tbuckley/cabot-search huggingface dataset:
HIF inhibition in metastatic renal cell carcinoma (mRCC): Final results of a phase Ib /IIa clinical trial evaluating the nanoparticle drug conjugate (NDC), CRLX101, in combination with bevacizumab (bev).
Authors: Stephen Michael Keefe, Jean H. Hoffman-Censits, Ronac Mamtani, Mary Walicki, Janelle Robinson, Abigail Smith, Orvar Gunnarsson, Anthony Piscitelli, Meliessa Hennessey, Lata Jayaraman, Andrew B. Nixon, Scott Eliasof, Roger B. Cohen, David J. Vaughn, Edward Graeme Garmey, Naomi B. Haas
Journal: Journal of Clinical Oncology (2015)

4543 Background: VHL inactivation occurs in most clear cell RCCs and results in expression of the HIF hypoxia response program and tumor angiogenesis. Antiangiogenic therapies are central to therapy for mRCC, but resistance develops in all patients (pts). We hypothesized that a dual inhibition strategy focused on HIF would be active in the refractory setting. CRLX101 (Cerulean Pharma, Inc., Cambridge, MA, USA), an NDC with a camptothecin payload, has been shown in preclinical models to durably inhibit both HIF1a and HIF2a. Synergy has been observed in the pre-clinical setting between this NDC and antiangiogenic agents including bev. Methods: Pts with refractory mRCC were treated every 2 weeks with bev (10 mg/kg) and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a 3+3 phase I design. A phase IIa expansion cohort of 10 pts was treated at the RP2D. Pts were treated until progressive disease (PD) or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v 4.0 and clinical outcome using RECIST v1.1. Correlative assays, designed to translate clinical results in terms of HIF expression and inhibition, were performed in parallel with the clinical investigation on baseline tumor material and on pre- and post-treatment bone marrow and plasma. Results: 22 response-evaluable pts were enrolled on study at two AMCs (12 clear cell, 5 papillary, 3 unclassified, 2 chromophobe). Pts had a median of 2 prior therapies, and all had at least 1 prior standard (std) therapy. No dose-limiting toxicities were observed. CRLX101 at its RP2D (15 mg/m2) combined safely with std bev. Grade 3 treatment-related AEs were observed - non-infectious cystitis (4) and hypertension (4). All other AEs were grade 1 or 2. The median PFS was 9.9 months. Overall response rate (ORR) was 23%, and 85% experienced either a PR or SD as best response. The 5 pts with a PR included 3 with clear cell and 2 with papillary RCC. The primary efficacy endpoint of this study was met. Conclusions: CRLX101 can be safely combined with std bev in mRCC. This two-drug combination demonstrated provocative PFS and ORR signals. A randomized phase II clinical trial in mRCC is enrolling pts. Clinical trial information: NCT01625936.
Prediction of indication for regulatory approval using a systems biological approach.
Authors: Peter Buhl Jensen, Steen Knudsen, Jon Askaa, Anker Hansen, Thomas Jensen
Journal: Journal of Clinical Oncology (2014)

e22055 Background: For drug development, it is of value to predict patient groups showing the highest response rates in the clinic. We have developed a biomarker for cytotoxic and targeted anticancer drugs based on a systems biological interpretation of the correlation between transcriptome and measured in vitro effects. Out of 24 retrospective clinical trials, there was a statistically significant agreement between predicted sensitivity based on a pre-treatment biopsy and measured clinical response in 20 trials. The response prediction method was recently independently evaluated by statisticians at MD Anderson Cancer Center, in all 3 clinical trials selected by the statisticians the method proved better than chance (Wang W, Baggerly KA, Knudsen S, Askaa J, Mazin W, Coombes KR Independent Validation of a Model Using Cell Line Chemosensitivity to Predict Response to Therapy. J Natl Cancer Inst; 2013;105:1284-1291). Methods: The biomarker can also be used for ranking different cancer types according to their sensitivity to a selected drug. Using a database of pre-treatment transcriptomics measurements from 3,522 cancer patients the biomarker for specific drugs can rank 28 different cancer types. This approach was tested retrospectively by developing biomarkers for 75 drugs approved for cancer treatment by the FDA. Results: Thirteen drug-biomarkers (17%) failed our in vitro quality criteria. Among the remaining 62 drug-biomarkers, the approved indication was correctly predicted for 13 drugs (21%, P=0.0005). The approved indication was among the top 5 predictions for 34 drugs (55%, P=0.002). A random prediction would on average rank at 10.9 out of 28 indications (determined by permutation). 74% of the predictions were better than random. The implementation of the biomarker was also compared to the relative response rates measured in different indications tested in phase I-II trials. Out of four drugs, there was a statistically significant positive correlation between predicted relative sensitivity and clinically determined relative sensitivity for three drugs. For the fourth drug, there was a trend. Conclusions: The biomarker can significantly better than random predict the indication that will obtain regulatory approval.
Inpatient care use among Californian patients with cancer in the year after diagnosis.
Authors: Robin L. Whitney, Janice Bell, Daniel J Tancredi, Patrick S. Romano, Richard J. Bold, Jill Joseph
Journal: Journal of Clinical Oncology (2017)

