Median Progression-free Survival Time Research Articles

Initial results of a phase II study of nivolumab(N) and ipilimumab(I) in genitourinary malignancies with neuroendocrine differentiation.

569 Background: Patients with metastatic genitourinary malignancies with neuroendocrine have limited therapeutic options following platinum therapy. Given encouraging results in initial cohort analysis for small cell urinary tract carcinoma, a cohort of any genitourinary malignancy with neuroendocrine differentiation was added to a multicenter, single arm, multi-cohort phase II trial to evaluate the efficacy of N and I in this setting. (NCT 03333616) Methods: Eligible patients had metastatic or locally advanced genitourinary malignancy with neuroendocrine differentiation with an ECOG performance status of 0-2; they may have received any line of prior therapy excluding prior immunotherapy. Patients underwent baseline biopsy and received treatment with N 3 mg/kg and I 1 mg/kg intravenously every 3 weeks for 4 cycles with continued maintenance of N 480 mg IV every 4 weeks. Imaging was performed at 12 weeks and then every 8 weeks through month 6 and then every 12 weeks thereafter. The primary endpoint was investigator assessed objective response rate (ORR) by RECIST 1.1. Results: A total of 27 patients were enrolled between 06/27/2018 and 06/21/2021, 10 (37%) had urinary tract cancer and 17 (63%) had prostate cancer (19 in expansion cohort, 3 urinary tract and 5 prostate cancer from earlier cohorts). The majority (n=25, 93%) patients received prior systemic therapy. Nine (33%) patients received all 4 doses of N and I during the induction period. Nine (33%) patients (7 of whom received 4 cycles N+I) received N maintenance (median number of cycles 9 (range, 2-37)). Median follow-up was 6.8 (range, 0.9-37.3) months. Objective response was achieved in 8 (30%, 80% CI 18%-44%) patients (Table). Median duration of response was not reached with 4 patients maintaining response >9 months. Median progression-free survival time was 2.6 (95% CI 1.8-6.5) months At time of analysis, 13 (48%) death events were reported due to progressive disease, in which 3 were bladder and 10 were prostate cancer. 8 (30%) patients developed treatment-related grade 3 or higher toxicities; one grade 5 toxicity was deemed treatment-unrelated. Conclusions: In this study we demonstrate N+I resulted in objective responses in patients with genitourinary malignancy with neuroendocrine differentiation. ORR of 50% in small cell carcinoma is bladder cancer is noteworthy and will be evaluated further in ongoing expansion cohort of bladder or upper tract carcinoma with variant histology. Clinical trial information: NCT03333616. [Table: see text]

Abstract P3-16-03: Clinical and pharmacoeconomic analyses of CDK4/6 inhibitors use in stage IV breast cancer females in the state of Qatar: A comparative retrospective observational study with cost effectiveness and cost utility analyses

Abstract Introduction: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are indicated in the first-line treatment of hormonal receptor positive and HER-2 negative (HR+/HER2- negative) metastatic breast cancer (MBC). Although phase III randomized controlled trials (RCTs) proved their clinical efficacy, they can increase healthcare expenditure. To date, there are no observational studies to validate the clinical findings of the existed RCTs. In addition, only a few pharmacoeconomic evaluations were published regarding the two common CDK4/6 inhibiting agents, palbociclib and ribociclib to evaluate their financial burden. Objectives: To evaluate the clinical efficacy of palbociclib and ribociclib in the local settings in Qatar. Moreover, to conduct a thorough pharmacoeconomic analysis for the two medications and compare them in terms of their cost-effectiveness and cost-utility. Methodology: A retrospective observational study on HR+/HER-2 negative stage IV breast cancer patients receiving palbociclib or ribociclib in Qatar was conducted, followed by a comparative pharmacoeconomic analysis. The primary outcomes were progression-free survival (PFS) and overall-survival (OS). Safety profiles of both medications were also evaluated. Clinical data of all MBC in Qatar were collected from the National Center for Cancer Care and Research (NCCCR) from January 2017 to December 2019 using Cerner ® system. To evaluate the long-term costs-effectiveness, a 10-year within-cycle corrected Markov’s model was developed. The Markov’s model consisted of three main health states: progression-free (PFS), progressed disease (PD), and death. Incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) were generated and compared to a three gross-domestic-product (3 GDP) per capita. Model costs were obtained from the department of accounting and finance in the NCCCR, transition probabilities were calculated from individual patient data obtained in the clinical phase, and utilities were summarized from the published literature. Deterministic and probabilistic sensitivity analyses were carried out. Modeling was conducted via TreeAge Pro ® software. Results: There was no statistically significant difference between palbociclib and ribociclib in PFS; median PFS time was 17.85 versus 13.55 months respectively; p> 0.05. Similarly, there was no statistically significant difference in OS (29.82 versus 31.72 months; p>0.05). For the pharmacoeconomic analysis, ribociclib dominated palbociclib in yielding an ICER of - 83,090.88 QAR per life-year gained, and ICUR of -31,868.06 QAR per quality-adjusted life-year gained. The results remained robust in all cases of the deterministic sensitivity analyses suggesting ribociclib is more cost-effective than palbociclib. Taking all combined uncertainties into account, the overall confidence in the base-case conclusion was around 60%. Conclusions: Both treatment strategies have similar efficacy and safety profiles. Nonetheless, ribociclib is a more cost-effective option than palbociclib based on the base-case results and based on the addressed uncertainties related to the model inputs. Citation Format: Nour Hisham Al-Ziftawi, Shereen Elazzazy, Mohammed Fasihul Alam, Asrul Akmal Shafie, Anas Hamad, Salha Bujassoum, Mohamed Izham Ibrahim. Clinical and pharmacoeconomic analyses of CDK4/6 inhibitors use in stage IV breast cancer females in the state of Qatar: A comparative retrospective observational study with cost effectiveness and cost utility analyses [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-16-03.

