Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

INTRODUCTION: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. METHODS: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). RESULTS: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. CONCLUSION: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.

The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.

Comparative analysis of recurrence rates between intravesical gemcitabine and bacillus Calmette-Guérin induction therapy following transurethral resection of bladder tumors in patients with intermediate- and high-risk bladder cancer: A retrospective multicenter study.

PURPOSE: This study investigated the efficacy of intravesical gemcitabine as an alternative to bacillus Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS: Data were retrospectively collected across seven institutions from February 1999 to May 2023. Inclusion criteria included patients with intermediate- or high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumors (TURBT) and received at least four sessions of intravesical gemcitabine or BCG induction therapy. Patient characteristics, complete remission (CR), occurrence, and progression rates were compared. RESULTS: In total, 149 patients were included in this study (gemcitabine, 63; BCG, 86). No differences were apparent between the two groups in baseline characteristics, except for the follow-up period (gemcitabine, 9.2±5.9 months vs. BCG, 43.9±41.4 months, p<0.001). There were no consistent significant differences observed between the two groups in the 3-month (gemcitabine, 98.4% vs. BCG, 95.3%; p=0.848), 6-month (94.9% vs. 90.0%, respectively; p=0.793) and 1-year CR rates (84.2% vs. 83.3%, respectively; p=0.950). Also, there was no significant statistical difference in progression-free survival between the two groups (p=0.953). The occurrence rates of adverse events were similar between the groups (22.2% vs. 22.1%; p=0.989); however, the rate of Clavien-Dindo grade 2 or higher was significantly higher in the BCG group (1.6% vs. 16.3%, respectively; p<0.001). CONCLUSIONS: Intravesical gemcitabine demonstrated efficacy comparable to BCG therapy for the first year in patients with intermediate- and high-risk NMIBC. However, long-term follow-up studies are warranted.

Risk factors for failing to complete gemcitabine-cisplatin neoadjuvant chemotherapy in muscle invasive bladder cancer patients.

PURPOSE: We evaluated the risk factors associated with failure to complete gemcitabine-cisplatin (GP) neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: In total, 231 patients with MIBC treated with NAC before undergoing radical cystectomy between 2013 and 2022 participated in this study. Logistic regression analysis was performed to assess the relationship between the likelihood of incomplete NAC and clinical and demographic variables, including age, sex, hypertension (HTN), diabetes mellitus (DM), prechemotherapy glomerular filtration rate, clinical T stage, clinical N stage, and body mass index (BMI). RESULTS: Of 231 patients, 209 (90.5%) and 22 (9.5%) completed and discontinued the NAC course, respectively. The mean age was 66.13±9.15, 65.63±9.07, and 70.86±8.66 years for the total sample, continuation, and discontinuation groups, respectively (p=0.010). No significant inter-group differences in sex, HTN, height, weight, BMI, pre-chemotherapy glomerular filtration rate, clinical T stage, or clinical N stage were observed. According to the results of the multivariable analysis, age (odds ratio [OR] 1.076, 95% confidence interval [CI] 1.013-1.143, p=0.018) and the presence of DM (OR 2.541, 95% CI 1.028-6.281, p=0.043) were significantly associated with NAC discontinuation. CONCLUSIONS: Thus, older age and presence of DM are potential risk factors for GP NAC discontinuation in patients with MIBC. Further studies are required to validate our findings and develop strategies to minimize the rate of GP NAC discontinuation in this population.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

BACKGROUND: Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. OBJECTIVE: A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. METHODS: We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. RESULTS: Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p = 0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p < 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). CONCLUSIONS: Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

[A Case of Adenocarcinoma of Pancreatic Head of Liver Disfunction after Pancreaticoduodenectomy with Celiac Artery Stenosis Treated by Urgent Median Arcuate Ligament Release].

This patient visited our hospital for the purpose of detailed examination of prostate cancer in his seventies. Abdominal contrast-enhanced computed tomography(CT)revealed a low-density mass of 2 cm in the pancreatic head. He was diagnosed with pancreatic cancer. Pancreaticoduodenectomy was performed after 2 courses of gemcitabine and S-1 therapy were performed as neoadjuvant chemotherapy. An intraoperative clamp test of the gastroduodenal artery showed that the pulsation of the common hepatic artery and the proper hepatic artery was weak but sufficient, so the gastroduodenal artery was cut and the operation was completed as planned. A blood test on the 1st day after the operation showed elevated levels of AST 537 U/L, ALT 616 U/L, and 7 hours later blood sampling showed further increases in AST 1,455 U/L, ALT 1,314 U/L. After a detailed review of the preoperative CT, celiac artery stenosis due to compression of the arcuate ligament was suspected, and urgent median arcuate ligament release was performed on the same day. Dissection of the arcuate ligament significantly improved the pulsation of the common hepatic artery and proper hepatic artery. Postoperatively, hepatic enzymes improved and ISGPS showed Grade B pancreatic juice leakage, but the patient was discharged from the hospital on the 49th postoperative day without any other complications. He took S-1 as adjuvant chemotherapy, and no signs of recurrence have been observed 9 months after the operation.

