Efficacy Of Combination Chemotherapy Research Articles

Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Clinical outcomes of liposomal irinotecan in advanced pancreatic adenocarcinoma patients previously treated with conventional irinotecan-based chemotherapy: a real-world study.

The efficacy of combination chemotherapy beyond the first-line setting remains modest in patients with advanced pancreatic adenocarcinoma (PAC). Evidence from recent clinical studies has shown that liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) resulted in survival benefits in patients with advanced pancreatic adenocarcinoma (APAC) after progression on gemcitabine-based treatment. However, the survival benefits of nal-IRI in the third and later lines, in which limited options are available, have yet to be extensively studied. Also, some studies have shown conflicting results regarding the impact of prior treatment with conventional IRI on patient outcomes following treatment with nal-IRI. Therefore, this real-world study aimed to evaluate the efficacy and safety of nal-IRI plus 5FU-LV in advanced PAC patients who progressed on conventional IRI-containing regimens. A retrospective chart review was conducted between November 2016 to December 2022 on 30 patients diagnosed with advanced PAC who completed at least one cycle of nal-IRI plus 5-FU- LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved. Thirty patients met the inclusion criteria. Overall, 76.7% of the patients received at least two lines of therapy prior to nal-IRI. The median overall duration of nal-IRI treatment was 2.0 months (IQR: 1.3 - 3.9 months). One patient (3.3%) had a partial response, and seven patients (23.3%) had stable disease as their best response. The median progression-free survival (PFS) was 1.9 months (95% CI 1.6 - 2.0) and the 6-month PFS rate was 20.0%. The median overall survival (OS) was 5.0 months (95% CI 3.4 - 7.0), and the 6-month OS rate was 36.7%. An interval between conventional IRI and nal-IRI ≥5.5 months was significantly associated with prolonged OS of 10.2 months (95% CI 3.3 - 12.1) versus 4.3 months (95% CI 2.1 - 5.9; p =0.003). Ten patients (33.3%) experienced grade 3 adverse events, most commonly nausea, fatigue, diarrhea, and non-neutropenic fever. Nal-IRI plus 5FU/LV had modest survival benefits and an acceptable safety profile in patients with prior conventional IRI. A longer interval between conventional IRI and nal-IRI was associated with increased survival outcomes.

Immunotherapy for early-stage non-small cell lung cancer: A system review.

With the addition of immunotherapy, lung cancer, one of the most common cancers with high mortality rates, has broadened the treatment landscape. Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of non-small cell lung cancer (NSCLC) and are now used as the first-line therapy for metastatic disease, consolidation therapy after radiotherapy for unresectable locally advanced disease, and adjuvant therapy after surgical resection and chemotherapy for resectable disease. The use of adjuvant and neoadjuvant immunotherapy in patients with early-stage NSCLC, however, is still debatable. We will address several aspects, namely the initial efficacy of monotherapy, the efficacy of combination chemotherapy, immunotherapy-related biomarkers, adverse effects, ongoing randomized controlled trials, and current issues and future directions for immunotherapy in early-stage NSCLC will be discussed here.

Assessment of the safety and efficacy of combination chemotherapy and PD-1/PD-L1 inhibitor treatment of breast cancer: A meta-analysis.

