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1.
Matthias Unseld Magdalena Drimmel Alexander Siebenhüner Andreas Gleiss Daniela Bianconi Markus Kieler Werner Scheithauer Thomas Winder Gerald W. Prager 《Clinical colorectal cancer》2018,17(4):274-279
Background
Treatment sequencing for patients with refractory metastatic colorectal cancer (mCRC) has been highly debated. The thymidine-based nucleoside trifluridine/tipiracil (TAS-102) and the multikinase inhibitor regorafenib have demonstrated clinical benefits in randomized phase III trials compared with placebo. However, limited data are available on the most optimal therapy sequence involving TAS-102 and regorafenib.Patients and Methods
In the present retrospective, observational, real-life study, clinical data on mCRC patients treated with TAS-102 or an alternative salvage treatment at the Medical University of Vienna and University Hospital Zurich were collected from January 2013 to December 2016.Results
A total of 85 patients whose disease had progressed during fluoropyrimidine-based therapy (FBT) with or without an antibody were included. The disease control rate in patients treated with TAS-102 after FBT-based treatment was 24% compared with 35% in patients treated with regorafenib after FBT-based treatment (adjusted odds ratio, 1.75; 95% confidence interval, 0.41-7.47; P = .449). The progression-free survival (PFS) and overall survival (OS) for patients treated with TAS-102 was 2.8 months (quartile, 2.0-4.8 months) and 15.9 months, respectively. When the data were analyzed according to the subgroups of patients with or without an FBT-free period, the TAS-102–treated patients with a previous FBT-free interval had a PFS of 3.1 months and OS of 17.7 months compared with a PFS of 2.2 months and OS of 8.1 months for patients who received TAS-102 immediately after FBT.Conclusion
Our results have confirmed the efficacy of TAS-102 and regorafenib in the real-life setting. The treatment sequence analysis showed a tendency for longer PFS and OS for TAS-102–treated patients after an FBT-free interval. Prospective randomized data are needed to gain more information about the most beneficial therapy sequence in the salvage treatment of mCRC. 相似文献2.
Background
Regorafenib and TAS-102 are standard treatment options in refractory metastatic colorectal cancer based on improvement in overall survival by 6 and 8 weeks, respectively, when compared with best supportive care alone (BSC). Given the small incremental clinical benefit, we evaluated their cost-effectiveness from a United States payer’s perspective.Materials and Methods
A Markov model was constructed to compare costs and effectiveness of regorafenib, TAS-102, and BSC. Model inputs for clinical efficacy and adverse events were from the CORRECT trial (Regorafenib monotherapy for previously treated metastatic colorectal cancer: an international, multicentre, randomised, placebo-controlled, phase 3 trial) for regorafenib and the RECOURSE trial (Randomized, Double Blind, Phase 3 Study of TAS-102 plus Best Supportive Care [BSC] versus Placebo plus BSC in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapies) for TAS-102. The incremental cost-effectiveness ratios (ICERs) were reported to compare treatments. Model robustness was checked with univariate and probabilistic sensitivity analyses as well as a scenario analysis using the CONCUR trial data for regorafenib.Results
In our base case, regorafenib and TAS-102 had the ICERs of $395,223 per quality-adjusted life year (QALY) and $399,740 per QALY versus BSC, respectively. Compared with regorafenib, TAS-102 provided an additional 0.041 QALY at the cost of $16,608 or $406,104 per QALY, but the differences were not robust in sensitivity analyses. The most influential parameters on the ICERs were efficacy and health state utility parameters as well as the cost of treating neutropenia. In probabilistic sensitivity analysis using cost-effectiveness acceptability curves, BSC was more cost-effective than both regorafenib and TAS-102 in 50% of repetitions at the willingness-to-pay threshold of $330,000 per QALY.Conclusion
Neither TAS-102 nor regorafenib are cost-effective at standard willingness-to-pay thresholds (ie, $150,000 per QALY) relative to BSC. There is no clear evidence that either treatment has better relative value. 相似文献3.