Abstract OT2-19-08: Phase IB/II trial of palbociclib and binimetinib in advanced triple-negative breast cancer with hyperactivation of ERK and/or CDK4/6

Abstract Background: Novel effective and safe therapies are required for advanced TNBC after progression to standard-of-care first line treatment with anti-PD-1/L1 + chemotherapy. We have found that the most aggressive TNBC variants are driven by a heterogeneous set of genetic aberrations that converge in the increased activity of 6 kinases: KIT, PNKP, PRKCE, P70S6K, ERK and CDK6 (Nat Commun; 9:3501-18). Although the inhibition of each kinase in monotherapy yielded little efficacy in preclinical models, the combinations targeting pairs of the former kinases led to therapeutic synergy in most cases. The combined inhibition of CDK6 and ERK led to 5-fold increase in overall survival in preclinical TNBC models (PDXs and spontaneous murine cancer models). The greatest activity was observed in models with increased activity of either CDK6 or ERK. Thus, we aimed to test the safety and preliminary efficacy of combined ERK and CDK6 inhibition with binimetinib and palbociclib in women with advanced TNBC with hyperactivation of ERK and/or CDK6. The combination has been preliminary tested in lung cancer, where a phase I dose-escalation trial established the RP2D in binimetinib 45 mg/BID plus Palbociclib 125 mg daily 21/7. Trial design: Single-arm, prospective, multicentric, open-label, phase IB/II trial with intra-patient dose-escalation. Patients candidate for pre-screening will have determined the activity of ERK and CDK6 with an in-house developed assay and acquisition algorithm at the central lab. Those testing positive for either marker will undergo full screening. Patients will start treatment with continuous oral binimetinib at 45 mg/BID and palbociclib 100 mg/day from days 1 to 21, in 28-day cycles. Patients experiencing ≤ grade 1 tolerable side effects as the greatest toxicity will be allowed to escalate to palbociclib to 125 in cycle 2. Fresh biopsies will be harvested at baseline and disease progression, in order to establish patient-derived organoids (PDOs) and perform WES. PBMCs will be harvested at baseline, +24 hours, and at the beginning of cycle 2, to study changes in the immunophenotype. RECIST 1.1 and NCI CTC AE V 5.0 criteria will be used for assessing disease control (q8 weeks) and toxicity. Eligibility criteria: Pre-screening: Women >18 year old diagnosed of advanced, non-curable TNBC; 2) who have received a minimum of 1 treatment line including immunotherapy; 3) no more than 2 treatment lines for advanced disease; 4) Adequate organ function and recovery from previous toxicity to < tolerable G2. Full screening: 5) Demonstration of hyper-activation of CDK6 and/or ERK in the tumor sample; 6) PD to the previous treatment regimen within the last 28 days. Specific aims: Primary: 1) To determine the progression-free survival time of the combination of binimetinib and palbociclib in TNBC patients with hyperactivation of ERK and/or CDK6 in second/third line 2) To assess the safety and tolerability of the former combination Secondary: 1) 6-month PFS rate, response rate, and overall survival of the combination 2) To study biomarkers of sensitivity and primary and acquired resistance to the combination taking advantage of PDOs 3) To determine the immunodynamics of the combination. Statistical methods: The null hypothesis is that the median PFS time for second/third line TNBC with best physician’s choice is 1.7 months (NEJM; 384:1529-41, 2021). With alpha and beta errors of 0.05 and 0.2, the minimum number of patients to demonstrate a 30% improvement in PFS to 2.5 months is 25. Preliminary data suggest that approximately 40% of the patients show hyper-activation of CDK6 and/or ERK; thus, and assuming a methodological failure of 10%, the minimum number of patients to screen is 69. Present accrual/target accrual: 27 screened of 69 planed; 11 accrued of 25 planned Citation Format: Luis Manso, Alfonso Cortes, Juan M Cejalvo, Serafin Morales, Jose A García Saenz, Ramon Colomer, Rodrigo Sanchez-Bayona, Jorge Silva, Juan A Guerra, Diego Malon, Silvana Mouron, Eduardo Caleiras, Miguel Quintela-Fandino. Phase IB/II trial of palbociclib and binimetinib in advanced triple-negative breast cancer with hyperactivation of ERK and/or CDK4/6 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-08.

Combination of Anti-PD-1 Antibody, Anlotinib and Pegaspargase "Sandwich" With Radiotherapy in Localized Natural Killer/T Cell Lymphoma.