As the efficacy of programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors combined with chemotherapy in curing breast cancer is still controversial, this meta-analysis compares the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in the treatment of breast cancer, which provides guidance for the clinical treatment. Relevant studies published as of April 2022 in the various databases including EMBASE, PubMed, and Cochrane Library were selected. Randomized controlled trials (RCTs) in which control patients underwent chemotherapy alone and experimental group patients underwent combination chemotherapy and PD-1/PD-L1 inhibitor treatment were included in this investigation. Investigations without complete information, researches from which information could not be extracted, duplicate articles, animal studies, review articles, and systematic reviews were excluded. STATA 15.1 was employed for all statistical analyses. In total, eight eligible studies were identified, revealing that combination chemotherapy and PD-1/PD-L1 inhibitor treatment was linked to significant increases in progression-free survival (PFS) relative to chemotherapy alone (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.70-0.99, P = 0.032) but not overall survival (HR = 0.92, 95% CI: 0.80-1.06, P = 0.273). Pooled adverse event rates were also increased within the group of combination treatment relative to the chemotherapy group (risk ratio [RR] = 1.08, 95% CI: 1.03-1.14, P = 0.002). Specifically, nausea rates were lesser within the group of combination treatment relative to the group of chemotherapy (RR = 0.48, 95% CI: 0.25-0.92, P = 0.026). Subgroup analyses indicated that the PFS of patients who underwent combination atezolizumab or pembrolizumab and chemotherapy treatment were substantially longer than those of patients who underwent chemotherapy alone (HR = 0.79, 95% CI: 0.69-0.89, P ≤0.001; HR = 0.79, 95% CI: 0.67-0.92, P = 0.002). The pooled results suggest that combination chemotherapy and PD-1/PD-L1 inhibitor treatment approaches help prolong PFS in breast cancer patients, but have no statistically significant effect on overall survival (OS). Additionally, combination therapy can significantly improve complete response rate (CRR) compared with chemotherapy alone. However, combination therapy was associated with greater rates of adverse events.

Identification and validation of a ferroptosis-related prognostic risk-scoring model and key genes in small cell lung cancer.

BackgroundSmall cell lung cancer (SCLC) is an aggressive lung malignancy with high relapse rates and poor survival outcomes. Ferroptosis is a recently identified type of cell death caused by excessive intracellular iron accumulation and lipid peroxidation, which may mediate tumor-infiltrating immune cells to influence anti-cancer immunity. But prognostic value of ferroptosis-related genes and its relationship with the treatment response of immunotherapies in SCLC have not been elucidated.MethodsThe RNA-sequencing and clinical data of SCLC patients were downloaded from the cBioPortal database. A ferroptosis-related prognostic risk-scoring model was constructed based on univariable and multivariable Cox-regression analysis. Kaplan-Meier (K-M) survival curves and receiver operating characteristics (ROC) curves were constructed to assess the sensitivity and specificity of the risk-scoring model. And the correlations between ferroptosis-related prognostic genes and immune microenvironment were explored. The IC50 values of anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database and the correlation analysis with the key gene thioredoxin-interacting protein (TXNIP) was performed. In addition, immunohistochemistry (IHC) staining was employed to detect the expression of TXNIP in 20 SCLC patients who received first-line chemo-immunotherapy. Immunotherapeutic response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded.ResultsWe constructed a risk-score successfully dividing patients in the low- and high-risk groups (with better and worse prognosis, respectively). The area under the curve (AUC) of this risk-scoring model was 0.812, showing it had good utility in predicting the prognosis of SCLC. Moreover, ferroptosis-related genes were associated with the degree of immune infiltration of SCLC. Most importantly, we found that the TXNIP expression was highly correlated with the degree of immune invasion and the efficacy of chemotherapy in combination with immunotherapy in SCLC patients.ConclusionsThe ferroptosis-related prognostic risk-scoring model proposed in this study can potentially predict the prognosis of SCLC patients. TXNIP may serve as a potential biomarker to predict the prognosis and efficacy of chemotherapy combined with immunotherapy in SCLC patients.

Efficacy of Combination Chemotherapy With Docetaxel, Estramustine and Carboplatin in Men With Castration-resistant Prostate Cancer.

The efficacy of docetaxel and carboplatin with oral estramustine was evaluated in patients with castration-resistant prostate cancer. Patients were treated with intravenous docetaxel at 30 mg/m2 on days 1, 8, 15, and 22 of a 28-day cycle. Intravenous carboplatin (area under the curve, 6 mg/ml/min) was administered on day 1. Patients received oral estramustine at 626.8 mg/day throughout the treatment protocol. Patients were evaluated for response, with treatment continued until cancer progression or onset of severe adverse events. Twenty patients with castration-resistant prostate cancer were treated for a median of 3.5 cycles. Prostate-specific antigen decreased by more than 30% in 18 patients, including 14 patients with a decrease of more than 50%. Median overall survival was 11 months, prostate-specific antigen progression-free survival was 6.5 months, and radiographic progression-free survival was 7 months. Docetaxel and carboplatin with oral estramustine shows efficacy against castration-resistant prostate cancer.

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in KRAS mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower (p < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.

