Prognostic significance of pan-immune-inflammation value in hepatocellular carcinoma treated by curative radiofrequency ablation: potential role for individualized adjuvant systemic treatment.

BACKGROUND: This study aimed to explore the prognostic role of pan-immune-inflammation value (PIV) and develop a new risk model to guide individualized adjuvant systemic treatment following radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Patients with early-stage HCC treated by RFA were randomly divided into training cohort A (n = 65) and testing cohort B (n = 68). Another 265 counterparts were enrolled into external validating cohort C. Various immune-inflammatory biomarkers (IIBs) were screened in cohort A. Prognostic role of PIV was evaluated and validated in cohort B and C, respectively. A nomogram risk model was built in cohort C and validated in pooled cohort D. Clinical benefits of adjuvant anti-angiogenesis therapy plus immune checkpoint inhibitor (AA-ICI) following RFA was assessed in low- and high-risk groups. RESULTS: The cutoff point of PIV was 120. High PIV was an independent predictor of unfavorable recurrence-free survival (RFS) and overall survival (OS). RFS and OS rates of patients with high PIV were significantly lower than those with low PIV both in cohort B (PRFS=0.016, POS=0.011) and C (PRFS<0.001, POS<0.001). The nomogram model based on PIV, tumor number and BCLC staging performed well in risk stratification in external validating cohort C. Adjuvant AA-ICI treatment showed an added benefit in OS (p = 0.011) for high-risk patients. CONCLUSIONS: PIV is a feasible independent prognostic factor for RFS and OS in early-stage HCC patients who received curative RFA. The proposed PIV-based nomogram risk model could help clinicians identify high-risk patients and tailor adjuvant systemic treatment and disease follow-up scheme.

Key findingsHigh pan-immune-inflammation value (PIV) is an independent indicator of unfavorable recurrence-free survival (RFS) and overall survival (OS) for early-stage hepatocellular carcinoma (HCC) patients who received curative radiofrequency ablation (RFA).Adjuvant anti-angiogenesis target therapy plus immune checkpoint inhibitor (AA-ICI) treatment showed added benefit in OS for the high-risk patients defined by a nomogram risk model based on PIV, tumor number and BCLC staging.What is known and what is new?Inflammation and impaired host immunity are associated with carcinogenesis and progression of HCC. Increasing evidences showed that immune-inflammatory biomarkers (IIBs) had prognostic roles in early-stage HCC patients who received RFA. However, prognostic potential of PIV has not been determined in this setting.Herein, high PIV was first reported to be an independent risk factor of poor RFS and OS in early-stage HCC patients treated by curative RFA and helped to discriminate patients between low- and high-risk groups. Adjuvant AA-ICI treatment following RFA was beneficial to OS of patients in the high-risk group.What is the implication, and what should change now?For early-stage HCC with high-risk factors (high PIV, multiple tumor foci and more advanced BCLC stage), intensive follow-up and adjuvant systemic therapy following curative RFA were warranted.

Liver-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab for advanced hepatocellular carcinoma: a retrospective observational study of 23 cases.