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Background: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙µg/mL) compared to oral free-GEM (19.04 hr∙µg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.

pH-responsive targeted nanoparticles release ERK-inhibitor in the hypoxic zone and sensitize free gemcitabine in mutant K-Ras-addicted pancreatic cancer cells and mouse model.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated by us and others. This study used pH-responsive nanoparticles encapsulated ERK inhibitor (SCH772984) and surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumors. We used a small molecule, SCH772984, to target ERK1 and ERK2 in PDAC and other cancer cells. This nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free-GEM, which is functionally weak when combined with nanoencapsulated ERKi, led to significant synergistic treatment outcomes in vitro and in vivo. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in a genetically engineered KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/Pdx-1-Cre) pancreatic cancer mouse model, which is not observed in a single therapy. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

Single dual-specific anti-PD-L1/TGF-ß antibody synergizes with chemotherapy as neoadjuvant treatment for pancreatic ductal adenocarcinoma: a preclinical experimental study.

AIMS: Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-ß bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-ß) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. METHODS: Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. RESULTS: BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. CONCLUSION: Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.

Sarcopenia is associated with leukopenia in urothelial carcinoma patients who receive tislelizumab combined with gemcitabine and cisplatin therapy.

BACKGROUND: In the era of combination therapy, there has been limited research on body composition. Specific body composition, such as sarcopenia, possesses the potential to serve as a predictive biomarker for toxic effects and clinical response in patients with urothelial carcinoma (UC) undergoing tislelizumab combined with gemcitabine and cisplatin (T + GC). MATERIALS AND METHODS: A total of 112 UC patients who received T + GC were selected at the Affiliated Hospital of Xuzhou Medical University from April 2020 to January 2023. Baseline patient characteristics and detailed hematological parameters were collected using the electronic medical system and laboratory examinations. The computed tomography images of patients were analyzed to calculate psoas muscle mass index (PMI). We evaluated the association between sarcopenia (PMI < 4.5 cm2/m2 in men; PMI < 3.3 cm2/m2 in women) and both hematological toxicity and tumor response. RESULTS: Overall, of the 112 patients (65.2% male, median age 56 years), 43 (38.4%) were defined as sarcopenia. Patients with sarcopenia were notably older (p = 0.037), more likely to have hypertension (p = 0.009), and had poorer ECOG-PS (p = 0.027). Patients with sarcopenia were more likely to develop leukopenia (OR 2.969, 95% CI 1.028-8.575, p = 0.044) after receiving at least two cycles of T + GC. However, these significant differences were not observed in thrombocytopenia and anemia. There were no significant differences in the tumor response and grade 3-4 hematological toxicity between patients with sarcopenia and those without sarcopenia. CONCLUSIONS: Patients with sarcopenia were more likely to develop leukopenia after receiving T + GC. There were no notable alterations observed in relation to anemia or thrombocytopenia. No significant difference was found between the sarcopenia group and non-sarcopenia group in terms of tumor response and grade 3-4 hematological toxicity.

First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL. METHODS: The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related. INTERPRETATION: Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL. FUNDING: National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.

Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.

BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Malakoplakia of urinary bladde: 3 cases reports and review.

OBJECTIVE: This study aims to explore the clinical diagnosis and treatment methods of bladder malakoplakia (MUB) to enhance the understanding of the disease. METHODS: A retrospective analysis of the diagnosis and treatment processes of three cases of MUB treated in our department was conducted. Relevant literature from both domestic and international sources was reviewed to provide a comprehensive analysis. RESULTS: All three patients underwent transurethral resection of bladder lesions combined with antibiotic therapy, and two of them received transurethral instillation of gemcitabine. There were two cases with two recurrences each, and one case with four recurrences, with the latter also concurrently presenting with unilateral ureteral malakoplakia. Postoperative pathology confirmed MUB in all three cases. Close follow-up revealed no significant recurrence in the patients. CONCLUSION: The effective diagnosis rate is increased by conducting multiple deep, repetitive, and randomly selected live tissue examinations. The definitive diagnosis of MUB relies on pathological histological examination. Treatment involving a combination of antibiotics and transurethral resection of bladder lesions proves to be effective. Exploring the use of bladder instillation of gemcitabine widens the spectrum of MUB treatment methods.

