Spatially confined sub-tumor microenvironments in pancreatic cancer.

Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.

Systemic inflammatory prognostic scores in advanced pancreatic adenocarcinoma.

BACKGROUND: Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC). METHODS: Unresectable/metastatic PDAC patients enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection trial (NCT02750657) were included. Patients had pre-treatment biopsies for whole genome and RNA sequencing. CD8 immunohistochemistry was available in a subset. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, Prognostic Nutritional Index, Gustave Roussy Immune Score (GRIm-S), and Memorial Sloan Kettering Prognostic Score (MPS) were calculated. Overall survival (OS) was estimated using Kaplan-Meier methods. Associations between inflammatory scores, clinical/genomic characteristics, and OS were analysed. RESULTS: We analysed 263 patients. High-risk NLR, GRIm-S and MPS were poorly prognostic. The GRIm-S had the highest predictive ability: median OS 6.4 vs. 10 months for high risk vs. low-risk (P < 0.001); HR 2.26 (P < 0.001). ECOG ≥ 1, the basal-like subtype, and low-HRDetect were additional poor prognostic factors (P < 0.01). Inflammatory scores did not associate with RNA-based classifiers or homologous recombination repair deficiency genotypes. High-risk MPS (P = 0.04) and GRIm-S (P = 0.02) patients had lower median CD8 + tumour-infiltrating lymphocytes. CONCLUSIONS: Inflammatory scores incorporating NLR have prognostic value in advanced PDAC. Understanding immunophenotypes of poor-risk patients and using these scores in trials will advance the field.

Symptom screening with Targeted Early Palliative care (STEP) versus usual care for patients with advanced cancer: a mixed methods study.

PURPOSE: Although early palliative care is recommended, resource limitations prevent its routine implementation. We report on the preliminary findings of a mixed methods study involving a randomized controlled trial (RCT) of Symptom screening with Targeted Early Palliative care (STEP) and qualitative interviews. METHODS: Adults with advanced solid tumors and an oncologist-estimated prognosis of 6-36 months were randomized to STEP or symptom screening alone. STEP involved symptom screening at each outpatient oncology visit; moderate to severe scores triggered an email to a palliative care nurse, who offered referral to in-person outpatient palliative care. Patient-reported outcomes of quality of life (FACT-G7; primary outcome), depression (PHQ-9), symptom control (ESAS-r-CS), and satisfaction with care (FAMCARE P-16) were measured at baseline and 2, 4, and 6 months. Semi-structured interviews were conducted with a subset of participants. RESULTS: From Aug/2019 to Mar/2020 (trial halted due to COVID-19 pandemic), 69 participants were randomized to STEP (n = 33) or usual care (n = 36). At 6 months, 45% of STEP arm patients and 17% of screening alone participants had received palliative care (p = 0.009). Nonsignificant differences for all outcomes favored STEP: difference in change scores for FACT-G7 = 1.67 (95% CI: -1.43, 4.77); ESAS-r-CS = -5.51 (-14.29, 3.27); FAMCARE P-16 = 4.10 (-0.31, 8.51); PHQ-9 = -2.41 (-5.02, 0.20). Sixteen patients completed qualitative interviews, describing symptom screening as helpful to initiate communication; triggered referral as initially jarring but ultimately beneficial; and referral to palliative care as timely. CONCLUSION: Despite lack of power for this halted trial, preliminary results favored STEP and qualitative results demonstrated acceptability. Findings will inform an RCT of combined in-person and virtual STEP.

Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer.

INTRODUCTION: Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem. METHODS: Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity. RESULTS: In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P > 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks. CONCLUSION: Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma.

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

Is Biannual Surveillance for Pancreatic Cancer Sufficient in Individuals With Genetic Syndromes or Familial Pancreatic Cancer?

BACKGROUND: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance. METHODS: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months. RESULTS: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient's PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations. CONCLUSIONS: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.

Correlation of transcriptional subtypes with a validated CT radiomics score in resectable pancreatic ductal adenocarcinoma.