Satoshi Hamauchi Kentaro Yamazaki Toshiki Masuishi Yosuke Kito Azusa Komori Takahiro Tsushima Yukiya Narita Akiko Todaka Makoto Ishihara Tomoya Yokota Tsutomu Tanaka Nozomu Machida Shigenori Kadowaki Akira Fukutomi Takashi Ura Yusuke Onozawa Masashi Ando Masahiro Tajika Hiroya Taniguchi 《Clinical colorectal cancer》2017,16(1):51-57
Background
TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer.Methods
We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS-102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4).Results
Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site ≥ 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P = .045) and between Category C and D (30.9% vs. 72.2%; P = .002). In multivariate analysis, Category D remained a significant predictive factor for progression-free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P = .01).Conclusion
Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102. 相似文献4.
Riccardo Giampieri Angelo Restivo Valeria Pusceddu Michela Del Prete Elena Maccaroni Alessandro Bittoni Luca Faloppi Kalliopi Andrikou Maristella Bianconi Francesco Cabras Rossana Berardi Luigi Zorcolo Francesco Scintu Stefano Cascinu Mario Scartozzi 《Clinical colorectal cancer》2017,16(1):38-43
Background
The potential clinical impact of aspirin use beyond its canonical indications is a novel matter of scientific debate. In patients with metastatic colorectal cancer failing all available options, regorafenib and TAS 102 represent the only chance of treatment. Although effective, these therapeutic options bring along a not-negligible burden in terms of economic costs and toxicity. In this setting, the indication to use aspirin in combination with chemotherapy would potentially represent a medical revolution under the economic and toxicity profile.Patients and Methods
We assessed the role of aspirin in patients with metastatic colorectal cancer who failed all previous treatments and were receiving capecitabine as a salvage option before the introduction of regorafenib and TAS-102.Results
Sixty-six patients were eligible. Twenty patients (30%) were on incidental treatment with aspirin for cardiovascular diseases. Twelve (60%) partial responses were seen in patients on treatment with aspirin, compared with 3 (6%) partial responses in the remaining patients (P = .00007). Sixteen patients on aspirin (80%) obtained disease control versus 14 (30%) patients who were not on aspirin (P = .000377). The median progression-free survival for patients receiving treatment with aspirin was 6.5 months versus 3.3 months for patients who were not on aspirin (hazard ratio, 0.48; 95% confidence interval, 0.30-0.79; P = .0042). A significantly improved overall survival was also evident in aspirin users (median overall survival, 14.7 vs. 8.7 months, respectively; hazard ratio, 0.43; 95% confidence interval, 0.26-0.72; P = .0023).Conclusion
Aspirin may improve the clinical outcome of heavily pre-treated patients with metastatic colorectal cancer receiving chemotherapy. Further studies are necessary before application in the clinical practice. 相似文献5.
Purpose of Review
This paper reviews the development, mechanism of action, clinical efficacy, and safety of regorafenib and TAS-102. Through this review, we aimed to help clinicians make an appropriate choice in patients who progressed after standard therapies.Recent Findings
Regorafenib and TAS-102 have shown superior survival results compared with placebo in refractory metastatic colorectal cancer (mCRC). In the phase III CORRECT study, regorafenib showed significant improvement in overall survival (OS) and progression-free survival (PFS). TAS-102 was associated with OS and PFS benefit as well in the phase III RECOURSE study. However, the toxicity profiles were quite different between the two agents.Summary
Regorafenib and TAS-102 are approved for the management of refractory mCRC. Optimal treatment sequence for using these two novel agents is not defined yet. Safety profiles and patient’s condition should be considered before using these two agents in clinical settings. Further investigation is needed to identify the predictive biomarkers of both agents. These results will allow patients to benefit more from regorafenib and TAS-102.6.
