Combination of CRAFITY score with Alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma

Immune checkpoint inhibitors (ICIs) with atezolizumab plus bevacizumab are promising agents for unresectable hepatocellular carcinoma (HCC). We tried to guide the treatment based on recent developed CRAFITY score combining with on-treatment AFP response. Eighty-nine patients who received atezolizumab plus bevacizumab regardless of as a first-line therapy or not for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 65.5%, respectively. Multivariate analysis showed that low CRAFITY score (AFP<100 ng/ml or CRP<10 mg/l) and satisfactory AFP response at 6 weeks (≥75% decrease or ≤10% increase from baseline) were independent factors determining good overall survival (OS) (hazard ratio [HR]=0.143, P=0.002 & HR=0.337, P=0.031), progression-free survival (PFS) (HR=0.419, P=0.022 & HR=0.429, P=0.025) and good responder (odds ratio [OR]=1.763, P=0.044 & OR=3.881, P=0.011). Patients were further divided into three classes by combination of CRAFITY score and AFP response at 6 weeks [The CAR (CRAFITY score and AFP-Response) classification)]: low CRAFITY score with satisfactory AFP response at 6 weeks (class I), either high CRAFITY score or unsatisfactory AFP response at 6 weeks (class II) and high CRAFITY score together with unsatisfactory AFP response at 6 weeks (class III). ORR was 35.0%, 18.2%, and 0% in class I, II and III patients, respectively (overall P=0.034). Patients in the class I had the best OS and PFS, followed by class II and class III (median OS: not reached vs. 11.1 vs. 4.3 months, log-rank P<0.001; median PFS: 7.9 vs. 6.6 vs. 2.6 months, log-rank P=0.001). Combination CRAFITY score and AFP response at 6 weeks with AUROC predicts OS and tumor response to be 0.809 and 0.798, respectively, better than either CRAFITY score (0.771 & 0.750) or AFP response at 6 weeks (0.725 & 0.680) alone. In conclusions, the CAR classification which combining CRAFITY score and AFP response at 6 weeks provides a practical guidance for atezolizumab plus bevacizumab therapy in unresectable HCC patients.     

Alpha-fetoprotein response predicts treatment outcomes in patients with unresectable hepatocellular carcinoma receiving immune checkpoint inhibitors with or without tyrosine kinase inhibitors or locoregional therapies

Combined immune checkpoint inhibitors (ICIs) along with tyrosine kinase inhibitors (TKIs) and locoregional therapies have been used increasingly to treat hepatocellular carcinoma (HCC). Biomarkers are required to predict the treatment efficacy of ICIs with or without combination therapies in patients with unresectable HCC. This study enrolled 95 consecutive patients with unresectable HCC from May 2017 to June 2021 from two hospitals retrospectively. Of the 95 patients, 15 and 80 had Barcelona Clinic Liver Cancer stages B and C, respectively. The median ICI treatment duration was 3.43 (1.87-7.87) months, and 77 patients received combination therapies. Radiological imaging was not performed in 13 patients. Objective response and disease control rates were 27.4% and 53.7%, respectively. The duration of progression-free survival (PFS) and overall survival (OS) was 4.07 (1.59-6.54) months and 14.53 (6.93-22.14) months, respectively. Alpha-fetoprotein (AFP) response was defined as a decline of >15% in the serum AFP level within the initial 3 months of ICI therapy according to Youden’s index. AFP response was determined to be a predictor of disease control (odds ratio: 11.657, 95% confidence interval [CI]: 2.834-47.941, P=.001). Macrovascular invasion (MVI), AFP response (hazard ratio [HR]: 0.488, 95% CI: 0.255-0.934, P=.030), combination therapy, and disease control were predictors of PFS, and MVI, AFP response (HR: 0.344, 95% CI: 0.160-0.737, P=.006), and disease control were predictors of OS. AFP response was a predictor of disease control, PFS, and OS. These findings indicate that AFP response can serve as a biomarker to predict treatment outcomes in patients with unresectable HCC receiving ICIs with or without TKIs or locoregional therapies.     