235 Background: Inpatient care use is the chief driver of regional spending variation among some cancer patients and contributes more to cancer-related healthcare spending than does any other service category– including costly chemotherapy drugs. However, few studies are available to describe population rates of and reasons for hospitalization. Methods: California Cancer Registry (CCR) data linked with administrative claims data were used to quantify and describe inpatient care use among individuals diagnosed with cancer in California between 2009-2012 (n = 412, 850). Multistate models were used to estimate age-adjusted hospitalization rates, accounting for survival. Characteristics of hospitalizations were described and tabulated, including reasons for admission, procedures, and emergency department (ED) origin. Results: Among individuals with cancer, 62% had at least one hospitalization in the year after diagnosis, nearly half of which originated in the ED (45%). Among individuals with late stage cancers, 73-77% had an admission, 42-66% of which originated in the ED. Many hospitalizations included at least one surgical procedure (54%), diagnostic procedure (24%), or chemotherapy (11%). The most frequent principal diagnoses (other than malignancy) were infection-related (11%), cardiovascular (4%) and complications of a medical device or care (4%). Estimated hospitalization rates were highest for individuals with hepatobiliary/pancreatic cancers (2.5 hospitalizations), bone/soft tissue cancers (2.1 hospitalizations), and digestive system cancers (2.0 hospitalizations), and lowest for individuals with melanoma (0.3 hospitalizations), and breast or prostate cancer (0.6 hospitalizations). Conclusions: The population burden of inpatient care use among individuals with newly diagnosed cancer is substantial. Many hospitalizations originate in the emergency room, suggesting that they are unplanned. Oncology care providers’ efforts to reduce acute care use might target subgroups with higher rates, including hepatobiliary/pancreatic, bone/soft tissue, digestive, and late-stage cancers. Further research is warranted that examines the extent to which such visits are avoidable.
Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes.
Authors: Rodrigo Dienstmann, Justin Guinney, Mauro Delorenzi, Aurelien De Reynies, Paul Roepman, Anguraj Sadanandam, Louis Vermeulen, Andreas Schlicker, Edoardo Missiaglia, Charlotte Soneson, Laetitia Marisa, Krisztian Homicsko, Xin Wang, Iris Simon, Pierre Laurent-Puig, Lodewyk F. A. Wessels, Jan Paul Medema, Scott Kopetz, Stephen Henry Friend, Sabine Tejpar
Journal: Journal of Clinical Oncology (2014)

