-
1.
Clinical and pharmacogenetic determinants of 5-fluorouracyl/leucovorin/irinotecan toxicity: Results of the PETACC-3 trial.
Tejpar, S, Yan, P, Piessevaux, H, Dietrich, D, Brauchli, P, Klingbiel, D, Fiocca, R, Delorenzi, M, Bosman, F, Roth, AD
European journal of cancer (Oxford, England : 1990). 2018;:66-77
Abstract
PURPOSE Irinotecan (CPT-11) in combination with 5-fluorouracil (5FU) is widely used in the treatment of colorectal cancer. We assessed potential clinical variables that may predict toxicity and more specifically the role of UGT1A1 polymorphisms associated with irinotecan toxicity. We used data from the PETACC3 trial, which randomised patients in adjuvant setting to 6 months of leucovorin (LV) and 5FU (LV5/FU2) or LV5/FU2 + irinotecan. PATIENTS AND METHODS Clinical and toxicity data were available for 2982 patients, DNA was available for 1200 (40%) of these patients. We genotyped the polymorphisms UGT1A1*28 and UGT1A1-3156G > A. Risk factors for neutropenia and diarrhoea were assessed by univariable and multivariable analyses. RESULTS In univariable analysis, UGT1A*28 genotype was associated with an increased incidence of grade III-IV neutropenia (incidence: 44% versus 26%; odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.4-3.7). In multivariable analysis, the most important predictors (ordered in terms of contribution to R2) were baseline neutrophil count (OR for 1-unit (109/l) decrease: 1.8, 95% CI: 1.3-1.7), female sex (OR: 1.8, 95% CI: 1.1-3.0), body surface area (OR for 0.1-unit increase: 0.8, 95% CI: 0.7-1.0), UGT1A1 (OR: 2.8, 95% CI: 1.6-5.0), age (OR per 10 years: 1.3, 95% CI: 1.1-1.6) and poor performance status (OR: 1.6, 95% CI: 1.0-2.6). The main predictors for grade IV neutropenia were sex, age, performance score and UGT1A1. The main predictors for diarrhoea were sex and age. CONCLUSIONS We found that a complex of risk factors is involved in the development of toxicity, including UGT1A1. Parameters that are readily available in clinical practice, notably sex, age and performance status, are stronger predictors than the UGT1A1*28 genotype. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the determinants of toxicity risk, notably in females.
-
2.
Circulating CD8+ T-cell repertoires reveal the biological characteristics of tumors and clinical responses to chemotherapy in breast cancer patients.
Lin, KR, Pang, DM, Jin, YB, Hu, Q, Pan, YM, Cui, JH, Chen, XP, Lin, YX, Mao, XF, Duan, HB, et al
Cancer immunology, immunotherapy : CII. 2018;(11):1743-1752
Abstract
PURPOSE CD8+ T cells are primarily cytotoxic cells that provide immunological protection against malignant cells. Considerable evidence suggests that the T-cell repertoire is closely associated with the host immune response and the development of cancer. In this study, we explored the characteristics of the circulating CD8+ T-cell repertoire and their potential value in predicting the clinical response of breast cancer patients to chemotherapy. EXPERIMENTAL DESIGN We applied a high-throughput TCR β-chain sequencing method to characterize the CD8+ T-cell repertoire of the peripheral blood from 26 breast cancer patients. In addition, changes in the circulating CD8+ T-cell repertoire during chemotherapy were analyzed. RESULTS We found that the HEC ratios of the CD8+ T-cell repertoires from HER2+ breast cancer patients were significantly higher than those of HER2- patients, suggesting that the HER2 protein is released into circulation where it is targeted by CD8+ T cells. Several Vβ and CDR3 motifs preferentially used in HER2+ patients were identified. Besides, we found that the circulating CD8+ T-cell repertoires evolved during chemotherapy and correlated with patient clinical responses to chemotherapy. Increased CD8+ T-cell repertoire heterogeneity during chemotherapy was associated with a better clinical response. CONCLUSIONS Although functional studies of clonally expanded CD8+ T-cell populations are clearly required, our results suggest that the circulating CD8+ T-cell repertoire reflects the characteristics of the tumor-associated biomolecules released into the blood and correlates with the clinical responses of the patients to chemotherapy which might assist in making treatment decisions.
-
3.
The Deauville criteria cannot differentiate between responding and non-responding non-Hodgkin lymphoma patients.
Adams, HJA, Kwee, TC
Annals of hematology. 2018;(4):719-720
-
4.
A multicenter, observational study of metastatic breast cancer patients who were treated with eribulin mesylate or taxane-based regimens.
Kikuchi, Y, Uchida, Y, Shirakawa, K, Kanauchi, H, Niwa, T, Nishioka, K, Tada, K, Hashimoto, M, Yasuda, H, Sugiura, R, et al
Asia-Pacific journal of clinical oncology. 2018;(5):e231-e237
Abstract
AIM: This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting. METHODS This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post-progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics. RESULTS In total, 216 patients receiving eribulin monotherapy (n = 101), taxane monotherapy (n = 73) or taxane plus bevacizumab (n = 42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events. CONCLUSION In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports.
-
5.
A Multicenter Open-Label Randomized Controlled Trial of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer.
