Ruey-Long Hong

Background: The treatment of HNSCC in Taiwan is still very challenging and might be related to betel-nuts use. Betel nut chewing might contribute to (1)strong inflammation, angiogenesis, and invasion ; (2)easy recurrence; (3)refractory to traditional therapies. In our previous research, we found betel-nuts exposed HNSCC cell line, TW2.6, might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan with high PDL1, defective p53 mutation, p16 loss, and BCL2 overexpression. PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, & VEGFR2/PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT/mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. Besides, polo like kinase inhibition seemed a good radiosensitizer for TW2.6. Methods: We try to prove the difference of TW2.6 reflecting clinical characteristics of HNSCC in Taiwan and design effective treatment combinations. Other HNSCC cell lines will also be evaluated for their genomic signatures. All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations. Results: Conclusions: Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC. Specific Tx for TW2.6 & others are listed above. Cell lines SCC25 KB SAS CAL27 FaDu SCC15 SCC9 SCC4 TW2.6 Differ- entiation Well Poor Poor Poor Poor Well Well Well Well, but rapidly replicated, with high hyper-diploidy & complex rearrangements HPV status HPV 16/18 HPV18 - - HPV 16/18 - - HPV 6/11 - EGFR status Medium Low High High Medium High Low Medium to high Unknown Docetaxel sensitivity +++ +++ ++ ++ + ++ to +++ ++ - + Cisplatin sensitivity +++ ++ +++ ++ ++ + - to + - - to + 5-FU sensitivity +++ + ++ +++ ++ - + to ++ - - to + Afatinib sensitivity +++ - to + - + ++ ++ to +++ +++ +++ - Polo-like kinase Inhibitor sensitivity +++ +++ ++ ++ + ++ to +++ - to + - - to + VEGFR2 Inhibitor sensitivity - - - - ++ +++ - - ++ PI3K/mTOR inhibitor All cell lines sensitive CDK4/6 Inhibitor response +++ - to + +++ ++ to +++ + ++++ + ++ ++ to +++ Western blots Weak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+) Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+) Moderate p-AKT & BMI-1, high PDL1, mild VEGF-A High p-AKT & VEGF-A, mild PDL1 & BMI-1 High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+) Weak p-AKT & VEGF-A, mild PDL1 & BMI-1 Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1 Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+) High p-AKT, PDL1, & VEGF-A and moderate BMI-1 NGS CCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutation STK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutation KRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutation CDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutation CCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutation CCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutation CDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutation CCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutation FAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53…

Background: Betel nut chewing might contribute to (1)strong inflammation, angiogenesis, & invasion; (2)resistance to traditional therapies. Betel-nuts related HNSCC in Taiwan might belong to mesenchymal differentiation and have the worst prognosis. Our group found betel-nuts exposed HNSCC cell line, TW2.6, was resistant to traditional therapies. PDL1 western blotting was strong over TW2.6 with defective p53 mutation, p16 loss, and BCL2 overexpression. In our previous studies, Astragalus polysaccharides, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. Afatinib & CDK4/6 inhibitors also have immuno-modulatory effects in our studies. Purpose & Methods: NGS studies will be introduced to representative HNSCC cell lines to study molecular phenotypes of these HNSCC cell lines (including SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, & TW2.6) for future drug combinations & basic/translational research. Results: TW2.6 had PIK3CA H1047R mutation, high TMB(8.42 muts/Mb)/MSS, and VEGF-A amplification. We found afatinib response on several cell lines not so correlated to EGFR expression & CNV status. Palbociclib response seemed to correlate to CCND1 gain and p16 loss; but FaDu had not so good palbociclib response even with these two changes and TW2.6 has good response even without these two. TW2.6 also had other genomic changes, such as HRAS & DDR2 mutations, FAT1 loss, amplification of FGF10/CCND3/SOX9, and deletions of STK11/ARID1B/TNFAIP3. Conclusions: PI3K inhibitor, anti-angiogenesis therapies, and immunotherapy-containing regimens will be future combination options for betel-nuts related HNSCC by TW2.6 molecular signatures. Afatinib, CDK4/6 inhibitors, or DDR interventions could also enhance ICIs efficacy. The genomic landscapes of TW2.6 also deserve further studies about CDK4/6 inhibitor resistance, immunotherapy resistance, epigenetic modifications, novel targeted therapy, & biomarkers exploration. Mutations in TW2.6TW2.6GenesN=1%TP531100%SPEN1100%FAT11100%MUC61100%BUB1B1100%EPHB11100%HRAS1100%PTPRD1100%ATM1100%CDK121100%CDK81100%DDR21100%GNAS1100%MYC1100%PDGFRB1100%PIK3CA1100%TNFSF111100%TSC21100% Citation Format: Jo-Pai Chen, Jui-Ying Chang, Ruey-Long Hong. Exploring possible drug resistance and sensitivity mechanisms in treatment-refracotry betel-nuts related HNSCC cell line(TW2.6) by whole exon sequencing and molecular signaling for future drug combinations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4741.