Asparaginase/pegaspargase containing regimens combined with radiotherapy are highly effective and considered the cornerstone of localized Natural killer/T-cell lymphoma (NKTL) treatment. However, these chemotherapy regimens inevitably cause relatively high incidence of treatment-related adverse events (TRAEs). Herein we retrospectively evaluated the efficacy and safety of the combined regimen of anti-PD-1 antibody, anlotinib and pegaspargase “sandwich” with radiotherapy in localized NKTL. Anti-PD-1 antibody and pegaspargase at 2500 U/m2 were administered on day 1, while anlotinib (12 mg once a day) was orally administered on days 1-14. The treatment was repeated every 3 weeks. All the eight patients included received 3 cycles of the regimen followed by radiotherapy and an additional 3 cycles. The overall response rate was 100%, and the complete response rate was 87.5%. With a median follow-up time of 35.5 months (range, 34.03-40.90 months), median PFS and OS times were not reached. The 3-year PFS and OS rates were 100% and 100%, respectively. All patients were alive at the last follow-up. No treatment-related death and no grade 4 TRAE was reported. No grade 3/4 hematological toxicity was detected, and half of the patients didn’t report any hematological toxicity. This study indicates that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising chemoradiotherapy regimen for localized NTKL, with mild toxicity and good tolerance.

Gadoxetic Acid-Enhanced MRI Features for Predicting Treatment Outcomes of Early Hepatocellular Carcinoma (< 3 cm) After Transarterial Chemoembolization

Magnetic resonance imaging (MRI) is the most useful imaging tool for small hepatocellular carcinoma (HCC) evaluation. Patients undergoing transarterial chemoembolization (TACE) might have predictive imaging prognostic factors. This study aimed to find predictive gadoxetic acid (GA)-enhanced MRI features that affect tumor response and outcomes in patients with early HCC who underwent conventional TACE. Among patients who underwent conventional TACE as a first-line treatment for Barcelona clinic liver cancer stage 0 or A (<3 cm), 135 patients who underwent GA-enhanced MRI before treatment were included in this retrospective study. The patients' pretreatment clinical characteristics and MRI features were evaluated. Post-treatment tumor response, progression-free survival (PFS), and overall survival (OS) were also investigated. The median follow-up period was 47 (range: 7-133) months, with 90 (67%) patients showing complete remission (CR) at the 1-month follow-up after TACE. Tumor number (odds ratio [OR] 0.602, 95% confidence interval [CI]: 0.375-0.967), central location (OR: 0.349, 95% CI: 0.145-0.837) were inversely associated with CR achievement. Median PFS and OS time were 22 (range: 1-133) and 67 (range: 7-133) months, respectively. The MRI features affecting poor survival outcomes were tumor number (PFS: hazard ratio [HR]=1.444, 95% CI=1.124-1.854; OS: HR=1.459, 95% CI=1.018-2.090), central location (PFS: HR=1.664, 95% CI=1.038-2.667; OS: HR=1.890, 95% CI=1.021-3.497), and marginal irregularity (PFS: HR=3.099, 95% CI=1.953-4.979; OS: HR=1.985, 95% CI=1.084-3.634). Multiplicity, central location, and marginal irregularity of HCC on GA-enhanced MRI were significant factors associated with poor prognosis of patients with early HCC after conventional TACE.

Analysis of 16S rRNA sequencing in advanced colorectal cancer tissue samples.

163 Background: Changes in the colon’s microbiota composition are contributors to the pathogenesis of colorectal cancer (CRC). Features of this microbiome may have prognostic significance. For this study, we analyzed 16S rRNA sequencing data from tumor tissue samples of advanced CRC patients and determined if there were potential correlations between microbiome composition and clinical outcomes. Methods: One hundred and thirty three advanced CRC patients in St. Vincent’s Hospital in Korea were enrolled. DNA was extracted from collected tissue samples, the V3-V4 regions were amplified, and a 16S rRNA gene amplicon library was prepared using an Illumina protocol. DNA was sequenced on an Illumina MiSeq instrument. We used three different bioinformatic packages to process the sequence data and evaluate the microbiome composition of each tumor. Results: The classification performances of three different analytic pipelines (Kraken2, QIIME2, and DADA2) were compared in a microbiome control sample. Among these, DADA2 and QIIME2 were chosen for use in subsequent analysis, due to their lower Chi-square (χ2) test statistic values on the control data. After excluding samples that retained less than 5% of total reads after merging, 120 samples were analyzed. The median age of the cohort was 63 years, 63.3% were male, and all were Korean. The distribution over primary sites was 27.5% from the right-side colon, 30.8% from the left-side colon, and 41.7% from the rectum. All subjects received the first line of systemic treatment. The median progression-free survival time was 8.9 months. Twenty-nine patients (24.2%) survived more than 24 months. When examining the results from the two bioinformatic packages, pairwise comparisons showed positive correlations in the relative abundances of the top 20 genera. Fusobacterium, a microbe known to relate to pathogenesis and prognosis of CRC, was not detected by QIIME2. Stratifying by primary site, rectal cancers showed higher alpha diversity than left- or right-side colon cancers. Separately, a higher serum CEA level (≥8) at diagnosis, and the presence of lung metastasis were both found to be related to higher alpha-diversity, a global indicator of microbiome composition. When excluding minimally abundant (&lt; 1% per patient) genera, beta-diversity was found to be differentiable by T stage, the presence of lung metastasis, and the presence of liver metastasis. Most notably, beta-diversity differed between patients who survived more than two years and patients who died within 2 years. Using the DADA2 results, we confirmed that the presence of Fusobacterium nucleatum in CRC tissue was found to be a strong predictor of poor overall survival (OS), along with old age and liver metastasis. Conclusions: This study suggests potential associations between microbiome composition and clinical parameters of advanced CRC. Microbial biomarkers may be a valuable prognostic tool in this population.