Efficacy and Safety of Regorafenib in Combination with Chemotherapy as Second-Line Treatment in Patients with Metastatic Colorectal Cancer: A Network Meta-Analysis and Systematic Literature Review.

Although various therapies are available for the treatment of metastatic colorectal cancer (mCRC), there is lack of head-to-head evidence. Recent studies have demonstrated the efficacy of chemotherapy in combination with different biological agents including regorafenib in second-line therapy in patients with mCRC. We conducted a network meta-analysis (NMA) to estimate the relative efficacy and safety of regorafenib in combination with chemotherapy compared to other biological agents with chemotherapy combinations. A literature search was conducted in PubMed, Embase, and Cochrane databases to identify all randomized controlled trials (RCTs) evaluating the efficacy and safety of bevacizumab, regorafenib, panitumumab, cetuximab, ramucirumab, conatumumab, ganitumab, and aflibercept in combination with chemotherapy against chemotherapy alone as second-line setting from inception to 7February 2019 in patients with mCRC. The survival outcomes were analyzed by the frequentist statistical approach (R software, netmeta package) while the level of individual treatment arms was assessed using the Bayesian method (R software, gemtc package). We identified 12 articles involving eight RCTs studies analyzing 6805 patients. The studies compared bevacizumab (3), regorafenib (1), panitumumab (2), cetuximab (3), ramucirumab (1), conatumumab (1), ganitumab (1), and aflibercept (1) against chemotherapy alone as comparator. The progression-free survival (PFS) revealed that regorafenib performed better than aflibercept (HR 0.9631, 95% CI 0.6785-1.367), ganitumab (HR 0.7228, 95% CI 0.3985-1.3109), panitumumab (HR 0.9653, 95% CI 0.6781-1.3742), and ramucirumab (HR 0.9206, 95% CI 0.6504-1.303). Regorafenib performed better than bevacizumab (OR 0.797, 95% CI 0.328-1.88) in terms of tumor response. Safety analysis showed that regorafenib performed better in reducing grade ≥ 3 adverse events (AE) than cetuximab and conatumumab, neutropenia than conatumumab, and fatigue than cetuximab. Regorafenib combined with chemotherapy might be a potential alternative to conventional therapeutic options in second-line treatment of patients with metastatic colorectal cancer and could be considered as the best option for treating patients with KRAS and BRAF mutated mCRC. However future RCTs are needed to confirm these results.

Association between continuous decrease of plasma VEGF-A levels and the efficacy of chemotherapy in combination with anti-programmed cell death 1 antibody in non-small cell lung cancer patients

ObjectivesVascular endothelial growth factor-A (VEGF-A) plays important roles in tumor immune suppression and thus correlates with the efficacy of anti-programmed cell death-1/ligand 1 (anti-PD-1/PD-L1) antibodies. We aimed to determine the association between change in plasma VEGF-A levels and the efficacy of chemotherapy combined with anti-PD-1/PD-L1 antibodies (chemo-PD1) in non-small cell lung cancer (NSCLC) patients. MethodsWe included NSCLC patients treated with chemo-PD1. Plasma VEGF-A levels were measured at baseline (Pre) and days 7 (D7) and 14 (D14) after the initiation of chemo-PD1. Continuous VEGF-A decrease was determined by comparing Pre with the median value of maximum change rate of posttreatment VEGF-A as cutoff. Patients whose change rates of VEGF-A at both D7 and D14 were consistently lower than the cutoff value were classified into the VEGF-A decrease group, whereas those whose VEGF-A at D7 or D14 were higher than the cutoff level were classified into the VEGF-A no-decrease group. The primary outcome was progression-free survival (PFS). ResultsA total of 32 patients were evaluated. The median Pre VEGF-A levels was 49 (range, 13–257). The median change rate of VEGF-A at D7 and D14 was -25.6% (range, -77.5–376.9) and -42.3% (range, -100–138.5) respectively. The cutoff value of posttreatment VEGF-A change rate was -9.3%. The PFS was significantly longer in the VEGF-A decrease group than that in the VEGF-A no-decrease group (median, not reached vs 2.4 months; p = 0.017). ConclusionsContinuous decrease of plasma VEGF-A levels during treatment may be associated with the efficacy of chemo-PD1.