e18502 Background: The treatment of HNSCC in Taiwan is still very challenging. Betel nut chewing might contribute to (1)strong invasion; (2)easy recurrence; (3)poor response to traditional therapies. In our retrospective analysis for 75 patients receiving front-line EPF, patients, with rapid progression within 3 months after previous CCRT, had significantly worse survival with only 2.6 months; however, the survival increased significantly to 7.5 months in the same population if under later-line immunotherapy. Methods: From 2016 to early 2020, 46 R/M HNSCC patients receiving immunotherapy-containing regimens in Yun-lin Branch of National Taiwan University Hospital were reviewed. Results: These patients consisted of 2 HPV and 44 non-HPV; 24 pembrolizumab and 22 nivolumab; 18 with afatinib(11 pembrolizumab & 7 nivolumab); 7 with bevacizumab; 9 with chemotherapy. The objective response rate was 48%(22/46) and clinical benefit was 80%(37/46). 20 patients were still under use(8 afatinib with pembrolizumab; 4 afatinib with nivolumab). 1 patient under afatinib and pembrolizumab had hyperprogression but then got pCR after bevacizumab & strong CT. 1 patient had rapid skin metastasis over previous radiation fields after pembrolizumab, bevacizumab, and CT. 5 patients under afatinib & pembrolizumab developed autoimmune cholestasis(3 also with pneumonitis). Afatinib with nivolumab had similar efficacy but less toxicity. 18 patients receiving afatinib combined with anti-PD1(11 failing EPF, 14 with pleural/pericardial/skin metastases, 13 rapid progression within 3 months after CCRT) had 67% response rate(12/18) and 89% clinical benefit(16/18). 11 patients under afatinib & anti-PD1, who had failed EPF, had the response rate in 55%(6/11). 7 patients under front-line afatinib & anti-PD1 had the response rate in 86%(6/7). Post-progression use of anti-PD1 with other treatments were seen in 12 patients(esp. 1 with nivolumab & ipilimumab; 3 with Avastin, taxane, cisplatin). 7 patients got benefits and had longer survivals. Conclusions: Novel immunotherapy-containing combinations are of clinical significance in refractory betel-nuts related HNSCC in Taiwan. Afatinib has several immuno-modulatory effects in high risk patients(pleural/pericardial/skin metastases failing EPF, rapid progression within 3 months after definite CCRT). Afatinib with anti-PD1 may be a good option to avoid hyperprogression for more immunotherapy efficacy. Adding on CTLA4 blockage to previous afatinib/anti-PD1 after progression seemed potential for further studies.

Purpose: To investigate the clinical presentation and analyze the outcome of primary lymphoma of bone (PLB) and secondary lymphoma of bone (SLB). Subjects and Methods: Four cases of primary lymphoma and 6 cases of sec-ondary lymphoma of bone were investigated. Their medical records, image stude-ies, laboratory data, histopathological specimen wee reviewed. Results: All the diagnosis was proved by well planned open biopsy or speci-men obtained from surgical procedures. All patients were treated with systemic chemotherapy. In two of them adjuvant local radiotherapy was added. The response of treatment was rather good for both PLB and SLB. However, the course of treatment in SLB was much more complicated and more intensive reg-imens of chemotherapy were indicated. The mean period of follow-up was 30.1 months (ranged 7-82 months). Eight patients achieved complete remission. One patient with PLB achieved partial response and one patient with SLb died from progressive disease and sepsis. There was no relapse in PLB, while 3 relapses in SLB during the period of follow-up. Three patients had pathological fractures in the involved bones. One of them was treated by custom-made total knee replace-ment due to severe genu varum deformity, the other two were treated by open reduction with internal fixation. One patient received partial scapulectomy due to massive bony destruction. Three patients received posterior decompression with instrumentation due to spinal cord compression by tumors or instability from bony destruction of spinal column. All these patients receiving surgeries regained their independency in daily activities. Conclusions: Primary lymphoma of bone is a potentially curable disease if appropriate treatment starts early. Treatment of SLB is much more complicated but still treatable with systemic chemotherapy. Surgical treatment is indicated if the function of the affected limb is compromised due to bony destruction or spinal cord compression b the tumor.

Non-Hodgkin lymphoma arising from the sinonasal tract is rare. We present hereby a 71 year-old man with the chief complaints of a left nasal mass, nasal obstruction, bleeding and anosmia. Functional endoscopic sinus surgery and biopsy yielded diffuse large B cell lymphoma. The patient remained disease-free for about 6 years after 4 courses of CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisolone) and consolidative involved field radiotherapy, and then the lymphoma recurred in the right nasal cavity. Lymphoblasts were present in the peripheral blood, which turned out to have originated from lymphoma with bone marrow involvement. A cerebrospinal fluid study was also positive for lymphoblasts. The patient died 3 months after the disease recurrence despite salvage chemotherapy. The clinical characteristic of sinonasal diffuse large B cell lymphoma is distinct, and there is no consensus regarding standard treatment in this rare group of patients.