Background: Programmed cell death protein 1 (PD-1) or its ligand (PD-L1) monoclonal antibody combined with bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor) has been established as first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Radiotherapy is a crucial local treatment for HCC. Mutual efficacy enhancement has been reported between radiotherapy, anti-angiogenesis therapy and immunotherapy in preclinical researches, but not been validated in clinical practice. Whether radiotherapy can enhance efficacy of anti-PD-1 immunotherapy plus bevacizumab for HCC remains unclear. This retrospective observational study aimed to appraise efficacy and safety of the combination of radiotherapy with pembrolizumab (a PD-1 monoclonal antibody) and bevacizumab for advanced HCC for the first time. Methods: Patients with advanced HCC treated by intrahepatic tumor-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab were consecutively included. Clinicopathological characteristics, therapeutic outcomes and treatment-related adverse events (TRAEs) were recorded and evaluated. Results: A total of 23 patients were eventually enrolled. Median cycles of pembrolizumab and bevacizumab were 4 (median, 1-8) and 4 (median, 1-9) cycles. The objective response rates and disease control rates of irradiated intrahepatic HCC and non-irradiated extrahepatic HCC were 34.8% [95% confidence interval (CI), 16.4-57.3%] vs. 10.0% (95% CI, 1.2-31.7%), and 91.3% (95% CI, 72.0-98.9%) vs. 70.0% (95% CI, 45.7-88.1%), respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.6 (95% CI, 4.7-8.5) and 18.3 (95% CI, 8.2-33.6) months, and 12-month PFS and OS rates were 17.5% (95% CI, 7.0-28.0%) and 60.9% (95% CI, 50.7-71.1%). Two patients (8.7%) with locally advanced, unresectable HCC eventually underwent curative resection of tumors after this trimodal treatment. Eighteen patients (78.3%) had ≥ grade 3 TRAEs, with myelosuppression and transaminase increase as the most common. Conclusions: This study firstly reported that combining radiotherapy with pembrolizumab and bevacizumab was preliminarily a feasible and effective therapeutic choice for advanced HCC in despite of more TRAEs. This tri-modal regimen may be a potential conversion therapy for unresectable, locally advanced HCC. The limitations of this study are its retrospective nature and small sample size; therefore, big-sample prospective studies are warranted to further investigate this tri-modal regimen.

Encouraging efficacy of a comprehensive therapy consisting of sintilimab, bevacizumab biosimilar IBI305, hypo-fractionated intensity-modulated radiotherapy, and oxaliplatin for a maxillary metastasis from hepatocellular carcinoma: A case report and literature review.

Oro-maxillo-facial metastasis from hepatocellular carcinoma (HCC) is very rare, and reports on treating maxillary metastasis from HCC are unavailable. Anti-angiogenesis therapy combined with immunotherapy represented by programmed cell death 1 (PD-1) or its ligand (PD-L1) inhibitor has become the standard treatment of advanced HCC. However, integrating chemoradiotherapy into immunotherapy-bevacizumab combination therapy has not been reported. Here, we presented a Chinese woman with maxillary metastasis from HCC who achieved a nearly complete response (CR) to a quadruple treatment scheme consisting of a PD-1 monoclonal antibody (sintilimab), bevacizumab biosimilar IBI305, hypo-fractionated intensity-modulated radiotherapy (hfIMRT), and concurrent oxaliplatin. This comprehensive treatment is an innovative and effective therapy for advanced HCC.

Efficacy and toxicity of three concurrent chemoradiotherapy regimens in treating nasopharyngeal carcinoma: Comparison among cisplatin, nedaplatin, and lobaplatin.

Few studies directly compare efficacy and toxicity among lobaplatin, nedaplatin and cisplatin concurrently with intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). Totally 141 treatment-naïve NPC without distant metastasis receiving IMRT concurrent with cisplatin or nedaplatin or lobaplatin were retrospectively enrolled. Their response rate, toxicity and long-term survival were compared. Complete response (CR) rates of concurrent lobaplatin (CR-nasopharynx [CR-nx], 82.7%; CR-cervical lymph node [CR-nd], 94.2%) were lower than those of cisplatin (CR-nx, 89.3%; CR-nd, 98.2%) and nedaplatin (CR-nx, 93.9%; CR-nd, 97.0%), but statistical significance wasn't detected. Estimated five-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) weren't statistically significant between three groups. Multivariable analysis by COX proportional hazards model showed concurrent chemotherapy regimen wasn't an independent prognostic factor. Gastrointestinal toxicity was prevalent in platinum-based concurrent chemotherapy; cisplatin group suffered heavier (≥grade 2) than other two groups. More nephrotoxicity happened in cisplatin group (17.9%) than nedaplatin (9.1%) and lobaplatin (2.0%) groups. Incidence of dermatitis of ≥grade 2 was higher in cisplatin group (60.7%) than nedaplatin (27.3%) and lobaplatin (9.6%) groups. More patients in lobaplatin and nedaplatin groups suffered from any grade thrombocytopenia (P < .001), but incidence of severe thrombocytopenia (≥grade 3) was similar. Economic cost was significant less in lobaplatin group. Cisplatin, nedaplatin and lobaplatin are equally effective when used concurrently with IMRT in NPC. Lobaplatin and nedaplatin have potential to be alternatives to cisplatin in terms of less severe acute side-effects and economic cost.

