AbstractBackground.Early detection and prompt access to quality treatment and palliative care are critical for good breast cancer outcomes. Interventions require understanding of identified barriers and facilitators to care. A hermeneutic phenomenological approach, whose purpose is to describe feelings and lived experiences of participants, can expand the existing scope of understanding of barriers and facilitators in accessing breast cancer care in Kenya.Methods.This is qualitative research applying focus groups and a hermeneutic phenomenological approach to identify barriers and facilitators to breast cancer care from the knowledge, perceptions, and lived experiences of women with and without a diagnosis of breast cancer in Kenya. We conducted four focus group discussions with 6–11 women aged 30–60 years in each. Groups were classified according to breast cancer diagnosis and socioeconomic status. The transcribed discussions were coded independently by two investigators. Together they reviewed the codes and identified themes.Results.The key barriers were costs, inadequate knowledge, distance to health facilities, communication with health providers, medicines stockouts, long waiting periods, limited or no counseling at diagnosis, patient vulnerability, and limited access to rehabilitation items. Facilitators were dependable social support, periodical access to subsidized awareness, and early detection services and friendly caregivers. We found no marked differences in perceptions between groups by socioeconomic status.Conclusion.There is need for targeted awareness and education for health providers and the public, early detection services with onsite counseling and cost mitigation. Support from the society and religious organizations and persons may be leveraged as adjuncts to conventional management. Further interpretations are encouraged.Implications for Practice.Continuing cancer education for health providers in technical skills for early detection, treatment, and survivorship care, as well as nontechnical skills like communication, and an understanding of their patients’ preferences and socioeconomic status may guide individualized management plans and positively affect patient experiences. Patients and the general public also need education on cancer to avoid misconceptions and inaccuracies that perpetuate fear, confusion, delayed presentation for treatment, and stigma. Critical analysis of the cancer care value chain and processes, development, and implementation of interventions to reduce costs while streamlining processes may improve client experiences.
AbstractLessons Learned.Concurrent ETBX‐011, ETBX‐051, and ETBX‐061 can be safely administered to patients with advanced cancer.All patients developed CD4+ and/or CD8+ T‐cell responses after vaccination to at least one tumor‐associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1‐specific T cells, 4/6 (67%) developed CEA‐specific T cells, and 3/6 (50%) developed brachyury‐specific T cells.The presence of adenovirus 5‐neutralizing antibodies did not prevent the generation of TAA‐specific T cells.Background.A novel adenovirus‐based vaccine targeting three human tumor‐associated antigens—CEA, MUC1, and brachyury—has demonstrated antitumor cytolytic T‐cell responses in preclinical animal models of cancer.Methods.This open‐label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX‐011 = CEA, ETBX‐051 = MUC1, and ETBX‐061 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 × 1011 viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated.Results.Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment‐related adverse events were temporary, self‐limiting, grade 1/2 and included injection site reactions and flu‐like symptoms. Antigen‐specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response.Conclusion.Concurrent ETBX‐011, ETBX‐051, and ETBX‐061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned.
AbstractBackground.The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus‐induced oral mucositis.Materials and Methods.This randomized, multicenter, open‐label, phase III study evaluated the efficacy of POC in preventing everolimus‐induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8‐week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2‐sided type I error rate of 5% and 80% power to detect 25% risk reduction.Results.Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction.Conclusion.POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT 02069093.Implications for Practice.The Oral Care‐BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor‐positive, HER2‐negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.
