present. On the contrary, after stratification by timing of metastasis, the prognostic role of CIL-1 was evident among patients with metachronous metastases, particularly among those with low SIRA and colon tumors, whereas the leukocyte reduction after the first cycle (WR) predicted longer survival of patients with synchronous metastases and a previous resection of the primary tumor (PTR). CONCLUSIONS: Absolute leukocyte reduction (CIL-1) predicts a better OS of patients with metachronous metastases, whereas relative leukocyte reduction (WR) could be prognostic among patients with synchronous metastases who have received PTR.

Tumor growth kinetics by CA 19-9 in patients with unresectable pancreatic cancer receiving chemotherapy: A retrospective analysis.

BACKGROUND: Recently, measures of tumor growth kinetics calculated by carbohydrate antigen 19-9 (CA 19-9) determinations after cytotoxic chemotherapy (CHT) have been reported as effective prognostic indicators in locally-advanced unresectable and metastatic pancreatic adenocarcinoma (mPDAC). The study aims to evaluate the prognostic role of tumor kinetics measured by CA 19-9 in patients with mPDAC, measuring it by three different ways. METHODS: Patients with mPDAC receiving a first-line CHT between 2009 and 2017 were identified, and those for whom CA 19-9 data were available were enrolled. Three CA 19-9-related variables were calculated: CA 19-9 related reduction rate (RR) and tumor growth rate (G), after 8 weeks of CHT, tumor growth and inflammation index (TGII), after 90 days of CHT. The relationships with the outcome were analysed, and a Cox model has been build with each of the three variables. RESULTS: Of 118 patients only 48 were eligible for the analysis. RR, G, or TGII appear as significant prognostic factors, and, after multivariate analysis, a reduction rate of 20% the baseline or more was associated with good survival (HR 0.321; CIs 0.156-0.661) as well as a G > -0.4%/day (HR 2.114; CIs 1.034-4.321), whereas TGII >190 was not correlated with the outcome (HR 1.788; CIs 0.789-4.055). CONCLUSIONS: In patients with mPDAC, after 8 weeks of first-line CHT, CA 19-9-related tumor reduction or growth rate appear as valuable prognostic factors.

Carcinoembryonic antigen reduction after medical treatment in patients with metastatic colorectal cancer: a systematic review and meta-analysis.

PURPOSE: The introduction of new drugs and multimodal treatments for the management of patients with metastatic colorectal cancer (mCRC) has reduced the importance of time-to-event endpoints and reported the attention on the response-related endpoints. Furthermore, the prognostic role of the surgical scores before the resection of metastases has not been confirmed for multimodal treatments. The purpose of this research is to perform a meta-analysis of the studies that evaluated the relationship between carcinoembryonic antigen (CEA) response and outcome in patients with mCRC receiving systemic chemotherapy. METHODS: A systematic review of the literature on two databases and a selection of studies that evaluated the relationship between CEA response and outcome were performed according to predefined criteria. After, three meta-analyses were carried out on the selected studies, each for each outcome variable. RESULTS: Nineteen studies have been selected. Fourteen studies (1475 patients) have documented a close association between radiological response and CEA response (odds ratio (OR), 9.03; confidence intervals (CIs), 5.14-15.87; I2 statistic (I2), 72%). Four studies have reported a longer progression-free survival for patients with a CEA response (hazard ratio (HR), 0.73; CIs, 0.64-0.83; I2, 23%). Finally, 10 studies (13 study cohorts) have shown a strong relationship between CEA response and overall survival (OS) (HR, 0. 62; CIs, 0.55-0.70; I2, 35%). CONCLUSIONS: CEA response merits further investigation as a surrogate endpoint of clinical trials of first-line medical therapy of patients with mCRC, and should be studied as a prognostic factor for those patients who are candidates for multimodal treatment strategies.