Significant prognostic impact of chemoradiotherapy-induced hemoglobin decrease on treatment outcomes of nasopharyngeal carcinoma.

PURPOSE: To investigate prognostic impact of chemoradiotherapy-induced hemoglobin (Hb) decrease on treatment outcomes of endemic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Eight hundred and fifteen non-metastatic NPC, receiving neoadjuvant chemotherapy followed by radiotherapy (NACT+RT group) or concomitant chemoradiotherapy (CCRT group), were enrolled in this study, who were regrouped according to pre-radiotherapy Hb (pre-RT Hb), post-radiotherapy Hb (post-RT Hb) and individual Hb decrease through radiotherapy or CCRT (△Hb), respectively. Survival curves were estimated using Kaplan-Meier method and compared by log-rank test. Multivariate analysis was performed using the COX proportional hazard model and binary logistic regression model. RESULTS: A poorer 5-year disease-free survival (DFS) was observed when pre-RT Hb<130.00 g/L. However, post-RT Hb<130.00 g/L was associated with significantly poorer 5-year locoregional recurrence-free survival (LRFS) (P=0.010) and disease specific survival (DSS) (P=0.008). Multivariate analysis with the COX proportional hazard model identified post-RT Hb<130.00 g/L as an independent negative prognostic factor for both LRFS (hazard ratio [HR], 1.896; 95% confidence interval [CI], 1.158-3.106; P=0.011) and DSS (HR, 1.767; 95% CI, 1.152-2.711; P=0.009). Similarly, △Hb <-15.00 g/L also predicted poorer 5-year LRFS (P=0.024) and DSS (P=0.015), which was confirmed in multivariate analysis as an independent adverse prognostic factor for LRFS (HR, 1.586; 95% CI, 1.058-2.377; P=0.026) and DSS (HR, 1.556; 95% CI, 1.087-2.227; P=0.016), respectively. Multivariate analysis with binary logistic regression model indicated that CCRT was a significantly independent predictor for post-RT Hb <130.00 g/L and △Hb < -15.00 g/L. CONCLUSIONS: Chemoradiotherapy-induced decreased Hb levels have negative influence on locoregional control and survival, and might counteract the benefit of neoadjuvant/concomitant chemotherapy. Further studies on supportive care to maintain sufficient Hb level during chemo-radiotherapy are warranted.

Nasopharyngeal carcinoma with paranasal sinus invasion: the prognostic significance and the evidence-based study basis of its T-staging category according to the AJCC staging system.