Prognostic factors affecting the success of conversion chemotherapy in patients with unresectable liver metastases from initially colorectal cancer

Objective: To investigate the factors affecting the success of conversion therapy in patients with initially unresectable colorectal cancer liver metastases (CRLM) in order to provide evidence-based medical evidence for formulating individualized treatment strategies for patients. Methods: A retrospective case-control study was used in this study. Clinical data of 232 patients with initially unresectable CRLM receiving first-line systemic treatment in Sun Yat-sen University Cancer Center from January 2013 to January 2020 were collected, including 98 patients of successful conversion and 134 patients of failed conversion as control. Conversion therapy scheme: 38 patients received FOLFOXIRI regimen chemotherapy (irinotecan, oxaliplatin, calcium folinate and fluorouracil), 152 patients received FOLFOX regimen (oxaliplatin, calcium folinate and fluorouracil), 19 patients received FOLRIRI regimen (irinotecan, calcium folinate and fluorouracil), 23 patients received systemic chemotherapy combined with fluorouridine hepatic artery infusion chemotherapy; 168 patients received targeted therapy, including 68 of bevacizumab and 100 of cetuximab. Logistics analysis was used to compare the factors affecting the success of conversion therapy. The Kaplan-Meier method was used to calculate progression-free survival (PFS), and the Log-rank test was used for survival comparison. Results: Among 232 patients, 98 patients had successful conversions and 134 patients had failed conversions with a successful conversion rate of 42.2%, meanwhile 30 patients underwent simple hepatectomy and 68 underwent hepatectomy combined with intraoperative radiofrequency ablation. After first-line chemotherapy, 111 patients (47.8%) were partial remission, 57 patients (24.6%) were stable disease, and 64 patients (27.6%) were progression disease. During the median follow-up of 18.8 (1.0-87.9) months, 148 patients were dead or with tumor progression. The median PFS time of patients with successful conversion was longer than that of patients with failed conversion (31.0 months vs. 9.9 months, P<0.001). Univariate analysis found that the bilobar distribution of liver tumors (P=0.003), elevated baseline carcinoembryonic antigen (CEA) levels (P=0.024), tumor invasion of the portal vein (P=0.001), number of metastatic tumor>8 (P<0.001), non-FOLFOXIRI (P=0.005), and no targeted therapy (P=0.038) were high risk factors for the failed conversion therapy. The results of multivariate logistics analysis indicated that the number of metastatic tumor >8 (OR=2.422, 95%CI: 1.291-4.544, P=0.006), portal vein invasion (OR=2.727, 95%CI: 1.237-4.170, P=0.008) were the independent risk factors for failed conversion therapy, while FOLFOXIRI regimen (OR=0.300, 95%CI: 0.135-0.666, P=0.003) and targeted drugs (OR=0.411, 95%CI: 0.209-0.809, P=0.010) were independent protective factors for successful conversion therapy. Conclusions: The number of metastatic tumor and portal vein invasion are key factors that affect the outcomes of conversion therapy for initially unresectable CRLM. If a patient can tolerate chemotherapy, a combination program of three-drug and targeted therapy is preferred for the active conversion therapy.

The Clinical Aspects and Prognostic Factors Concerning Survival in Patients With Recurrent Cervical Cancer After Radical Hysterectomy and Adjuvant Chemoradiotherapy.

PurposeTo investigate the recurrence patterns and prognostic factors of patients with recurrent cervical cancer after radical hysterectomy with node dissection (RHND) followed by adjuvant radiotherapy (RT)/concurrent chemoradiotherapy (CCRT).MethodsThe medical records of 153 patients with pre-operative International Federation of Gynecology and Obstetrics stage IB-IIA cervical cancer, who were treated with RHND followed by adjuvant RT/CCRT at the Liaoning Cancer Hospital between January 1, 2012 and May 31, 2018, were retrospectively analyzed.ResultsThe median disease progression-free survival time was 16 months, and 75.2% (115/153) of patients had a relapse within two years. The survival of patients with multi-site relapse was significantly lower in comparison to those with relapse in a single site (p < 0.001). The survival rate of patients with distant metastasis (DM) and combined recurrence (DM with localregional recurrence [LR]) was significantly lower than that of patients with only LR (p = 0.006, p < 0.001). Furthermore, the survival rate of patients with combined recurrence was significantly lower than that of patients with only DM (p = 0.046). Multivariate analysis showed that resection margin involvement, para-aortic and common iliac lymph node metastasis, DM, no treatment after disease relapse, and early disease relapse were independent prognostic factors associated with poor survival.ConclusionMost of the cervical cancer patients who received initial RHND followed by adjuvant RT/CCRT had a relapse within two years. Resection margin involvement, para-aortic and common iliac lymph node metastasis, DM, no treatment after recurrence, and early disease relapse were found to be prognostic factors in patients with recurrent cervical cancer after RHND followed by adjuvant RT/CCRT.