Kenji Tsuchihashi Mamoru Ito Toshikazu Moriwaki Shota Fukuoka Hiroya Taniguchi Atsuo Takashima Yosuke Kumekawa Takeshi Kajiwara Kentaro Yamazaki Taito Esaki Akitaka Makiyama Tadamichi Denda Hironaga Satake Takeshi Suto Naotoshi Sugimoto Kenji Katsumata Toshiaki Ishikawa Tomomi Kashiwada Eishi Baba 《Clinical colorectal cancer》2018,17(4):e687-e697
Background
Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated.Patients and Methods
A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS-102 as Salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later-line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C-reactive protein, and compared.Results
The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95% confidence interval [CI], 9.2-11.6 months), 6.5 months (95% CI, 5.3-7.1 months), and 3.9 months (95% CI, 3.3-4.9 months), respectively. The median progression-free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95% CI, 2.1-3.0 months), 2.0 months (95% CI, 1.9-2.3 months), and 1.7 months (95% CI, 1.4-1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P < .001). No significant differences in OS and PFS were observed between the patient groups treated with TFTD and regorafenib in each mGPS group. In patients aged ≥ 65 years with mGPS 2, the OS and PFS were worse with regorafenib than with TFTD (OS: hazard ratio, 1.45; 95% CI, 0.93-2.25; P = .097; PFS: hazard ratio, 1.57, 95% CI, 1.01-2.44; P = .047), but there were no consistent trends observed as mGPS increased. The frequency of grade 3 and more adverse events was generally similar in each mGPS group. The multivariate analyses showed that mGPS was the strongest predictive factor for OS.Conclusions
The mGPS before later-line chemotherapy is strongly correlated with survival in patients with mCRC. 相似文献7.
Ash Bullement Stuart Underhill Ronan Fougeray Anthony James Hatswell 《Clinical colorectal cancer》2018,17(1):e143-e151
Background
Treatment options at third-line and beyond for patients with late-line metastatic colorectal cancer (mCRC) are limited, and outcomes are poor with best supportive care (BSC). This study investigated the cost-effectiveness of trifluridine/tipiracil and regorafenib relative to BSC alone in patients with mCRC who have been previously treated with, or are not considered candidates for, standard chemotherapies.Materials and Methods
A partitioned survival model was constructed to assess the lifetime costs and benefits accrued by patients. Clinical data were derived from the pivotal phase III (Randomized, Double-Blind, Phase 3 Study of TAS-102 plus Best Supportive Care [BSC] versus Placebo plus BSC in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapies [RECOURSE]) and supporting phase II (J003-10040030) randomized controlled trial of trifluridine/tipiracil + BSC versus placebo + BSC, as well as the phase III Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy (CORRECT) randomized controlled trial of regorafenib, and were extrapolated to estimate lifetime outcomes. Costs were taken from published sources, and health effects sourced from previous mCRC studies.Results
Trifluridine/tipiracil was associated with a 0.27 incremental life year versus BSC alone, which corresponds to a 0.17 quality-adjusted life year gain. The incremental cost of treatment with trifluridine/tipiracil was £8,479, resulting in an incremental cost-effectiveness ratio of £51,194 per quality-adjusted life year gained. Trifluridine/tipiracil was shown to dominate regorafenib (improve outcomes with reduced costs). Sensitivity analyses showed principal areas of uncertainty were survival estimates and patient utility.Conclusions
The results show that trifluridine/tipiracil is more clinically and cost-effective than regorafenib, with clinical outcomes greatly exceeding those for patients treated with BSC alone. Based on the results of the analysis, trifluridine/tipiracil offers an important new treatment option for patients with mCRC maintaining good performance status at the end of life. 相似文献8.
Lijun Liang Lei Wang Panrong Zhu Youyou Xia Yun Qiao Jiang Wu Wei Zhuang Jiayan Fei Yixuan Wen Xiaodong Jiang 《Clinical colorectal cancer》2018,17(3):e443-e449
Background
Antiangiogenic therapy has shown improved clinical outcome in metastatic colorectal cancer (mCRC). After the failure of standard treatments, regorafenib and TAS-102 would be recommended for patients with mCRC, however, they have not been approved in China during this study period.Patients and Methods
This pilot study aimed to assess the efficacy and safety of apatinib, a novel oral inhibitor targeting vascular endothelial growth factor receptor 2, as third-line treatment for patients with mCRC refractory to standard therapies. In this retrospective study, all patients received apatinib treatment until progressive disease (PD), death, unacceptable toxicity, and curative surgery. The dose or treatment schedule was modified according to the physician's discretion according to the toxicity profiles.Results
Between March 2015 and June 2017, 36 patients were enrolled and eligible for evaluation of the safety and efficacy. One patient (2.8%) achieved complete response, 3 (8.3%) achieved partial response, 24 (66.7%) achieved stable disease, and 8 (22.2%) PD. The objective response rate and the disease control rate were 11.1% (4 of 36), and 77.8% (28 of 36), respectively. Moreover, the median overall survival (OS) since the initiation of first-line treatment was 33.2 months. The median progression-free survival (PFS) and median OS from apatinib treatment were 4.8 and 10.1 months, respectively. Intergroup analysis showed that there was no significant difference in median PFS and median OS between patients who were previously treated with and without bevacizumab. The most common Grade 3 to 4 adverse reactions were hand-foot syndrome, hypertension, and proteinuria.Conclusion
Our results suggested that apatinib was active as a third-line treatment of refractory mCRC with a manageable tolerability profile. In addition, preliminary data suggested that the efficacy of apatinib would not be affected by previous bevacizumab treatment. Further prospective randomized controlled clinical trials are urgently needed. 相似文献9.
