tbuckley/cabot-search huggingface dataset:
Safety and effectiveness of bevacizumab plus chemotherapy in patients with advanced cervical cancer in real world practice in Argentina.
Authors: Juan Jose Zarba, Diego Kaen, Bruno Alberto Bustos, Sandra Anabel Ostoich, Miriam Gabriela Raimondo, Martin Guillermo Roa, Marcelo Jesus, Clelia Maria Vico, María Soledad Bover, Pablo Capellino, Ana Carolina Ituarte, Maria Del Carmen Gramuglia, Jimena Andrea Tejada, Maria V. Caceres
Journal: Journal of Clinical Oncology (2018)

e17500 Background: In Argentina, 5000 women are diagnosed every year with cervical cancer and half of them die from the disease. Cisplatin-Paclitaxel + Bevacizumab (TP-B) had improved the survival of these patients (GOG 240). We aimed to evaluate Carboplatin-Paclitaxel + Bevacizumab (TC-B) that is the standard of care in our country. Methods: This retrospective cohort included 84 patients with metastatic, recurrent or persistent CC treated with TC-B (86%) or TP-B (14%) during 2015 in Argentina (Avastin was used in all patients). Main objective: evaluate the effectiveness and safety (incidence of grade 3 or more treatment related adverse events) in the total population and in both treatment subgroups (TC-B and TP-B). Results: Patients had predominant recurrent (48%) or persistent (36%) disease over metastatic (17%), with high proportion of pelvic involvement (69%) and prior platinum radiosensitizer (82%). According Moore Criteria, patients were categorized as Low (12%), Mid (58%) and High Risk (30%). Median follow up was 14 months (1,4 – 32,3). ORR, mPFS and mOS were, considering Moore criteria: Low: 70%; 15,4; NR, Mid: 59%; 10,2; 25,4 and High Risk: 20,5; 4,8; 19, 2 months. High risk Moore score was associated with an increased hazard rate of progression or death of 2.16 (95% CI: 1.22-3.81; p = 0,007). Most frequent grade 3 or more adverse events were fistulas 15% (CI 9-25%); Thromboembolic events 7% (CI: 3-15%); Bleeding 5% (95% CI: 2-12%) and isolated gastrointestinal perforations 4% (CI: 0.9-11%). Time from diagnosis to first recurrence of one year or less was more frequent in patients with fistula and/or gastrointestinal perforations (76% versus 55%, p: 0,11). There was a borderline statistical trend (p: 0,066) towards higher pelvic involvement in patients with persistent disease (83%) compared with stage IVB (71%) or recurrent disease (58%). Conclusions: In this real world patients’ cohort, the combination of TC-B has shown to be safe and effective. Moore criteria have shown real world clinical applicability and High Risk score was an independent predictor of increased hazard rate of progression or death.
P01.009 Micro-infiltration before growth: the inverse paradigm of primary glioblastoma is crucial to overcome resistance and develop effective therapies
Authors: E Brognaro
Journal: Neuro-Oncology (2018)

Primary glioblastoma (IDH-wildtype within the 2016 WHO classification) behaves differently from all other solid tumors. Indeed, many clues (radiological, clinical, surgical) and recent indirect experimental evidence converge to indicate that primary glioblastoma has already micro-infiltrated the entire brain parenchyma before starting its growth. Thus, only in IDH-wildtype glioblastoma the malignant (i.e. distantly infiltrating the organ of origin) and deadly (leading cause to patient’s death) phases coincide and overlap in one single phase. Glioblastoma research studies must absolutely take into consideration both the tumor bulk and the micro-infiltrated brain parenchyma and can be performed (with full respect for ethical issues) analyzing neoplastic and “healthy” material obtained from living patients (a), using animal models (b), studying post-mortem samples from rapid autopsies (c), comparing local and distant recurrences with the primary bulk (d). The study and analysis of the bulk tumor must be carried out by collecting multiple multiregional spatially separated samples throughout the whole tumor mass. The analysis of the micro-infiltrated brain parenchyma in living patients is undoubtedly the most difficult task. However, it can be performed appropriately, after correct sampling procedures, also from the surgical patient tissue. In the bulk, the collection and analysis of multiple separated samples can allow us to infer and reconstruct the phylogenetic tree of the tumor. At the same time, driver and passenger events must be identified as well as the CSCs of samples. The methods to sample the micro-infiltrated brain parenchyma can enable us to identify the founder CSCs which lie quiescent in the perivascular parenchymal niches across the whole brain (their activation being the cause of the distant recurrences). Two causes of resistance are currently invalidating all therapeutic strategies. The first is the process of bottleneck selection in the tumor mass or in its post-surgical residues of those subclones with particular characteristics to survive therapy which will emerge, expand and give rise to a new bulk. The second is the silent presence in the whole brain (even before the bulk growth) of founder CSCs which reside dormant (in G0 state) in perivascular parenchymal niches protected by their properties, the niche-milieu and the blood-brain barrier. Therefore, novel therapies must identify and selectively target either CSCs unique properties (not shared by normal stem cells) related to their impaired asymmetrical division or stable driver lesions of the founder CSC, without alternative mutations and pathways, or the exclusive marker(s) used by the founder CSCs to settle quiescent (involving mechanisms of adhesion, anchorage and cell cycle arrest) in the perivascular parenchymal niches.
Costs and values of nivolumab in second-line cancer.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2017)