Predictors of response and survival in patients with unresectable hepatocellular carcinoma treated with nivolumab: real-world experience

Real-world predictors of the treatment efficacy of immune checkpoint inhibitors for hepatocellular carcinoma (HCC) are unknown. This retrospective study enrolled 87 consecutive patients with unresectable HCC from May 2017 to December 2019 at two hospitals. Of the 87 patients, 7, 9, 60, and 11 patients had Barcelona Clinic Liver Cancer stages A, B, C, and D, respectively, and 45, 30, and 10 patients were Child-Pugh class A, B, and C, respectively. The median injection numbers of nivolumab and treatment duration were 6 (3-8) and 2.53 (1.47-4.23) months, respectively, and 64.4% of patients received combination therapy. Radiological imaging was not assessed for 25 patients. Objective response (OR) and disease control rates were 19.5% and 39.1%, respectively. A single tumor (odds ratio: 9.542, P = .015) and ≥20% decline in serum α-fetoprotein protein (AFP) levels within the first 3 months of treatment (defined as AFP response, odds ratio: 5.997, P = .042) were predictors of OR. Lack of macrovascular invasion, combination therapy, and AFP response were predictors of progression-free survival. A Cancer of the Liver Italian Program (CLIP) score of 0-2 (hazard ratio [HR]: 3.717, P = .004) and grade 1-2 immune-related adverse events (irAEs, HR: 2.217, P = .049) were predictors of overall survival (OS) in the entire cohort, and a CLIP score of 0-2 (HR: 3.257, P = .009) was a predictor of OS in evaluable patients. IrAEs ≥ grade 3 were noted in 14 patients, and three died as a result. Having a single tumor and AFP response were predictors of OR, and CLIP score was a predictor of OS.     

Predictive value of baseline 18F-FDG PET/CT and interim treatment response for the prognosis of patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy

The present study aimed to investigate the prognostic value of baseline ¹⁸F-FDG PET/CT quantitative parameters and interim treatment response, and to assess whether the combination of these could improve the predictive efficacy in patients with diffuse large B-cell lymphoma (DLBCL) receiving R-CHOP chemotherapy. PET/CT images and clinical data of 64 patients with DLBCL who had undergone ¹⁸F-FDG PET/CT scan before and after 3 or 4 cycles of R-CHOP chemotherapy were retrospectively reviewed. The quantitative parameters including standardized uptake value (SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum diameter of the maximum lesion (Dmax) were measured on baseline PET/CT images. Cox proportional hazards model was used to evaluate the influence of baseline PET/CT parameters, clinical indicators and interim treatment response on prognosis. Survival analysis was performed using Kaplan-Meier method. Receiver operating characteristic (ROC) curve analysis was performed to estimate the predictive efficacy of the combination of baseline PET/CT parameters and interim treatment response. Ann Arbor stage, International Prognostic Index (IPI), lactate dehydrogenase (LDH), necrosis, MTVmax, TLGmax, Dmax and interim treatment response showed association with 2-year progression-free survival (PFS, P<0.05). LDH, necrosis, MTVmax, MTVsum, TLGmax, TLGsum, Dmax and interim treatment response showed association with 2-year overall survival (OS, P<0.05). Ann Arbor stage, Dmax and interim treatment response were found to be independent predictors of 2-year PFS (P<0.05), while Dmax and interim treatment response were found to be independent predictors of 2-year OS (P<0.05). The PFS and OS curves of Dmax <5.7 cm group and Dmax ≥5.7 cm group, complete response (CR) group and non-CR group were significantly different, respectively (P<0.05). The baseline ¹⁸F-FDG PET/CT parameters and interim treatment response have important prognostic values in DLBCL patients who received R-CHOP chemotherapy. Combined application of Dmax and interim treatment response improved the predictive efficacy of 2-year PFS. It may be helpful to identify patients who are at high-risk of relapse and to guide early clinical intervention of these patients.     

The influence of radiation therapy dose escalation on overall survival in unresectable pancreatic adenocarcinoma

Purpose

Radiation therapy (RT) dose escalation in unresectable pancreatic adenocarcinoma (PAC) remains investigational. We examined the association between total RT dose and overall survival (OS) in patients with unresectable PAC.