AbstractAxicabtagene ciloleucel is the first U.S. Food and Drug Administration–approved autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy for the treatment of patients with relapsed or refractory large B‐cell lymphoma after ≥2 prior systemic therapies. Although axicabtagene ciloleucel is administered only at authorized treatment centers, community oncologists play a critical role in the CAR T‐cell treatment journey, recognizing potentially eligible patients for referral and then, after treatment, closely collaborating with treatment centers to monitor and manage patients long term. ZUMA‐1, the pivotal, multicenter, phase I/II study of 108 patients treated with axicabtagene ciloleucel, resulted in an objective response rate of 83%, including 58% complete responses. With a 27.1‐month median follow‐up, 39% of patients had ongoing responses. CAR T‐cell therapy is associated with the potentially life‐threatening adverse events (AEs) of cytokine release syndrome and neurologic events, which generally occur early after treatment. In ZUMA‐1, cytokine release syndrome and neurologic events were generally reversible and grade ≥3 cytokine release syndrome and neurologic events occurred in 11% and 32% of patients, respectively. Frequent prolonged AEs included hypogammaglobulinemia, B‐cell aplasia, and cytopenias requiring supportive care until recovery of hematopoietic function. Rate of treatment‐related mortality was low, at <2%. With appropriate management of common AEs, axicabtagene ciloleucel offers the potential for long‐term durable responses in patients who otherwise lack curative treatment options.Implications for Practice.Community oncologists should be familiar with key aspects of chimeric antigen receptor (CAR) T‐cell indications and eligibility to help recognize and refer potential patients for this paradigm‐changing treatment option at the appropriate time during the disease course. To ensure optimal long‐term outcomes for patients who have been treated with CAR T‐cell therapy, oncologists must also be familiar with common prolonged AEs and their monitoring and management.
AbstractBackground.Pancreatic neuroendocrine tumors (panNETs) are a rare group of tumors that make up 2%–3% of pancreatic tumors. Recommended treatment for panNETs generally consists of resection for symptomatic or large asymptomatic tumors; however, optimal management for localized disease is still controversial, with conflicting recommendations in established guidelines. Our study aim is to compare surgical intervention versus active surveillance in nonmetastatic panNETs by size of primary tumor.Materials and Methods.Using the National Cancer Database, we identified 2,004 patients diagnosed with localized well‐differentiated, nonfunctional panNETs (NF‐panNETs) between 2004 and 2015. Patients’ clinicopathologic characteristics, treatment modalities, and overall survival (OS) were analyzed using frequency statistics, chi‐square, and Kaplan‐Meier curves. The objective of the study is to assess the outcome of surgical resection versus nonoperative management in patients with panNETs with different tumor sizes.Results.Tumor sizes were divided into three categories: <1 cm, 1–2 cm, and >2 cm. The number of patients with tumor size <1 cm, 1–2 cm, and >2 cm was 220 (11%), 794 (39.6%), and 990 (49.4%), respectively. Overall, 1,781 underwent surgical resection, whereas 223 patients did not. Median follow‐up was 25.9 months. After adjusting for covariates, surgical resection was associated with improved OS in patients with tumor size 1–2 cm (hazard ratio [HR] = 0.37) and >2c m (HR = 0.30) but not <1 cm (HR = 2.81). Independent prognostic factors were age at diagnosis, Charlson‐Deyo comorbidity score, stage, tumor location, and surgical resection. Higher tumor grade was not associated with worse OS.Conclusion.Our findings suggest that active surveillance is potentially a safe approach for NF‐panNETs <1 cm. Larger tumors likely need active intervention. Intermediate‐grade tumors did not result in worse survival outcome compared with low‐grade tumors. Future studies might consider prospective randomized clinical trials to validate our findings.Implications for Practice.The present study seeks to address the discrepancy in treatment recommendations in the management of nonfunctional pancreatic neuroendocrine tumors (NF‐panNETs) by evaluating whether surgical resection is associated with improved overall survival in different tumor size groups as well as elucidating independent prognostic factors in patients with NF‐panNETs. Data from the National Cancer Database were reviewed. This study's findings suggest that active surveillance is potentially a safe approach for NF‐panNETs <1 cm. Larger tumors likely need active intervention. Independent prognostic factors include age at diagnosis, Charlson‐Deyo comorbidity score, stage, tumor location, and surgical resection. These findings will help guide medical and surgical oncologists when formulating treatment plans for patients with small NF‐panNETs.
AbstractBackground.Patients with RAS wild‐type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti‐epidermal growth factor receptor (EGFR) combined with first‐line, 5‐fluorouracil‐based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti‐EGFR. Our objective was to compare both strategies in a routine practice setting.Materials and Methods.This multicenter, retrospective, propensity score–weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5‐FU‐based chemotherapy, with either delayed anti‐EGFR or immediate anti‐vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression‐free survival (PFS) and objective response rate (ORR).Results.A total of 262 patients (129 in the anti‐VEGF group and 133 in the anti‐EGFR group) were included. Patients receiving an anti‐VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13–26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69–1.08, p = .2024). The delayed introduction of anti‐EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61–0.90, p = .0024). ORR was significantly higher in the anti‐EGFR group (66.7% vs. 45.6%, p = .0007).Conclusion.Delayed introduction of anti‐EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti‐VEGF.Implications for Practice.For RAS/RAF wild‐type metastatic colorectal cancer, patients may receive 5‐fluorouracil‐based chemotherapy plus either bevacizumab or an anti‐epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti‐EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti‐EGFR on survival, compared with the introduction of an anti‐vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti‐EGFR while waiting for RAS status.