Roberto Petrioli Martina Chirra Luciana Messuti Anna Ida Fiaschi Vinno Savelli Ignazio Martellucci Edoardo Francini 《Clinical colorectal cancer》2018,17(4):307-312
Background
In the CORRECT (patients with metastatic COloRectal Cancer treated with REgorafenib or plaCebo after failure of standard Therapy) trial, regorafenib was proven to extend survival of patients with metastatic colorectal cancer (mCRC) that progressed after all available therapies. Grade 3 to 4 toxicity occurred in 54% of patients, and data on the activity and tolerability of regorafenib in elderly patients were scarce. The aim of this study was to evaluate the efficacy and safety of an alternative schedule, 2-week-on treatment and 1 week-off (2/1 schedule), of regorafenib for elderly patients with mCRC.Patients and Methods
Patients ≥ 75 years with mCRC who progressed after oxaliplatin- and irinotecan-based chemotherapy received regorafenib on a 2/1 schedule. Potentially frail subjects were identified by G8 screening tool and excluded. The 2-month disease-control rate was the primary endpoint, and the secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and objective response rate.Results
Between February 2014 and May 2017, 23 patients with mCRC were recruited at our institution. No partial or complete responses were observed, and the stable disease and disease-control rate were 52.2%. The median PFS was 4.8 months (95% confidence interval, 3.8-6.3 months), and the median OS was 8.9 months (95% confidence interval, 6.9-10.6 months). Adverse events were uncommon, and the most frequent grade 3 toxicity adverse events were hand-foot skin reaction (9%) and fatigue (9%). Toxicity-related dose reductions and discontinuations occurred in 5 and 2 patients, respectively.Conclusion
Regorafenib administered with a modified 2/1 schedule to patients who were aged ≥ 75 years and non-frail with treatment-refractory mCRC seems to be tolerable and achieve encouraging results in terms of PFS and OS. 相似文献10.
11.
Mitsukuni Suenaga Marta Schirripa Shu Cao Wu Zhang Dongyun Yang Yan Ning Chiara Cremolini Carlotta Antoniotti Beatrice Borelli Tetsuo Mashima Satoshi Okazaki Martin D. Berger Yuji Miyamoto Roel Gopez Afsaneh Barzi Sara Lonardi Toshiharu Yamaguchi Alfredo Falcone Heinz-Josef Lenz 《Clinical colorectal cancer》2018,17(2):e395-e414
Background
The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib.Patients and Methods
We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing.Results
CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand–foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026).Conclusion
Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand–foot skin reaction in mCRC patients receiving regorafenib therapy. 相似文献12.