OBJECTIVES: Transcriptional classifiers (Bailey, Moffitt and Collison) are key prognostic factors of pancreatic ductal adenocarcinoma (PDAC). Among these classifiers, the squamous, basal-like, and quasimesenchymal subtypes overlap and have inferior survival. Currently, only an invasive biopsy can determine these subtypes, possibly resulting in treatment delay. This study aimed to investigate the association between transcriptional subtypes and an externally validated preoperative CT-based radiomic prognostic score (Rad-score). METHODS: We retrospectively evaluated 122 patients who underwent resection for PDAC. All treatment decisions were determined at multidisciplinary tumor boards. Tumor Rad-score values from preoperative CT were dichotomized into high or llow categories. The primary endpoint was the correlation between the transcriptional subtypes and the Rad-score using multivariable linear regression, adjusting for clinical and histopathological variables (i.e., tumor size). Prediction of overall survival (OS) was secondary endpoint. RESULTS: The Bailey transcriptional classifier significantly associated with the Rad-score (coefficient = 0.31, 95% confidence interval [CI]: 0.13-0.44, p = 0.001). Squamous subtype was associated with high Rad-scores while non-squamous subtype was associated with low Rad-scores (adjusted p = 0.03). Squamous subtype and high Rad-score were both prognostic for OS at multivariable analysis with hazard ratios (HR) of 2.79 (95% CI: 1.12-6.92, p = 0.03) and 4.03 (95% CI: 1.42-11.39, p = 0.01), respectively. CONCLUSIONS: In patients with resectable PDAC, an externally validated prognostic radiomic model derived from preoperative CT is associated with the Bailey transcriptional classifier. Higher Rad-scores were correlated with the squamous subtype, while lower Rad-scores were associated with the less lethal subtypes (immunogenic, ADEX, pancreatic progenitor). KEY POINTS: • The transcriptional subtypes of PDAC have been shown to have prognostic importance but they require invasive biopsy to be assessed. • The Rad-score radiomic biomarker, which is obtained non-invasively from preoperative CT, correlates with the Bailey squamous transcriptional subtype and both are negative prognostic biomarkers. • The Rad-score is a promising non-invasive imaging biomarker for personalizing neoadjuvant approaches in patients undergoing resection for PDAC, although additional validation studies are required.

Impact of Definitive Chemoradiation on Quality-of-Life Changes for Patients With Anal Cancer: Long-term Results of a Prospective Study.

BACKGROUND: Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors. OBJECTIVE: Long-term QOL after chemoradiation for patients with anal cancer was evaluated. DESIGN: This was a prospective cohort study. SETTINGS: This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013. PATIENTS: Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included. INTERVENTIONS: English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually. MAIN OUTCOMES MEASURES: Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy. RESULTS: Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL. LIMITATIONS: Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose). CONCLUSIONS: Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905. IMPACTO DE LA QUIMIORRADIACIN DEFINITIVA EN CAMBIOS EN LA CALIDAD DE VIDA DE LOS PACIENTES CON CNCER ANAL RESULTADOS A LARGO PLAZO DE UN ESTUDIO PROSPECTIVE: ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon).

Phase II clinical trial of cabozantinib for the treatment of recurrent hepatocellular carcinoma after liver transplantation.

Recurrent hepatocellular carcinoma (HCC) develops in 15-20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatments and no prior treatment with cabozantinib. In this study, 60 mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8 weeks to evaluate response. The primary end point of this study will be the disease control rate at 4 months after treatment. The secondary end points will be overall survival, progression-free survival and safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3 years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.

Liver cancer is the sixth most diagnosed cancer worldwide with few available curative treatments. Liver transplantation (LT) is considered as one of the treatments for liver cancer especially in earlier stages of cancer. However, after LT, cancer develops again in 15­20% of the patients who undergo transplant for liver cancer. Compared with liver cancer in the nontransplant population, recurrent cancer grows faster and spreads in the body very quickly. Therefore, unfortunately, to date there are limited treatment options for these patients without significant effect on their survival. In this study, we aim to evaluate the effect of a new medication called cabozantinib on patients who develop recurrent liver cancer after their LT. Cabozantinib has been already tested in patients with liver cancer and was shown to be effective and safe in nontransplant patients. However, this is the first study to evaluate the effect of cabozantinib in liver transplant recipients with recurrent liver cancer. Clinical Trial Registration: NCT04204850 (ClinicalTrials.gov).

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma.

OBJECTIVE: To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP). DESIGN: We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)). RESULTS: 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity. CONCLUSIONS: MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

Chemoradiotherapy Using Carboplatin plus Paclitaxel versus Cisplatin plus Fluorouracil for Esophageal or Gastroesophageal Junction Cancer.

BACKGROUND: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT. METHODS: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis. RESULTS: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2-7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4-8.9) on multivariable and IPTW sensitivity analyses. CONCLUSIONS: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.

Phase II Trial of Symptom Screening With Targeted Early Palliative Care for Patients With Advanced Cancer.