3511 Background: Recently, a number of independent groups reported novel molecular subtypes in colorectal cancer (CRC). A formal comparison across these classifiers is needed to reconcile findings and accelerate clinical translation. The CRCSC was formed to identify a consensus among the subtyping systems through large scale data sharing and meta-analysis. Methods: The CRCSC consists of 6 groups (15+ institutions) that analyzed more than 30 patient cohorts with gene expression data, spanning multiple platforms and sample preparation methods. Each of the 6 classifiers (with 3-6 subtypes) was applied to the collection of public and proprietary datasets encompassing over 4,000 samples, mostly stage II-III CRC. Concordance of subtype calls and associations with clinical, molecular and pathway features were assessed centrally by an independent team. Results: Despite heterogeneities in cohorts and methods, subtype concordance analysis readily yielded a clear consensus on 4 CRC molecular subtypes (CMS1-4), with significant interconnectivity among the calls from the participating groups. The remaining 16% of samples did not have a consensus assignment, which may be partly explained by an additional mixed subtype with variable epithelial-mesenchymal activation; further refinement is needed. Conclusions: This is the first example of a large-scale, community based comparison of cancer subtypes. Within the largest collection of CRC samples we identified recurrent signals of 4 biologically distinct subtype classes enriched for key clinical, pathway and molecular traits. Ongoing efforts are attempting to improve the granularity of these subtypes. CMS1 14% MSI, immune pathway activation/expression, right-side tumors, older age at diagnosis, females, hypermutation, BRAF mut, intermediate survival CMS2 41% High CIN, MSS, strong WNT/MYC pathway activation, left-side tumors, TP53 mut, EGFR amplification/overexpression, better survival CMS3 8% Low CIN, moderate WNT/MYC pathway activation, KRAS mut, PIK3CA mut, IGFBP2 overexpression, intermediate survival CMS4 20% CIN/MSI heterogeneous, mesenchymal/TGF-beta activation, younger age at diagnosis, NOTCH3/VEGFR2 overexpression, worse survival
Ancestry and prostate cancer genetic risk loci in Hispanic Puerto Rican men: Comparative study with African American men.
Authors: Margarita Irizarry-Ramirez, Rick Kittles, Xuemei Wang, Graciela M. Nogueras-Gonzalez, Jeannete Salgado-Montilla, Pamela Roberson, Patricia Troncoso, Keila Rivera-Ramon, Ricardo Sanchez-Ortiz, Lourdes Guerrios, Marievelisse Soto-Salgado, Erick Suarez, Curtis Alvin Pettaway
Journal: Journal of Clinical Oncology (2015)

e16033 Background: The mortality from prostate cancer (PCA) is high in Hispanic Puerto Rican males (HPRM) living on the island of Puerto Rico (PR) and in African American (AA) menliving in the continental US. The PR population is a racially admixed population with significant West African Ancestry(WAA). We hypothesized that WAA was associated with PCA in the HPRM population. Methods: A case/control study was performed recruiting subjects from PR (HPRM) and Texas (AA). Controls (N = 342) were healthy men (209 AA and 133 PR) with no cancer history and PSA < 2.5 ng/ml and a negative Digital Rectal Examination (DRE). Cases (N = 491) were radical prostatectomy specimens (RPS) from 291HPRM and 200AA. DNA was extracted from whole blood of controls and from paraffin embedded normal seminal vesicle from the RPS. We assessed the association of PCA and aggressiveness with genetic ancestryusing an Ancestry Informative Marker panel (AIMs) and with 15 previously associated single nucleotide polymorphisms (SNPs). Ancestry was determined using the STRUCTURE software. The difference in SNPs frequency between various groups was assessed using Pearsons’ Chi square test. The ancestry data were compared between groups using Wilcoxon rank-sum test. Gleason Score (GS) and pathologic stage (pT) were used to define low risk (GS ≤ 7[3+4]),pT ≤ pT2) and high risk (GS ≥ 7[4+3],pT > pT2) PCA. All statistical analyses were done using SAS and STATA. Results: There were significant differences in WAA between AA and the HPR men (p < 0.0001). No difference in ancestry was found between HPRM cases and controls. Among HPRM cases WAA was not associated with disease severity based upon risk group, GS or pT. Among AA controls WAA was significantly higher than in cases. No correlation was found among AA cases with WAA and risk group,pT, or GS. However SNP rs7824364 (chromosome 8q24 region) was significantly associated with PCA in both AA (p < 0.0001) and HPRM (p = 0.0001). Conclusions: We found no association between increasing WAA and prostate cancer presence or aggressiveness among HPRM or AA men. Additional genetic loci studied in tandem with clinical epidemiologic and biologic data to characterize PCA in these two high risk cohorts are in progress.
Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group
Authors: J.J.M. Kwakman, L.H.J. Simkens, J.M. van Rooijen, A.J. van de Wouw, A.J. ten Tije, G.J.M. Creemers, M.P. Hendriks, M. Los, R.J. van Alphen, M.B. Polée, E.W. Muller, A.M.T. van der Velden, T. van Voorthuizen, M. Koopman, L. Mol, E. van Werkhoven, C.J.A. Punt
Journal: Annals of Oncology (2017)

