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The Efficacy and Safety of Anlotinib in Neoadjuvant Treatment of Locally Advanced Thyroid Cancer: A Single-Arm Phase II Clinical Trial.
Huang, NS, Wei, WJ, Xiang, J, Chen, JY, Guan, Q, Lu, ZW, Ma, B, Sun, GH, Wang, YL, Ji, QH, et al
Thyroid : official journal of the American Thyroid Association. 2021;(12):1808-1813
Abstract
Background: Surgery is the primary treatment for locally advanced thyroid cancer. For some cases, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. Anlotinib is a multitarget tyrosine kinase inhibitor, which demonstrated antitumor activity in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer. We aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting. Methods: This single-arm phase II study investigated the efficacy and safety of anlotinib (12 mg orally daily, 2 weeks on/1 week off) for 2-6 cycles in patients with locally advanced thyroid cancer in the neoadjuvant setting. The key eligibility criteria included age 14-80 years old; locally advanced thyroid cancer that would benefit from surgery, and at least one measurable lesion. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were enrolled and received an average of 3.5 cycles of anlotinib treatment. The ORR of anlotinib was 76.9% (95% confidence interval: 46.2-95.0%). The R0/R1 resection rate in the intent-to-treat population was 61.5% and in the per-protocol population was 72.7%. The median time to response was 61.5 days, and the disease control rate at 18 weeks was 92.3%. No patients had blood transfusion or tracheotomy. Most adverse events (AEs) were grade 1 or 2 and tended to discontinue when neoadjuvant treatment ceased. Common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (53.8%), and hand-foot syndrome (38.5%). Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer. Clinical Trial Registration Number: NCT04309136.
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Chemoreduction with topotecan and vincristine: Quantifying tumor response in bilateral retinoblastoma patients.
King, BA, Sahr, N, Sykes, A, Wilson, MW, Brennan, RC
Pediatric blood & cancer. 2021;(4):e28882
Abstract
BACKGROUND Evaluate the efficacy of two courses of vincristine and topotecan (VT) neoadjuvant intravenous chemotherapy in reducing retinoblastoma tumor volumes. METHODS Twenty-seven patients with previously untreated, bilateral advanced retinoblastoma who were enrolled on a prospective treatment protocol (NCT00186888). Patients underwent high-resolution ophthalmic imaging at diagnosis and were reimaged following treatment with two cycles of VT. Tumor height and diameter were measured before and after treatment, and tumor volumes were calculated. Statistical methods for dependent samples were used. RESULTS Imaging was completed for 75 tumors in 23 patients (43 eyes). After two cycles of VT, median decrease in tumor height was 47% and median decrease in tumor diameter was 22%. Median decrease in estimated tumor volume was 74%. Sixty-one of 75 tumors demonstrated >50% reduction in tumor volume. Distance from the optic nerve (=0 vs >0), age (<4 vs >4 months), macular location (within vs outside), and time (pre- and posttreatment) were found significantly associated with log-transformed tumor volume adjusting for the repeated effect of patient eye using generalized estimating equations to estimate the parameters of a generalized linear model (P < .0001 [ β : 1.95, CI: 1.53-2.36], P = .0031 [ β : 1.49, CI: 0.57-2.41], P < .0001 [ β : .94, CI: 0.54-1.35], and P < .0001 [ β : 1.43, CI: 1.15-1.71]). CONCLUSION Chemoreduction was achieved in all patients and most retinoblastoma tumors following two cycles of VT. Reduction in tumor dimensions was comparable to that reported with platinum-based chemotherapy. Tumor location, distance from the optic nerve, and age at diagnosis were significant predictors of treatment response.
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Impact of sodium phenylbutyrate treatment in acute management of maple syrup urine disease attacks: a single-center experience.
Zubarioglu, T, Dede, E, Cigdem, H, Kiykim, E, Cansever, MS, Aktuglu-Zeybek, C
Journal of pediatric endocrinology & metabolism : JPEM. 2021;(1):121-126
Abstract
OBJECTIVES Accurate management of metabolic decompensation in maple syrup urine disease (MSUD) has a crucial role, as acute attacks can cause neurological sequels and can be life threatening. Here, we aimed to evaluate effect of sodium phenylbutyrate (NaPBA) in acute management of MSUD attacks. METHODS Episodes with an initial plasma leucine (Leu) level above 750 µmoL/L and that require hospitalization due to clinical findings of Leu neurotoxicity and/or feeding difficulties were included to the study. Patients who had no molecular diagnosis and a regular follow-up were excluded. Clinical findings, laboratory results and therapy responses were reviewed, retrospectively. RESULTS Ten patients who experienced 19 distinct episodes of MSUD attacks were enrolled. Initial median Leu level was 901.67 (range 756-1989.11) and 33.9 µmoL/L (range 7.91-347.3 µmoL/L) at the end of therapy. None of our patients underwent extracorporeal toxin removal during the course of attack. In patients with serial plasma quantitative amino acid sampling, mean Leu reduction rate was calculated to be 529.68 ± 250.08 µmoL/L/day at the 24th h of treatment and 318.72 ± 191.52 µmoL/L/day at the 48th h of treatment. CONCLUSIONS This study is the first original study that investigates the effect of NaPBA in management of acute attacks of MSUD patients from Turkey. We suggest that NaPBA treatment in MSUD attacks can ameliorate clinical and biochemical findings. This therapeutic option should be considered especially in smaller centers without the toxin removal chance and for patients who were not appropriate for extracorporeal toxin removal like hemodynamic instability.