Methods and materials

National cancer data base (NCDB) data were obtained for patients who underwent definitive chemotherapy and RT (chemo-RT) for unresectable PAC. Univariate (UV) and multivariate (MV) survival analysis were performed along with Kaplan-Meier (KM) estimates for incremental RT dose levels.

Results

A total of 977 analyzable patients met inclusion criteria. Median tumor size was 4.0 cm (0.3-40 cm) and median RT dose was 45 Gy. Median OS was 10 months (95% CI, 9-10 months). On MV analysis RT dose <30 Gy [HR, 2.38 (95% CI, 1.85-3.07); P<0.001] and RT dose ≥30 to <40 Gy [HR, 1.41 (95% CI, 1.04-1.91); P=0.026] were associated with lower OS when compared with dose ≥55 Gy. Patients receiving RT doses from 40 to <45, 45 to <50, 50 to <55, and ≥55 Gy did not differ in OS.

Conclusions

Lack of benefit to OS with conventionally delivered RT above 40 Gy is shown. Optimal RT dose escalation methods in unresectable PAC remain an important subject for investigation in prospective clinical trials.     

Comparison of initial tumor responses to transarterial bland embolization and drug-eluting beads-transarterial chemoembolization in the management of hepatocellular carcinoma: a propensity-score matching analysis

BackgroundTransarterial bland embolization (TABE) is widely used to treat the spontaneous rupture of hepatocellular carcinoma (HCC), and can lead to ischemic necrosis of the tumor. In this study, we used the propensity-score matching (PSM) method to compare the initial responses of treatment-naïve HCC patients to TABE and drug-eluting beads-transarterial chemoembolization (DEB-TACE), and the safety of these treatments.MethodsPatients with treatment-naïve HCC, who had been admitted to 2 medical centers from January 2016 to December 2020, were enrolled as the research subjects. The data of 26 patients treated with TABE for ruptured HCC and 52 patients treated with DEB-TACE for primary HCC were collected according to our inclusion and exclusion criteria, and a PSM analysis was conducted to assess the safety and effectiveness of these two interventional techniques 1 month postoperatively.ResultsIn relation to ruptured HCC, TABE had a hemostatic success rate of 97.0%. Before PSM, the TABE group had a larger maximum tumor diameter (P<0.05), a higher proportion of multiple tumors (P<0.05), a higher proportion of Child-Pugh class B (P<0.05), and a higher proportion of Barcelona Clinic Liver Cancer (BCLC) stage B (P<0.05) than the DEB-TACE group. After PSM, the baseline characteristics of these two groups were well balanced, and there was no significant difference in patients’ initial therapeutic responses and tumor recurrence rates (both P>0.05). The multivariate regression analysis showed that tumor size was an independent predictor of the objective response rate (ORR) [odds ratio (OR): 3.312; 95% CI: 0.152–5.944; P<0.05]. Tumor number and BCLC stage also affected ORR; however, ORR was not significantly correlated with the interventional technique (TABE vs. DEB-TACE; P>0.05). The incidences of post-embolization syndrome (PES) and 48-h hepatotoxicity were significantly lower in the TABE group than the DEB-TACE group (both P<0.05), but there was no significant difference in hepatotoxicity after 1 month (P>0.05).ConclusionsTABE is highly effective at managing hemorrhage from ruptured HCC. The initial therapeutic response of HCC to TABE is similar to that to DEB-TACE; however, TABE is associated with lower hepatotoxicity and fewer adverse effects, which paves the way for subsequent treatments and systemic therapies.     

Study of PD-1 Inhibitors in Combination with Chemoradiotherapy/Chemotherapy in Patients with Esophageal Squamous Carcinoma