Early tumor shrinkage after first-line medical treatment of metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Early tumor shrinkage (ETS) is a response-related endpoint of clinical trials of chemotherapy (CHT) of patients with metastatic colorectal cancer (mCRC). It identifies a dimensional reduction of tumor size by at least 20-30% after 6-8 weeks of CHT. METHODS: A literature search of randomized trials of systemic treatment including CHT with or without antiangiogenics or anti-EGFR inhibitors in patients with mCRC has been conducted, and studies reporting the results of the relationship of ETS with overall survival (OS) and progression-free survival (PFS) were selected. RESULTS: Twelve trials, including 3117 patients, have been included; all data were retrospective and only 72% of the enrolled patients have been evaluated for ETS. Two meta-analyses, each including 20 study cohorts from the selected 12 trials, reported a strong relationship of ETS with OS (HR 0.62; CIs 0.55-0.69) and of ETS with PFS (HR 0.66; CIs 0.60-0.73). However, both meta-analyses displayed a high level of heterogeneity. Among nine possible moderators, three variables (median age, surgery of metastases, and publication year) were able to explain at least a part of this heterogeneity. CONCLUSION: ETS is a simple and interesting intermediate endpoint for clinical practice and future trials of medical treatments of patients with mCRC, but a large prospective analysis and validation are mandatory.

Analysis of response-related endpoints in trials of first-line medical treatment of metastatic colorectal cancer.

BACKGROUND: Tumor radiologic response after systemic chemotherapy has been used as endpoint of trials of patients with metastatic colorectal cancer (mCRC), which can report the best overall response rate (ORR) and the disease control rate (DCR) by RECIST criteria as well as the early tumor shrinkage (ETS). The present study perform a trial-level analysis to verify whether such response-related endpoints are predictive of overall survival (OS). METHODS: After a systematic search, randomized clinical trials (RCTs) were selected each time they evaluated the three response endpoints and progression-free survival (PFS). Two arms per trial were selected, and the correlation between the difference in each endpoint and the difference in OS was calculated. The analysis then evaluated the effects of treatment on ∆ORR, or ∆DCR, ∆ETS, ∆PFS, and on ∆OS, using separate linear regressions for each of them, and the proportion of variability explained (R2trial) on OS for each of the four endpoints was calculated. RESULTS: The systematic review of the literature led to the selection of 12 RCTs, 7 phase-3 and 5 phase-2. ETS reported a different performance in the entire sample compared to phase-3 trials (R2trial = 0.172 vs. 0.842), differently from DCR (R2trial = 0.541 vs. 0.816) and ORR (R2trial = 0.349 vs. 0.740). Surprisingly, PFS predicted OS with a weak correlation, which was not significant in the subgroup of phase-3 studies (R2trial = 0.455 vs. 0.466). CONCLUSION: The results of the present trial-level analysis report a good performance of two response-related endpoints, DCR and ETS, and suggest that they could be differently used depending on the setting of disease and the type of medical treatment.

Outcomes and Prognostic Factors of Patients with Unresectable or Metastatic Esophageal Squamous Cell Carcinoma Undergoing Immunotherapy- Versus Chemotherapy-Based Regimens: Systematic Review and Pooled Analyses.

OBJECTIVE: Immunotherapy-based regimens (IMT) versus cytotoxic chemotherapy (CHT) improved overall survival (OS) of patients with unresectable or metastatic esophageal squamous cell carcinoma (mESCC), but the role of prognostic variables is unclear. The study aims to explore the interaction of prognostic factors with survival after IMT or CHT. METHODS: A systematic review was performed to select trials comparing IMT and CHT regimens in mESCC patients. A meta-analysis of upfront IMT + CHT vs. CHT trials evaluated the overall effect size and heterogeneity between studies. In view of the expected differences between chemotherapy and immunotherapy on the survival curve, to better explore the effect of any prognostic variables on OS, before and after progression, the treatment arms were evaluated as independent cohorts, and ten baseline variables were extracted and assessed by linear regression. RESULTS: Fourteen trials were identified. Seven studies compared upfront CHT + IMT vs. CHT documenting longer OS for CHT + IMT (HR 0.69, CI 0.65-0.72), without heterogeneity (Q = 1.43, p value = 0.968) or differences in the most represented subgroups. Twenty-nine study cohorts were selected from the 14 trials. Median OS and PPS, but not PFS, were significantly increased after IMT compared with CHT. The analysis of baseline variables after CHT documented a favorable prognostic effect for advanced age (ß = 0.768, p value = 0.016), involvement of 0-1 metastasis sites (ß = 0.943, p value = 0.005), and absence of previous radiation therapy (ß = - 0.939, p value = 0.006), while none of them influenced prognosis after IMT. CONCLUSION: The introduction of upfront IMT prolonged mESCC patients OS, mostly improving the outcomes of young patients, with multiple metastasis sites and without previous radiotherapy.