BACKGROUND: Routine early palliative care (EPC) improves quality of life (QoL) for patients with advanced cancer, but it may not be necessary for all patients. We assessed the feasibility of Symptom screening with Targeted Early Palliative care (STEP) in a phase II trial. METHODS: Patients with advanced cancer were recruited from medical oncology clinics. Symptoms were screened at each visit using the Edmonton Symptom Assessment System-revised (ESAS-r); moderate to severe scores (screen-positive) triggered an email to a palliative care nurse, who called the patient and offered EPC. Patient-reported outcomes of QoL, depression, symptom control, and satisfaction with care were measured at baseline and at 2, 4, and 6 months. The primary aim was to determine feasibility, according to predefined criteria. Secondary aims were to assess whether STEP identified patients with worse patient-reported outcomes and whether screen-positive patients who accepted and received EPC had better outcomes over time than those who did not receive EPC. RESULTS: In total, 116 patients were enrolled, of which 89 (77%) completed screening for ≥70% of visits. Of the 70 screen-positive patients, 39 (56%) received EPC during the 6-month study and 4 (6%) received EPC after the study end. Measure completion was 76% at 2 months, 68% at 4 months, and 63% at 6 months. Among screen-negative patients, QoL, depression, and symptom control were substantially better than for screen-positive patients at baseline (all P<.0001) and remained stable over time. Among screen-positive patients, mood and symptom control improved over time for those who accepted and received EPC and worsened for those who did not receive EPC (P<.01 for trend over time), with no difference in QoL or satisfaction with care. CONCLUSIONS: STEP is feasible in ambulatory patients with advanced cancer and distinguishes between patients who remain stable without EPC and those who benefit from targeted EPC. Acceptance of the triggered EPC visit should be encouraged. CLINICALTRIALS: gov identifier: NCT04044040.

Prognostic value of early changes in CT-measured body composition in patients receiving chemotherapy for unresectable pancreatic cancer.

OBJECTIVES: Skeletal muscle mass is a prognostic factor in pancreatic ductal adenocarcinoma (PDAC). However, it remains unclear whether changes in body composition provide an incremental prognostic value to established risk factors, especially the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). The aim of this study was to determine the prognostic value of CT-quantified body composition changes in patients with unresectable PDAC starting chemotherapy. METHODS: We retrospectively evaluated 105 patients with unresectable (locally advanced or metastatic) PDAC treated with FOLFIRINOX (n = 64) or gemcitabine-based (n = 41) first-line chemotherapy within a multicenter prospective trial. Changes (Δ) in skeletal muscle index (SMI), subcutaneous (SATI), and visceral adipose tissue index (VATI) between pre-chemotherapy and first follow-up CT were assessed. Cox regression models and covariate-adjusted survival curves were used to identify predictors of overall survival (OS). RESULTS: At multivariable analysis, adjusting for RECISTv1.1-response at first follow-up, ΔSMI was prognostic for OS with a hazard ratio (HR) of 1.2 (95% CI: 1.08-1.33, p = 0.001). No significant association with OS was observed for ΔSATI (HR: 1, 95% CI: 0.97-1.04, p = 0.88) and ΔVATI (HR: 1.01, 95% CI: 0.99-1.04, p = 0.33). At an optimal cutoff of 2.8 cm2/m2 per 30 days, the median survival of patients with high versus low ΔSMI was 143 versus 233 days (p < 0.001). CONCLUSIONS: Patients with a lower rate of skeletal muscle loss at first follow-up demonstrated improved survival for unresectable PDAC, regardless of their RECISTv1.1-category. Assessing ΔSMI at the first follow-up CT may be useful for prognostication, in addition to routine radiological assessment. KEY POINTS: • In patients with unresectable pancreatic ductal adenocarcinoma, change of skeletal muscle index (ΔSMI) in the early phase of chemotherapy is prognostic for overall survival, even after adjusting for Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) assessment at first follow-up. • Changes in adipose tissue compartments at first follow-up demonstrated no significant association with overall survival. • Integrating ΔSMI into routine radiological assessment may improve prognostic stratification and impact treatment decision-making at the first follow-up.

Validation of Prognostic Radiomic Features From Resectable Pancreatic Ductal Adenocarcinoma in Patients With Advanced Disease Undergoing Chemotherapy.