In this study, we aimed to evaluate the efficacy of PD-1 inhibitors in combination with concurrent CRT/CT for patients with inoperable ESCC in the real world and to find predictors for the efficacy of PD-1 inhibitors. Patients with unresectable ESCC were evaluated at baseline. The clinical data of patients with ESCC who received CRT/CT with or without PD-1 inhibitor were collected and retrospectively reviewed. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were analyzed statistically. A total of 96 patients with ESCC were included. As compared with a control group (n = 48), the PFS (6.0 months vs. 5.0 months, p = 0.025) and 6-month OS (70.8% vs. 47.9%, p < 0.001) were significantly longer in the ICIs group (n = 48). There were no significant differences in ORR and 12-month OS between the two groups. In addition, we found that body mass index (BMI) was associated with PFS (HR 0.85, 95% CI 0.76–0.95, and p = 0.004) and OS (HR 0.82, 95% CI 0.69–0.98, and p = 0.033) in the ICIs group. PD-1 inhibitors combined with CRT/CT is safe with acceptable complications and improved survival for patients with inoperable ESCC. CRT plus PD-1 inhibitor has superior antitumor efficacy. BMI was positively correlated with the efficacy of PD-1 inhibitors.     

Nomogram for the prediction of lymph node metastasis and survival outcomes in rectal neuroendocrine tumour patients undergoing resection

BackgroundThe current study analysed rectal neuroendocrine tumour (RNET) patients undergoing resection to identify predictive factors and construct nomograms for lymph node metastasis, cancer-specific survival (CSS) and overall survival (OS).MethodsRNET patients registered in the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. Multivariable logistic regression analysis was used to investigate the relationships between clinicopathological factors and lymph node metastasis. A multivariate competing risk model was applied to investigate factors independently associated with CSS. Through the Cox regression model, a multivariable analysis of OS was performed. Nomograms were established based on independent predictive factors. Calibration plots, receiver operating characteristic (ROC) curves and Brier scores were used to evaluate the predictive accuracy of the nomograms.ResultsIn this study, 1,253 RNET patients were included for further analysis. Tumour size ≥12 mm (P<0.001), T3/T4 stage (P<0.001) and M1 stage (P=0.001) were independently associated with lymph node metastasis. The performance of the nomogram was acceptable for predicting lymph node metastasis, with an area under the ROC curve (AUC) of 0.937 [95% confidence interval (CI): 0.874–1.000]. Calibration curves and the Hosmer-Lemeshow test revealed desirable model calibration (P=0.99996). The multivariate competing risk model analysis showed that grade II (P=0.017), tumour size ≥12 mm (P=0.007), AJCC TNM stage II (P=0.002), stage III (P<0.001) and stage IV (P<0.001) were significantly associated with worse CSS. In the competing risk nomogram model, the time-dependent AUC revealed good discriminatory ability of the model (time from 1 to 107 months, AUC >0.900), and the Brier score showed good accuracy of the nomogram, which was greater than that of the AJCC TNM stage. Multivariate Cox analysis showed that age >60 years (P=0.002), median income ≥$65,000 (P=0.013), AJCC TNM stage III (P=0.038) and AJCC TNM stage IV (P<0.001) were independently associated with worse OS. In the nomogram for the prediction of OS, the C-statistic was 0.703 (95% CI: 0.615–0.792), which was significantly better than that of the AJCC TNM stage (0.703 vs. 0.607, P=0.009). A calibration plot for the probability of survival demonstrated good calibration.ConclusionsThe present study is the first to establish nomograms with great discrimination and accuracy for the prediction of lymph node metastases, CSS and OS in RNET patients, which can be used to guide treatment decision-making and surveillance.     

Prognostic value and association of sarcopenic obesity and systemic inflammatory indexes in patients with hepatocellular carcinoma following hepatectomy and the establishment of novel predictive nomograms