Marta Schirripa Giuseppe Pasqualetti Riccardo Giampieri Mario Scartozzi Sara Lonardi Laura Rumanò Francesca Bergamo Silvia Stragliotto Sabina Murgioni Giulia Alberti Mario Domenico Rizzato Alessandra Anna Prete Marco Puzzoni Valeria Pusceddu Pina Ziranu Fabiana Pani Stefano Mariotti Vittorina Zagonel Fotios Loupakis 《Clinical colorectal cancer》2018,17(3):e601-e615
Background
The impact of free triiodothyronine (FT3)/free thyroxine (FT4) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT3/FT4 ratio in patients with advanced cancer. We evaluated the impact of FT3/FT4 ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib.Methods
Patients with metastatic CRC treated with regorafenib with available clinical data and baseline measurement of FT3, FT4, and thyroid-stimulating hormone (TSH) were considered eligible. Exploratory analyses included subjects treated at Istituto Oncologico Veneto. A confirmatory analysis was planned based on FT3/FT4 ratio tertile results, and a validation cohort was built on data retrieved from University of Cagliari.Results
In an exploratory cohort, the median overall survival in patients with low, intermediate, and high FT3/FT4 ratios, according to tertiles' value, was 4.8, 5.0, and 7.6 months, respectively (P = .003). The differences were significant in the multivariate model (hazard ratio, 0.43; 95% confidence interval, 0.28-0.68; P = .0003). Confirmatory results were obtained in a validation cohort, both in univariate (P = .0002) and in multivariate (hazard ratio, 0.56; 95% confidence interval, 0.36-0.88; P = .0118) models.Conclusions
High baseline FT3/FT4 ratio is strongly associated to better outcome in patients with progressive metastatic CRC treated with regorafenib. Further investigations are ongoing to draw definitive conclusions regarding a potential predictive effect. 相似文献13.
Raghav Sundar Susana Miranda Daniel Nava Rodrigues Maxime Chénard-Poirier David Dolling Matthew Clarke Ines Figueiredo Claudia Bertan Wei Yuan Ana Ferreira Rossitza Chistova Gunther Boysen Desamparados Roda Perez Nina Tunariu Joaquin Mateo Andrew Wotherspoon Ian Chau David Cunningham Johann de Bono 《Clinical colorectal cancer》2018,17(4):280-284
Background
Loss of ataxia telangiectasia mutated (ATM), a key protein regulating DNA repair signaling, has been suggested to increase sensitivity to DNA damaging agents. We conducted a study analyzing the loss of ATM protein expression in colorectal cancer and correlated this with clinical outcomes.Materials and Methods
The clinical outcomes data and tumor samples from metastatic colorectal cancer patients referred to the Royal Marsden Hospital Drug Development Unit (United Kingdom) from 2012 to 2016 and providing consent for a molecular characterization study were analyzed. Immunohistochemistry (IHC) slides were assessed by a pathologist for nuclear staining intensity of ATM and semiquantitatively scored. ATM loss was defined as a nuclear H-score of ≤ 10.Results
Of 223 colorectal cancer samples, ATM IHC loss was identified in 17 (8%). ATM loss was independent of the RAS and RAF mutational status. ATM loss was associated with superior overall survival after first-line oxaliplatin-based therapy (49 vs. 32 months; hazard ratio [HR], 2.52) but not with irinotecan-based therapy (24 vs. 33 months; HR, 0.72). ATM loss was not prognostic for survival from the diagnosis (50 vs. 44 months; HR, 1.43).Conclusion
ATM could be considered a biomarker for the development of novel DNA repair targeting agents and treatment of colorectal cancer. 相似文献14.
Hiroyuki Uetake Kenichi Sugihara Kei Muro Toshiyuki Sunaya Yuka Horiuchi-Yamamoto Hajime Takikawa 《Clinical colorectal cancer》2018,17(1):e49-e58
Background
Regorafenib (Stivarga) is an oral multikinase inhibitor currently approved for patients with metastatic colorectal cancer or gastrointestinal stromal tumor. Although hepatotoxicity has been a known product profile feature of regorafenib since its initial approval, its clinical features are limited to those found in the clinical trials.Patients and Methods
The present study was conducted in 2 analysis sets: a safety analysis set for metastatic colorectal cancer from solicited postmarketing surveillance (PMS) in Japan (n = 1227) and an analysis set for serious hepatic adverse drug reactions (n = 210) from all patients registered for regorafenib use.Results
The features of liver injury compatible with current product labeling included the second cycle as the most frequently observed time to onset, hepatocellular type as the typical pattern of liver injury, idiosyncratic occurrence as the possible mechanism, and rare fatal outcomes (0.33%; 4 of 1227). In addition to the known features, the present study found unpredictability in the outcome of hepatic events using the onset values of liver chemistry tests and delayed improvement of hepatic parameters after drug withdrawal. Owing to multiple confounding factors in patients with advanced cancer, difficulty remains in the interpretation of exploration for background factors and evaluation using Hy’s law in oncology products.Conclusion
Regorafenib-induced liver injury can be considered idiosyncratic and typically of hepatocellular type, with fatal outcomes rare. Early recognition and timely drug withdrawal are the most important strategies to prevent progression to severe outcomes. At occurrence, careful observation until improvement and monitoring for fulminant hepatic failure are also essential. 相似文献15.