Surrogate Indicators of Overall Survival in Advanced Hepatocellular Carcinoma

To the Editor, For more than a decade, the targeted drug sorafenib[1, 2] has been the dominant first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, due to the low overall response rate and high drug resistance rate, many new targeted drugs have been developed, including sunitinib, brivanib, linifanib, nintedanib, dovitinib, sorafenib plus erlotinib, lenvatinib, and donafenib. On the other hand, with the increasing use of immune checkpoint inhibitors in solid tumors, several trials investigated the efficacy and safety of immune checkpoint inhibitors in advanced HCC. Among these trials, only lenvatinib and donafenib as monotherapy were non-inferior to sorafenib in overall survival in untreated advanced HCC. Most of other trials did not meet their primary end point of overall survival. However, the efficacy of the combination therapy with PD-1 or PD-L1 inhibitor plus bevacizumab (VEGF inhibitor) is amazing.[3, 4] An expert panel convened by the American Association for the Study of Liver Diseases recommended time to progression as the primary endpoint in randomized phase 2 trials and overall survival as the main endpoint to measure effectiveness in phase 3 trials.[5, 6] In real world clinical practice, subsequent antitumor therapies after tumor progression and/or therapies for concurrent liver disease can confound the assessment of clinical benefit. In the recent issue of Journal of Hepatology, on behalf of EASL, Bruix and coworkers updated the recommendations of systemic treatment of HCC.7 This review proposed that “overall survival is the sole robust endpoint to assess the benefit from any intervention in advanced HCC” and “all proposed surrogates lack adequate validation”. Here, we tried to reveal the relationship among objective response rate (ORR), median overall survival (OS) time and median progression-free survival (PFS) time by presenting them in a same curve graph. The potential relationship between PFS and OS is revealed by representing the hazard ratio (with 95% confidence interval) of PFS and OS with a forest plot. We systematically searched PubMed and EMBASE databases and analyzed phase 3 clinical trials with large sample size. A total of 11 trials about first-line systemic therapies for advanced HCC published from 2008 to 2021 were included into analysis. All these 11 trials included a group of patients treated with sorafenib. In addition, 7 trials about second-line systemic therapies published from 2015 to 2021 were also included into analysis. The control group received placebo treatment in all these 7 trials. All these 18 trials reported ORR, median PFS and OS time. The ORR according to RECIST 1.1 in the sorafenib group ranged from 0.7% to 11.9% (median 6.1%). Among patients with sorafenib therapy, the median PFS and OS time was 3.75 (range 2.8 to 5.5) and 10.4 (range 6.5 to 14.7) months, re-spectively. The mean ORR of sorafenib was also calculated. The denominator equals the sum of the sample sizes for each sorafenib group. Percentage was obtained by the sum number of cases with complete or partial response in each trial divided by the denominator. The mean ORR of sorafenib was 6.0%. Actually, atezolizumab plus bevacizumab was associated with the highest ORR (27.3%) while donafenib with the lowest (4.6%). In addition, the median OS time of each trial tended to increase gradually with the increase of ORR and median PFS time (Fig. 1a). However, this trend was not significant in second-line treatment (Fig. 1b). And then, we describe the association between PFS and OS with forest plot (Fig. 1c). We found (1) PD-1 (sintilimab) or PD-L1 (atezolizumab) inhibitor plus bevacizumab was associated with the best survival benefit for patients with advanced HCC;[3, 4] (2) the significant benefit of PFS may not translate into significant benefit of OS (linifanib, lenvatinib, ramucirumab in REACH trial, S-1); (3) similar PFS generally does not translate into OS benefits (sunitinib, brivanib, sorafenib plus erlotinib), except in the ZGDH3 trial (donafenib); (4) a benefit in PFS could predict a benefit in OS when the hazard ratio for PFS is lower than 0.6 in most trials, except ZGDH3[8] (hazard ratio 0.91) and KEYNOTE 240 trial (hazard ratio 0.72).[9] Tumor progression is the leading cause of death in patients with HCC. Increased ORR and PFS may increase OS in firstline setting, but not in second-line therapy. In addition, the optimum cut-off value of hazard ratio for PFS in predicting benefit in OS is still pending.

Tislelizumab Combined with Carboplatin-Paclitaxel for Treatment of Metastatic or Recurrent Endometrial Cancer: a Retrospective Clinical Study.

Metastatic or recurrent endometrial cancers with low survival rate had no standard or limited therapy choice. The aim of our study was to determine the efficiency and safety of tislelizumab combined with carboplatin-paclitaxel as a front-line therapy for patients with metastatic or recurrent endometrial cancer. This clinical retrospective cohort study examined 24 Chinese patients with metastasis or recurrence but had not yet received treatment. The therapeutic regimen consisted of 6 cycles of intravenous paclitaxel (175 mg/m2) and carboplatin (target AUC: 5 mg/mL/min) with tislelizumab (200 mg) once every 3 weeks, and then intravenous tislelizumab (200 mg) once every 3 weeks until disease progression or unacceptable toxicity. At the 18-month follow-up, 8 patients were still receiving treatment, 13 were dead, and 3 withdrew. The objective response rate (ORR) was 62.5%, the disease control rate was 75.00%. The ORR was 77.78% for patients positive for PD-L1 and 69.23% for patients positive for MSI-H. The median overall survival time was 11.50 months, and the median progression-free survival time was 6.00 months. Half of the patients experienced 3 - 4 grade adverse events. There were no allergic reactions or treatment-related deaths. Tislelizumab combined with carboplatin-paclitaxel was used as a front-line therapy, had a beneficial effect and was safe for patients with metastatic or recurrent endometrial cancer.

Optimal Treatments for NSCLC Patients Harboring Primary or Acquired MET Amplification.

Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.

A retrospective analysis of 32 small and well-differentiated rectal neuroendocrine tumors with regional or distant metastasis.

Rectal neuroendocrine neoplasms (NENs) are a group of rare and heterogeneous diseases and are classified as well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on histological differentiation. The patients were followed up with a median period of 32.5 (range 2-123) months and no patients were lost to follow-up. The median PFS time could not be obtained, as only less than half of the patients suffered tumor progression by the end of follow-up. The 1-year and 3-year PFS rates were 73.5% and 69.2%, respectively. The median OS was 86 months in the entire cohort. The 1-year and 3-year OS rates were 100% and 96.0%, respectively.