To report outcomes of the rare disease of squamous cell carcinoma (SCC) of the external auditory canal (EAC) and middle ear treated with surgery and postoperative intensity-modulated radiotherapy (IMRT). Failure patterns related to spatial dose distribution were also analyzed to provide insight into target delineation. A retrospective review was conducted of the records of 11 consecutive patients with SCC of the EAC and middle ear who were treated with curative surgery and postoperative IMRT at one institution between January 2007 and February 2010. The prescribed IMRT dose was 60 to 66 Gy at 2 Gy per fraction. Three patients also received concurrent cisplatin-based chemotherapy, and 1 patient received concurrent oral tegafur/uracil. The median follow-up time was 19 months (range, 6-33 months). Four patients had locoregional recurrence, yielding an estimated 2-year locoregional control rate of 70.7%. Among them, 1 patient had persistent disease after treatment, and 3 had marginal recurrence. Distant metastasis occurred in 1 patient after extensive locoregional recurrence, yielding an estimated 2-year distant control rate of 85.7%. The estimated 2-year overall survival was 67.5%. The three cases of marginal recurrence were near the preauricular space and glenoid fossa of the temporomandibular joint, adjacent to the apex of the ear canal and glenoid fossa of the temporomandibular joint, and in the postauricular subcutaneous area and ipsilateral parotid nodes, respectively. Marginal misses should be recognized to improve target delineation. When treating SCC of the EAC and middle ear, care should be taken to cover the glenoid fossa of the temporomandibular joint and periauricular soft tissue. Elective ipsilateral parotid irradiation should be considered. The treatment planning procedure should also be refined to balance subcutaneous soft-tissue dosimetry and toxicity.

Sterically stabilized liposome is characterized by a surface coating of polyethylene glycol (PEG) or other polymers that can reduce opsonization of the liposome by plasma proteins. It has a higher plasma area under the concentration-time curve (AUC), which is believed to correlate with better therapeutic efficacy. However, the presence of large molecules on the liposomal surface may reduce the interactions of liposomes with cells and hinder entry of liposomes into the tumor tissue. Using a stable liposomal system composed of distearoyl phosphatidylcholine/cholesterol, we examined the effect of PEG (Mr 2000) on the pharmacokinetics and on the efficacy of liposomal doxorubicin with C-26 syngeneic tumor model in BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol-% PEG-modified distearoyl phosphatidylethanolamine (PEG-DSPE) was approximately twice that of liposomal doxorubicin without PEG at various dosages, regardless of whether the mice were tumor-bearing. Paradoxically, the group of mice treated with liposomal doxorubicin without PEG had higher tumor doxorubicin concentrations. The 72-h tumor AUC was 1.44 times that of liposomal doxorubicin with 6% PEG-DSPE. The tumor-accumulation efficiency (AUC(Tumor)/AUC(Plasma)) of liposomal doxorubicin without PEG was 0.87, and this was more than twice that of the liposomal doxorubicin with 6% PEG-DSPE (0.31). At a dose of 10 mg/kg, although both liposomal groups were better than the free drug group in terms of clinically relevant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between the two liposomal drug groups. In this stable liposome system, surface coating with PEG offered no benefit for liposomal doxorubicin in the C-26 tumor model. To enhance the therapeutic index of liposomal doxorubicin, simply increasing plasma AUC by surface coating with PEG may not be satisfactory.

Background and ObjectivesPhotodynamic therapy (PDT) has been proposed as an alternative approach in overcoming multidrug resistance (MDR) phenotype. To verify whether 5‐aminolevulinic acid (ALA)‐mediated PDT is effective in MDR cells, we studied the protoporphyrin IX (PpIX) content, intracellular localization, and phototoxicity in human breast cancer cells MCF‐7 and derived MDR subline, MCF‐7/ADR.Study Design/Materials and MethodsThe fluorescence kinetics of ALA‐induced PpIX was evaluated by spectrofluorometer. The phototoxicity of MCF‐7 and MCF‐7/ADR cells was determined by tetrazolium (MTT) assays and clonogenic assay. Furthermore, Annexin V and propidium iodide (PI) binding assays were performed to analyze the characteristics of cell death after ALA–PDT.ResultsMCF‐7/ADR accumulated a lower level of PpIX as compared to parental MCF‐7 cells. Significant phototoxicity was observed in MCF‐7 and increased in a fluence‐dependent manner with LD50 around 8 J/cm2. Compared to its parental counterpart, MCF‐7/ADR cells were less sensitive to ALA photodynamic treatment and PDT‐induced cytotoxicity did not increase in a dose responsive manner as the concentration of ALA increased or the fluence of light increased. ALA–PDT was less effective for MCF‐7/ADR cells than MCF‐7 cells even under the condition when these two cell lines contained the similar amounts of PpIX.ConclusionsThese results indicate that, except for the MDR related characteristics, MCF‐7/ADR cells might possess intrinsic mechanisms that render them less sensitive to ALA–PDT induced phototoxicity. Lasers Surg. Med. 34:62–72, 2004. © 2004 Wiley‐Liss, Inc.

Supplementary figure 1. Characterization of the cisplatin-resistant HNSCC cell lines. Supplementary figure 2. Genetic or pharmacological inhibition of G9a promotes cisplatin-induced apoptosis in SAS-CR cells.Supplementary figure 3. Depletion of G9a increases the sensitivity to cisplatin in OECM-1 cells.Supplementary figure 4. Depletion of G9a increases the platinum-DNA adduct accumulation. Supplementary figure 5. Inhibition of G9a by shRNA or enzymatic inhibitor decreases intracellular GSH levels. Supplementary figure 6. Multi-drug resistance to chemotherapeutic agents in G9a-overexpressed SAS cells. Supplementary figure 7. Effect of G9a on the expression of GSH synthesis enzymes. Supplementary figure 8. The expression of GSH synthesis enzymes in mouse xenograft tumors. Supplementary figure 9. ATF4 upregulates GCLC in cisplatin-resistant cells. Supplementary figure 10. Upregulated GCLC is required for G9a to promote cisplatin resistance.