Hand-foot syndrome (HFS) is a common side-effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients.Patients with previously untreated mCRC and planned treatment with fluoropyrimidine monochemotherapy were randomized 1 : 1 to receive either capecitabine (1250 mg/m2 orally for patients <70 years; 1000 mg/m2 for patients ≥70 years, twice daily on days 1-14) or S-1 (30 mg/m2 orally twice daily on days 1-14) in 3-weekly cycles, with bevacizumab optional in both groups. The primary endpoint was the incidence of any grade HFS, as assessed by both physicians and patients (diaries). Secondary endpoints included grade 3 HFS, other toxicities, relative dose intensity, progression-free survival, response rate and overall survival.A total of 161 patients were randomized in 27 centres. The incidence of any grade HFS as assessed by physicians was 73% in the capecitabine group (n = 80) and 45% in the S-1 group (n = 80) [odds ratio (95% confidence interval) 0.31 (0.16-0.60), P = 0.0005]. The incidence of grade 3 HFS was 21% and 4% (P = 0.003), respectively. Patient-assessed any grade HFS was 84% and 58%, respectively (P = 0.004). Grade 3 anorexia was more common in the S-1 group (3% versus 13%, P = 0.03). Median relative dose intensity was 88% in the capecitabine group and 95% in the S-1 group (P = 0.026). There were no statistically significant differences in median progression-free survival, response rate and overall survival rates.Treatment with S-1 in Western mCRC patients is associated with a significantly lower incidence of HFS compared with capecitabine, with comparable efficacy.NCT01918852.
Phase II study of CVP followed by tositumomab and iodine I 131 tositumomab (Bexxar therapeutic regimen) in patients with untreated follicular non-Hodgkin's lymphoma (NHL)
Authors: B. Link, M. S. Kaminiski, M. Coleman, J. P. Leonard
Journal: Journal of Clinical Oncology (2004)

6520 Background: A phase II, open-label, multicenter study was conducted to determine the efficacy of Bexxar therapy following CVP in pts with previously untreated follicular NHL. Methods: Pts received cyclophosphamide (400 mg/m2, days 1–5), vincristine (1.4 mg/m2, day 1), and prednisone (100 mg/m2, days 1–5) followed by Bexxar therapy (65 or 75 cGy total body dose). Treatment with CVP was repeated every 21 days for 6 cycles followed by Bexxar therapy within 56 days. The primary endpoint was overall response (CR, CRu, PR). Secondary endpoints were CR, duration of response, progression-free survival (PFS), and safety. Pts with untreated, stage III/IV or bulky stage II, follicular NHL were enrolled from Feb 2000 to Jan 2001. Inclusion/exclusion criteria were similar to previous Bexxar therapy studies. Results: All enrolled pts (n = 30) completed all therapy and were included in the analysis. Median age was 52 yrs (range, 34–72 yrs). Histology: 77% follicular grade 1, 17% follicular grade 2, 7% follicular unclassified. The majority (97%) of pts had stage 3/4 disease and 50% had a maximum tumor diameter ≥ 5.0 cm. Following CVP 100% pts had a response (50% CR; 50% PR). Following Bexxar therapy, 9 of 15 pts converted from PR to CR. With a median follow-up of 2.3 yrs from start of therapy, median PFS has not been reached, and 23 (77%) pts continue in response for 0.6 to 3.4 yrs. Following Bexxar therapy, grade 4 neutropenia and thrombocytopenia occurred in 33% and 23% pts, respectively; there were no serious infections; 1 patient has developed AML; and there were no reported cases of conversion to HAMA positivity. Conclusions: Treatment of pts with newly diagnosed follicular NHL with CVP followed by the Bexxar therapeutic regimen produced an overall response rate of 100% and a CR rate of 80%. Among pts who achieved less than a CR with CVP, 60% achieved a CR after Bexxar therapy. With a median follow-up of 2.3 yrs, 77% of pts continue in response. This study suggests that CVP/Bexxar is a promising therapeutic regimen for patients with previously untreated, advanced-stage, follicular NHL. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Corixa; GlaxoSmithKline
Quality of life and burden of oncologic patients’ main caregiver throughout different treatment stages.
Authors: Isalia Margarida Campos Miguel, Joäo Geraldes Freire
Journal: Journal of Clinical Oncology (2014)