e20629 Background: Nivolumab (Nivo) has been approved in 2nd-line treatment of melanoma, squamous (sq) and non-sq- non-small cell-lung (NSCLC), renal cell, and sq-cell of head and neck (SCCHC). Our objective was to screen and compare values (V) of Nivo in cancer. Methods: Nivo median overall survival gain over control (OS), hazard ratios (HR), doses and frequency were extracted from previously published clinical trials. Data and prices posted by the parent company were utilized. Probability of survival (PoS) was calculated as (1.0- HR). Costs (C) were computed at 4 week (w), V as 4wC/PoS (4wV) and year-C/life-year gain (C/LYG). Relative values (RV) were expressed as $100,000/C/LYG. Adverse events C were not accounted for. Results: Estimated Nivo 4wC in early 2016 was $10,021. Conclusions:HR- based platform was proposed to screen and compare V of Nivo. At 0.42 HR in melanoma and &gt;150 day-OS in renal cell, the results suggested that Nivo was fairly-priced for its V. In non-enriched non-sq-NSCLC and SCCHN, the PD-L1 enrichment was necessary to enhance V significantly and justify C. [Table: see text]
Use of 18F-FDG PET/CT to select candidates for active surveillance: Results of the SEMITEP trial of PET-directed strategy for stage 1 seminoma.
Authors: Yohann Loriot, Serena Grimaldi, Aude Flechon, Hakim Mahammedi, Emmanuelle Bompas, Christine Chevreau, Marine Gross Goupil, Gwenaelle Gravis, Stephane Culine, Thierry Nguyen, Sylvain Ladoire, Philippe Barthelemy, Carole Helissey, Brigitte Laguerre, Emmanuelle SEVIN, Jerome Rigaud, Sophie Abadie Lacourtoisie, Lionnel Geoffrois, Lionel Texier, Karim Fizazi
Journal: Journal of Clinical Oncology (2018)

4548 Background: Stage I seminoma patients (pts) run a relapse risk of 15-20% without further adjuvant treatment. Pts are usually offered active surveillance or an adjuvant treatment with a risk of overtreatment of about 80%. There is no robust prognostic factor associated with the risk of relapse. 18F-FDG PET/CT (PET) demonstrates high diagnostic accuracy for restaging pts with metastatic seminoma. Our hypothesis was that PET scanning accurately detects micrometastasis and may help better select patient for therapy. Methods: In the SEMITEP trial (NCT01887340), pts with newly diagnosed stage 1 seminoma underwent PET scanning before any decision for adjuvant treatment. PET scans were assessed by a local nuclear physician but were centrally retrospectively reviewed. A PET was interpreted as positive if any non-physiological 18F-FDG uptake was observed. Pts with negative PET findings were assigned to a surveillance protocol with no further adjuvant treatment and alleged surveillance work-up; pts with positive PET findings were recommended to receive immediate therapy (preferentially 2 cycles of carboplatin at a dose of AUC = 7). The first endpoint was the proportion of pts in whom an adjuvant therapy could be omitted. The secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 169 pts were recruited, and 166 patients underwent PET. The PET findings were negative in 160 of these pts (96%), 150 (94%, 95% confidence interval [CI], 90 -98) of whom were assigned to surveillance. PET was positive in 6 pts, 5 of whom were treated with immediate treatment. At a median follow-up of 2.5 years 22/150 (15%) pts with PET-negative experienced a relapse. No relapse occurred among the 15 pts treated with immediate treatment. There was one chemotherapy-related death. The 2-year PFS and OS rates were 88 % (95% CI, 81.7-92.1) and 99.4 % (95% CI, 96.6-99.9), respectively. Conclusions: Post-orchidectomy treatment can be avoided in a majority of pts with stage 1 seminoma. PET may help identifying about one fifth (6/28) pts with disseminated seminoma that are not detected by CT-scan. Surveillance remains necessary in men with negative PET. Clinical trial information: NCT01887340.
Results of a randomized, placebo (PBO) controlled, double-blind P2b trial of GC4419 (avisopasem manganese) to reduce duration, incidence and severity and delay onset of severe radiation-related oral mucositis (SOM) in patients (pts) with locally advanced squamous cell cancer of the oral cavity (OC) or oropharynx (OP).
Authors: Carryn M. Anderson, Christopher M Lee, Deborah Saunders, Amarinthia Curtis, Neal Dunlap, Chaitali Singh Nangia, Arielle Shebay Lee, Jon Holmlund, Jeffrey Mark Brill, Stephen T. Sonis, John Michael Buatti
Journal: Journal of Clinical Oncology (2018)