Establishment of an optimized CTC detection model consisting of EpCAM, MUC1 and WT1 in epithelial ovarian cancer and its correlation with clinical characteristics.

ObjectiveEmerging studies have demonstrated the promising clinical value of circulating tumor cells (CTCs) for diagnosis, disease assessment, treatment monitoring and prognosis in epithelial ovarian cancer. However, the clinical application of CTC remains restricted due to diverse detection techniques with variable sensitivity and specificity and a lack of common standards.MethodsWe enrolled 160 patients with epithelial ovarian cancer as the experimental group, and 90 patients including 50 patients with benign ovarian tumor and 40 healthy females as the control group. We enriched CTCs with immunomagnetic beads targeting two epithelial cell surface antigens (EpCAM and MUC1), and used multiple reverse transcription-polymerase chain reaction (RT-PCR) detecting three markers (EpCAM, MUC1 and WT1) for quantification. And then we used a binary logistic regression analysis and focused on EpCAM, MUC1 and WT1 to establish an optimized CTC detection model.ResultsThe sensitivity and specificity of the optimized model is 79.4% and 92.2%, respectively. The specificity of the CTC detection model is significantly higher than CA125 (92.2% vs. 82.2%, P=0.044), and the detection rate of CTCs was higher than the positive rate of CA125 (74.5% vs. 58.2%, P=0.069) in early-stage patients (stage I and II). The detection rate of CTCs was significantly higher in patients with ascitic volume ≥500 mL, suboptimal cytoreductive surgery and elevated serum CA125 level after 2 courses of chemotherapy (P<0.05). The detection rate of CTCEpCAM+ and CTCMUC1+ was significantly higher in chemo-resistant patients (26.3% vs. 11.9%; 26.4% vs. 13.4%, P<0.05). The median progression-free survival time for CTCMUC1+ patients trended to be longer than CTCMUC1− patients, and overall survival was shorter in CTCMUC1+ patients (P=0.043). ConclusionsOur study presents an optimized detection model for CTCs, which consists of the expression levels of three markers (EpCAM, MUC1 and WT1). In comparison with CA125, our model has high specificity and demonstrates better diagnostic values, especially for early-stage ovarian cancer. Detection of CTCEpCAM+ and CTCMUC1+ had predictive value for chemotherapy resistance, and the detection of CTCMUC1+ suggested poor prognosis.

TACE Plus Lenvatinib Versus TACE Plus Sorafenib for Unresectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Prospective Cohort Study.

Background and ObjectivesThis study aimed to compare the efficacy of transarterial chemoembolization (TACE) plus sorafenib (TACE-S) to TACE plus lenvatinib (TACE-L) for the treatment of HCC with portal vein tumor thrombus (PVTT).MethodsThis cohort study recruited patients from September 2017 to September 2020. A total of 59 and 57 consecutive patients were treated with TACE-L and TACE-S, respectively.ResultsBefore propensity score matching (PSM), comparing TACE-L to TACE-S, the median overall survival (OS) time was 16.4 months and 12.7 months, respectively [hazard ratio (HR) 1.34; 95% confidence interval (CI): 0.81–2.20; p = 0.25]. The median progression-free survival (PFS) time was 8.4 months and 7.43 months, respectively (HR 1.54; 95% CI: 0.98–2.41; p = 0.081). After PSM, the median OS time was 18.97 months and 10.77 months, respectively (HR 2.21; 95% CI: 1.12–4.38; p = 0.022); the median PFS time was 10.6 months (95% CI: 6.6–18.0 months) and 5.4 months (95% CI: 4.2–8.1 months), respectively (HR 2.62; 95% CI: 1.43–4.80; p = 0.002). After PSM, the overall response rate (ORR) was 66.8% vs. 33.3% [odds ratio (OR) 0.85; 1.05–6.90; p = 0.037].ConclusionBoth TACE-L and TACE-S are safe, well-tolerated treatments for HCC with PVTT. In HCC with PVTT, TACE-L was significantly superior to TACE-S with respect to OS, PFS, and ORR. A larger-scale randomized clinical trial is needed.

Computed Tomography Features and Clinical Prognostic Characteristics of Hepatoid Adenocarcinoma of the Stomach.