Expression of the c-erbB-2 oncogene protein was investigated by immunohistochemistry in 149 cases of primary gastric cancer. Positive staining, regarded as on indication of gene amplification, was evident in 38(25.5%) of the tumors. Of various clinicopathological factors considered, a statistically significant difference in association with frequency of expression was noted only for the histological type(39.3% positive staining in intestinal type, 15.4% in diffuse type, P＜0.01), but not for age, sex, tumor site, gross type, size, depth of invasion, node metastases, and TNM stage. However, in seven of ten metastatic lymph nodes, the cancer cells stained positive for c-erbB-2, even when the primary tumor stained negative. This finding suggests that c-erbB-2 overexpression may be associated with the metastatic potential of gastric cancer. The 2-year survival rates of patients with positive and negative c-erbB-2 protein were 44% and 56%, respectively, which is without statistical difference. In subgroup analysis, erbB-2 expression was not associated with poorer prognosis in the intestinal type or the diffuse type gastric cancer. These findings indicate that, in the case of human gastric cancer, expression of c-erbB-2 protein is correlated with tumor histological type, and that the presence or absence of c-erbB-2 protein may serve as on indicator for potential of distant metastases.

6024 Background: Epidermal growth factor receptor (EGFR) pathway inhibition may synergize with anti-PD1 activity by inhibiting macrophage function, increasing antigen presentation, and augmenting T cell responses. Afatinib, an irreversible EGFR tyrosine kinase inhibitor (TKI), has been shown to enhance anti-PD1 activity in in vitro and animal studies. We thus hypothesized that adding afatinib to pembrolizumab may improve the treatment outcomes for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Methods: The ALPHA study (NCT03695510) is a single-arm, phase II study with a Simon 2-stage design. Patients with platinum-refractory, recurrent, or metastatic HNSCC are eligible for the study. Afatinib (40mg, oral, daily) and pembrolizumab (200mg, every 3 weeks) are administered to eligible patients. The primary endpoint is the objective response rate (ORR). PD-L1 IHC testing (22C3), comprehensive genomic profiling (CGP, Roche Foundation Medicine One CDx), and targeted multiplexed gene expression profiling (Nanostring nCounter PanCancer Immune Profiling Panel) were applied for biomarker analysis. Results: From JAN 2019 to MAR 2020, 29 patients were enrolled in the study. Age: mean = 53.4 years old; M/F = 27/2. Tumor type: oral cavity: 19; oropharynx: 6, hypopharynx: 2, larynx: 2. PD-L1 TPS > = 50: 7/29 (24.1%), CPS > = 20: 8/29 (27.6%), TMB > 10: 0/25 (0%). The common treatment-related adverse events (AEs; all grades, grade > = 3) were skin rash (22/29, 4/29), diarrhea (17/29, 3/29), paronychia (13/29, 0/29), mucositis (9/29, 1/29), and weight loss (2/29, 0/29). One patient experienced grade 2 pneumonitis. Twelve patients had partial responses to the treatment (12/29, ORR: 41.4%). The data cut-off date was 11FEB2021. The median progression free survival (PFS) was 4.1 (95% confidence interval [CI], 1.9-6.3) months. The median overall survival (OS) was 8.4 (95% CI, 4.1-10.8) months. Patients with high PD-L1 expression had a higher response rate (TPS > = 50: ORR = 0.71, CPS > = 20: ORR = 0.63). EGFR amplification might also predict a higher response rate (ORR: 3/3, 100%). MTAP loss or mutation may predict a poor response to the treatment (ORR: 0/5, 0%), shorter PFS (HR: 4.21, [95% CI: 1.34-13.24], p = 0.014), and shorter OS (HR: 4.20 [95% CI: 1.32-13.41], p = 0.015). Nine patients underwent paired pre-treatment and post-treatment biopsies for gene expression analysis. The mRNA of HLA-A, HLA-B, CXCL13, CXCL9, and CD8A were elevated in the post-treatment biopsies. Three patients underwent post-progression biopsies for CGP study. One patient had a new MTAP mutation. Conclusions: Afatinib can modify tumor microenvironment and increase the clinical response rate in pembrolizumab-based therapy in HNSCC patients. PD-L1, EGFR amplification, and MTAP loss/mutation could be biomarkers for cancer immunotherapy. Clinical trial information: NCT03695510.

There is lack of effective and safe chemotherapy for advanced hepatocellular carcinoma. Polyethylene glycol-coated (pegylated) liposomal doxorubicin (PLD) has long circulation time and enhanced drug accumulation in the tumor tissues. It has significant activity in Kaposi's sarcoma, breast and ovarian cancers and the acute adverse effects of free drug are reduced. A patient with advanced hepatocellular carcinoma was treated with PLD and a pharmacokinetic study was performed. Initial serum total and direct bilirubin were 3.6 and 6.8 folds of upper normal, respectively, and an indocyanine green clearance test at 15 minutes was 26.3% (normal < 15%). Compared to cases with normal liver function, increased volume of distribution of doxorubicin correlated with a large amount of ascites (P < 0.05). The clearance of drug was unexpectedly higher than in cases with normal liver function (P < 0.05). According to the pharmacokinetic studies, the disposition of PLD in this case has not been retarded even in the presence of severe liver dysfunction. Only minimal toxicities including grade 2 stomatitis and moderate leukopenia were observed. The tumor had a partial remission and the patient survived nine months after PLD treatment. PLD could serve as a safe and effective treatment for hepatocellular carcinoma even in the presence of impaired liver function. Its role in treating advanced hepatocellular carcinoma is worthy of further study.