Effect of Subgroups on Study Outcomes in Unresectable Hepatocellular Carcinoma Undergoing Upfront Systemic Treatment: A Meta-analysis.

OBJECTIVES: Immunotherapy improved the outcome of patients with unresectable hepatocellular carcinoma, but not all studies are in agreement, nor is it clear whether certain subgroups have really benefited. This study aims to perform an updated meta-analysis of trials comparing upfront immunotherapy-based regimens versus tyrosin-kinase inhibitors, and some exploratory analyses. METHODS: After a systematic review, randomized trials of immunotherapy-based regimens versus tyrosin-kinase inhibitors were selected. A meta-analysis assessed the relationship between treatment arm and overall survival. Based on the resulting heterogeneity, a further investigation of 11 variables by meta-regression and an exploration of subgroups were planned. RESULTS: Eight studies were selected. From the meta-analysis, the overall survival improvement for the immunotherapy-based arms was consistent (HR: 0.77, CI: 0.68-0.88), although heterogeneity between studies was significant ( Q =16.37; P =0.0373; I2 =51.1%). After meta-regression, the effect of the experimental arm was more pronounced in the elderly and lost among patients with HCV-related liver disease. Subgroups suggested a favorable effect of immunotherapy in patients with HBV-related hepatocellular carcinoma, extrahepatic dissemination, and elevated alpha-fetoprotein. CONCLUSION: The study results confirm the significant overall survival improvement after immunotherapy-based regimens but suggest different effects on the outcome depending on age, etiology of liver disease, and tumor burden.

CA125-related measures of tumor kinetics and outcome of patients with recurrent ovarian cancer receiving chemotherapy: a retrospective evaluation.

OBJECTIVE: Defining the reliability of cancer antigen-125-related kinetics criteria versus Gynecologic Cancer Inter Group criteria in predicting the tumor outcome after chemotherapy in patients with recurrent ovarian cancer. METHODS: A retrospective monoinstitutional assessment of CA125-related versus Gynecologic Cancer Inter Group-related parameters was performed after cytotoxic chemotherapy in patients with metastatic ovarian cancer treated from 2006 to 2011. A correlation analysis between the response and progression measurements has been performed, and the outcome has been reported. RESULTS: Among 42 eligible patients, tumor response and progression calculated by CA125 kinetics, with tumor response at 8 weeks and specific growth rate at progression, exhibited a significant correlation with progression-free and overall survival, similar to tumor response and progression by Gynecologic Cancer Inter Group criteria. CONCLUSIONS: The tumor response at 8 weeks higher than 1.77 appears to be a good surrogate of clinical response, whereas the definition of progression when CA125 increases above a value double than the nadir suggests a similar performance of growth rate at progression versus Gynecologic Cancer Inter Group criteria and warrants further investigation.

Neutrophil-to-lymphocyte ratio predicts survival of patients with rectal cancer receiving neo-adjuvant chemoradiation followed by radical resection: a meta-analysis.