BackgroundThe specific impacts of sarcopenic obesity (SO) on hepatocellular carcinoma (HCC) and the association between SO and systemic inflammation remain unclear. This study aimed to investigate the prognostic value and association of SO and systemic inflammation with outcomes after hepatectomy for HCC and develop novel nomograms based on SO and inflammatory indexes for survival prediction.MethodsWe retrospectively enrolled 452 patients with HCC who underwent radical hepatectomy between January 2012 and March 2015 in Fujian Provincial Hospital as the training cohort. In addition, 275 patients during the same period were enrolled as the external validation cohort. Patients were classified into different groups according to the presence of sarcopenia and obesity. Different inflammation indexes were evaluated to select the best predictor of overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate logistic regression were performed to investigate the associations between inflammatory indexes and SO. The inflammatory indexes with the highest predictive values and SO were selected for subgroup analyses to establish a novel classification system: the SOLMR grade. SOLMR grades identified in the multivariate Cox analysis were selected to construct novel nomograms for OS and RFS.ResultsSO (P<0.001) was an independent risk factor for OS and RFS. The lymphocyte‐monocyte ratio (LMR) had the highest areas under the receiver operating characteristic (ROC) curves (AUCs) for OS (P<0.001) and RFS (P<0.001) and was identified as an independent factor of SO (P=0.001). SO and the LMR were selected to establish the SOLMR grade. Multivariate Cox analysis revealed that SOLMR grade was a significant independent predictor of OS (P<0.001) and RFS (P<0.001). Nomograms based on SOLMR grades were generated and accurately predicted 1-, 3- and 5-year OS and RFS in HCC patients. The C-index of the novel nomograms was higher than those of the other conventional staging systems (P<0.001).ConclusionsBoth SO and the LMR were independent risk factors for OS and RFS in HCC patients after hepatectomy. The LMR was an independent factor of SO. The novel nomograms developed from the SOLMR grading system combining SO with the LMR provide good prognostic estimates of the outcomes of HCC patients.     

Eribulin Monotherapy in Patients Aged 70 Years and Older With Metastatic Breast Cancer

Purpose.

Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients.

Methods.

Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m² as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups (<50 years, 50–59 years, 60–69 years, ≥70 years).

Results.

Overall, 827 patients were included in the analysis (<50 years, n = 253; 50–59 years, n = 289; 60–69 years, n = 206; ≥70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia).

Conclusion.

Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups.     

Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer?

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) might be new therapeutic strategies for advanced non-small cell lung cancer (NSCLC). Here a total of 12,520 patients from 23 randomized controlled trials (RCTs) were enrolled to evaluate the efficacy and safety of VEGFR-TKIs quantitatively in advanced NSCLC. Compared with non-VEGFR-TKIs, VEGFR-TKIs regimen significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.805-0.874, P < 0.001], objective response rates (ORR) [relative risk (RR): 1.374, 95% CI: 1.193-1.583, P < 0.001] and disease control rates (DCR) (RR: 1.113, 95% CI: 1.027-1.206, P = 0.009), but not overall survival (OS) (HR: 0.960, 95% CI: 0.921-1.002, P = 0.060) for NSCLC patients. The RR of all-grade neutropenia, thrombocytopenia, hypertension, hemorrhage, fatigue, anorexia, stomatitis, diarrhea, rash, hand-foot skin reaction (HFSR) were increased in patients received VEGFR-TKIs. As for high-grade (≥ 3) adverse events (AEs), VEGFR-TKIs were associated with higher RR of neutropenia, thrombocytopenia, hypertension, fatigue, stomatitis, diarrhea, rash and HFSR. This study demonstrates VEGFR-TKIs improve PFS, ORR and DCR, but not OS in advanced NSCLC patients. VEGFR-TKIs induce more frequent and serious AEs compared with control therapies.     

FDA Supplemental Approval Summary: Lenvatinib for the Treatment of Unresectable Hepatocellular Carcinoma