In vitro effects of arsenic trioxide, interferon α and zidovudine in adult T cell leukemia/lymphoma cells.

Despite the efficacy of combination chemotherapy with arsenic trioxide (ATO), interferon α (IFN) and zidovudine (AZT) for adult T cell leukemia/lymphoma (ATL), the precise mechanism underlying this combination treatment effect is unknown. In the present study, ATO/IFN/AZT was examined in an ATL leukemic cell line (S1T, non-Tax expressing), a human T-lymphotropic virus 1 (HTLV-1)-infected cell line (MT2, Tax-expressing) and primary ATL cells from patients with acute and chronic ATL. IFN/AZT marginally inhibited MT2 cell proliferation, but substantially inhibited S1T cell proliferation. IFN/AZT increased the cleavage of numerous caspases and PARP in S1T cells, and regulated the signal transducer and activator of transcription 1 and nuclear factor-κB signaling pathway. These effects represent the potential anti-ATL mechanisms of INF/AZT in vitro. In addition, the combination of ATO and IFN/AZT demonstrated synergistic effects on S1T cells. Therefore, the Tax-independent mechanism underlying the anti-ATL effect of ATO must be further elucidated.

Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL cell lines.

Prognosis of childhood acute lymphoblastic leukemia (ALL) has been dramatically improved. However, prognosis of the cases refractory to primary therapy is still poor. Recent phase 2 study on the efficacy of combination chemotherapy with bortezomib (BTZ), a proteasome inhibitor, for refractory childhood ALL demonstrated favorable clinical outcomes. However, septic death was observed in over 10% of patients, indicating the necessity of biomarkers that could predict BTZ sensitivity. We investigated in vitro BTZ sensitivity in a large panel of ALL cell lines that acted as a model system for refractory ALL, and found that Philadelphia chromosome-positive (Ph+) ALL, IKZF1 deletion, and biallelic loss of CDKN2A were associated with favorable response. Even in Ph-negative ALL cell lines, IKZF1 deletion and bilallelic loss of CDKN2A were independently associated with higher BTZ sensitivity. BTZ showed only marginal cross-resistance to four representative chemotherapeutic agents (vincristine, dexamethasone, l-asparaginase, and daunorubicin) in B-cell precursor-ALL cell lines. To improve the efficacy and safety of proteasome inhibitor combination chemotherapy, we also analyzed the anti-leukemic activity of carfilzomib (CFZ), a second-generation proteasome inhibitor, as a substitute for BTZ. CFZ showed significantly higher activity than BTZ in the majority of ALL cell lines except for the P-glycoprotein-positive t(17;19) ALL cell lines, and IKZF1 deletion was also associated with a favorable response to CFZ treatment. P-glycoprotein inhibitors effectively restored the sensitivity to CFZ, but not BTZ, in P-glycoprotein-positive t(17;19) ALL cell lines. P-glycoprotein overexpressing ALL cell line showed a CFZ-specific resistance, while knockout of P-glycoprotein by genome editing with a CRISPR/Cas9 system sensitized P-glycoprotein-positive t(17;19) ALL cell line to CFZ. These observations suggested that IKZF1 deletion could be a useful biomarker to predict good sensitivity to CFZ and BTZ, and that CFZ combination chemotherapy may be a new therapeutic option with higher anti-leukemic activity for refractory ALL that contain P-glycoprotein-negative leukemia cells.

Efficacy of combination chemotherapy using irinotecan and nedaplatin for patients with recurrent and refractory endometrial carcinomas: preliminary analysis and literature review

We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40-70mg/m2 of CPT-11 on days 1, 8, and 15, and 50mg/m2 of nedaplatin on day 1, q4 weeks. The median patient age was 63years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma.

159P - Efficacy of combined chemotherapy and surgical resection on survival of patients with colorectal liver metastases and concurrent extrahepatic disease

159P - Efficacy of combined chemotherapy and surgical resection on survival of patients with colorectal liver metastases and concurrent extrahepatic disease

A phase 3, randomized study of first-line durvalumab (D) ± tremelimumab (T) + platinum-based chemotherapy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.