BACKGROUND: Neutrophil-to-lymphocyte ratio is suggested as a prognostic and predictive factor for patients with rectal cancer. The purpose of the current meta-analysis is to evaluate the relationship between neutrophil-lymphocyte ratio (NLR) and the outcome of patients, with rectal cancer receiving chemoradiation and surgery. METHODS: A systematic review on two databases and a selection of studies were done. Thereafter, two meta-analyses were performed, evaluating the relationship of baseline NLR with overall survival (OS) and disease-free survival (DFS). RESULTS: Thirty-one retrospective studies were selected. Twenty-six studies have documented a significant relationship of NLR to OS (HR 2.05, CI 1.66-2.53), whereas 23 studies have reported a weaker but significant relationship of NLR to DFS (HR 1.78, CI 1.49-2.12). Among the moderator variables, a possible effect for age and sex on the relationship of NLR with DFS is suggested. CONCLUSIONS: Baseline NLR >3 is a simple and reproducible prognostic factor, with a more consistent effect in the elderly. It could be a reliable variable to support clinicians in defining personalized treatment strategies, even though a standardization of the cutoff and a better characterization among microsatellite unstable rectal tumors are necessary.

Prognostic Effect of Performance Status on Outcomes of Patients with Colorectal Cancer Receiving First-Line Chemotherapy: A Meta-analysis.

BACKGROUND: Performance status (PS) is a variable derived from the assessment of a patient's functional status, originally proposed to predict drug toxicity. However, despite its characteristic of being subjective and unidimensional, it has become one of the most important prognostic variables for patients with metastatic colorectal cancer (mCRC). In light of the considerable progressive prolongation of median overall survival (OS) of patients with mCRC, it is unclear whether PS continues to be a valid prognostic factor. This article aims to perform a meta-analysis to verify the current prognostic role of PS. METHODS: A search on two databases of prospective trials of first-line chemotherapy in mCRC patients, published in English from 1991 to 2020, was done by predefined criteria. After the selection of phase III trials evaluating the prognostic role of PS, a meta-analysis has been performed. RESULTS: Thirteen trials were included in the meta-analysis. They reported a reduction in the risk of death with a PS 0 compared to a PS 1 or more (HR 0.63, CI 0.54-0.72; 13 studies), which was confirmed for the comparison between PS 0 and PS 1. However, the study found significant heterogeneity (Q = 68.10; p-value < 0.001) and high-grade inconsistency (I2 = 82.38%). Therefore, to explore the reasons for the heterogeneity, a univariate meta-regression was performed, which suggested a possible moderating activity for liver metastases and timing of metastasis. CONCLUSIONS: PS is a reliable prognostic factor for patients with mCRC receiving first-line chemotherapy but is poorly evaluated in phase III trials.

Primary tumor resection in patients with unresectable colorectal cancer with synchronous metastases could improve the activity of poly-chemotherapy: A trial-level meta-analysis.

INTRODUCTION: Primary tumor resection (PTR) in patients with metastatic unresectable colorectal cancer is less and less used to prevent local complications. Although its therapeutic effect is debated, poor data are available about the activity of chemotherapy (CHT) after PTR. The study aims to evaluate trials that compared PTR followed by CHT vs. CHT alone. METHODS: After a literature search on two databases by predefined criteria, studies published from 2011 to 2021 were selected. All studies evaluating the progression-free survival (PFS) of patients receiving CHT after PTR or not were included in a meta-analysis. Finally, 18 possible moderating variables were extracted from each study and examined. RESULTS: Eleven trials reported a reduced risk of progression after first-line CHT among patients receiving PTR (HR 0.72, CI 0.66-0.79). The heterogeneity was moderate (Q = 17.52; p-value = 0.093) and the grade of inconsistence intermediate (I2 = 37.21%). Among moderating variables, female sex and low percentage of patients with liver metastases were related with a stronger effect size of PTR on PFS, whereas a longer OS and a trend to better PFS was evident after poly-chemotherapy regimens. CONCLUSION: PTR could improve the results of first-line CHT in patients with unresectable colorectal cancer with low tumor burden only in the subgroup receiving more aggressive chemotherapy.

The evolving role of familial history for prostate cancer.

BACKGROUND: family history of prostate cancer is a risk factor for prostate cancer occurrence. Differently from other neoplasms no major predisposing gene has been identified. MATERIAL AND METHODS: this review article presents the controversial results of studies about the prognostic and predictive role of family history in prostate cancer, reports the discovered predisposing genes, and biologic and pathologic findings. RESULTS: mortality from PC remains a significant health care problem, but no trial investigated if it changed in presence of positive family history. The largest family study yet published concluded that men with family history are diagnosed and die at earlier ages than men without it. However, it failed to stress the prognostic value of family history. Genome-wide association studies of prostate cancer have identified a number of genetic variants at different loci in different populations. Prostate neoplasms of patients with positive family history exhibit a different pattern of expression of genes related with estrogen and androgen metabolism within the tumor. High-penetrance and low-penetrance genes in diagnosis and prognosis of prostate cancer, difficulties to define a classification and to quantify relative risks of single genes, documented gene-environment interactions are discussed. CONCLUSION: family history stands for both shared genetic and environmental factors and their interaction. The availability of prostate-specific antigen test could explain partly the high familial risk, among brothers or shortly after the diagnosis of prostate cancer. Polymorphisms in genes associated with prostate cancer probably represent the most part of familial prostate cancer burden. An increasing knowledge of disregulated cellular pathways of lethal prostate cancer could define which of all genetic alterations have a role in defining new preventive and therapeutic strategies.

Peripheral Blood Cell Variables Related to Systemic Inflammation in Patients With Unresectable or Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

ABSTRACT: Systemic inflammatory response (SIR) plays a central role in the prognosis of unresectable or metastatic pancreatic ductal adenocarcinoma (mPDAC), and many SIR-related peripheral blood cell (PBC)-derived variables have been proposed as prognostic factors. The study aims to perform a systematic review and, for the more studied PBC-derived variables, a meta-analysis. A systematic review from 2000 to 2020 on 2 databases by predefined criteria was performed for PBC-derived variables in patients with mPDAC receiving chemotherapy in relation with overall survival. Eligible studies were selected by inclusion criteria, and only the PBC variables reported in at least 10 studies were evaluated by meta-analysis. Three hundred and eighty articles were found, and 28 studies were selected. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were reported in 28 and 10 articles, respectively. The subsequent meta-analyses supported the prognostic effect for both, NLR (hazard ratio, 2.10; 95% confidence interval, 1.87-2.37) and PLR (hazard ratio, 1.22; 95% confidence interval, 1.08-1.37). Heterogeneity was significant for NLR (I2 = 62%) and low for PLR (I2 = 24%). Among SIR-related PBC-derived variables, NLR is the most suitable prognostic factor for future clinical trials of patients with mPDAC.

Management of anaemia in prostate cancer.

Anaemia is a frequent complication of prostate cancer and of its treatments. In Europe prostate cancer accounts for the 10.8% of all malignant neoplasms. Iatrogenic hypogonadism and age-related physiologic changes along with nutritional deficits contribute to increase prevalence of prostate cancer related anaemia. The reason of the present review is to provide clinicians with all aspects of a frequent and multifactorial co-morbidity, whose effects are often underestimated. Erythropoiesis pathology and causes of anaemia in prostate cancer are reviewed. Critical issues of clinical management of anaemia in prostate cancer are discussed.

Neutrophil count kinetics during the first cycle of chemotherapy predicts the outcome of patients with locally advanced or metastatic pancreatic cancer.

BACKGROUND: Neutrophil count reduction after chemotherapy has been related with longer survival of patients with metastatic pancreatic adenocarcinoma, but there is not a standardized measurement for this phenomenon. METHODS: Some parameters related to the change in neutrophil count between the first and the second cycle of chemotherapy or between the baseline count and the nadir have been evaluated among patients with advanced pancreatic cancer at a single institution. A Cox regression model was built which included, in addition to the common prognostic variables, some variables related to the change of the neutrophil count after chemotherapy. RESULTS: One hundred patients were selected. Two neutrophil kinetics related variables predicted overall survival independently, such as the neutrophil count growth rate (hazard ratio [HR] = 1.245; confidence intervals [CIs], 1.077-1.440) and the chemotherapy-induced neutropenia after one cycle (HR = 0.499; CIs, 0.269-0.927). CONCLUSION: The kinetics of neutrophil count after chemotherapy is an early and independent prognostic factor, which appears to be simple to measure at the start of the second cycle of chemotherapy by means of the neutrophil count growth rate.