BACKGROUND: To evaluate the prognostic significance of paranasal sinus invasion for patients with NPC and to provide empirical proofs for the T-staging category of paranasal sinus invasion according to the AJCC staging system for nasopharyngeal carcinoma. METHODS: The clinical records and imaging studies of 770 consecutive patients with newly diagnosed, untreated, and nondisseminated NPC were reviewed retrospectively. The overall survival, distant metastasis-free survival, and local relapse-free survival of these patients were analyzed using the Kaplan-Meier method, and the differences were compared using the log-rank test. RESULTS: The incidence of paranasal sinus invasion was 23.6%, with the rate of incidence of sphenoid sinus invasion being the highest. By multivariate analysis, paranasal sinus invasion was shown to be an independent prognostic factor for overall survival, distant metastasis-free survival, and local relapse-free survival (p < 0.05 for all). No significant differences in overall survival, distant metastasis-free survival, and local relapse-free survival were observed between patients with sphenoid sinus invasion alone and those with maxillary sinus and ethmoid sinus invasion (p = 0.87, p = 0.80, and p = 0.37, respectively). The overall survival, distant metastasis-free survival, and local relapse-free survival for patients with stage T3 disease with paranasal sinus invasion were similar to the survival rates for patients with stage T3 disease without paranasal sinus invasion (p = 0.22, p = 0.15, and p = 0.93, respectively). However, the rates of overall survival and local relapse-free survival were better for patients with stage T3 disease with paranasal sinus invasion than for patients with stage T4 disease (p < 0.01, and p = 0.03, respectively). CONCLUSIONS: Paranasal sinus invasion is an independent negative prognostic factor for NPC, regardless of which sinus is involved. Our results confirm that it is scientific and reasonable for the AJCC staging system for nasopharyngeal carcinoma to define paranasal sinus invasion as stage T3 disease.

Friend leukemia virus integration 1 expression has prognostic significance in nasopharyngeal carcinoma.

This study aimed to investigate the expression pattern and prognostic value of friend leukemia virus integration 1 (FLI-1) in nasopharyngeal carcinoma (NPC). Immunohistochemistry (IHC) staining of FLI-1 was performed in specimens from 198 untreated NPC patients. Ninety-nine patients were randomly assigned to the training set to analyze the prognostic value of FLI-1 and other clinicopathological characteristics, while the others were assigned to the testing set for validation. Clinicopathological data were compared using the Pearson chi-square test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to test independent prognostic factors and calculate the hazard ratio (HR) and 95% confidence interval (CI). Cytoplasmic FLI-1 expression positively correlated with N stage, distant metastasis and death (P<0.05) and also predicted poorer overall survival (OS) (P=0.014), distant metastasis-free survival (DMFS) (P=0.010), progression-free survival (PFS) (P=0.031). In multivariate analysis, FLI-1 expression and clinical stage were both independent prognostic factors of poor OS and DMFS. Prognoses of patients in the training set, the testing set, and the entire set were clearly divided into four risk subgroups by supplementing FLI-1 with clinical stage. These results indicate that FLI-1 expression is an independent prognostic factor for NPC patients and suggest that supplementing FLI-1 with clinical stage could be helpful for more accurate risk definition.

Prognostic impact of cigarette smoking on the survival of patients with established nasopharyngeal carcinoma.

BACKGROUND: Cigarette smoking is associated with the etiology of nasopharyngeal carcinoma; however, the influence of smoking on survival in patients with established nasopharyngeal carcinoma remains unknown. METHODS: We retrospectively analyzed 1,849 patients with nasopharyngeal carcinoma who were categorized as never, former, and current smokers. Cumulative effect of smoking was defined in terms of pack-years. Associations between cigarette exposure and survival were estimated by Cox proportional hazards model. RESULTS: The risks of death, progression, locoregional relapse, and distant metastasis were significantly higher for former and current smokers (all P ≤ 0.002) than never smokers. Heavy smokers with high pack-years had HRs for death of 3.31 [95% confidence interval (CI), 2.58-4.26; P < 0.001], for progression of 2.53 (95% CI, 2.03-3.16; P < 0.001), and for distant metastasis of 2.65 (95% CI, 1.89-3.70; P < 0.001). Specifically, in the cohort of 495 patients treated with intensity-modulated radiotherapy/three-dimensional conformal radiotherapy, we obtained similarly significant results. All of the survival outcomes remained significant in multivariate analyses. CONCLUSIONS: Pretreatment cigarette smoking is an independent, poor prognostic factor for patients with nasopharyngeal carcinoma, which is associated with increased risk of death, progression, locoregional relapse, and distant metastasis, with the risk increasing with pack-years. IMPACT: It is clear that cigarette smoking not only promotes carcinogenesis in the normal nasopharyngeal epithelium, but also affects the survival of patients with nasopharyngeal carcinoma.