The presence of brain metastasis in lung cancer patients is a highly unfavorable event that usually allows only palliative treatment. A retrospective study was conducted to evaluate the prognostic factors in patients with non-small cell lung cancer (NSCLC) associated with brain metastases. From July 1984 through June 1990, a total of 50 patients with NSCLC associated with symptomatic brain metastasis seen at National Taiwan University Hospital were included. Patients who had incomplete cancer staging workup or loss of follow-up were excluded. Several possible prognostic variables were analyzed initially with univariate analysis and subsequently with multivariate analysis with maximal partial likelihood ratio test in the Cox model. In the univariate analysis, several factors, including number of brain metastases, treatment for brain metastasis with brain tumor resection (BTR) or whole brain radiation therapy (WBRT), and chemotherapy (C/T) after brain metastasis were found to have significant influence on the survival. However, in the multivariate analysis, patients receiving BTR, WBRT, and/or C/T lived significantly longer. The median survival of patients treated with BTR was nine months, eight months in patients with C/T, and seven months in patients with WBRT. Taken together, these patients had a median survival of seven months, which was significantly longer than patients treated with supportive care only (with a median survival of two months). Treatment of brain metastases with WBRT, BTR, C/T, or in combinations also improved the quality of life. We conclude that NSCLC patients with brain metastases should be more aggressively treated with WBRT, BTR, C/T, or in combinations than supportive care only.

Cell type predictive of treatment efficacy. Cell type differences of (a) partial response vs non-partial responders (b) progression-free survival longer vs shorter than 6 months by MCP-Counter. All p-values were derived from non-parametric Wilcoxon test.

Supplementary Table 1a. Differentially expressed genes between Post-treatment vs Pre-treatment; Supplementary Table 1b. Differentially expressed genes between Responders vs Nonresponders; Supplementary Table 1c. Differentially expressed genes between PFS longer than 6 months vs PFS shorter than 6 months.

e15632 Background: Hepatocellular carcinoma (HCC) is a common malignant disease. Promising results of prospective clinical trials using systemic therapy for patients with advanced HCC are emerging. The aim of this study was to explore prognostic factors of survival in advanced HCC patients eligible for clinical trials of systemic therapy. Methods: From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into 6 phase II trials of systemic therapy using the following regimens: (1) oral etoposide + tamoxifen, (2)doxorubicin + tamoxifen, (3)IFN-α2b + doxorubicin + tamoxifen, (4)pegylated liposomal doxorubicin, (5)thalidomide, and (6)arsenic trioxide. Univariate and multivariate analyses of 23 relevant clinical characteristics/staging systems were used to identify prognostic factors of survival. Results: Baseline characteristics: median age 55; male/female: 192/44; HBsAg(+) 71%; anti-HCV(+) 30%; Okuda stage I/II/III: 42%/55%/3%; AJCC stage III/IV: 30%/61%; BCLC stage B/C/D: 1%/94%/5%; CLIP score 0–3/4–6: 70%/30%; portal vein thrombosis 53%; extrahepatic metastasis 59%; prior chemoembolization 46%. The objective response rate according to WHO criteria was 11.4%. The median overall survival was 118 days (95% CI, 103–133). In the multivariate analysis, significant predictors of a shorter overall survival were: HBsAg(+) with a hazard ratio (HR) = 1.808 (95% CI, 1.121–2.916; P= 0.015), symptomatic with HR = 1.745 (95% CI, 1.072–2.840; P= 0.025), ECOG≥2 with HR = 1.763 (95% CI, 1.040–2.988; P= 0.035), and high BCLC stage with HR = 3.282 (95% CI, 1.129–9.541; P= 0.029). Conclusions: Patients with advanced HCC who are eligible for systemic therapeutic trials have patient- and disease-related prognostic factors. Positive HBsAg, symptomatic, ECOG performance≥2, and high BCLC stage predict a shorter overall survival. No significant financial relationships to disclose.

e20069 Background: Ipilimumab is proved effective in treating patient with advanced melanoma. However, the clinical experiences of ipilimumab have been limited in Asia. In this preliminary report of Taiwan extended access program (EAP) cohort, the efficacy and safety of ipilimumab in Asian patient with advanced melanoma was accessed. Methods: Patients with advanced melanoma which progressed after at least one line of systemic therapy are eligible in our EAP. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumor assessments were conducted at baseline and week 12. Results: In the Taiwan EAP cohort, 31 were evaluable for response. Of these, 9.6% had an objective immune response, and the immune-related disease control rate was 29.1%. The median duration of follow up were 6.2 (95% CI, 5.3 to 7.5) months. Median progression-free survival was 4.14 (95%CI, 2.8 to 4.5) mont...