《Clinical colorectal cancer》2020,19(2):82-90.e9
BackgroundIn the absence of head-to-head comparison studies, the present network meta-analysis evaluated and compared the efficacy of 4 therapeutic alternatives for refractory colorectal cancer.Materials and MethodsThe search focused on results from phase III randomized controlled trials. Separate (subgroup) network meta-analyses were conducted to obtain drug comparisons stratified by various patient characteristics. The principal outcome of interest was overall survival (OS).ResultsNo difference in OS was found between regorafenib and TAS-102. For a rectal primary location, TAS-102 conferred benefit versus placebo (hazard ratio [HR], 0.671), but regorafenib did not (HR, 0.950). For patients aged > 65 years, TAS-102 showed benefit versus placebo (HR, 0.579) but regorafenib did not (HR, 0.816). For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 in the indirect comparison, regorafenib showed benefit versus placebo (HR, 0.687), as did TAS-102 (HR, 0.756) but with a lower advantage. For patients with RAS wild type not previously treated with anti-EGFR antibodies, panitumumab was the optimal choice for OS.ConclusionsNo differences in OS were found between regorafenib and TAS-102. Possible greater efficacy was found for TAS-102 compared with regorafenib for patients with a rectal primary location, ECOG PS > 0, and age > 65 years. In contrast, regorafenib showed possible greater effectiveness for patients with ECOG PS 0 and age < 65 years. In the RAS WT population, the anti-EGFR drug showed superiority with respect to TAS-102 and regorafenib. These results should be viewed as only exploratory, and further prospective studies are warranted to validate these data. 相似文献
16.
Takayuki Yoshino Kentaro Yamazaki Eiji Shinozaki Yoshito Komatsu Tomohiro Nishina Hideo Baba Akihito Tsuji Yasushi Tsuji Kensei Yamaguchi Naotoshi Sugimoto Tadamichi Denda Kei Muro Tetsuji Takayama Taito Esaki Yasuo Hamamoto Toshikazu Moriwaki Yasuhiro Shimada Masahiro Goto Atsushi Ohtsu 《Clinical colorectal cancer》2018,17(4):e719-e732
Background
High thymidine kinase 1 (TK1) activity increases the incorporation of trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer.Patients and Methods
Individual patient data from 2 randomized placebo-controlled trials were analyzed. We measured TK1 protein expression in tumor tissue samples and its relationship with FTD/TPI clinical efficacy using overall survival (OS), progression-free survival, and disease control rate.Results
This study comprised 329 patients (FTD/TPI, 224; placebo, 105). FTD/TPI significantly improved OS versus placebo in the high-expression (cutoff ≥ 15%) TK1 group (median OS, 7.8 vs. 6.8 months; hazard ratio = 0.65; 95% confidence interval, 0.46-0.93; P = .018). The low-expression (cutoff < 15%) TK1 group experienced a smaller OS benefit (9.3 vs. 7.4 months; hazard ratio = 0.88; 95% confidence interval, 0.63-1.23; P = .45). For patients who received placebo, the high-expression TK1 group had a slightly worse prognosis than the low-expression TK1 group. The tendency of FTD/TPI efficacy concerning progression-free survival and disease control rate was not similar to that concerning OS between groups.Conclusion
Patients with high TK1 expression showed an improvement in OS when treated with FTD/TPI. Further investigations are warranted to confirm this relationship. 相似文献17.