TPS8586 Background: SCLC accounts for ~13% of all lung cancers and is characterized by rapid growth and early metastases development. Standard of care CT for pts presenting with ED-SCLC is associated with the development of resistance, leading to poor treatment outcomes. As such, new therapies are needed. The high mutation burden associated with SCLC provides a rationale for investigating immune checkpoint blockade in this tumor type. D is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. T is a selective human IgG2 mAb against CTLA-4. D alone and in combination with T has demonstrated a manageable safety profile and encouraging antitumor activity in non-small cell lung cancer (NSCLC). D ± T in combination with CT has also shown acceptable tolerability and preliminary signs of clinical activity in advanced NSCLC and thus may provide benefit in SCLC. Methods: CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study to determine the efficacy of CT in combination with D ± T as first-line treatment in ED-SCLC (Stage IV). Treatment-naïve pts (N = ~795; WHO/ECOG PS 0 or 1) will be randomized 1:1:1 to receive D (1500 mg) + T (75 mg) i.v. every 3 weeks (q3w) + CT (Arm 1); D (75 mg) i.v. q3w + CT (Arm 2); or CT alone (Arm 3). D ± T will be concurrently administered with CT in Arms 1 and 2 and will continue post-CT (1 further dose for T; until confirmed progressive disease for D). CT (etoposide [80–100 mg/m2] i.v. on Days 1–3 q3w + carboplatin [AUC 5–6] i.v. on Day 1 q3w or cisplatin [75–80 mg/m2] i.v. on Day 1 q3w) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS) using blinded independent central review (RECIST v1.1), for Arm 1 vs Arm 3. Secondary endpoints include OS and PFS for Arm 2 vs Arm 3 and Arm 1 vs Arm 2, ORR, OS at 18 months, proportion of patients alive and progression free at 6 and 12 months, PK, immunogenicity, HRQoL, and safety and tolerability. Exploratory endpoints include PFS after subsequent anticancer therapy and correlation of biomarkers with response to treatment. Recruitment is ongoing. Clinical trial information: NCT03043872.

Safety of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection: A randomized, multicenter, prospective, phase III IOCCRC trial (IOCCRC).

e15002 Background: The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. Patients and Methods: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative plus surgery group to receive intraoperative chemotherapy (portal vein, intraluminal, and intraperitoneal chemotherapy plus surgical resection), whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. Surgical complications and side effects of intraoperative chemotherapy were compared between the two groups. Results: Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. There were no significant differences in the length of hospital stay (8.31 vs. 7.98 days, P = 0.138), length of surgery (170.4 vs. 167.0 min, P = 0.526), length of antibiotic use (2.28 vs. 2.15 days, P = 0.322), or length of drain usage (6.37 vs. 6.16 days, P = 0.387) between the intraoperative chemotherapy and control groups. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2% vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group (0% vs. 0.3%, P = 0.99). Intraoperative chemotherapy did not decrease the rate of patients who received postoperative adjuvant chemotherapy between the intraoperative group and control group (29.3% vs. 30.2%, P = 0.795). Conclusions: Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. Register Number: NCT01465451. Clinical trial information: NCT01465451.

Sorafenib in combination with chemotherapy as first-line therapy for FLT3-ITD positive acute myeloid leukemia

目的探讨Fms样酪氨酸激酶3内部串联重复（FLT3-ITD）突变阳性的急性髓系白血病（AML）患者的临床特征及预后，分析索拉非尼联合化疗一线治疗该类患者的疗效。方法回顾性分析2013年1月至2016年8月河南省肿瘤医院确诊的53例初治伴FLT3-ITD突变的AML患者资料，研究该类患者发病时生物学特征，并对比分析化疗联合与不联合索拉非尼治疗的疗效。结果53例FLT3-ITD突变阳性AML患者中，M5型所占比例最高（41.5%），外周血WBC中位数为61.00（0.98~920.00）×109/L，其中高白细胞计数（>10×109/L）患者50例（94.3%）；骨髓原始细胞比例中位数为0.730（0.234~0.966）。53例患者总诱导缓解率为56.6%，索拉非尼联合化疗组与单纯化疗组诱导缓解率分别为86.4%（19/22）和35.5%（11/31），差异有统计学意义（P<0.001）。索拉非尼联合化疗组与单纯化疗组患者1年总生存率分别为78.3%和50.0%（P=0.041），1年无进展生存率分别为75.9%和42.4%（P=0.044）。结论FLT3-ITD突变阳性AML具有初发时外周血WBC及骨髓原始细胞比例高、与M5亚型高度伴随的临床特征，索拉非尼联合化疗可明显改善该类患者的诱导缓解率及短期生存。