6006 Background: Intensity-modulated radiotherapy (IMRT) plus cisplatin is established treatment for locally advanced OC/OP cancer, but appx. 70% of patients develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring artificial nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by potently converting superoxide to H2O2. It showed promising reductions of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). Methods: 223 pts with OC or OP cancer receiving 70 Gy IMRT (≥50 Gy to > 2 oral sites) plus cisplatin (qwk or q3wk), were randomized 1:1:1 to PBO, 30 or 90 mg of GC4419, by 60-minute IV infusion, M-F before each RT fraction. OM by the WHO scale was assessed by trained evaluators biw during RT & qwk for up to 8 wks post RT. Primary endpoint was duration of SOM. Secondary endpoints included incidence & time to onset of SOM. Analyses (each active dose v PBO, ITT) proceeded by a sequential, conditional approach; 2-sided α = 0.05. Results: 90 mg GC4419 reduced SOM across endpoints, including a statistically significant reduction in the primary endpoint of duration. Efficacy results with 30 mg were intermediate and did not reach significance. Baseline patient & tumor characteristics, & treatment delivery, were well-balanced. Safety was comparable across arms with no significant GC4419-specific toxicity or increased toxicity of IMRT/cisplatin. Conclusions: GC4419 provides a clinically meaningful reduction of SOM in terms of duration, incidence and severity (Grade 4), with a safety profile comparable to placebo. Clinical trial information: NCT02508389. PBO 30mg 90mg 90mg vs. PBO N 74 73 76 Relative δ p = Duration SOM, median days 19 8 1.5 92% 0.024 Incidence SOM thru 60 Gy 58% 40% 37% 36% 0.010* Incidence SOM thru last RT 65% 60% 43% 34% 0.009* Incidence Grade 4 OM 30% 21% 16% 47% 0.045* Onset SOM, median days 39 47 61 56% 0.080* *nominal p value, pre-specified secondary endpoint
Is CA19-9 response following induction and consolidation therapy in locally advanced pancreatic cancer (LAPC) an early surrogate marker for eventual survival outcomes?
Authors: Awalpreet Singh Chadha, Mediha Ahmad, Prajnan Das, Bruce D. Minsky, Jason B. Fleming, Gauri R. Varadhachary, Sushovan Guha, Christopher H. Crane, Sunil Krishnan
Journal: Journal of Clinical Oncology (2015)