On August 16, 2018, the U.S. Food and Drug Administration approved lenvatinib (Lenvima, Eisai Inc.) for first‐line treatment of patients with unresectable hepatocellular carcinoma (HCC). Approval was based on an international, multicenter, randomized, open‐label, noninferiority trial (REFLECT; {"type":"clinical-trial","attrs":{"text":"NCT01761266","term_id":"NCT01761266"}}NCT01761266) conducted in 954 patients with previously untreated metastatic or unresectable HCC. Patients were randomized (1:1) to receive lenvatinib (12 mg orally once daily for patients with a baseline body weight ≥60 kg and 8 mg orally once daily for patients with a baseline body weight <60 kg) or sorafenib (400 mg orally twice daily) until radiological disease progression or unacceptable toxicity. REFLECT demonstrated that lenvatinib was noninferior but not statistically superior to sorafenib for overall survival (OS; hazard ratio, [HR] 0.92; 95% confidence intervals [CI], 0.79–1.06), with median OS of 13.6 and 12.3 months in the lenvatinib and sorafenib arms, respectively. REFLECT also demonstrated statistically significant improvements in investigator‐assessed progression‐free survival (PFS; HR, 0.66; 95% CI, 0.57–0.77]; p < 0.001), corresponding to median PFS of 7.4 and 3.7 months and overall response rate of 24.1% vs 9.2% per modified RECIST for HCC (mRECIST) in the lenvatinib and sorafenib arms, respectively. Consistent results were observed by an independent review facility per RECISTv1.1 and per mRECIST. The most common adverse reactions observed in the lenvatinib‐treated patients (≥20%) in decreasing frequency were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar‐plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.Implications for PracticeThis article describes the U.S. Food and Drug Administration''s review of data from a single trial, REFLECT, that supported the approval of lenvatinib, as a single agent, for the first‐line treatment of unresectable hepatocellular carcinoma (HCC). REFLECT was an open‐label, noninferiority trial that randomized 954 patients with HCC who were ineligible for liver‐directed therapy with no prior systemic therapy for HCC to lenvatinib or sorafenib. REFLECT demonstrated that lenvatinib‐treated patients had similar survival, more responses, and longer time to progression than those receiving sorafenib. Serious side effects were more common among lenvatinib‐treated patients. Lenvatinib is an effective treatment for patients with previously untreated HCC.     

Long‐term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer

The long‐term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment‐refractory advanced esophageal cancer who participated in an open‐label, single‐arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand‐1 (PD‐L1) and CD8⁺ status of tumors and tumor‐infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end‐points included objective response rate (ORR), overall survival (OS), progression‐free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD‐L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut‐off 1%) and OS (11.33 vs 6.24 months, cut‐off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long‐term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD‐L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.     

Comparable benefits of HCV eradication by direct acting antivirals and interferon-based therapy in patients with hepatocellular carcinoma undergoing surgical resection

Whether direct-acting antivirals (DAA) provide comparable survival benefit with interferon (IFN)-based therapy remains unclear. The aim of this study was to compare the outcomes after achieving SVR by IFN-based and DAA therapy after resection of HCV-related hepatocellular carcinoma (HCC). Consecutive 285 patients receiving curative resection for HCV-related HCC were retrospectively enrolled, including 103 (36.1%) and 69 (24.2%) patients with IFN-based and DAA therapy, respectively. Factors associated with recurrence, overall survival (OS) and hepatic decompensation-free survival were evaluated. The SVR rate of DAA was 95.7% in HCC patients. During a median follow-up period of 49.6 months, 102 (35.8%) patients died and 63 (24%) developed hepatic decompensation. By multivariate analysis, SVR by DAA or IFN-based therapy was not associated with early or late HCC recurrence. Achieving SVR (by IFN-based therapy: HR=0.321, P<0.001; by DAA: HR=0.396, P=0.011), BCLC stage B-C (HR=1.914, P=0.024), FIB-4 score >3.25 (HR=1.664, P=0.016) and microvascular invasion (HR=1.603, P=0.048) were independent predictors of OS. Achieving SVR (by IFN-based therapy: HR=0.295, P<0.001; by DAA: HR=0.193, P=0.002), BCLC stage B-C (HR=2.975, P=0.001), GGT >70 U/L (HR=1.931, P=0.015) and cirrhosis (HR=2.035, P=0.007) were independent predictors of decompensation-free survival. The benefit of achieving SVR was consistently observed in cirrhotic and non-cirrhotic patients, and in patients with and without HCC recurrence. In conclusion, achieving SVR by either DAA or IFN-based therapy provide comparable and significant reduction of mortality and hepatic decompensation after surgical resection of HCV-related HCC. DAA therapy should be prescribed for all HCC patients after curative surgical resection.     

Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study

BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225.     

The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib

Background.

The role of serum alpha-fetoprotein (AFP) changes in predicting the treatment outcomes of advanced hepatocellular carcinoma (HCC) patients to sorafenib remains unknown.

Methods.