Abstract 3004: Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with nintedanib on human colorectal cancer xenografts

Abstract Background: TAS-102 (also named TFTD) is a novel antitumor nucleoside. This is a combination of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and tipiracil hydrochloride (TPI) at a molar ratio 1:0.5. FTD is the active antitumor component of TAS-102 and its triphosphate form is incorporated into DNA in tumor cells. TPI is an inhibitor of thymidine phosphorylase, which strongly inhibits the biodegradation of FTD. In a recent global, multicenter, randomized, double-blind Phase III study (RECOURSE), TAS-102 showed to significantly improve overall survival and progression-free survival and had a favorable safety profile in comparison to those achieved with placebo in patients with metastatic colorectal cancer refractory to standard chemotherapies. Nintedanib is an oral triple angiokinase inhibitor that simultaneously inhibits vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. It is currently being investigated in Phase III studies of advanced non-small cell lung cancer, colorectal cancer, and ovarian cancer. In this study, we evaluated the antitumor effects of TAS-102 in combination with nintedanib on human colorectal tumor xenografts in a nude mouse model. Method: Drug cytotoxicity was determined by the crystal violet staining method using DLD-1, HT-29, and HCT116 colorectal cancer cell lines. Drug interaction was evaluated by performing isobologram analysis. Furthermore, the human colorectal cancer cell lines were implanted into nude mice subcutaneously, and TAS-102 (150 mg/kg/day) and/or nintedanib (20 or 40 mg/kg/day) were orally administered twice daily from Days 1 to 14. Growth inhibitory activity was evaluated based on tumor volume. Results: The combination of TAS-102 and nintedanib exerted an additive effect on growth inhibition of DLD-1 and HT-29, and a sub-additive effect on HCT116 in vitro. TAS-102 and nintedanib monotherapies were both active on all of the evaluated colorectal cancers in vivo. Tumor growth inhibition by combination therapy (150 mg/kg/day TAS-102 plus 40 mg/kg/day nintedanib) was 61.5%, 67.6%, and 67.5% for DLD-1, HT-29, and HCT116 xenografts, and that was significantly superior to that of either monotherapy for all evaluated cancer xenografts (P &amp;lt; 0.05). These results demonstrate that combination therapy with TAS-102 and nintedanib is significantly more effective than either monotherapy in colorectal cancer xenografts. This combination therapy appeared to be well tolerated because neither a reduction in body weight of more than 20% nor drug-related death was observed. Conclusion: Combination therapy of TAS-102 and nintedanib is significantly more effective than either monotherapy in preclinical models and should be considered for investigation in metastatic colorectal cancer patients. Citation Format: Norihiko Suzuki, Fumio Nakagawa, Mamoru Nukatsuka, Kazuaki Matsuoka, Hiroshi Tsukihara, Teiji Takechi. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with nintedanib on human colorectal cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3004.