e20533 Background: In current clinical practice the main focus of attention is on the patient (pt), the caregiver remains in the background. However, caregivers face emotional and physical challenges that evolve as the disease progresses. The aim of this study was to evaluate the quality of life (QoL) and burden of cancer pts’ caregivers throughout different stages of treatment. Methods: We conducted an exploratory study with a sample of 90 caregivers. The pts were in curative treatment, palliative chemotherapy or symptomatic treatment. Zarit Burden Interview and Caregiver Quality of Life Index – Cancer (CQOLC) Scale were applied. Scores are expressed as means and comparisons were made using ANOVA and Bonferroni correction. Results: The caregiver’s most common profile included female sex (76.7%), 45 years median age, usually the spouse (40%) or daughter (31.1%). Throughout the disease progression there was an increase in burden (mean score: 21.1 – 26.4 – 28.6, respectively in each phase) as well as decreased QoL (mean score: 67.4 – 67.9 – 58.6). Burden was moderate in 59.5% and moderate-severe in 8.9%, influenced by feelings of dependency and loss of control of pts’ life. QoL differences between groups were mostly influenced by emotional overload scores (ANOVA p=0.029). Female caregivers played an increasingly important role throughout the disease progression (66.7 – 76.7 – 86.7%) and showed further deterioration of well-being (increased burden, ANOVA p=0.008; decreased QoL, ANOVA p=0.040). Non-cohabitants and non-spouse caregivers also showed an increased burden (ANOVA p=0.050 & p=0.035, respectively), while burden remained stable in spouse and cohabitants. Conclusions: The stage of cancer pt‘s treatment, as determined by disease progression influences his/her main caregivers QoL and burden. Regular assessment of caregivers is needed, to allow for early emotional and physical support, and should be included in treatment plans. Portuguese society still relies mostly on women for caring for pts, but they show a progressive reduction of their well-being. On the other hand, close relatives (spouse and cohabitants) showed a stable burden, probably due to a longer adaptation process during disease progression.
Improving end-of-life care: Palliative care embedded in an outpatient oncology clinic.
Authors: David Johnson Einstein, Susan DeSanto-Madeya, Matt Gregas, Jessica A. Lynch, David F. McDermott, Mary K. Buss
Journal: Journal of Clinical Oncology (2017)

77 Background: Patients with advanced cancer benefit from early involvement of palliative care. Nonetheless, the ideal method of palliative care integration remains to be determined. Prior studies proposed automatic referral criteria and embedding palliative care teams within specialty clinics. Methods: We studied the impact of an embedded palliative care team that saw patients in an academic oncology clinic based on automatic referral criteria. Patients seen in this clinic on a specific day had access to the “embedded” model, whereas patients seen on two other days could access a separate palliative care clinic upon oncologist referral (usual care). We abstracted data from the medical records of 118 patients who were cared for in this oncology clinic and died during the 3 years following implementation of the embedded model. Results: Compared with those with access to usual care (n = 88), patients with access to the embedded model (n = 30) encountered palliative care as outpatients more often (p &lt; 0.001) and twice as long before death (mean 223 versus 106 days, p = 0.001). Hospice enrollment rates were similar (p = 0.717) but duration was twice as long (mean 53.5 versus 25.3 days, p = 0.03), and enrollment greater than 7 days before death—a core Quality Oncology Practice Initiative metric—was significantly higher in the embedded model (OR 5.60, p = 0.034). Place of death (p = 0.505) and end-of-life chemotherapy (OR 0.361, p = 0.204) did not differ significantly. Conclusions: A model of embedded palliative care with automatic referral criteria, compared with usual practice, was associated with significant improvements in utilization and timing of palliative care and hospice.