Serum AFP was collected prospectively at baseline and subsequent follow-up visits in parallel with clinical and survival outcomes. AFP response was defined as a relative drop of AFP >20% of the baseline level after 6 weeks of sorafenib. The relationship between AFP response and the treatment outcomes was first explored in patients who received sorafenib in a phase II study. Subsequently, an independent validation set of patients were obtained to validate the association of AFP response to clinical outcomes.

Results.

Included in the exploration and validation sets for analysis were 41 and 53 patients, respectively, with baseline AFP level >20 μg/L. In the exploration cohort, AFP response was significantly associated with clinical benefit (CB) rate (relative chance 3.4, 95% confidence interval [CI], 1.1–11.1), and multivariate analysis indicated that AFP response was associated with significantly better progression-free survival (PFS) (hazard ratio [HR], 0.31; 95% CI, 0.13–0.76) and marginally better overall survival (OS) (HR, 0.30; 95% CI, 0.09–1.02). When applying AFP changes in the validation set, significant associations were again found between AFP response with CB rate (relative chance, 5.5; 95% CI, 2.3–13.6) and PFS (HR, 0.12; 95% CI, 0.04–0.30) but not OS (HR, 0.61; 95% CI, 0.27–1.26).

Conclusion.

Drop in AFP level at 6 weeks is an exploratory early surrogate for both CB and PFS in advanced HCC patients receiving sorafenib.     

Safety and efficacy of nivolumab in the treatment of cancers: A meta‐analysis of 27 prospective clinical trials

Immune checkpoint inhibition therapy has benefited people and shown powerful anti‐tumor activity during the past several years. Nivolumab, a fully human IgG4 monoclonal antibody against PD‐1, is a widely studied immune checkpoint inhibitor for the treatment of cancers. To assess the safety and efficacy of nivolumab, 27 clinical trials on nivolumab were analyzed. Results showed that the summary risks of all grade adverse effects (AEs) and grade ≥3 AEs were 0.65 and 0.12. The rate of nivolumab‐related death was 0.25%. The most common any grade AEs were fatigue (25.1%), rush (13.0%), pruritus (12.5%), diarrhea (12.1%), nausea (11.8%) and asthenia (10.4%). The most common grade ≥3 AEs were hypophosphatemia (only 2.3%) and lymphopenia (only 2.1%). The pooled objective response rate (ORR), 6‐month progression‐free survival (PFS) rate and 1‐year overall survival (OS) rate were 0.26, 0.40 and 0.52, respectively. The odds ratio of ORR between PD‐L1 positive and negative was 2.34 (95% CI 1.77–3.10, p < 0.0001). The odds ratios of ORR, 6‐month PFS rate and 1‐year OS rate between nivolumab and chemotherapeutics were 2.77 (95% CI 1.69–4.56, p < 0.0001), 1.97 (95% CI 1.02–3.81, p = 0.04) and 1.87 (95% CI 1.46–2.40, p <0.0001), respectively. In conclusion, nivolumab has durable outcomes with tolerable AEs and drug‐related deaths in cancer patients. Nivolumab monotherapy has better treatment response compared with chemotherapy, whereas chemotherapeutics have significantly higher risk of adverse effects than nivolumab.     

Long‐term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma

The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long‐term follow up of a single‐arm, open‐label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post–hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression‐free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment‐related adverse events (TRAE), including select immune‐related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the ORR was 66.7% (90% CI: 34.7, 88.3) for superficial spreading, 33.3% (90% CI: 11.7, 65.3) for mucosal, and 28.6% (90% CI: 10.0, 59.1) for acral lentiginous tumors. The median OS was 32.9 months, the 3‐year OS rate was 43.5%, and the 3‐year PFS rate was 17.2%. A long‐term response was observed in all the tumor types. The most common TRAE included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long‐term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type.     

Post-treatment plasma EBV-DNA positivity predicts early relapse and poor prognosis for patients with extranodal NK/T cell lymphoma in the era of asparaginase

Circulating Epstein-Barr virus (EBV) DNA is a biomarker of EBV-associated malignancies. Its prognostic value in early stage NK/T-cell lymphoma (NKTCL) in the era of asparaginase was investigated. 68 patients were treated with a median of 4 cycles of asparaginase-based chemotherapy followed by a median of 54.6Gy (range 50–60Gy) radiation. The amount of EBV-DNA was prospectively measured in both pretreatment and post-treatment plasma samples by real-time quantitative PCR. At the end of treatment, complete response (CR) rate was 79.4%, and overall response rate (ORR) was 88.2%. Patients with negative pretreatment EBV-DNA had a higher CR rate (96.0% vs. 69.8%, p = 0.023). The 3-year progression-free survival (PFS) rate and overall survival (OS) rate was 71% and 83%, respectively. In multivariate survival analysis, post-treatment EBV-DNA positivity and treatment response (non-CR) were prognostic factors for both worse PFS and OS (p < 0.05). Local tumor invasion was also a prognostic factor for worse OS (p = 0.010). In patients with CR, post-treatment EBV-DNA positivity correlated with inferior PFS and OS (both p < 0.0001). In patients with positive pretreatment EBV-DNA, negative post-treatment EBV-DNA correlated with better PFS and OS (both p < 0.0001). These findings indicate that post-treatment EBV-DNA positivity can predict early relapse and poor prognosis for patients with early stage NKTCL in the era of asparaginase, and may be used as an indicator of minimal residual disease.     

Neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 as prognostic markers for advanced pancreatic cancer patients receiving first-line chemotherapy

BACKGROUNDA decline in serum carbohydrate antigen 19-9 (CA19-9) levels during systemic chemotherapy is considered as a prognostic marker for patients with advanced pancreatic cancer. Neutrophil-to-lymphocyte ratio (NLR) has been extensively studied as a simple and useful indicator of prognosis in various cancers including pancreatic cancer.AIMTo assess the prognostic significance of NLR and CA19-9 in patients with advanced pancreatic adenocarcinoma received first-line chemotherapy according to CA19-9 positivity.METHODSWe retrospectively analyzed patients diagnosed with advanced pancreatic cancer who received first-line chemotherapy between January 2010 and July 2017 at the Catholic University of Seoul St. Mary’s Hospital. Patients were divided according to CA19-9 positivity (CA19-9-positive vs -negative groups) and pre-and post-treatment NLR levels. To determine cut-off value of NLR and CA19-9 reduction, time-dependent receiver operating characteristic curve was applied. We evaluated overall survival (OS) and progression-free survival (PFS) for each group using Kaplan-Meier method, and we performed multivariate analyses on the entire cohort.RESULTSWe included 271 patients in this study. Cut-off value of NLR and CA19-9 reduction was determined as 2.62 and 18%. Multivariate analysis showed that post-treatment NLR < 2.62 and reduction of ≥ 18% of baseline CA19-9 were significantly associated with OS and PFS. Post-treatment NLR ≥ 2.62 showed hazard ratio (HR) of 2.47 [95% confidence interval (CI): 1.84-3.32, P < 0.001] and CA19-9 decline (≥ 18%) showed HR of 0.51 (95%CI: 0.39-0.67, P < 0.001) for OS. When CA19-9-positive patients were divided into groups according to CA19-9 response (responder vs non-responder) and post-treatment NLR (< 2.62 vs ≥ 2.62), CA19-9 responder and post-treatment NLR < 2.62 group showed better survival than CA19-9 non-responder and post-treatment NLR ≥ 2.62 group (OS 11.0 mo vs 3.9 mo, P < 0.001; PFS 6.3 mo vs 2.0 mo, P < 0.001). The combination of CA19-9 decline and post-treatment NLR showed a significant correlation with clinical response in CA 19-9 positive group. Within the CA19-9-negative group, the post-treatment NLR < 2.62 group showed better survival than the post-treatment NLR ≥ 2.62 group (OS 12.7 mo vs 7.7 mo, P < 0.001; PFS 6.7 mo vs 2.1 mo, P < 0.001), and post-treatment NLR showed correlation with clinical response.CONCLUSIONIn advanced pancreatic cancer patients positive for CA19-9 and treated with systemic chemotherapy, the combination of post-treatment NLR < 2.62 and 18% decline of CA19-9 at the first response evaluation is a good prognostic marker. Post-treatment NLR < 2.62 alone could be used as a prognostic marker and an adjunctive tool for response evaluation in CA19-9-negative patients.