PurposeHepatoid adenocarcinoma of the stomach (HAS) is a highly malignant and aggressive tumor. The purpose of this study was to describe the clinical, computed tomography (CT), and prognostic features of HAS to increase the awareness of this entity and determine its distinguishing features from non-HAS tumors.MethodsThe CT features and clinical data of 47 patients in our hospital with pathologically documented HAS were retrospectively analyzed, and the relevant differences between pure HAS (pHAS) and mixed HAS (mHAS) were determined. In addition, 141 patients with non-HAS tumors in the same T stage in the same period were selected as the control group. The data were compared between the two groups, and factors affecting the prognosis of HAS were analyzed. In addition, we included 9 patients with HAS and 27 patients with non-HAS tumors from another center for external validation.ResultsThe patients in the HAS group were predominantly men (n = 33), and the tumor location was mostly the cardia or fundus (n = 27). Between the HAS and non-HAS groups, there were observed differences in terms of: sex, serum alpha-fetoprotein (AFP), carbohydrate antigen (CA)-125, and CA-724 levels; longest tumor diameter; degree of differentiation; vascular invasion; N stage, M stage, and tumor-node-metastasis (TNM) stage; thickest tumor diameter; plain CT attenuation; arterial-phase CT attenuation; CT attenuation between the venous and arterial phases; enhancement modes; and degrees of enhancement (all P < 0.05). In the data from another center for external validation, there were observed differences in terms of: age, degree of differentiation, vascular invasion, thickest tumor diameter, the ratio of arterial CT attenuation to CT attenuation of the abdominal aorta at the same level (RA), CT attenuation difference between the venous phase and arterial phase (HUv-a) (all P < 0.05). The results of the multivariate analysis revealed that the independent factors for differentiation were serum AFP level (P = 0.001), M stage (P = 0.038), and tumor enhancement on CT (P = 0.014). Among patients in the HAS group, 72.34% had pHAS and 27.66% had mHAS. The thickest tumor diameter and the longest short diameter of the metastatic lymph nodes of the mHAS group were on average 6.39 cm and 1.45 cm, respectively, which were larger than those in the pHAS group. The median progression-free survival time was 18.25 months in the HAS group, which was shorter than that in the non-HAS group (72.96 months; P = 0.001). The median overall survival time in the HAS group was 24.80 months, which was shorter than that in the non-HAS group (67.96 months; P = 0.001). The factors affecting the prognosis of HAS were M stage (P = 0.001), overall TNM stage (P = 0.048), presence of vascular cancer emboli (P = 0.040), and pHAS type (P = 0.046). Multifactorial analysis revealed that M stage (P = 0.027) and pHAS type (P = 0.009) were independent risk factors affecting the prognosis of HAS.ConclusionAlthough HAS is a rare clinical entity, it should be considered in the differential diagnosis of gastric tumors. Patients with HAS often have advanced-stage disease at presentation and a worse prognosis than patients with non-HAS tumors. CT findings, combined with laboratory results, can support the diagnosis of HAS. However, the final diagnosis needs to be confirmed with a histopathologic examination. If the postoperative pathologic findings reveal the mHAS type, a rapid clinical intervention and a detailed follow-up with CT are essential.

Sequence Therapy with FOLFIRINOX and Gemcitabine/Nab-Paclitaxel for Patients with Advanced Pancreatic Cancer: A Monocentre Retrospective Cohort Study

Background and Aims: While irresectable pancreatic cancer has still a dismal overall prognosis, evidence about the optimal chemotherapy sequence is scarce. After treatment with FOLFIRINOX in first-line, gemcitabine monotherapy was established for years. As a potential treatment alternative after failure of FOLFIRINOX therapy, combination of gemcitabine and nab-paclitaxel is used. However, this combination has formally not yet been approved for second-line treatment and investigation of efficiency and treatment tolerance is the aim of this trial. Methods: Therefore, we investigated 225 patients with histologically confirmed local advanced or metastatic pancreatic cancer in this retrospective monocentre study (November 2010 – July 2019). Of this, 44 patients received FOLFIRINOX therapy and outcome was further analysed. The primary end point of this cohort was overall survival (OS), and secondary end points included progression-free survival (PFS), response rate, and safety. Results: In most of the patients, FOLFIRINOX as first-line treatment of irresectable pancreatic cancer resulted in temporary cancer control (partial response [PR]: 50% and stable disease [SD]: 18%), whereas tumour progression was observed in 23% of the patients. The median PFS time for FOLFIRINOX treatment was 7.3 months and median OS 10.3 months. Seven (16%) patients received additional local radio chemotherapy of the pancreatic tumour. During first-line therapy, in 8 (18%) patients, laparotomy was performed to proof resectability of the tumour. Hereby, in 3 patients R0- and in 3 patients R1 resection was achieved, whereas 2 patients stayed irresectable. Twenty-five of the 44 patients (57%) received second-line therapy, namely, 24 patients gemcitabine/nab-paclitaxel and 1 patient gemcitabine and erlotinib. Hereby, gemcitabine/nab-paclitaxel led again to temporary tumour control in 46% of the patients (PR: 21%, SD: 25%), while in 29% of the patients, disease progression was observed. Corresponding median PFS for gemcitabine and nab-paclitaxel treatment was 3.5 months. Patients who received second-line treatment with nab-paclitaxel and gemcitabine had a more favourable prognosis (median OS: 17 vs. 9.2 months; HR 0.32 [0.14–0.70], p < 0.001) than patients who were not eligible for second-line treatment. Moreover, in multivariate analyses association with patients’ survival and tumour response to chemotherapy in both therapeutic lines and µGT concentrations below 100 IU/L in first-line FOLFIRINOX chemotherapy were observed. Conclusion: These real-world data suggest that gemcitabine/nab-paclitaxel may be feasible after FOLFIRINOX therapy in patients with irresectable pancreatic cancer. However, prospective randomized data about the superiority to gemcitabine monotherapy are needed.

STMO-17 Treatment outcome of photodynamic therapy using talaporfin sodium for recurrent high-grade glioma

Objective: Photodynamic therapy (PDT) using Talaporfin Sodium (TS) is a novel therapeutic strategy to improve local tumor control in high-grade glioma. TS is a photosensitizer that accumulates in tumor cells and produces highly toxic free radicals by intraoperative irradiation of laser with a 664nm wavelength. However, little is known about the treatment outcomes of PDT in recurrent high-grade gliomas (rHGG). In this study, we investigated the treatment outcome of PDT in rHGG and evaluated the correlation between intratumoral TS accumulation and outcomes. Methods: We included 21 patients with rHGG and 22 tumors, who were treated by PDT between June 2016 and March 2021. TS was transvenously administered 22–26 hours before PDT. Intratumoral TS concentrations were measured by liquid chromatography using frozen tissue. Results: The rHGGs included 10 glioblastoma, IDH1/2-wildtype (GBM, IDH1/2-WT: 45.5%), 3 GBM, IDH1/2-mutant (GBM, IDH1/2-Mut: 13.6%), 7 anaplastic oligodendroglioma, IDH1/2-Mut/codel (AO, IDH1/2-Mut/codel: 31.8%), 1 anaplastic astrocytoma, IDH1/2-WT (AA, IDH1/2-WT: 4.5%), 1 high-grade astrocytoma, IDH1/2-WT (4.5%). The median local progression free survival (PFS) time after PDT was 3.6 months and the median survival time from PDT was 19.4 months. The intratumoral TS concentrations of 7 tumors (TS(-): 31.8%) were below the limit of quantification, and the intratumoral TS concentrations of the remaining 15 tumors (TS(+)) were 43.5 ng/mg-protein (14.7–132 ng/mg-protein). The intratumoral TS concentrations were not significantly associated with IDH1/2 mutation status, cellularity, tumor grade, and pattern of enhancement. The median PFS from PDT tended to be longer in TS(+) than in TS(-) (TS(+): 6.3 vs TS(-): 1.4 months, p = 0.054). Conclusions: We found that the intratumoral TS concentrations were heterogeneous and 31.8% were below the limit of quantification. TS(+) tended to have better local tumor control than TS(-), suggesting the intratumoral TS accumulation have an impact of treatment outcomes of PDT.

RT-4 Treatment outcome of proton beam therapy for glioblastoma

Introduction: Proton beam therapy enables high dose irradiation for tumors while reducing the dose to surrounding normal tissue due to the sharp energy peak called the Bragg peak. We retrospectively analyzed the efficacy of the high dose radiotherapeutic strategy using proton beam for glioblastoma (GBM) in our institution. Methods: Twenty-nine patients with newly diagnosed GBM who underwent high dose proton beam therapy concomitant with temozolomide were investigated. All patients received hyperfractionated concomitant radiotherapy consisting of X-ray radiotherapy (50.4Gy in 28 fractions) and proton beam therapy (46.2Gy [RBE] in 28 fractions). The survival outcome and adverse events were analyzed. Results: The median overall survival time and progression free survival time for all 29 patients were 31.0 months (95%CI, 25.9–36.1) and 11.0 months (95%CI, 7.8–14.2), respectively. No significant survival difference according to the MGMT methylation status was shown. Failure patterns after proton beam therapy included 17 cases of local recurrence, 3 cases of distant recurrence, and 5 cases of dissemination. Although there was no significant difference in time to recurrence according to the failure pattern, there was a tendency of longer survival in the local recurrence group. Regarding adverse events, radiation necrosis was observed in 8 cases (including 2 asymptomatic cases). The median time to onset of necrosis after radiation was 18.2 months (95%CI, 10.3–26.2). There were 5 cases of long survivor over 5 years out of 29 cases (17.2%). Of these, 4 cases developed radiation necrosis. Conclusions: Our results indicate that high dose proton beam therapy of 96.6Gy (RBE) prolonged survival in selected GBM patients. Particularly in long survivors, special attention and effective treatment to radiation necrosis is a remaining problem.

Efficacy and Safety of Epirubicin Combined with Temozolomide for Treatment of Advanced Leiomyosarcoma.

BackgroundLeiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS.MethodsThis was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020.ResultsWe examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths.ConclusionEPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.

Clinical characteristics and survival analysis of colorectal cancer in China: a retrospective cohort study with 13,328 patients from southern China.

BackgroundColorectal cancer (CRC) is one of the most common cancers in China. However, detailed clinical characteristics and survival information are limited. This study aimed to investigate the potential epidemiological and clinical risk factors affecting the survival of CRC patients in southern China.MethodsPatients with primary CRC between 1994 and 2019 at the First and the Sixth Affiliated Hospitals of Sun Yat-sen University (Guangzhou, China) were included. Clinical characteristics and survival outcomes were collected from medical records. The Kaplan–Meier method was used to estimate overall survival (OS) and progression-free survival (PFS), and Cox’s proportional-hazards regression model was used to estimate hazard ratios and 95% confidence intervals.ResultsOf all 13,328 patients, 60.1% were men; the mean age was 61.3 years; 53.5% had colon cancer. Among all patients, 1,864 (14.0%) were diagnosed with stage IV disease. The 3- and 5-year OS rates were 79.90% and 71.50%, respectively, whereas the 3- and 5-year PFS rates were 70.30% and 63.90%, respectively. The median OS and PFS times were 189 and 149 months, respectively. Among 13,328 patients, 428 (14.0%) patients with poor/undifferentiated cancer suffered recurrence. In patients with stage III and stage IV diseases, the median PFS times of the patients who received chemotherapy were significantly longer than those in patients who had not received chemotherapy (stage III: 147 vs 62 months, P < 0.001; stage IV: 14 vs 9.5 months, P < 0.001).ConclusionsThis retrospective cohort study illustrates the current status of the clinical characteristics of patients with CRC in southern China. Sex, age, family history, location of cancer occurrence, differentiation status, T status, N status, M status, clinical stage, operation, and surgical margin are independent factors associated with the OS of CRC patients.