Saito, T, Nakai, Y, Isayama, H, Hirano, K, Ishigaki, K, Hakuta, R, Takeda, T, Saito, K, Umefune, G, Akiyama, D, et al
Pancreas. 2018;(7):800-806
Abstract
OBJECTIVE Exocrine pancreatic insufficiency may impair the nutritional status in pancreatic cancer (PC), but the role of pancreatic enzyme replacement therapy (PERT) is not fully evaluated. Therefore, we conducted this multicenter open-label randomized controlled trial to evaluate the role of PERT in PC patients. METHODS Patients with unresectable PC receiving chemotherapy were randomly assigned to pancrelipase and nonpancrelipase groups. Patients in the pancrelipase group took oral pancrelipase of 48,000 lipase units per meal. N-benzoyl-tryrosyl para-aminobenzoic acid (NBT-PABA) test was performed at baseline. Our primary endpoint was change in body mass index (BMI) at 8 weeks. Secondary endpoints were change in other nutritional status at 8 weeks and overall survival. RESULTS A total of 88 patients were enrolled between May 2014 and May 2016. The NBT-PABA test was lower than the normal range in 90%. There were no significant differences in change in BMI at 8 weeks: 0.975 and 0.980 in the pancrelipase and the nonpancrelipase groups, respectively (P = 0.780). The other nutritional markers were also comparable. The median overall survival was 19.0 and 12.0 months (P = 0.070). CONCLUSIONS In this randomized controlled trial, pancrelipase failed to improve the change in BMI at 8 weeks in PC patients receiving chemotherapy.
-
6.
The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer.
Bahrami, A, Hesari, A, Khazaei, M, Hassanian, SM, Ferns, GA, Avan, A
Journal of cellular physiology. 2018;(3):2162-2169
Abstract
Colorectal cancer is among the most lethal malignancies globally. BRAF is a member of the RAS/RAF/MEK/ERK signaling pathway. Its constitutive activation can result in increased cellular growth, development, invasion, and resistance to therapy. A mutation of the BRAF gene is present in 5-10% of metastatic colorectal cancers. BRAF mutations have been found to predict a lack of benefit to anti-EGFR therapy in metastatic CRC. Furthermore, CRC containing the BRAF V600E mutation display an innate resistance to BRAF inhibitors. The mechanisms of cell resistance can be explained at least in part by ERK dependent and ERK in-dependent pathway. Clinical trials evaluating the combinations of BRAF, PI3K, EGFR, and/or MEK inhibitors have revealed promising activity in BRAF mutant containing CRCs. There may be some benefit from future studies that focus on improving the efficacy of combined therapy in CRC with respect to the sustained effects. The aim of current review is to give an overview about the current status and prospective regarding the therapeutic potential of targeting BRAF mutant colorectal cancer.
-
7.
Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer.
Van Cutsem, E, Hidalgo, M, Canon, JL, Macarulla, T, Bazin, I, Poddubskaya, E, Manojlovic, N, Radenkovic, D, Verslype, C, Raymond, E, et al
International journal of cancer. 2018;(8):2053-2064
-
-
Free full text
-
Abstract
The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.
-
8.
Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.
Ettrich, TJ, Berger, AW, Perkhofer, L, Daum, S, König, A, Dickhut, A, Wittel, U, Wille, K, Geissler, M, Algül, H, et al
BMC cancer. 2018;(1):1298
Abstract
BACKGROUND Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION ClinicalTrials.gov : NCT02047513, 08/13/2014.
-
9.
A phase I study of nintedanib combined with cisplatin/gemcitabine as first-line therapy for advanced squamous non-small cell lung cancer (LUME-Lung 3).
Forster, M, Hackshaw, A, De Pas, T, Cobo, M, Garrido, P, Summers, Y, Dingemans, AC, Flynn, M, Schnell, D, von Wangenheim, U, et al
Lung cancer (Amsterdam, Netherlands). 2018;:27-33
Abstract
BACKGROUND There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. MATERIALS AND METHODS A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2-7, 9-21) were given for 4-6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs. RESULTS Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17-35 months). CONCLUSIONS The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.
-
10.
Assessment of chemotherapy on various biochemical markers in breast cancer patients.
Paz, MFCJ, Gomes, AL, Islam, MT, Tabrez, S, Jabir, NR, Alam, MZ, Machado, KC, de Alencar, MVOB, Machado, KC, Ali, ES, et al
Journal of cellular biochemistry. 2018;(3):2923-2928
Abstract
Chemotherapy is a standard treatment method for the patients with locally advanced breast cancer. Lately, cyclophosphamide (CYP) and doxorubicin (DOX) are used as the major chemotherapeutic agents especially for the treatment of breast cancer. Till date, no serum biomarker has been able to provide an early diagnosis of breast cancer. This study aimed to assess inflammatory, cardiac, renal and hematological markers in 56 breast cancer patients (BCP) before, during and after termination of chemotherapy with CYP and DOX. Blood samples were collected from the patients at the each treatment stages mentioned above. These samples were assessed for interleukin 6 (IL-6), interleukin 10 (IL-10), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine, hemoglobin (Hb), leukocyte, platelet and Na+ /K+ -ATPase levels either by ELISA or colorimetric methods. The results suggest a significant increase in IL-6 level at all the stages in BCP as compared to control group. On the other hand, IL-10, CK and Na+ /K+ -ATPase levels were found to be significantly declined during all the stages. Moreover, the majority of hematological parameters remained unchanged throughout the treatment period with the exception of creatinine and Hb which showed slight modulation in their level at different stages. Based on the results, we conclude that breast cancer and co-treatment with CYP and DOX, interfere arious biological markers, thereby, showing the physiological imbalance.