BACKGROUND: Radiomic features in pancreatic ductal adenocarcinoma (PDAC) often lack validation in independent test sets or are limited to early or late stage disease. Given the lethal nature of PDAC it is possible that there are similarities in radiomic features of both early and advanced disease reflective of aggressive biology. PURPOSE: To assess the performance of prognostic radiomic features previously published in patients with resectable PDAC in a test set of patients with unresectable PDAC undergoing chemotherapy. METHODS: The pre-treatment CT of 108 patients enrolled in a prospective chemotherapy trial were used as a test cohort for 2 previously published prognostic radiomic features in resectable PDAC (Sum Entropy and Cluster Tendency with square-root filter[Sqrt]). We assessed the performance of these 2 radiomic features for the prediction of overall survival (OS) and time to progression (TTP) using Cox proportional-hazard models. RESULTS: Sqrt Cluster Tendency was significantly associated with outcome with a hazard ratio (HR) of 1.27(for primary pancreatic tumor plus local nodes), (Confidence Interval(CI):1.01 -1.6, P-value = 0.039) for OS and a HR of 1.25(CI:1.00 -1.55, P-value = 0.047) for TTP. Sum entropy was not associated with outcomes. Sqrt Cluster Tendency remained significant in multivariate analysis. CONCLUSION: The CT radiomic feature Sqrt Cluster Tendency, previously demonstrated to be prognostic in resectable PDAC, remained a significant prognostic factor for OS and TTP in a test set of unresectable PDAC patients. This radiomic feature warrants further investigation to understand its biologic correlates and CT applicability in PDAC patients.

Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer.

BACKGROUND & AIMS: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis. METHODS: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated. RESULTS: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p <0.001). This reduced risk vs. GBC was maintained in those receiving cisplatin/gemcitabine for extrahepatic cholangiocarcinoma (p<0.001) and intrahepatic cholangiocarcinoma (IHC, p<0.001), but not in cholangiocarcinoma-not specified (CCA-NS, p = 0.82) or ampullary carcinoma (p = 0.96). One-year OS rates amongst patients who survived beyond 1, 2, 3 and 4 years post-trial registration were 37%, 45%, 61%, and 63%, respectively. For patients who survived 1 year, those receiving combination therapy vs. mono (p = 0.008) (acknowledging potential selection bias) and those with IHC and CCA-NS vs. GBC had better LS (both p <0.05). Metastatic disease was associated with shorter LS than locally advanced disease (p = 0.002). ECOG-PS and gender were not associated with LS (p >0.05, p = 0.08 respectively). CONCLUSIONS: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors. LAY SUMMARY: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.

NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121).

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).

Reducing dexamethasone antiemetic prophylaxis during the COVID-19 pandemic: recommendations from Ontario, Canada.

PURPOSE: People with cancer face an elevated risk of infection and severe sequelae from COVID-19. Dexamethasone is commonly used for antiemetic prophylaxis with systemic therapy for cancer. However, dexamethasone is associated with increased risk of viral and respiratory infections, and causes lymphopenia, which is associated with worse outcomes during COVID-19 infections. Our purpose was to minimize dexamethasone exposure during antiemetic prophylaxis for systemic therapy for solid tumors during the COVID-19 pandemic, while maintaining control of nausea and emesis. METHODS: We convened an expert panel to systematically review the literature and formulate consensus recommendations. RESULTS: No studies considered the impact of dexamethasone-based antiemetic regimens on the risk and severity of COVID-19 infection. Expert consensus recommended modifications to the 2019 Cancer Care Ontario Antiemetic Recommendations. CONCLUSION: Clinicians should prescribe the minimally effective dose of dexamethasone for antiemetic prophylaxis. Single-day dexamethasone dosing is recommended over multi-day dosing for regimens with high emetogenic risk excluding high-dose cisplatin, preferably in combination with palonosetron, netupitant, and olanzapine. For regimens with low emetogenic risk, 5-HT3 antagonists are recommended over dexamethasone.

A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial.

BACKGROUND: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited. METHODS: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks. RESULTS: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment. CONCLUSION: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.

Pantoprazole Affecting Docetaxel Resistance Pathways via Autophagy (PANDORA): Phase II Trial of High Dose Pantoprazole (Autophagy Inhibitor) with Docetaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BACKGROUND: Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. MATERIALS AND METHODS: Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m2) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two-stage design. RESULTS: Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. CONCLUSION: The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. IMPLICATIONS FOR PRACTICE: To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.

An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: TKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent. BACKGROUND: Polo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation. METHODS: A 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days. RESULTS: The study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months. CONCLUSION: TKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted.