Achieving white blood cell equity: are the safety profiles of biosimilar and reference pegfilgrastims comparable?

Biosimilars can provide choices for patients and may provide cost savings; however, their uptake has been slow in the USA, in part due to limited knowledge. To provide additional confidence in US pegfilgrastim biosimilars, this narrative review compared the safety profiles of biosimilar pegfilgrastims, currently approved or filed for approval in the USA, with the EU- and US-approved reference pegfilgrastims. Headache and bone pain were common to biosimilars and reference products and occurred at a similar incidence. Clinical trial data on the safety profiles of biosimilar pegfilgrastims and reference products have demonstrated similarity and comparability, with no unexpected safety outcomes. Overall, the safety profiles of biosimilar pegfilgrastims and reference pegfilgrastims demonstrated a high degree of similarity and comparability.

Pegfilgrastim is a biologic drug (one made in living cells such as bacteria) that is given to some patients being treated for cancer. Pegfilgrastim is prescribed to reduce a patient's risk of infection due to a weakened immune system caused by various chemotherapy treatment plans. A biosimilar is a type of biologic medicine that is highly similar to a US FDA-approved reference biologic, and is often cheaper, making it more widely available to patients. As of March 2023, there are eight pegfilgrastim biosimilars (six approved and two awaiting approval by the FDA). This review compared the side effects for the reference pegfilgrastim with the biosimilar pegfilgrastims. The side effects in general and the side effects from treatment were similar for the reference pegfilgrastim and for the biosimilar pegfilgrastims, with the most common side effects being headache and bone pain. Serious side effects such as allergic reactions or problems with the spleen were very low and were also similar between the reference pegfilgrastim and the biosimilar pegfilgrastims. These results show that the safety of the biosimilar pegfilgrastims was similar to the reference pegfilgrastim, with no unexpected side effects. With comparable safety to their reference product, biosimilars have the potential to improve patient access to more affordable treatment options.

Novel Tumor Growth Rate Analysis in the Randomized CLARINET Study Establishes the Efficacy of Lanreotide Depot/Autogel 120 mg with Prolonged Administration in Indolent Neuroendocrine Tumors.

INTRODUCTION: Tumor quantity while receiving cancer therapy is the sum of simultaneous regression of treatment-sensitive and growth of treatment-resistant fractions at constant rates. Exponential rate constants for tumor regression/decay (d) and growth (g) can be estimated. Previous studies established g as a biomarker for overall survival; g increases after treatment cessation, can estimate doubling times, and can assess treatment effectiveness in small cohorts by benchmarking to large reference data sets. Using this approach, we analyzed data from the clinical trial CLARINET, evaluating lanreotide depot/autogel 120 mg/4 weeks (LAN) for treatment of neuroendocrine tumors (NETs). METHODS AND MATERIALS: Computed tomography imaging data from 97 LAN- and 101 placebo-treated patients from CLARINET were analyzed to estimate g and d. RESULTS: Data from 92% of LAN- and 94% of placebo-treated patients could be fit to one of the equations to derive g and d (p < .001 in most data sets). LAN-treated patients demonstrated significantly slower g than placebo recipients (p = .00315), a difference of 389 days in doubling times. No significant difference was observed in d. Over periods of LAN administration up to 700 days, g did not change appreciably. Simulated analysis with g as the endpoint showed a sample size of 48 sufficient to detect a difference in median g with 80% power. CONCLUSION: Although treatment of NETs with LAN can affect tumor shrinkage, LAN primarily slows tumor growth rather than accelerates tumor regression. Evidence of LAN efficacy across tumors was identified. The growth-retarding effect achieved with LAN was sustained for a prolonged period of time. IMPLICATIONS FOR PRACTICE: The only curative treatment for neuroendocrine tumors (NETs) is surgical resection; however, because of frequent late diagnosis, this is often impossible. Because of this, treatment of NETs is challenging and often aims to reduce tumor burden and delay progression. A novel method of analysis was used to examine data from the CLARINET trial, confirming lanreotide depot/autogel is effective at slowing tumor growth and extending progression-free survival. By providing the expected rate and doubling time of tumor growth early in the course of treatment, this method of analysis has the potential to guide physicians in their management of patients with NETs.

Use of Molecular Assays and Circulating Tumor DNA in Early-Stage Colorectal Cancer: A Roundtable Discussion of the Gastrointestinal Cancer Therapy Expert Group.

The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic. IMPLICATIONS FOR PRACTICE: The Gastrointestinal Cancer Therapy Expert Group seeks to provide practical guidance and opinion on the treatment of gastrointestinal malignancies, including colorectal cancer (CRC), for the practicing community oncologist in situations for which guidelines from established bodies, such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology, may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA to detect minimal/molecular residual disease in patients with successfully resected early-stage CRC.

Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution.

Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma (COAD). We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data. One hundred and twenty three cases of routinely collected mismatch repair proficient COAD were sequenced on the Illumina Truseq Amplicon assay. Measures of intratumoral heterogeneity and the preferential timing of mutational events were assessed and compared to clinicopathologic data. Survival subanalysis was performed on 55 patients. Patient age (p = 0.013) and specimen percent tumor (p = 0.033) was associated with clonal diversity, and biopsy (p = 0.044) and metastasis (p = 0.044) returned fewer mutations per case. APC and TP53 mutations preferentially occurred early while alterations in FBXW7, FLT3, SMAD4, GNAS and PTEN preferentially occurred as late events. Temporal heterogeneity was evident in KRAS and PIK3CA mutations. Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events. Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype (8 months vs. 13 months; univariate logrank p = 0.0380, cox model p= 0.018). Neoadjuvant therapy associated mutations were found for ERBB2 (p = 0.0481) and FBXW7 (p = 0.015). Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes. Furthermore, we report treatment acquired and/or selected mutations in ERBB2 and FBXW7.

Full dose neoadjuvant FOLFIRINOX is associated with prolonged survival in patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX. METHODS: Between 2008 and 2013, 51 treatment-naïve patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (R0) resection rate, and toxicity profile. RESULTS: A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2-29) per patient; 66% of cycles were full dose. After chemotherapy, 27 (53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8-45). Ten (4 borderline resectable and 6 unresectable) patients had successful R0 resections; those who had R0 resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen. CONCLUSIONS: FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the R0 resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen.

Percutaneous irreversible electroporation for the treatment of colorectal cancer liver metastases with a proposal for a new response evaluation system.

PURPOSE: To describe an initial experience with irreversible electroporation (IRE) in patients with colorectal liver metastasis (CLM). MATERIALS AND METHODS: A retrospective analysis of patients undergoing IRE for the management of CLM was performed. Procedures were done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. RESULTS: Between March 2010 and February 2013, 29 patients underwent percutaneous ablation of 58 tumors in 36 IRE sessions. Most patients (89%) had an absolute or relative contraindication to thermal ablation. The median age was 62 years, and the median time from diagnosis to IRE was 28 months. The median number of lesions treated per patient was two, and the median tumor size was 2.7 cm. Patients had received previous chemotherapy regimens (range, 1-5 per patient). A new Metabolic Imaging And Marker Integration response evaluation criteria was used for response assessment, and was a predictor of progression-free and overall survival. The 2-year progression-free survival rate was 18% (95% confidence interval, 0%-35%), and the 2-year overall survival rate was 62% (95% confidence interval, 37%-87%). Complications included arrhythmias (n = 1) and postprocedure pain (n = 1). Both patients recovered without sequelae. CONCLUSIONS: Percutaneous IRE of CLM is feasible and safe. A new response evaluation system for colorectal cancer appears to be prognostic.

A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma.

BACKGROUND: 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC). METHODS: In this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate. RESULTS: Eighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22-69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %). CONCLUSIONS: FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.

Novel approaches for myelodysplastic syndromes: beyond hypomethylating agents.

PURPOSE OF REVIEW: Several novel therapeutic approaches exist for treatment of patients with myelodysplastic syndrome, with goals to improve quality of life and prolong survival. This review highlights new therapies from the last 18 months. RECENT FINDINGS: Immunosuppressants, erythropoiesis-stimulating agents in combination with granulocyte colony-stimulating factor or all-trans-retinoic-acid have shown improvement in decreasing the need for transfusions and improving quality-of-life and/or survival. Eltrombopag has shown promising results in the treatment of thrombocytopenia. However, determination of an optimal chemotherapeutic approach remains elusive and controversial. DNA methyltransferase inhibitors are well tolerated in outpatient settings, with azacitidine prolonging survival and decreasing time to acute myeloid leukemia progression in patients with high-risk myelodysplastic syndromes. A novel erythroid-specific gene expression profile may predict response to lenalidomide in patients who lack the deletion of 5q31.1. Tools such as the Charlson comorbidity index may help select appropriate patients for allogeneic stem cell transplant. A variety of promising new agents are under investigation. SUMMARY: This review focuses on recent advances in new strategies and targeted therapies for treatment of myelodysplastic syndrome.

Clinical and treatment characteristics of patients treated with the first therapeutic oncology biosimilars bevacizumab-awwb and trastuzumab-anns in the US.

BACKGROUND: In July 2019, bevacizumab-awwb and trastuzumab-anns were marketed in the USA as the first therapeutic oncology biosimilars. We aimed to investigate the initial real-world use of bevacizumab-awwb and trastuzumab-anns for cancer management in US oncology practices. METHODS: A retrospective, observational analysis of data from US cancer patients (⩾18 years of age) was carried out to describe the use of bevacizumab-awwb and trastuzumab-anns during the first 12 months following their market entry, using structured data from the Flatiron Health electronic health record-derived database. RESULTS: A total of 2952 and 2997 patients with recorded use of bevacizumab-awwb and trastuzumab-anns, respectively, were included in the analysis. The first use of bevacizumab-awwb and trastuzumab-anns was in a patient with metastatic colorectal cancer (mCRC) within 10 days of market availability and in a patient with early stage breast cancer (eBC) within 4 days, respectively. The use of these biosimilars was observed across all approved cancer indications; 68% of bevacizumab-awwb users were those diagnosed with mCRC and 72% of trastuzumab-anns users were those diagnosed with eBC. Approximately half the patients were previously exposed to reference product (RP) prior to initiation of bevacizumab-awwb or trastuzumab-anns. Among pre-exposed patients, the majority received the biosimilars [bevacizumab-awwb (63-85%) or trastuzumab-anns (75-81%)] within 28 days of the last infusion of the RP. For both biosimilars, no major differences were observed in patient characteristics between RP-naïve and pre-exposed patients. CONCLUSION: Initial evidence from the first 12 months following market entry suggests rapid clinical adoption of bevacizumab-awwb and trastuzumab-anns across all approved tumor types. Usage of these two biosimilars was observed in both RP-naïve patients and patients who were previously treated with RP, with no distinctive differences in patient characteristics between the two groups.A video abstract is available for this article as part of the Kanjintionline supplemental material.

Concurrent Nab-paclitaxel and Radiotherapy: Novel Radiosensitization for Borderline Resectable or Unresectable Pancreatic Cancer.

PURPOSE: This study evaluates the toxicity and tumor response with concurrent nab-paclitaxel chemoradiotherapy (CRT) compared with standard (5-fluorouracil or gemcitabine) CRT. MATERIALS AND METHODS: Fifty patients with borderline resectable or unresectable pancreatic adenocarcinoma from 2014 to 2017 were divided into 2 groups: concurrent nab-paclitaxel (100 to 125 mg/m2 weekly) CRT (median: 2.1 Gy fraction size and 52.5 Gy total) or standard CRT (median: 1.8 Gy fraction size, 54.5 Gy total). The primary endpoint was toxicity, and secondary endpoints were local failure and conversion to resectability. Comparisons were made using rank-sum or Fisher exact test and multivariable competing risk regression for the cumulative incidence of local failure. RESULTS: There were 28 patients in the nab-paclitaxel CRT group and 22 in the standard CRT group; 88% had the unresectable disease. The median follow-up was 18 months. The median duration of chemotherapy before concurrent CRT was 1.9 and 2.3 months in the nab-paclitaxel and standard CRT groups (P=0.337), and radiotherapy dose was 52.5 Gy (range, 52.5 to 59.4 Gy) and 54.5 Gy (range, 45.0 to 59.4 Gy), respectively. There were no statistically significant grade ≥2 toxicities. The nab-paclitaxel CRT group experienced a nonstatistically significant lower incidence of local failure (hazard ratio=0.91, 95% confidence interval: 0.27-3.03, P=0.536). More patients in the nab-paclitaxel CRT group proceeded to surgery (9/28 compared with 3/22 in the standard CRT, P=0.186); of which 6 (25%) in the nab-paclitaxel CRT and 2 (10%) in the standard CRT groups were initially unresectable. CONCLUSIONS: Nab-paclitaxel CRT had similar toxicity compared with standard CRT in the treatment of borderline resectable or unresectable pancreatic cancer. Its use was associated with an arithmetically lower cumulative incidence of local failure and an arithmetically higher conversion to resectability, both of which were not statistically significant.

A phase 2 study of vorinostat in acute myeloid leukemia.

BACKGROUND: This two-stage, multi-institutional, randomized phase 2 trial assessed the toxicity and response rate associated with two treatment schedules of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid; SAHA) in patients with relapsed acute myeloid leukemia and in selected untreated patients with high-risk acute myeloid leukemia. DESIGN AND METHODS: Patients with relapsed or untreated acute myeloid leukemia who were not candidates for chemotherapy entered one of the two treatment arms. In both arms a total dose of 8400 mg of vorinostat was delivered in each 21-day cycle of treatment: in arm A the dose regimen was 400 mg daily whereas in arm B the dose regimen was 200 mg three times daily for 14 days followed by 1 week rest. RESULTS: Data from all 37 patients were used for the analyses. In arm A (n=15), the confirmed complete remission rate was 0% (95% CI, 0% to 23%); this arm was closed at the planned interim analysis. In arm B (n=22), the confirmed complete remission rate was 4.5% (1 response; 95% CI, 0.4% to 24%), with a duration of response exceeding 398 days. The median time to treatment failure in arm A was 42 days (95% CI, 26 to 57); although a minimum of four cycles of treatment were planned, 11 patients (79%) received no more than two cycles. The median time to treatment failure in arm B was 46 days (95% CI, 20 to 71); 13 patients (59%) received no more than two cycles of treatment. CONCLUSIONS: Vorinostat monotherapy demonstrated minimal activity in this group of patients with acute myeloid leukemia. Therapy was discontinued in many patients before the planned four cycles had been administered, either because of failure of vorinostat to control the leukocyte count or patients' and physicians' preference. Future studies of vorinostat in acute myeloid leukemia should focus on combinations with other drugs with which it might interact pharmacodynamically. ClinicalTrials.gov Identifier: NCT00305773.

Effect of Gemcitabine and nab-Paclitaxel With or Without Hydroxychloroquine on Patients With Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Autophagy is a mechanism of treatment resistance to chemotherapy that has a role in the maintenance of pancreatic cancer. Hydroxychloroquine sulfate (HCQ) is an inhibitor of autophagy that inhibits the fusion of the autophagosome to the lysosome. OBJECTIVE: To determine whether HCQ improves overall survival at 1 year in combination with gemcitabine hydrochloride and nab-paclitaxel (GA) among patients with metastatic pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS: Open-label, phase 2 randomized clinical trial conducted between March 18, 2013, and November 16, 2017, at the University of Pennsylvania, HonorHealth, and The Johns Hopkins University among 112 patients with previously untreated metastatic or advanced pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate marrow and organ function. All efficacy analyses were performed for the intention-to-treat population. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive GA with or without HCQ. All patients received standard doses of GA, and those randomized to receive HCQ were treated continuously with 600 mg orally twice daily. MAIN OUTCOME AND MEASURE: Overall survival at 1 year. RESULTS: A total of 112 patients (45 women and 67 men; median age, 65 years; range, 43-86 years) were enrolled; 55 were randomized to receive GA plus HCQ, and 57 to receive GA. Overall survival at 12 months was 41% (95% CI, 27%-53%) in the HCQ group and 49% (95% CI, 35%-61%) in the non-HCQ group. Median progression-free survival was 5.7 months (95% CI, 4.0-9.3 months) in the HCQ group and 6.4 months (95% CI, 4.5-7.6 months) in the non-HCQ group. Median overall survival was 11.1 months (95% CI, 9.0-14.2 months) in the HCQ group and 12.1 months (95% CI, 9.3-15.5 months) in the non-HCQ group. Overall response rate was 38.2% (n = 21) in the HCQ group and 21.1% (n = 12) in the non-HCQ group (P = .047). Treatment-related grade 3 or 4 adverse events that differed between the HCQ and non-HCQ groups were neutropenia (23 of 54 [42.6%] vs 12 of 53 [22.6%]), anemia (2 of 54 [3.7%] vs 9 of 53 [17.0%]), fatigue (4 of 54 [7.4%] vs 0), nausea (5 of 54 [9.3%] vs 0), peripheral neuropathy (7 of 54 [13.0%] vs 3 of 53 [5.7%]), visual changes (3 of 54 [5.6%] vs 0), and neuropsychiatric symptoms (3 of 54 [5.6%] vs 0). CONCLUSIONS AND RELEVANCE: The addition of HCQ to block autophagy did not improve the primary end point of overall survival at 12 months. These data do not support the routine use of GA plus HCQ for metastatic pancreatic cancer in the absence of a biomarker. However, improvement seen in the overall response rate with HCQ may indicate a role for HCQ in the locally advanced setting, where tumor response may permit resection. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01506973.

Differences in overall survival and mutation prevalence between right- and left-sided colorectal adenocarcinoma.

BACKGROUND: Prior reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease, as well as differences in treatment response based on disease sidedness. Differences in prognosis remain even among patients with metastatic disease, indicating that anatomy or stage at diagnosis alone cannot explain all of these findings. While genetic differences between right- and left-sided CRC have long been described, the genetic and molecular drivers underlying differences in prognosis and treatment response remain incompletely understood. METHODS: We compared mutation prevalence between right- (cecum to splenic flexure) and left-sided (descending colon to rectum) CRC among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. RESULTS: Among 288 cases (167 left-sided, 103 right-sided, 18 synchronous or without clear primary), patients with left-sided primaries had a longer overall survival from pathologic diagnosis (median 1,823 days vs. 1,006 days for right-sided cases, P=0.004). Among the assessed genes, BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5-22.5%) compared to 4.8% (95% CI: 1.6-8.0%) (P=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (95% CI: 0.2-7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (P=0.01). CONCLUSIONS: This difference in mutation prevalence may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right- and left-sided CRC described in this and prior studies.

Cardiotoxicity: Myocardium or Endothelium.

Endothelial biomarkers are gaining interest in the stratification of cardiovascular risk and early diagnosis of cardiotoxicity secondary to antineoplastic drugs. Interestingly, some drugs, such as anthracyclines, have been recently associated with vascular damage, which reveals the pivotal role of research in identifying biomarkers that could potentially be included into more specific cardiotoxicity risk scores. An extensive report of the incidences of cardiovascular adverse effects of oncologic drugs is presented, with the main purpose of highlighting not only the risk of developing heart failure but also the importance of associated vascular adverse effects (i.e., hypertension, venous, and arterial thrombosis) experienced by patients in the post-chemotherapy phase.

A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma.

BACKGROUND: The KRAS oncogene is a driver mutation and is present in greater than 90% of pancreatic ductal adenocarcinomas (PDAC). A subset of these tumors, however, do not harbor mutations in KRAS (wild type KRAS). Studies have shown that patients with mutated KRAS have a poorer survival on first-line gemcitabine-based chemotherapy compared to wild type KRAS. In this study, we examined a cohort of patients with PDAC at our institution who were either wild type or mutant for the KRAS gene and assessed for differences in survival and response to different chemotherapeutic regimens. METHODS: We examined clinical records of patients treated at the Abramson Cancer Center of the University of Pennsylvania from 2013 to 2017. Patients with a pancreatic mass and a histologic diagnosis of pancreatic or pancreaticobiliary adenocarcinoma were identified. Thirty-nine patients with PDAC who underwent tumor sequencing at Penn Medicine's Center for Personalized Diagnostics (CPD) were selected for further study. Twelve patients were identified whose tumors were KRAS wild type. Twenty-seven patients with PDAC whose tumors harbored KRAS mutations were selected as controls (KRAS mutant). RESULTS: We noted a longer overall survival (OS) among KRAS wild type patients compared to KRAS mutant patients (P=0.026). This was independent of the age at diagnosis, patient gender, stage of diagnosis, tumor morphology, mismatch repair (MMR) status, and chemotherapeutic regimen. CONCLUSIONS: Similar to previously reported studies, PDAC with a KRAS wild type mutational profile has a better prognosis with a longer OS. This improved prognosis is independent of the protocol utilized in therapy for these patients. Our findings suggest that future clinical trials in pancreatic cancer should take into consideration the presence of KRAS mutations in their pre-planned analysis when assessing the efficacy of a novel therapeutic approach. This may be a crucial factor in trial concepts and outcomes.

Neoadjuvant Nab-paclitaxel and Gemcitabine in Borderline Resectable or Locally Advanced Unresectable Pancreatic Adenocarcinoma in Patients Who Are Ineligible for FOLFIRINOX.

BACKGROUND/AIM: Combination nab-paclitaxel/gemcitabine (AG) is superior to gemcitabine in patients with metastatic pancreatic cancer (PC). There are limited data for AG in borderline resectable (BR) or locally advanced pancreatic cancer (LAPC). Herein, we report our experience with neoadjuvant AG for BR/LAPC in patients ineligible for FOLFIRINOX. PATIENTS AND METHODS: This retrospective series, included patients with BR/LAPC who received AG as neoadjuvant therapy for 3-4 months followed by radiation, then re-evaluation for surgery. RESULTS: Between 10/2013-2/2018, 32 patients (22 BR, 10 LAPC) were treated with this approach. Median age was 70 years. Nine patients were converted to resectability by imaging; six had R0 resections (19%), five (16%) achieved a partial response and 24 (75%) had stable disease. CONCLUSION: In this small series, the R0 resection rate and response rate were 19% and 16% respectively. These data suggest that neoadjuvant AG may be an alternate option for patients ineligible for FOLFIRINOX.

A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer.

PURPOSE: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma. METHODS: We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. RESULTS: Nine patients received nab-paclitaxel at a dose level of either 100 mg/m2 (n = 3) or 125 mg/m2 (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability. CONCLUSIONS: The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.

Somatostatin Receptor Avidity in Gastrointestinal Stromal Tumors: Theranostic Implications of Gallium-68 Scan and Eligibility for Peptide Receptor Radionuclide Therapy.

This manuscript reports on a patient with a metastatic gastrointestinal stromal tumor (GIST) refractory to standard first-line treatment, who underwent a gallium-68 scan based on pre-clinical data of somatostatin receptor (SSTR) expression in such tumors. The gallium-68 DOTATATE scan determined significant somatostatin receptor avidity as hypothesized, suggesting that this imaging modality may be used as an option for diagnostic and follow-up purposes in GIST patients. In addition, peptide receptor-mediated radiotherapy (177Lu-PPRT) via SSTR may provide a novel treatment strategy in carefully selected SSTR-avid GIST patients with thyrosine kinase inhibitor (TKI)-resistant tumors such as this case, and this warrants further investigation in novel clinical trial concepts.

The Role of Biosimilars in Patient Access to Therapeutic Antibodies for Immune Mediated Inflammatory Diseases.

BACKGROUND: Biosimilars have the potential to create competition, lower costs, and increase patient access to biological medications. However, biological medications are sensitive to their manufacturing processes and difficult to precisely characterize, leading to questions about substitution and interchangeability among products. METHODS: This article reviews the role of biosimilars in patient access to therapeutic antibodies. RESULTS: Although pathways for the approval of biosimilars have been developed, important issues remain unresolved. Interchangeability, or the designation of one medicine as clinically similar to and/or substitutable for another, is specified in some countries but restricted or awaiting policy resolution in others. Non-medical switching, or the switching among biological medications to select a less expensive product, for reasons unrelated to patient health and safety, is controversial because of the potential for complications related to repeated switching (e.g., immunogenicity and loss of therapeutic effect), and transfer of prescribing responsibility for patient medications from the physician to the insurance company. Although biosimilars have different names in different countries, the World Health Organization (WHO) calls for nomenclature that incorporates the international nonproprietary name of the original biological medication followed by a distinguishing suffix qualifier. Naming consistency across countries seems sensible, and adoption of the WHO recommended suffix would greatly simplify pharmacovigilance. CONCLUSIONS: Support for the WHO proposal is advised by numerous stakeholders, and resolution of the remaining outstanding issues is urged so that patients and physicians can safely access biosimilars.

Cardio-Oncology: Cancer Therapy-related Cardiovascular Complications in a Molecular Targeted Era: New Concepts and Perspectives.

Cardio-oncology is a medical discipline that identifies, prevents, and treats the cardiovascular complications related to cancer therapy. Due to the remarkable proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia, we provide an extensive, comprehensive revision of the most up-to-date scientific information available on the cardiovascular complications associated with the use of newer, novel chemotherapeutic agents, including their reported incidence, suggested pathophysiology, clinical manifestations, potential treatment, and prevention. The authors consider this topic to be relevant for the clinicians since cardiovascular complications associated with the administration of recently approved drugs are relatively underappreciated. The purpose of this article is to provide a state-of-the-art review of cardiovascular complications associated with the use of newer, novel chemotherapeutic agents and targeted therapies, including their reported incidence, suggested pathophysiology, clinical manifestations, potential treatment, and prevention.  Ongoing efforts are needed to provide a better understanding of the frequency, mechanisms of disease, prevention, and treatment of cardiovascular complications induced by the newer, novel chemotherapeutic agents. Development of a cardio-oncology discipline is warranted in order to promote task forces aimed at the creation of oncology patient-centered guidelines for the detection, prevention, and treatment of potential cardiovascular side effects associated with newer cancer therapies.