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[Economic Evaluation of mFOLFOX6-based First-line Regimens for Unresectable Advanced or Recurrent Colorectal Cancer Using Clinical Decision Analysis].
Shida, T, Endo, Y, Shiraishi, T, Yoshioka, T, Suzuki, K, Kobayashi, Y, Ono, Y, Ito, T, Inoue, T
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2018;(1):83-90
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Abstract
We evaluated four representative chemotherapy regimens for unresectable advanced or recurrent KRAS-wild type colorectal cancer: mFOLFOX6, mFOLFOX6+bevacizumab (Bmab), cetuximab (Cmab), or panitumumab (Pmab). We employed a decision analysis method in combination with clinical and economic evidence. The health outcomes of the regimens were analyzed on the basis of overall and progression-free survival. The data were drawn from the literature on randomized controlled clinical trials of the above-mentioned drugs. The total costs of the regimens were calculated on the basis of direct costs obtained from the medical records of patients diagnosed with unresectable advanced or recurrent colorectal cancer at Yamagata University Hospital and Yamagata Prefecture Central Hospital. Cost effectiveness was analyzed using a Markov chain Monte Carlo (MCMC) method. The study was designed from the viewpoint of public medical care. The MCMC analysis revealed that expected life months and expected cost were 20 months/3,527,119 yen for mFOLFOX6, 27 months/8,270,625 yen for mFOLFOX6+Bmab, 29 months/13,174,6297 yen for mFOLFOX6+Cmab, and 6 months/12,613,445 yen for mFOLFOX6+Pmab. Incremental costs per effectiveness ratios per life month against mFOLFOX6 were 637,592 yen for mFOLFOX6+Bmab, 1,075,162 yen for mFOLFOX6+Cmab, and 587,455 yen for mFOLFOX6+Pmab. Compared to the conventional mFOLFOX6 regimen, molecular-targeted drug regimens provide better health outcomes, but the cost increases accordingly. mFOLFOX 6+Pmab is the most cost-effective regimen among those surveyed in this study.
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Clinical Trials of Novel Targeted Therapies in Ovarian Cancer: Moving Beyond Poly ADP Ribose Polymerase (PARP) Inhibitors.
Guo, Q, Yang, Q, Li, J, Liu, G, Nikoulin, I, Jia, S
Current pharmaceutical biotechnology. 2018;(14):1114-1121
Abstract
BACKGROUND Epithelial ovarian cancer (EOC) is one of the most common cancers in the female reproductive system and deadliest gynecological cancer in the United States. Standard treatments by surgery and platinum-based chemotherapy are not satisfied for the patients with high risk of relapse. Advances in molecular biology for EOC development have brought several targeted therapies to benefit recurrent patients. Poly-ADP-ribose polymerase inhibitors (PARPi) may be one of the most successful classes of targeted therapies with three approved medicines. For better clinical outcomes and more comprehensive disease management of EOC, more novel classes of targeted therapies are needed. METHOD We focus on non-PARPi novel targeted therapies that are completed or on-going in phase III clinical trials by searching databases of Pubmed and Clinicaltrials.gov. Keywords of "ovarian cancer, targeted therapy and phase III trial" were used for publications and information from May 2012 to May 2018. RESULTS There are total 150 viable EOC phase III studies listed in Clinicaltrials.gov., including 20 completed studies with results and 73 on-going studies. Bevacizumab plus chemotherapy is the only medication with government approval for recurrent EOC. Targeted therapies against other growthrelated factors, cytokines and folate receptor are failed in phase III trials or still on-going. CONCLUSION Implications of on-going phase III trials are: 1) combination therapy of bevacizumab with atezolizumab may be the most anticipated studies for approvals; 2) mirvetuximab soravtansine plus chemotherapy may generate positive results to justify an approval; and 3) Immune therapy for EOC may bring new treatments for the patients.
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Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial.
Schlumberger, M, Leboulleux, S, Catargi, B, Deandreis, D, Zerdoud, S, Bardet, S, Rusu, D, Godbert, Y, Buffet, C, Schvartz, C, et al
The lancet. Diabetes & endocrinology. 2018;(8):618-626
Abstract
BACKGROUND In ESTIMABL1, a randomised phase 3 trial of radioactive iodine (131I) administration after complete surgical resection in patients with low-risk thyroid cancer, 92% of patients had complete thyroid ablation at 6-10 months, defined as a recombinant human thyroid-stimulating hormone (rhTSH)-stimulated serum thyroglobulin concentration of 1 ng/mL or less and normal findings on neck ultrasonography. Equivalence was shown between low-activity (1·1 GBq) and high-activity (3·7 GBq) radioactive iodine and also between the use of rhTSH injections and thyroid hormone withdrawal. Here, we report outcomes after 5 years of follow-up. METHODS This multicentre, randomised, open-label, equivalence trial was done at 24 centres in France. Between March 28, 2007, and Feb 25, 2010, we randomly assigned (1:1:1:1) adults with low-risk differentiated thyroid carcinoma who had undergone total thyroidectomy to one of four strategies, each combining one of two methods of thyrotropin stimulation (rhTSH or thyroid hormone withdrawal) and one of two radioactive iodine activities (1·1 GBq or 3·7 GBq). Randomisation was by computer-generated sequence, with variable block size. Follow-up consisted of a yearly serum thyroglobulin measurement on levothyroxine treatment. Measurement of rhTSH-stimulated thyroglobulin and neck ultrasonography were done at the discretion of the treating physician. No evidence of disease was defined as serum thyroglobulin of 1 ng/mL or less on levothyroxine treatment and normal results on neck ultrasonography, when performed. This study was registered with ClinicalTrials.gov, number NCT00435851. FINDINGS 726 patients (97% of the 752 patients originally randomised) were followed up. At a median follow-up since randomisation of 5·4 years (range 0·5-9·2), 715 (98%) had no evidence of disease. The other 11 had either structural disease (n=4), raised serum thyroglobulin concentration (n=5), or indeterminate findings on neck ultrasonography (n=2). At ablation, six of these patients had received 1·1 GBq radioactive iodine (five after rhTSH and one after withdrawal) and five had received 3·7 GBq (two after rhTSH and three after withdrawal). TSH-stimulated (either after rhTSH injections or thyroid hormone withdrawal according to the treatment group) thyroglobulin concentration measured at the time of ablation was prognostic for structural disease status at ablation, ablation status at 6-10 months, and the final outcome. INTERPRETATION Our findings suggest that disease recurrence was not related to the strategy used for ablation. These data validate the use of 1·1 GBq radioactive iodine after rhTSH for postoperative ablation in patients with low-risk thyroid cancer. FUNDING French National Cancer Institute (INCa), French Ministry of Health, and Sanofi Genzyme.
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Brachytherapy of Intracranial Gliomas.
Nachbichler, SB, Kreth, FW
Progress in neurological surgery. 2018;:72-86
Abstract
Interstitial implantation of radioactive materials (brachytherapy [BT]) has been designed to protractedly deliver a high radiation dose to a well-defined target volume, while minimizing irradiation of the adjacent normal tissues. Even though promising results have been reported over time, the role of this treatment modality in the management of brain tumors is still poorly defined, and only a few centers worldwide apply it in clinical practice. Nevertheless, temporary or permanent interstitial implantation of low activity (<20 mCi) and low dose rate (≤10 cGy/h) iodine-125 (125I) seeds as possible therapy of intracranial gliomas is currently undergoing a definite revival, and several indications for its use have been identified. Generally, 125I-BT may be considered a reasonable option in cases of unresectable, well-circumscribed, either newly diagnosed or recurrent tumors with a diameter of ≤4 cm, virtually in any location within the brain. Importantly, this treatment does not narrow down the spectrum of the possible subsequent salvage therapeutic options, since neither repeated interstitial nor additional external beam irradiation at the time of tumor progression after BT is associated with a significantly increased risk of radiogenic complications. Using correct patient selection criteria, appropriate surgical technique, and established treatment parameters, would make BT a truly minimally invasive procedure with a low risk of complications and reasonable efficacy.
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Diagnostic Accuracy of Amino Acid and FDG-PET in Differentiating Brain Metastasis Recurrence from Radionecrosis after Radiotherapy: A Systematic Review and Meta-Analysis.
Li, H, Deng, L, Bai, HX, Sun, J, Cao, Y, Tao, Y, States, LJ, Farwell, MD, Zhang, P, Xiao, B, et al
AJNR. American journal of neuroradiology. 2018;(2):280-288
Abstract
BACKGROUND Current studies that analyze the usefulness of amino acid and FDG-PET in distinguishing brain metastasis recurrence and radionecrosis after radiation therapy are limited by small cohort size. PURPOSE Our aim was to assess the diagnostic accuracy of amino acid and FDG-PET in differentiating brain metastasis recurrence from radionecrosis after radiation therapy. DATA SOURCES Studies were retrieved from PubMed, Embase, and the Cochrane Library. STUDY SELECTION Fifteen studies were included from the literature. Each study used PET to differentiate radiation necrosis from tumor recurrence in contrast-enhancing lesions on follow-up brain MR imaging after treating brain metastasis with radiation therapy. DATA ANALYSIS Data were analyzed with a bivariate random-effects model. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were pooled, and a summary receiver operating characteristic curve was fit to the data. DATA SYNTHESIS The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of PET were 0.85, 0.88, 7.0, 0.17, and 40, respectively. The area under the receiver operating characteristic curve was 0.93. On subgroup analysis of different tracers, amino acid and FDG-PET had similar diagnostic accuracy. Meta-regression analysis demonstrated that the method of quantification based on patient, lesion, or PET scan (based on lesion versus not, P = .07) contributed to the heterogeneity. LIMITATIONS Our study was limited by small sample size, and 60% of the included studies were of retrospective design. CONCLUSIONS Amino acid and FDG-PET had good diagnostic accuracy in differentiating brain metastasis recurrence from radionecrosis after radiation therapy.
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Effect of antihypertensive drugs on breast cancer risk in female hypertensive patients: Evidence from observational studies.
Zhao, Y, Wang, Q, Zhao, X, Meng, H, Yu, J
Clinical and experimental hypertension (New York, N.Y. : 1993). 2018;(1):22-27
Abstract
This systematic review aimed to evaluate the association between antihypertensive drugs and risk of breast cancer, and provide therapeutic implications for female hypertensive patients with different physical appearance. The prevalence of hypertension and female breast cancer is on the rise with age. It has been suggested that ARBs (angiotensin receptor blockers), ACEi (angiotensin-converting enzyme inhibitor), CCBs (calcium channel blockers), and BBs (beta-blockers) were widely used in hypertensive patients. Some researches have shown ARBs, ACEis, and beta-blockers to be effective drugs for blood pressure lowering as well as for reducing the risk of breast cancer in women. However, the research conclusions were inconsistent. To address the conflicting evidence from previous study, the study evaluates the risk of breast cancer in hypertensive women. In conclusion, we report the evidence that beta-blockers can reduce the risk of breast cancer recurrence, while ACEi and CCBs were not associated with an increased risk of breast cancer.
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A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma.
Amengual, JE, Lichtenstein, R, Lue, J, Sawas, A, Deng, C, Lichtenstein, E, Khan, K, Atkins, L, Rada, A, Kim, HA, et al
Blood. 2018;(4):397-407
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Abstract
Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m2) and romidepsin (12 to 14 mg/m2) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140.
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Impact of dietary patterns and the main food groups on mortality and recurrence in cancer survivors: a systematic review of current epidemiological literature.
Jochems, SHJ, Van Osch, FHM, Bryan, RT, Wesselius, A, van Schooten, FJ, Cheng, KK, Zeegers, MP
BMJ open. 2018;(2):e014530
Abstract
OBJECTIVE To determine whether there is an association between dietary patterns/indices and foods from the main food groups (highest vs lowest intakes) prior to or after cancer diagnosis and mortality and cancer recurrence in cancer survivors. PARTICIPANTS Survivors of common cancers with a 10-year survival rate of ≥50%: bladder, bowel, breast, cervical, kidney, laryngeal, prostate, testicular, uterine cancer, malignant melanoma and (non-)Hodgkin's lymphoma. OUTCOME MEASURES Mortality (overall, cancer-specific, from other causes) and cancer recurrence. INFORMATION SOURCES PubMed, Embase and the Cochrane Library were searched from inception to April 2017. Additional studies were identified by searching reference lists. Two authors independently screened titles and abstracts, assessed study quality and extracted the data. RESULTS A total of 38 studies were included. The risk of bias was rated low for the included randomised controlled trials (RCTs) and moderate for the cohort studies. The quality of evidence was assessed with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach and was rated moderate (RCTs), and (very)low (cohort studies). Reducing the amount of fat after diagnosis appears to decrease the risk of breast cancer recurrence. Adherence to a high-quality diet and prudent diet after diagnosis appears to decrease the risk of death from other causes (and overall mortality for high-quality diet) in breast cancer survivors. Adherence to a Western diet, before and after diagnosis, appears to increase the risk of overall mortality and death from other causes among breast cancer survivors. Evidence from studies among other cancer survivors was too limited or could not be identified. CONCLUSION For many cancer survivors, there is little evidence to date to indicate that particular dietary behaviours influence outcomes with regard to recurrence and mortality. Notwithstanding, limited evidence suggests that a low-fat diet, a high-quality diet and a prudent diet are beneficial for breast cancer survivors, while a Western diet is detrimental for breast cancer survivors.
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Mechanisms underlying the effects of n-3 polyunsaturated fatty acids on fear memory processing and their hypothetical effects on fear of cancer recurrence in cancer survivors.
Okubo, R, Chen, C, Sekiguchi, M, Hamazaki, K, Matsuoka, YJ
Prostaglandins, leukotrienes, and essential fatty acids. 2018;:14-23
Abstract
The relationship of n-3 polyunsaturated fatty acids (PUFAs) and gut microbiota with brain function has been extensively reported. Here, we review how n-3 polyunsaturated fatty acids affect fear memory processing. n-3 PUFAs may improve dysfunctional fear memory processing via immunomodulation/anti-inflammation, increased BDNF, upregulated adult neurogenesis, modulated signal transduction, and microbiota-gut-brain axis normalization. We emphasize how n-3 PUFAs affect this axis and also focus on the hypothetical effects of PUFAs in fear of cancer recurrence (FCR), the primary psychological unmet need of cancer survivors. Its pathophysiology may be similar to that of post-traumatic stress disorder (PTSD), which involves dysfunctional fear memory processing. Due to fewer adverse effects than psychotropic drugs, nutritional interventions involving n-3 PUFAs should be acceptable for physically vulnerable cancer survivors. We are currently studying the relationship of FCR with n-3 PUFAs and gut microbiota in cancer survivors to provide them with a nutritional intervention that protects against FCR.
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Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.
Chari, A, Lonial, S, Mark, TM, Krishnan, AY, Stockerl-Goldstein, KE, Usmani, SZ, Londhe, A, Etheredge, D, Fleming, S, Liu, B, et al
Cancer. 2018;(22):4342-4349
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Abstract
BACKGROUND Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). METHODS A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. RESULTS Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. CONCLUSIONS The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.