Lotte Keikes Martijn G.H. van Oijen Valery E.P.P. Lemmens Miriam Koopman Cornelis J.A. Punt 《Clinical colorectal cancer》2018,17(1):58-64
Background
Clinical guidelines are generated to preserve high-quality evidence-based care. Data on the implementation of guidelines into clinical practice are scarce, despite that guideline adherence prevents over- and undertreatment and correlates with survival. Therefore, we investigated guideline adherence for the systemic treatment in high-risk stage II and stage III colon cancer and metastatic colorectal cancer.Patients and Methods
In all Dutch hospitals (n = 88) 1 medical oncologist involved in colorectal cancer care was approached to participate. An online survey was conducted regarding the local standard of care for adjuvant chemotherapy in high-risk stage II and stage III colon cancer and first-line treatment regimens in metastatic colorectal cancer. Frequency tables were provided for categorical variables and compared for differences in guideline adherence according to hospital type (academic/teaching/regional).Results
The overall response rate was 70% (62 of 88). Reported guideline adherence was at least 60% of all presented settings. For high-risk stage II and stage III colon cancer, treatment strategies agreed with national guidelines in 66% and 84% of hospitals, and overtreatment patterns were identified in 28% and 13%, respectively. Targeted therapy was not routinely administered as first-line treatment in metastatic colorectal cancer (range from 63% to 71% in different settings). No differences in guideline adherence were observed among different hospital types.Conclusion
Guideline adherence as reported by medical oncologists in The Netherlands is suboptimal. Possible explanations include unawareness or disagreement with the guidelines, or local financial restrictions. Our results recommend additional support of guideline implementation and monitoring in clinical practice, and investigating underlying causes in case of nonadherence. 相似文献18.
Cynthia Gail Leichman Shannon L. McDonough Stephen R. Smalley Kevin G. Billingsley Heinz-Josef Lenz Matthew A. Beldner Aram F. Hezel Mario R. Velasco Katherine A. Guthrie Charles D. Blanke Howard S. Hochster 《Clinical colorectal cancer》2018,17(1):e121-e125
Background
Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%. Cetuximab improves response in KRAS (KRAS proto-oncogene) wild type (wt) metastatic colorectal cancer. S0713 was designed to assess improvement in pCR with additional use of cetuximab with induction chemotherapy and NCRT for locally advanced, KRAS-wt rectal cancer.Patients and Methods
Patient eligibility: stage II to III biopsy-proven, KRAS-wt rectal adenocarcinoma; no bowel obstruction; adequate hematologic, hepatic and renal function; performance status of 0 to 2. Target enrollment: 80 patients. Treatment: induction chemotherapy with wCAPOX (weekly capecitabine and oxaliplatin) and cetuximab followed by the same regimen concurrent with radiation (omitting day 15 oxaliplatin). If fewer than 7 pCRs were observed at planned interim analysis after 40 patients received all therapy, the study would close. Eighty eligible patients would provide 90% power given a true pCR rate > 35% at a significance of 0.04. The regimen would lack future interest if pCR probability was ≤ 20%.Results
Between February 2009 and April 2013, 83 patients registered. Four were ineligible and 4 not treated, leaving 75 evaluable for clinical outcomes and toxicity, of whom 65 had surgery. Of 75 patients, 20 had pCR (27%; 95% confidence interval [CI], 17%-38%); 19 (25%) had microscopic cancer; 36 (48%) had minor/no response (including 10 without surgery). Three-year disease-free survival was 73% (95% CI, 63%-83%).Conclusion
Our trial did not meet the pCR target of 35%. Toxicity was generally acceptable. This regimen cannot be recommended outside the clinical trial setting. 相似文献19.
Cristina Grávalos Alfredo Carrato María Tobeña Mercedes Rodriguez-Garrote Gemma Soler José Mª Vieitez Luis Robles Manuel Valladares-Ayerbes Eduardo Polo Mª Luisa Limón Mª José Safont Eva Martínez de Castro Pilar García-Alfonso Enrique Aranda 《Clinical colorectal cancer》2018,17(2):e323-e329
Introduction
The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC).Patients and Methods
In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B).Results
Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment.Conclusions
In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC. 相似文献20.
Javier Cortes José Pérez-García Scott Whiting Yin Wan Caitlyn Solem Ming-Hui Tai Sandra Margunato-Debay Amy Ko Abderrahim Fandi Marc Botteman 《Clinical breast cancer》2018,18(5):e919-e926