ABSTRACT Aim: Pazopanib is a multi-targeted tyrosine kinase inhibitor, blocking VEGF-A, B, C and FGF pathways and might suppress tumor angiogenesis and growth in HNSCC. In a phase II trial of pazopanib in R/M HNSCC, our group tried to point out some obstacles that maybe common in anti-angiogenesis treatments in this patient group. Methods: We planned a single-arm phase II trial of pazopanib in patients with platinum-refractory recurrent or metastatic HNSCC. The screening process and follow-up images after pazopanib would be presented. Results: We screened 43 patients in about 6 months. 30 (about 70%) were excluded due to easy bleeding and vessel contact. In the initial 10 patients, the objective response was seen in 1; 6 had clinical benefits just comparable with the outcomes of sorafenib or sunitinib. 2 patients experienced severe fatal bleeding; 2 suffered from grade 3 or 4 bleeding. The first enrolled patient had partial response initially but then soon suffered from fatal bleeding; therefore, this patient was finally not categorized as a partial response. Median progression-free survival was 70 days. Median overall survival was 129 days. The image pattern of tumor response was usually central cavity or necrosis formation, typical of the effect of anti-angiogenesis treatments in the literature. However, the rim of the cavity would extend outside and finally led to future resistance. Conclusions: The risk of bleeding in our patient group (platinum-refractory R/M HNSCC) was very high (about 70%) in our enrollment screening process. The disease status was so advanced to cause unpredictable bleeding events & death and also too risky to receive anti-angiogenesis treatments. Besides, peripheral invasion phenomenon in our observation was one possible resistance pattern, maybe resulting from tumor invasion/migration signals and epithelial-mesenchymal transition (EMT). This phenomenon might further aggravate bleeding complications due to easy vessel rupture. Earlier combined blockage of angiogenesis and invasion (such as c-MET) is necessary for better tumor control and to prevent bleeding. Disclosure: All authors have declared no conflicts of interest.

Abstract Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of pembrolizumab (pembro) or pembro + chemotherapy (chemo) vs EXTREME (E) as first-line therapy for recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). At the second interim analysis, overall survival (OS) was significantly longer with pembro than E in patients with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). Pembro + chemo significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Patients with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to pembro 200 mg Q3W, pembro + chemo (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + chemo) until progressive disease, unacceptable toxicity, 6 cycles of chemo, or 24 months of pembro. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with pembro vs E were 28.6% vs 76.9% in the Asia subgroup and 13.9% vs 67.2% in the non-Asia subgroup; rates with pembro + chemo vs E were 71.9% vs 76.9% in the Asia subgroup and 70.8% vs 67.2% in the non-Asia subgroup. Table: 286O Asia CPS ≥20 Asia CPS ≥1 Asia Tot Pop Non-Asia CPS ≥20 Non-Asia CPS ≥1 Non-Asia Tot Pop HR; 95% CI P vs E 22 v 23 P+C v E 22 v 21 P v E 48 v 46 P+C v E 45 v 43 P v E 56 v 53 P+C v E 57 v 49 P v E 111 v 99 P+C v E 104 v 89 P v E 209 v 209 P+C v E 197 v 192 P v E 245 v 247 P+C v E 224 v 229 OS 0.39; 0.19-0.80 0.80; 0.41-1.58 0.80; 0.51-1.27 1.13; 0.71-1.79 0.74; 0.48-1.13 1.03; 0.68-1.58 0.75; 0.54-1.04 0.68; 0.48-0.96 0.76; 0.61-0.95 0.65; 0.51-0.82 0.87; 0.71-1.06 0.71; 0.57-0.88 PFS 1.16; 0.63-2.11 1.07; 0.58-1.99 1.25; 0.82-1.91 1.14; 0.74-1.76 1.39; 0.94-2.05 1.12; 0.75-1.66 0.95; 0.70-1.28 0.65; 0.47-0.89 1.10; 0.89-1.35 0.74; 0.60-0.92 1.27; 1.05-1.54 0.82; 0.67-1.00 HRs, Kaplan-Meier method; 95% CIs, Cox regression model. Conclusions Pembro vs E showed favorable OS in Asia and non-Asia subgroups, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgroups; safety was favorable. Pembro + chemo vs E showed favorable OS in patients with CPS ≥20 in Asia and non-Asia subgroup regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, CMPP, and Holly Cappelli, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. K. Tanaka: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R-L. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia, MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim (M), Merck Serono (M), Roche (M), Eli Lilly (M), Amgen (M); Speaker Bureau / Expert testimony: Eli Lilly Inc; Research grant / Funding (self): Amgen Inc, MSD, Roche & Genetech, AstraZeneca; Travel / Accommodation / Expenses: Eisai (M), Eli Lilly (M), AstraZeneca (M), MSD Inc, Roche (M), Merck Serono (M), Mundipharma (M), Novartis (M), Pfizer (M), Amgen (M), Menarini (M). V. Sriuranpong: Honoraria (self): MSD; Advisory / Consultancy: MSD. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. N. Nohata: Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: MSD KK. A. Roy: Shareholder / Stockholder / Stock options,…

OBJECTIVES To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). MATERIALS AND METHODS HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. RESULTS Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. CONCLUSIONS Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.

Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC. Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified. Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect. This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age.

Background Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information NCT00201396.

Background: Chemoradiation (CRT) with cisplatin is the standard of care for patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) not treated by surgery. Preclinical data in murine cancer models show improved tumor growth control and survival when radiation therapy (RT) is combined with a PD-1 inhibitor. Pembrolizumab is effective for treatment of recurrent/metastatic HNSCC, and initial results from a phase 1b study suggest that pembrolizumab plus CRT is tolerable in patients with LA-HNSCC. KEYNOTE-412 (NCT03040999) is a phase 3, randomized, placebo-controlled, double-blind trial to determine the efficacy and safety of pembrolizumab given with CRT and as maintenance therapy versus placebo plus CRT in LA-HNSCC. Trial design: Patients will be randomly assigned (1:1) to receive pembrolizumab 200 mg every 3 weeks plus cisplatin-based CRT or placebo plus cisplatin-based CRT. Treatment will be stratified by RT regimen (accelerated RT [56-70 Gy, 6 fractions/week for 6 weeks] or standard RT [56-70 Gy, 5 fractions/week for 7 weeks]), tumor site/p16 status (oropharynx p16 positive vs p16 negative or larynx/hypopharynx/oral cavity), and disease stage (III vs IV). A priming dose of pembrolizumab or placebo will be given 1 week before CRT, followed by 2 doses during CRT and an additional 14 doses after CRT, for a total of 17 pembrolizumab or placebo infusions. Eligibility criteria include age ≥18 years; newly diagnosed, treatment-naive, oropharyngeal p16 positive (any T4 or N3), oropharyngeal p16 negative (any T3-T4 or N2a-N3), or larynx/hypopharynx/oral cavity (any T3-T4 or N2a-N3) SCC; evaluable tumor burden (RECIST v1.1); and ECOG performance status 0-1. Treatment will be discontinued at centrally confirmed disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Response will be assessed by computed tomography or magnetic resonance imaging 12 weeks after CRT, every 3 months for 3 years, then every 6 months for years 4 and 5. Patients will be evaluated to determine the necessity of neck dissection 12 weeks after completion of CRT; neck dissection will be recommended in cases of persistent disease. After a patient experiences disease progression or starts new anticancer therapy, the patient will begin survival follow-up and will be contacted every 3 months during years 1 through 3 and every 6 months during years 4 and 5 until death, withdrawal of consent, or the end of the study, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment end. The primary end point is event-free survival. Secondary end points include overall survival, safety, and patient-reported outcomes. Recruitment is ongoing in 21 countries and will continue until ~780 patients are enrolled. Citation Format: Lillian L. Siu, Lisa Licitra, Yun Gan Tao, Chia-Jui Yen, Danny Rischin, John Waldron, Barbara Burtness, Vincent Gregoire, Sanjiv Agarwala, Jeffrey Yorio, Jean-Pierre DeLord, Sercan Aksoy, Sadakatsu Ikeda, Ruey-Long Hong, Joy Yang Ge, Holly Brown, Behzad Bidadi, Jean-Pascal Machiels. KEYNOTE-412: Pembrolizumab plus chemoradiation vs chemoradiation alone for locally advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT163.

Previous report suggested that weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin is a highly active and relatively low toxic regimen for the treatment of colorectal carcinoma (J Clin Oncol 9: 625-30, 1991). This phase II study was conducted to test this important observation by a slightly modified regimen in a larger group of patients. The weekly HDFL regimen consisted of 5-FU 2600 mg/m2/week and leucovorin 300 mg/m2/week (maximum 500 mg) in a 24-hour intravenous infusion. Between February 1992 and December 1995, a total of 42 patients with non-resectable, recurrent or metastatic colorectal adenocarcinoma were enrolled onto the study. Twenty-nine (69.0%) patients had prior exposure to lower-dose 5-FU. There were 22 men and 20 women with median age of 60 (20-75) years. They received a total of 855 and an average of 20.4 (4 to 65) courses of HDFL chemotherapy. Most patients were treated at outpatient clinics and the drugs were infused by an ambulatory pump system via a Port-A catheter. The median duration of follow-up was 22 months. ECOG Gr 2-3 stomatitis, diarrhea, nausea, and vomiting developed in 6 (14.3%), 6 (14.3%), 5 (11.9%), and 5 (11.9%) patients, respectively. Twenty (47.6%) patients had developed hand-foot syndrome. There was no hematological toxicities except 3 (7.1%) patients developed ECOG Gr 1-2 leucopenia. The overall response rate was 42.9% (28%-59%, 95% C.I.) with 2 complete responses and 16 partial responses. Eight (61.5%; 31%-86%, 95% C.I.) of 13 patients, who had no previous 5-FU exposure, responded (1 complete response, 7 partial responses). Ten (34.5%, 17%-54%, 95% C.I.) of 29 patients, who had had previous lower-dose 5-FU exposure, responded (1 complete response and 9 partial responses). The median duration of response was 5 months (1+ to 23+ months). The median overall survival of the whole group of 42 patients and the 18 responders was 10 and 22 months, respectively. Our data supported the original results of HDFL regimen in the treatment of colorectal cancers. HDFL regimen can be used either as first-line or second-line treatment for non-resectable, recurrent or metastatic colorectal cancers.

We have systemically analyzed, both in vitro and in vivo, the effect of 13-cis-retinoic acids (RA) on non-Hodgkin's lymphoma (NHL). The in vitro growth-inhibitory effect of 13-cis-RA was examined in 11 (T cell, five; B cell, six) lymphoma cell lines by a tetrazolium colorimetric assay. A pilot clinical trial with oral 13-cis-RA 1 mg/kg/d was conducted in a selected group of 18 lymphoma patients, of whom 16 had failed to respond to at least one regimen of intensive chemotherapy. The in vitro and in vivo effects of 13-cis-RA were correlated with immunophenotypes, RA-induced changes of morphology, and patterns of DNA fragmentation of the lymphoma cells. Four of five T-lymphoma cell lines and none of six B-lymphoma cell lines were sensitive (concentration of 50% growth inhibition [IC50] < 1.5 microns) to 13-cis-RA (P = .015). In the clinical trial, five (two Ki-1, one angioinvasive type, one diffuse mixed cell, and one diffuse large cell) complete remissions and one (Ki1) partial remission were observed in 12 patients with peripheral T-cell lymphoma (PTCL), while none of six patients with B-cell lymphoma responded to 13-cis-RA. 13-cis-RA-induced cellular differentiation and apoptosis, as evidenced by the more mature morphology, characteristic nuclear condensation, and DNA ladder pattern signifying internucleosomal fragmentation, were demonstrated in the sensitive cell lines, as well as in the remitting lymphoma tissues. The 13-cis-RA appears to be active on lymphomas of T-lineage and their therapeutic indication may be extended to include some subtypes of PTCL. The mechanisms of action are related to differentiation and apoptosis of lymphoma cells. There appears to be no cross-resistance between 13-cis-RA and conventional chemotherapy.

Purpose:Satisfactory treatment options for advanced leiomyosarcoma and liposarcoma are limited. The LEADER study (NCT03526679) investigated the safety and efficacy of lenvatinib plus eribulin.Patients andMethods:LEADER is a multicenter phase Ib/II study for advanced leiomyosarcoma or liposarcoma. The phase Ib part enrolled 6 patients to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) with the starting dose of lenvatinib 18 mg/day and eribulin 1.1 mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors 1.1, with phase Ib patients preplanned to be included in the efficacy analysis. Translational analyses were based on the transcriptomic data obtained from the NanoString nCounter platform.Results:Thirty patients were enrolled (leiomyosarcoma 21, liposarcoma 9); the median age was 59. One patient had to temporarily stop lenvatinib due to grade 2 arthritis in the first cycle, meeting DLT criteria. Four of 6 patients had to decrease the dose of lenvatinib to 14 mg between cycles two and three. RP2D was determined at lenvatinib 14 mg/day and eribulin 1.1 mg/m2. The confirmed ORR was 20%, and the ORR was not significantly different between phase Ib/II cohorts (P = 0.23). The median progression-free survival was 8.56 months (95% confidence interval, 4.40–not reached). Translational studies suggested increased dendritic cells in the tumor microenvironment (TME) after treatment.Conclusions:Lenvatinib plus eribulin has a manageable safety profile and exhibits promising efficacy for treating advanced leiomyosarcoma and liposarcoma.

Abstract Background The benefit of focal treatments, including surgery and radiotherapy, in mSTS patients has not been clear, especially for mSTS patients who had received systemic treatments. Methods Medical records of mSTS patients treated at National Taiwan University Hospital from 2011 to 2017 were collected. The focal tx collected included surgery (either for the primary or metastatic tumors) and radiation therapy (RT). The analysis was limited to patients who had received at least one-line of systemic treatment. Overall survival (OS) was measured from the time of mSTS diagnosis to the date of death or the last follow-up, whichever is later. Results A total of 199 patients, 78 (39%) de novo and 121 (61%) recurrent, mSTS were identified. The median age was 55 (range 20-89) and male to female ratio was 0.86. The most common histologies are leiomyosarcoma (16.5%), liposarcoma (15.6%), and sarcoma NOS (15.6%). Of them, 72 (36.2%) and 48 (24.1%) patients received surgery and RT, respectively. Metastatic STS patients who had received surgical treatment had a significantly better OS as compared with those who did not (median OS 21.9 vs 16.5 months, p = 0.0296). There was a trend that the OS benefit of surgery was mostly in patients with recurrence but not de novo mSTS (p for interaction = 0.08). The type of surgery (primary vs metastatic vs primary + metastatic) did not significantly affect OS (p = 0.608). Patients who received RT had a numerically better survival (median OS 24.4 vs 16.9 months, p = 0.12). In the multivariate Cox model, the OS benefit of surgery remained significant (Table). Table . 407P Adjusted hazard ratio of OS for mSTS patients who received palliative systemic treatment HR 95% CI p-value Female vs male 1.22 (0.85, 1.76) 0.2852 Age 1.01 (1.00, 1.02) 0.0830 Histology Other 1 0.0436 Leiomyosarcoma + Liposarcoma 0.65 (0.43, 0.99) Anthracycline 1.63 (1.12, 2.37) 0.0109 Focal treatment 0.0731 No focal treatment 1 RT 0.62 (0.36, 1.08) 0.0923 Surgery 0.63 (0.40, 0.99) 0.0452 RT + Surgery 0.55 (0.30, 1.00) 0.0502 Conclusions Patients with mSTS had improved OS with focal treatments, especially with surgery. A multi-disciplinary team approach to include the surgeons and radiation oncologists to discuss the optimal treatment of mSTS patients should be advocated. Legal entity responsible for the study The authors. Funding Eli Lilly and Company. Disclosure All authors have declared no conflicts of interest.