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.

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.

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.

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.

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.

Retrospective analysis by site of primary tumor of patients with unresectable locally-advanced or metastatic pancreatic adenocarcinoma receiving chemotherapy.

The primary tumor site of pancreatic cancer has been suggested as a recommended variable in future studies of treatments of patients with unresectable or metastatic pancreatic adenocarcinoma (mPDAC). The aim of the current study is to analyze the differences between mPDAC of the head and mPDAC of the body-tail, both in prognostic and predictive terms in patients with mPDAC receiving palliative chemotherapy. Data of patients with a diagnosis of mPDAC and receiving chemotherapy (CHT), registered in the database of the division of Medical Oncology of the Ospedale Civile di Sanremo, were analyzed. Thirty-two variables were extracted, and their relationship with primary tumor site and outcome were analyzed. One hundred twenty-nine patients were eligible. The characteristics of patients were different between those with the primary tumor of the pancreatic head or body-tail. After construction of two Cox models, two prognostic factors (the number of CHT lines, the neutrophil reduction after one cycle of CHT) were identified as independent among mPDAC of the head, while only one variables (the number of drugs in the CHT regimen) predicted the outcome of patients with body-tail tumors; after statistical correction for false discovery rate, all the three variables maintained their significant relationship with OS. Despite a similar overall survival among parients with tumors of the head compared to those with tumors of body-tail, a very different disease course was reported, with different prognostic and predictive variables.

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.

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.

Second-generation inflammation-related scores are more effective than systemic inflammation ratios in predicting prognosis of patients with unresectable or metastatic pancreatic cancer receiving cytotoxic chemotherapy.

Inflammation is known to play an important role in the biology of metastatic pancreatic adenocarcinoma (mPDAC), and systemic inflammatory response (SIR) is reported to be closely related to outcome in mPDAC. The aim of the present paper is to assess the prognostic performance of SIR-related variables in patients with mPDAC receiving cytotoxic chemotherapy. Data of patients with mPDAC, who were registered in the database of the division of Medical Oncology of the G. Borea Hospital in Sanremo, were retrospectively collected. Three SIR-related variables were calculated. Univariate and multivariate analyses have been performed by Cox regression, and every SIR-related variable was added to the Cox model. After univariate analyses, four variables reported a significant relationship with overall survival (OS) and were included in a Cox model. Two of the three SIR-related variables were related with OS in the bivariate analyses, and maintained their independent prognostic effect when added to the previous Cox model in multivariate analysis. These variables were two scores, such as neutrophil-platelet score (NPS; HR 2.144, CIs 1.392-3.300) and tri-linear peripheric blood cell score (TRIS; HR 1.813, CIs 1.331-2.468). It appears that the second-generation inflammation-related variables are more effective in predicting prognosis of patients with mPDAC receiving chemotherapy.