Abstract 262: Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models

Abstract The PD-1/PD-L1 (programmed cell death protein 1; programmed death-ligand 1) pathway plays a key role in immunological tolerance and autoimmunity. PD-1 is primarily expressed on activated T and B cells while its receptor, PD-L1, is expressed in a variety of cell types including resting lymphocytes, DCs, and macrophages. Recently, multiple human solid tumor types (melanoma, NSCLC, RCC, ovarian, and colorectal cancer) have been found to overexpress PD-L1 within its tumor microenvironment. More importantly, PD-1/PD-L1 blocking agents (pembrolizumab, nivolumab, lambrolizumab, MPDL3280A) have been found active as a single agent or in combination with chemotherapy and some have produced durable clinical responses. On the other hand, human epithelial tumors are also known to overexpress the high-affinity folate receptor (FR)-alpha that is capable of bringing folate-linked drugs into the cell cytosol via endocytosis. Using flow cytometry, we assessed PD-L1 expression in various FR-positive syngeneic mouse tumor models (M109, Renca, L1210A, 4T1-Cl2, ID8-Cl15). PD-L1 expression was found to vary significantly among different tumor types and could be found not only on CD45- malignant cells but also on tumor stromal cells such as F4/80+CD11b+ tumor-associated macrophages. Using a rat anti-mouse PD-1 antibody (clone RMP1-14), we studied in-vivo efficacy of a folate-targeted chemotherapy in combination with PD-1/PD-L1 blockage in PD-L1-expressing tumor models. In syngeneic models with high PD-L1 expression and tumor-infiltrating lymphocytes, a synergistic and curable anti-tumor effect was observed and the animals developed tumor-protective immunity against rechallenge. Thus, our preliminary results suggest that folate-targeted chemotherapeutics may also be enhanced by PD-1/PD-L1 blockage by means of overcoming tumor-mediated immune suppression Citation Format: Yingjuan June Lu, Leroy W. Wheeler, Vicky Cross, Elaine Westrick, Alex Lloyd, Christopher P. Leamon. Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 262.

Treatment of cutaneous angiosarcoma of the face: efficacy of combined chemotherapy and radiotherapy.

Cutaneous angiosarcoma (AS) is a rare form of soft tissue sarcoma. It is aggressive and has a poor prognosis. The aim of our report is to show that with combined chemotherapy and radiotherapy it is possible to obtain good results in terms of local control, complete response, and aesthetic outcome. We present the case of a 60-year-old man affected by AS covering the entire surface of the nose. Surgery, although indicated, was excluded because it was considered mutilating and would give a poor cosmetic result. The patient was treated with chemotherapy consisting of paclitaxel 80 mg/m2 for 6 cycles followed by radiotherapy at a dose of 50 Gy. Then 3 additional cycles of chemotherapy were administered according to the same scheme. A complete response was obtained. At 40 months after treatment, the patient did not show any signs of late toxicity, all lesions had disappeared, and all laboratory tests were negative. Our experience shows that concomitant chemoradiotherapy can be delivered safely and can be tolerated with low toxicity and good results in terms of local control and complete response. We obtained an excellent aesthetic result with improvement of the patient's quality of life.

Comparative effectiveness of FOLFIRINOX (FOL) versus gemcitabine and nab-paclitaxel (GNP) for the first-line treatment of metastatic pancreatic cancer.

306 Background: ACCORD-11 and IMPaCT established the efficacy of combination chemotherapy with FOL and GNP in metastatic pancreatic cancer (mPC). These two regimens have different administration schedule and toxicity profile. In this study we compare the effectiveness and costs of the two regimens including the costs of toxicities and supportive medications from a societal perspective. Methods: A Markov model was developed to simulate a cohort of mPC patients to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) for treatment with FOL and GNP. The model has three states: stable disease, progressive disease, and death. The cohorts were modeled over a 3-year time horizon in a one-month cycle length. Efficacy data were obtained from respective trials. Drug acquisition costs were extracted from Veteran Affairs Federal Supply Schedules. Other costs including visits, tests, and procedures were derived from the Medicare physician-fee-schedule. Literature was reviewed to estimate the adverse event costs and the utility scores for each health state. One-way sensitivity analyses were performed to determine the robustness of the model to changes in key parameters. Results: The model projected a life expectancy of 9 months and 7 months for FOL and GNP, respectively. FOL group showed a higher QALY than GNP group (0.51 vs. 0.40). Although the drug acquisition costs were significantly lower in FOL compared with GNP, FOL yielded a slightly higher cost after 3-years period ($55,944 vs. $56,628). FOL treatment incurred an incremental cost of $1,334 per additional life-month ($16,012 per life-year) and an incremental cost of $30,870 per QALY gained. The median overall survival and progression-free survival point estimate greatly influenced model results based on the results of sensitivity analysis. Conclusions: Compared with GNP, FOL showed a slightly higher cost but higher life expectancy and QALY as a first-line treatment in mPC. Given that the toxicity profile account for a significant portion of cost for FOL providing best supportive care and management of side effects can significantly impact the overall costs of treatment.