Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.
In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ...endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly with a cycle of 3 weeks on and 1 week off). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed.
A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval CI, 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy.
Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme a subsidiary of Merck; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.).
Abstract Background/purpose Accurate target volume delineation is essential for radiotherapy delivery, yet significant intra and inter-observer variability is documented. We analysed the variation in ...cervical cancer clinical target volume (CTV) delineation. Materials/methods All INTERLACE participating centres completed two RTQA outlining exercises. The Trial Management Group created a consensus outline. A separate STAPLE algorithm outline was created. Using these two outlines an optimised gold standard was generated. Volume, maximum distance from DICOM centre in all directions, and Jaccard Conformity Index (JCI) were calculated and compared for each centres’ outlines. Anatomical areas included within CTV were recorded to detect systematic differences. Results 21 outlines were compared for case 1 and 22 for case 2. Volume ranged from 340 cc to 676 cc (case 1) and from 458 cc to 806 cc (case 2). A maximum 4 cm difference between outlines was observed in one direction. JCI ranged from 0.51 to 0.81 (case 1) and 0.57 to 0.81 (case 2). Variation in anatomical areas included in CTV exists between the two cases and between centres. Conclusions Significant inter-observer variation in cervical cancer delineation has been demonstrated. Ongoing efforts are needed to ensure inter-observer consistency through education, guidelines and multi-centre collaboration.
Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon ...27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.
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•ALS-associated KIF5A mutations result in a common novel toxic C-terminal sequence•ALS mutant KIF5A lacks autoinhibition resulting in a constitutively active kinesin•ALS mutant KIF5A displays a distal accumulation and altered axonal transport•ALS-associated KIF5A mutations result in novel protein and RNA interactions
ALS-associated KIF5A mutations alter the C terminus, the effect of which had yet to be elucidated. Here, Baron et al. discover that these mutations impair KIF5A autoinhibition resulting in a hyperactive kinesin that displays altered protein function and aberrant cellular interactions. These observations shed light on the mechanisms contributing to ALS.
Radical hysterectomy and complete pelvic lymphadenectomies are the most commonly performed procedures for women with early-stage cervical cancer. Sentinel lymph node (SLN) mapping could be an ...alternative to routine pelvic lymphadenectomy, aiming to diagnose accurately nodal extension and decrease lymphatic morbidity.
To compare 3-year disease-free survival and health-related quality of life after SLN biopsy or SLN biopsy + pelvic lymphadenectomy in early cervical cancer.
We hypothesize that disease-free survival is non-inferior and health-related quality of life superior after SLN biopsy compared with SLN biopsy + pelvic lymphadenectomy.
International, randomized, multicenter, single-blind trial. The study will be run by teams trained to carry out SLN biopsy, belonging to clinical research cooperative groups or recognized as experts in this field. Patients with an optimal mapping (Memorial Sloan Kettering Cancer Center MSKCC criteria) and a negative frozen section will be randomized 1:1 to SLN biopsy only or SLN biopsy + pelvic lymphadenectomy.
Patients with early stages (Ia1 with lymphovascular invasion to IIa1) of disease. Histological types are limited to squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
Main endpoint will be co-primary endpoint, associating 3-year disease-free survival and quality of life (QLQ-C30 and QLQ-CX24).
950 patients need to be randomized.Estimated dates for completing accrual and presenting results: study started on Q2 2018, last accrual is scheduled for Q2 2021, and last follow-up in Q2 2026.
ClinicalTrials.gov identifier: NCT03386734.
To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), ...Australia/New Zealand (ANZ), Europe (E), and North America (NAm).
A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey.
A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation SD 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4.96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05; p = 0.02 for Asia vs. other regions).The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002).
Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials.
Abstract Background Cervical cancer inter-observer delineation variation has been demonstrated. This article addresses its dosimetric impact. Methods 21 centres outlined two INTERLACE trial quality ...assurance test cases. A gold standard clinical target volume (GSCTV) was created from a consensus and STAPLE outline. RapidArc plans were created for all centres’ planning target volumes (PTVs; PTV1 + 2). Gold standard PTVs (GSPTVs) were created for each plan by applying each centre’s CTV–PTV margins to GSCTV. DVH parameters including D95% and Dmean for each PTV1 + 2 and GSPTV were compared, representing planned versus GSPTV delivered dose. PTV1 + 2 and GSPTV V95% was also calculated. Results Reviewing all parameters, no plans achieved acceptable GSPTV coverage. GSPTV V95% ⩾ 95% was not achieved for any plan. GSPTV V95% < 90% in 15/21 (case 1) and 14/22 (case 2) and <80% in 2 plans from both cases. GSPTV V95% is on average 10–15% lower than planned and GSPTV D95% is 10–20% lower than planned. Most common GSCTV anatomical areas not receiving 95% dose were vagina, obturator and external iliac nodes and, in case 1, the superior nodal aspect. Conclusion Cervical cancer CTV delineation variation leads to significant reductions in dose delivered to GSPTV. This highlights the ongoing importance of standardising delineation in the IMRT era.