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Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors.
Thompson, PA, Huang, C, Yang, J, Wertheim, BC, Roe, D, Zhang, X, Ding, J, Chalasani, P, Preece, C, Martinez, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(20):5660-5668
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Abstract
PURPOSE To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer. EXPERIMENTAL DESIGN An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor-positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy. RESULTS In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), -14.6 to -4.7] at 12 months, an absolute decrease of -1.4% (95% CI, -2.5 to -0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40). CONCLUSIONS This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.
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Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.
Finn, RS, Kudo, M, Cheng, AL, Wyrwicz, L, Ngan, RKC, Blanc, JF, Baron, AD, Vogel, A, Ikeda, M, Piscaglia, F, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(17):4848-4858
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PURPOSE In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.
Kunzmann, V, Siveke, JT, Algül, H, Goekkurt, E, Siegler, G, Martens, U, Waldschmidt, D, Pelzer, U, Fuchs, M, Kullmann, F, et al
The lancet. Gastroenterology & hepatology. 2021;(2):128-138
Abstract
BACKGROUND The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. METHODS In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. FINDINGS Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. INTERPRETATION Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. FUNDING Celgene.
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PML-RARA transcript levels at the end of induction therapy are associated with prognosis in non-high-risk acute promyelocytic leukaemia with all-trans retinoic acid plus arsenic in front-line therapy: long-term follow-up of a single-centre cohort study.
Tang, FF, Lu, SY, Zhao, XS, Qin, YZ, Liu, XH, Jia, JS, Wang, J, Gong, LZ, Jiang, Q, Zhao, T, et al
British journal of haematology. 2021;(5):722-730
Abstract
Despite the high cure probability for acute promyelocytic leukaemia (APL), a minority of patients will relapse and the risk factors for relapse are unclear. We retrospectively analysed 212 patients who were diagnosed with non-high-risk APL and received all-trans retinoic acid (ATRA) plus arsenic as front-line therapy at Peking University Institute of Hematology from February 2014 to December 2018. A total of 176 patients (83%) received oral arsenic (realgar-indigo naturalis formula) plus ATRA, 36 patients (17%) received arsenic trioxide plus ATRA and 203 patients were evaluable for relapse. After a median (range) follow-up of 53·6 (24·3-85·4) months, two patients had molecular relapse and eight had haematological relapse. A promyelocytic leukaemia/retinoic acid receptor alpha (PML-RARA) transcript level of ≥6·5% at the end of induction therapy was associated with relapse (P = 0·031). The 5-year cumulative incidence of relapse, event-free survival and overall survival were 5·5%, 92·3% and 96·3% respectively. In conclusion, the present long-term follow-up study further confirmed the high cure probability of ATRA plus oral arsenic as front-line therapy for non-high-risk APL and showed that the PML-RARA transcript level at the end of induction therapy was associated with relapse.
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The use of vitamin E in preventing taxane-induced peripheral neuropathy.
Heiba, MA, Ismail, SS, Sabry, M, Bayoumy, WAE, Kamal, KA
Cancer chemotherapy and pharmacology. 2021;(6):931-939
Abstract
PURPOSE Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy. Several trials have evaluated the protective effect of vitamin E in preventing CIPN with controversial results. This study aims to outline the role of vitamin E in preventing CIPN. METHODS A prospective phase II, open-label randomized controlled study was conducted in patients receiving taxane-based chemotherapy in Ain Shams University Hospitals, using vitamin E at a dose of 400 mg twice daily. The primary endpoint was the incidence of grade ≥ 2 sensory neuropathy according to CTCAE v 5.0 in each treatment arm. Secondary endpoints include time to onset and the duration of grade ≥ 2 sensory neuropathy. RESULTS A total of 140 patients were randomized between the control and vitamin E arms. There was no difference in the incidence of grade ≥ 2 sensory neuropathy between the two arms (25.7% in each arm; P = 1.0), as well as the time to onset of neuropathy (P = 0.24). However, there was a statistically significant difference between the 2 arms as regards the duration of neuropathy. The median duration was 12.5 vs. 5 weeks in the control and vitamin E arms respectively (P = 0.01). CONCLUSION Our study did not demonstrate a protective role of vitamin E in decreasing the incidence of CIPN in patients receiving taxane-based chemotherapy. However, the recovery from CIPN was much better as compared to the control arm, which may indicate a role for vitamin E in decreasing the duration and severity of CIPN.
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A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer.
Zheng, X, Xu, Z, Ji, Q, Ge, M, Shi, F, Qin, J, Wang, F, Chen, G, Zhang, Y, Huang, R, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(20):5502-5509
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PURPOSE Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. PATIENTS AND METHODS Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. RESULTS Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9-not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9-5.6; hazard ratio = 0.16; 95% CI, 0.10-0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0-78.8) in the lenvatinib arm and 0% (95% CI, 0-0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). CONCLUSIONS Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.
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Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT): A Randomized Multicenter Phase II Trial.
Chen, AP, Kummar, S, Moore, N, Rubinstein, LV, Zhao, Y, Williams, PM, Palmisano, A, Sims, D, O'Sullivan Coyne, G, Rosenberger, CL, et al
JCO precision oncology. 2021
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UNLABELLED This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.