e15230 Background: Early surrogate markers of progression-free survival (PFS) and overall survival (OS) in LAPC patients who receive consolidative chemoradiation therapy (CRT) following induction chemotherapy (CTX) have been poorly studied. The current study was conducted to determine whether Carbohydrate Antigen 19-9 (CA19-9) is an independent prognostic biomarker in LAPC. Methods: LAPC patients treated with CTX followed by CRT at our center from 2007 to 2013 were identified. CA19-9 levels were recorded at baseline, prior to CRT and 1-3 months after CRT. Patients with pre-CRT Ca19-9 levels that were unrecorded, ≤ 50 U/mL or associated with a bilirubin > 2 were excluded from the analysis. 101 patients met the inclusion criteria. Ninety four (93%) underwent induction CTX before consolidative CRT. Median radiation dose was 50.4 Gy, induction CTX was gemcitabine-based (79%), and FOLFIRINOX (21%). Concurrent chemotherapy during CRT was 5-fluorouracil (2%), gemcitabine-based (12%) and capecitabine-based (86%). Univariate and multivariate statistical methods were used to determine significance of the post-treatment changes in CA19-9 on PFS and OS outcomes calculated from start of treatment. Results: Median CA19-9 at baseline was 363 U/mL. After CTX, this dropped to 178 U/mL (p < 0.0001) and further decreased to 108 U/mL post CRT (p < 0.0001, compared to baseline; p = 0.004, compared to pre-CRT). The estimated median OS and PFS were 20.1 months and 11.2 months, respectively. On univariate analysis, patients with post-CRT CA19-9 levels ≤ 90U/mL had an improved OS (25 vs 16.4 months; p < 0.0001) and PFS (13.6 vs 10.3 months; p = 0.001). A reduction in CA19-9 level of ≥ 50% from baseline to post-CRT was associated with improved OS (21.7 vs 16.8 months; p = 0.003) and PFS (12.4 vs 10.3 months; p = 0.02). On multivariate analysis, only post-CRT CA19-9 level ≤ 90 U/mL was associated with improved OS (HR = 0.19; p < 0.0001) and PFS (HR = 0.55; p = 0.049). Conclusions: Post- treatment CA19-9 independently predicts and serves as an early surrogate for OS and PFS in patients with LAPC, offering the potential to tailor subsequent therapy.
Phylogenetic characteristics as a potential prognostic factor in serous ovarian cancer.
Authors: Qin Zhang, Li Jin, Su Yao, Lianpeng Chang, Yanfang Guan, Qi Liu
Journal: Journal of Clinical Oncology (2018)

e17523 Background: Patients with serous ovarian cancer (SOC) have suffered from frequent recurrence after the standard platinum-based combination chemotherapy. Evolutionary models of cancer have been recently approved to be associated with chemotherapy response and prognosis. However, relatively little is known of the genomic heterogeneity and evolution in SOC patients. Methods: A total of 25 pts with SOC were enrolled, including 10 pts defined as platinum-sensitive (5 pts) or platinum-resistant recurrent group (5 pts), and 15 pts with significantly different OS (8 pts, more than 5 years; 7pts, less than 2 years). Primary tissue, relapsed tissue and matched paracancerous samples were collected. Hybrid capture sequencing were performed with a pan-cancer panel of 1021 genes related to solid tumors. Somatic mutations were used to reconstruct the phylogenetic tree and analyze the genomic heterogeneity. Results: 43/47 (91.5%) specimens were successfully sequenced, with the mean effective depth of coverage of 842. The most frequently altered gene was tumor protein p53 gene (TP53) (100%). For 20 patients, paired primary and relapsed samples were sequenced successfully to explore the heterogeneity and evolution of the recurrent or metastatic landscape. By comparing with the primary cancer, the result showed metachronous relapsed samples significantly harboring less shared mutations (33.4% vs. 90.5%, p < 0.001) and more private mutations (53.7% vs. 4%, p < 0.001) than synchronous lesions. The mutation burden of relapsed samples was greater in platinum-resistant group than that in platinum-sensitive cohort (mean: 7.6 v.s. 1.8). Particularly, new copy number variation of BRAF (2/5), NF1 (2/5) and PTCH2 (2/5) mutations were detect in relapsed samples of platinum-resistance patients. Interestingly, BRCA1 germline mutation enriched in patients with better OS (mutated frequency: 57 % v.s. 14 %). Conclusions: Based on panel sequencing, tumor phylogenetic characteristics were related to therapeutic effect of Platinum chemotherapy. The genomic information may be potentially used to predict outcome of SOC.
The impact of pathologic characteristics (lymphovascular invasion/squamous differentiation) on the efficacy of adjuvant chemotherapy for patients with upper tract urothelial cancer.
Authors: Yi-Huei Chang, Guang-Heng Chen, Po-Fan Hsieh, Chi-Shun Lien, Chi-Ping Huang, Chin-Chung Yeh, Wen-Chi Cheng, Yu-Min Liao, Che hung Lin, Ching Chan Lin, Chao-Hsiang Chang, Hsi-Chin Wu, Su-Peng Yeh, chi-Rei Yang, Chang-Fang Chiu
Journal: Journal of Clinical Oncology (2016)

e16139 Background: The benefit of adjuvant chemotherapy (AC) for upper tract urothelial cancer (UTUC) is controversial. Pathologic characteristics such as lymphovascular invasion (LVI) and squamous differentiation (SD) are prognostic and may help decision-making in selecting patients who need adjuvant chemotherapy. We evaluated the impact of pathologic characteristics on the efficacy of adjuvant chemotherapy in UTUC Methods: We retrospectively reviewed records on 200 consecutive patients with UTUC (pathologic stage II, III, and non-metastasis IV) treated with radical nephroureterectomy between January 2004 and September 2014 and obtained free surgical margins. Adjuvant chemotherapy of gemcitabine and cisplatin was given. Overall survival (OS), recurrence-free survival, local-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. The values of prognostic factors were evaluated by Cox regression analysis. Results: The median follow up is 19.5 months. LVI was found in 74 (37.0%) patients and SD in 57 patients (28.5%). AC was administered in 60 (30%) patients. Multivariate analysis showed LVI, SD and AC were independent prognostic factors in terms of OS and DMFS but not in LRFS. For patients with LVI, AC improved OS and DMFS, but the benefit of AC was not observed in patients without LVI. In contrast, there was no improvement of OS and DMFS in patients with squamous differentiation when AC was administered, but AC significantly improved OS and DMFS in patients without squamous differentiation. Conclusions: Lymphovascular invasion and squamous differentiation had differential impact on the efficacy of adjuvant chemotherapy in UTUC. The design of chemotherapy for UTUC should consider pathologic characteristics. OS (%) P DMFS (%) P With LVI (with vs without AC) 83.3 vs 21 < 0.001 85.1 vs 32.4 < 0.001 Without LVI (with vs without AC) 65.2 vs 63.2 0.832 77.8 vs 82.4 0.692 With SD (with vs without AC) 44.9 vs 39.3 0.268 67.6 vs 49.3 0.250 Without SD (with vs without AC) 85.9 vs 55.7 0.005 86.7 vs 72.6 0.039
Association of anticonvulsant prophylaxis in patients with primary and metastatic brain tumors and 1-year overall survival: A systematic review and meta-analysis.
Authors: Timothy J Brown, Christina Marie Zoccoli, Ayesha Ali, Lyndon J. Kim, Michael J. Glantz
Journal: Journal of Clinical Oncology (2018)

2043 Background: Despite high-quality evidence suggesting anticonvulsant prophylaxis in primary and metastatic brain tumors does not improve seizure outcomes, debate persists on the use of anticonvulsants in these patients. Valproic acid use has attracted particular interest due to its histone deacetylase and CYP2C9 inhibitory action. We sought to determine if the body of the world’s literature supports the use of anticonvulsant prophylaxis to improve survival in patients with primary or metastatic brain tumors. Methods: A systematic review of PubMed and EMBase was performed with MeSH headings to identify all studies of anticonvulsant prophylaxis in adult patients with primary or metastatic brain tumors. Data was extracted from the text of included studies or from survival curves. Statistics were performed using Cochrane ReviewManager software. Endpoints of interest were one-year overall survival. Results: Two-hundred seventy-six studies were reviewed. Eleven studies of 3767 patients with primary and metastatic brain tumors were included in the analysis of survival with any anticonvulsant, while ten studies of 3576 patients provided survival data with valproic acid. Compared to control, any anticonvulsant prophylaxis was associated with a relative risk (RR) of death of 0.88 [95% confidence interval 0.81-0.94, p = 0.0006]. Valproic acid compared to control was associated with RR of death at one year of 0.86 [95% CI 0.78-0.95, p = 0.003]. Eight studies of 3194 patients with glioblastoma associated a RR of death at one year of 0.86 [95%CI 0.75-0.99, p = 0.04] with any valproic acid prophylaxis compared to none. Two studies of 344 patients examined the effects of non-valproic acid anticonvulsant prophylaxis demonstrated no significant effect on the RR of death at one year, 0.90 [95%CI 0.79-1.03, p = 0.13], compared to control. Conclusions: In this meta-analysis of anticonvulsant prophylaxis in patients with primary and metastatic brain tumors, anticonvulsant prophylaxis was associated with a significant survival benefit at one year. This association appears to be driven primarily by valproic acid prophylaxis.