Despite advances in cervical cancer prevention and diagnosis, outcomes for patients given a diagnosis of advanced and recurrent disease are poor. In the GOG240 trial, the addition of bevacizumab to ...paclitaxel-topotecan or paclitaxel-cisplatin has been shown to prolong survival compared with paclitaxel-topotecan or paclitaxel-cisplatin in patients with persistent, recurrent, or metastatic disease. However, standards of care vary between regions and countries. The purpose of this systematic review and network meta-analysis was to enable a comparison between bevacizumab + chemotherapy with multiple monotherapy or combination chemotherapy regimens in the treatment for women with advanced, recurrent, or persistent cervical cancer.
A systematic literature review was conducted to identify randomized or nonrandomized controlled trials of patients with recurrent, persistent, or metastatic cervical cancer published in English from 1999 to 2015. A feasibility study was performed to assess the heterogeneity of the trials, and a network meta-analysis was conducted. Fixed- and random-effects models were fitted to calculate the hazard ratio for overall survival (OS) for all pairwise comparisons and ranking of all interventions.
Twenty-three studies (19 trials) met inclusion criteria and were included in the review. Sample sizes ranged from 69 to 452, and median patient age ranged from 45 to 53 years. There was a trend toward prolonged OS with cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab compared with all non-bevacizumab-containing therapies. Cisplatin-paclitaxel-bevacizumab had the highest probability of being the most efficacious compared with all regimens (68.1%), and cisplatin monotherapy had the lowest (0%).
The results of this network meta-analysis show that bevacizumab in combination with paclitaxel-topotecan or paclitaxel-cisplatin is likely to prolong OS over other non-bevacizumab-containing chemotherapies (eg, paclitaxel-carboplatin), which were not included in the GOG240 trial. In patients with advanced, persistent, and recurrent cervical cancer, cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab showed the highest efficacy in all regimens investigated in this analysis.
Abstract Background Advanced radiotherapy techniques reduce normal tissue dose by conforming closely to target volumes. In cervical cancer radiotherapy, organ filling affects clinical target volume ...(CTV; cervix, uterus) position. This study estimates the dosimetric effect of this primary CTV position variation during chemoradiation. Methods/materials Twice weekly cone-beam computed tomography (CBCT) images of ten patients undergoing cervical chemoradiation were retrospectively analysed. Primary CTV, bladder and rectum were delineated. RapidArc plans were created using 10–15 mm CTV–PTV margins and dose delivered to CTV based on each CBCT position was calculated using a novel vector approach. Dose delivered along the central uterine, mid-uterus and cervix vectors were analysed as well as dose delivered to points at uterine tip, anterior mid-uterus and anterior cervix. Additional RapidArc plans were created for large planning bladder volume cases using the CTV acquired with bladder volume at 150–300 cc. Results 105 scans for 10 patients were analysed. Vector analysis revealed CTV underdosing in certain cases. Below 95% average vector coverage was found for all three vectors in 2 cases and one vector in 1 case. Volumetric analysis revealed D99 < 95% in 48% of fractions. Patients with large planning bladder volumes (>300 cc) demonstrated the largest variation. Replanning improved this coverage. The anterior mid-uterus point was least well-covered; median 98.7% dose, reducing to 91.4% in cases with large planning bladder volumes. Again, replanning significantly improved this. D99 > 95% was maintained in 93% of fractions when bladder volume was 50 cc below to 150 cc above planning volume compared to 24% of fractions if bladder volume was outside this range. Similarly, D95 > 95% was 100% versus 84%. Conclusion Organ position variation detrimentally affected dose delivered to CTV including cervix. Large planning bladder volumes (>300 cc) led to more variation. We recommend bladder volumes of 150–300 cc at planning and a range of 50 cc below to 150 cc above planning for treatment.
The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR ...inhibitors show clinical activity in endometrial cancer.
An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review.
One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021).
Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
The dorsal striatum is composed of the caudate nucleus and the putamen in human and non-human primates. These two regions receive different cortical projections and are functionally distinct. The ...caudate is involved in the control of goal-directed behaviors, while the putamen is implicated in habit learning and formation. Previous reports indicate that ethanol differentially influences neurotransmission in these two regions. Because neurotransmitters primarily signal through G protein-coupled receptors (GPCRs) to modulate neuronal activity, the present study aimed to determine whether ethanol had a region-dependent impact on the expression of proteins that are involved in the trafficking and function of GPCRs, including G protein subunits and their effectors, protein kinases, and elements of the cytoskeleton. Western blotting was performed to examine protein levels in the caudate and the putamen of male cynomolgus macaques that self-administered ethanol for 1 year under free access conditions, along with control animals that self-administered an isocaloric sweetened solution under identical operant conditions. Among the 18 proteins studied, we found that the levels of one protein (PKCβ) were increased, and 13 proteins (Gαi1/3, Gαi2, Gαo, Gβ1γ, PKCα, PKCε, CaMKII, GSK3β, β-actin, cofilin, α-tubulin, and tubulin polymerization promoting protein) were reduced in the caudate of alcohol-drinking macaques. However, ethanol did not alter the expression of any proteins examined in the putamen. These observations underscore the unique vulnerability of the caudate nucleus to changes in protein expression induced by chronic ethanol exposure. Whether these alterations are associated with ethanol-induced dysregulation of GPCR function and neurotransmission warrants future investigation.
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