LogP of N-acyl-gemcitabine and lectin-corona emerge as key parameters in nanoparticulate intravesical cancer therapy.

After surgical removal of the tumour tissue, bladder cancer is treated by intravesical instillation of cytotoxic drugs such as gemcitabine. Gemcitabine, however, is highly hydrophilic and possesses a short half-life due to fast enzymatic deamination. Additionally, continuous dilution by urine, a hardly permeable urothelial barrier and rapid excretion by urination make therapy difficult. To modify lipophilicity of the drug, N-acyl-gemcitabine derivatives with quite different solubility and logP were synthesized, purified and characterized. The loading of PLGA nanoparticles with the N-acyl-gemcitabine derivatives followed by release in artificial urine, revealed that the drug content increases but the subsequent release decreases with lipophilicity. Additionally, acylation increased cytotoxicity and opened passive diffusion as an additional pathway into cancer cells. To address physiological constraints, the surface of the monodisperse nanoparticles was grafted with bioadhesive wheat germ agglutinin. Cytoadhesion to artificial bladder cancer tissue and even uptake into the cells as indicated by microscopic imaging are expected to prolong the retention time in the bladder cavity as well as to promote uptake into the cells. By using N-caprylic-gemcitabine as most appropriate gemcitabine-derivative for drug loading and making use of the bioadhesive characteristics of wheat germ agglutinin for grafting the corona of PLGA-nanoparticles, an innovative strategy towards smart drug delivery for instillative therapy of bladder cancer is proposed.

A randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer.

Platinum is recommended in combination with gemcitabine in the treatment of metastatic triple-negative breast cancer (mTNBC). We conduct a randomized phase 3, controlled, open-label trial to compare nab-paclitaxel/cisplatin (AP) with gemcitabine/cisplatin (GP) in mTNBC patients (ClinicalTrials.gov NCT02546934). 254 patients with untreated mTNBC randomly receive AP (nab-paclitaxel 125 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) or GP (gemcitabine 1250 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) intravenously every 3 weeks until progression disease, intolerable toxicity or withdrawal of consent. The primary endpoint is progression-free survival (PFS); secondary endpoints are objective response rate (ORR), safety and overall survival (OS). The trial has met pre-specified endpoints. The median PFS is 9.8 months with AP as compared to 7.4 months with GP (stratified HR, 0.67; 95% CI, 0.50-0.88; P = 0.004). AP significantly increases ORR (81.1% vs. 56.3%, P < 0.001) and prolongs OS (stratified HR, 0.62; 95% CI, 0.44-0.90; P = 0.010) to GP. Of grade 3 or 4 adverse events, a significantly higher incidence of neuropathy in AP and thrombocytopenia in GP is noted. These findings warrant further assessment of adding novel agents to the nab-paclitaxel/platinum backbone due to its high potency for patients with mTNBC.

Neoadjuvant concurrent chemoradiotherapy using infusional gemcitabine in locally advanced rectal cancer: A phase II trial.

INTRODUCTION: Gemcitabine is a well-known radiosensitizer. Herein, we tested the efficacy and toxicity of preoperative concurrent infusional gemcitabine and radiotherapy in locally advanced rectal cancer. PATIENTS AND METHODS: This was a phase II, single-arm trial. Eligible patients had a diagnosis of rectal adenocarcinoma with clinical stage T3-T4 and/or nodal involvement, age ≥18 years, and no prior chemotherapy or radiotherapy. Patients received preoperative radiation at a dose of 50.4-54 Gy over 28 days with concurrent infusional gemcitabine administered at a dose of 100 mg/m2 over the course of 24 h weekly for 6 weeks. The primary endpoint was pathological complete response (pCR). RESULTS: Forty patients were recruited. Only one patient did not complete therapy due to death. Eight patients did not undergo surgery, one died, two progressed to nonresectable disease, and five withdrew consent. Five patients progressed prior to surgery, with two having unresectable metastases and three having resectable liver metastases. One was found to have peritoneal metastasis during surgery. Out of the 32 patients who underwent surgery, seven achieved pCR at a rate of 20%. With a median follow-up of 30 months, four additional patients had a distant relapse (one had a subsequent local relapse). The 3-year event-free and overall survival rates were 70% and 85%, respectively. The commonest preoperative grade 3-4 toxicity included lymphopenia (50%), neutropenia (41%), anemia (15%), diarrhea (12%), abdominal pain (12%), and proctitis (8%). CONCLUSION: Concurrent preoperative chemoradiotherapy using infusional gemcitabine for locally advanced rectal cancer achieved an encouraging degree of local control with manageable toxicity.