AbstractBackground.Vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) administered every 2 weeks demonstrated a superior event‐free survival compared with 3‐week dosing in a landmark pediatric trial and is now standard of care for younger patients. Only 12% of patients enrolled in that trial were over 18 years of age; thus, the feasibility of interval‐compressed VDC/IE in adults remains poorly described. We conducted a retrospective analysis of our institutional experience using this regimen.Materials and Methods.Pharmacy administration records at Oregon Health and Science University were reviewed to identify patients with Ewing and Ewing‐like sarcoma aged 18 years and older who received VDC/IE every 2 weeks.Results.We identified 24 patients. Median age was 28 years (range 18–60 years). At diagnosis, 67% had localized disease. The most common primary sites were extremity (38%) and pelvis (17%); another 25% had extraosseous disease. The median interval between cycles was 15.0 days, with no difference between patients aged <30 years versus ≥30 years. The median number of admissions for toxicity per patient was two, primarily for febrile neutropenia. Early treatment discontinuation occurred in 17%. Dose reductions were minimal, with mean cumulative doses achieved comparable to original planned dose and no difference between patients aged <30 years versus ≥30 years.Conclusion.For adults with Ewing and Ewing‐like sarcoma, administration of interval‐compressed chemotherapy is feasible, without significant dose reductions required. Our results are comparable to prior studies involving a primarily pediatric population.Implications for Practice.For Ewing sarcoma, interval‐compressed vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide administered every 2 weeks rather than every 3 weeks has been shown to improve event‐free survival in pediatric patients. However, in adults, oncologists may be hesitant to pursue interval‐compressed therapy because of concerns for feasibility. In the adult population in this study, a median interval between cycles of 15.0 days (mean 17.0 days) was achieved, comparable to the interval achieved in AEWS0031 (median 15.0, mean 17.3 days). Given that this was achieved without unexpected toxicity or substantial dose reductions and that clinical outcomes were favorable compared with adult historical controls, these results support the use of this regimen in adults.
AbstractBackground.Primary vaginal melanomas are uncommon and aggressive tumors with poor prognosis, and the development of new targeted therapies is essential. This study aimed to identify the molecular markers occurring in these patients and potentially improve treatment strategies.Materials and Methods.The clinicopathological characteristics of 36 patients with primary vaginal melanomas were reviewed. Oncogenic mutations in BRAF, KIT, NRAS, GNAQ and GNA11 and the promoter region of telomerase reverse transcriptase (TERT) were investigated using the Sanger sequencing. The expression and copy number of programmed death‐ligand 1 (PD‐L1) were also assessed.Results.Mutations in NRAS, KIT, and TERT promoter were identified in 13.9% (5/36), 2.9% (1/34), and 5.6% (2/36) of the primary vaginal melanomas, respectively. PD‐L1 expression and amplification were observed in 27.8% (10/36) and 5.6% (2/36) of cases, respectively. PD‐L1 positive expression and/or amplification was associated with older patients (p = .008). Patients who had NRAS mutations had a poorer overall survival compared with those with a wild‐type NRAS (33.5 vs. 14.0 months; hazard ratio [HR], 3.09; 95% CI, 1.08–8.83). Strikingly, two patients with/without PD‐L1 expression receiving immune checkpoint inhibitors had a satisfying outcome. Multivariate analysis demonstrated that >10 mitoses per mm2 (HR, 2.96; 95% CI, 1.03–8.51) was an independent prognostic factor.Conclusions.NRAS mutations and PD‐L1 expression were most prevalent in our cohort of primary vaginal melanomas and can be potentially considered as therapeutic targets.Implications for Practice.This study used the Sanger sequencing, immunohistochemistry, and fluorescence in situ hybridization methods to detect common genetic mutations and PD‐L1 expression and copy number in 36 primary vaginal melanomas. NRAS mutations and PD‐L1 expression were the most prevalent, but KIT and TERT mutations occurred at a lower occurrence in this rare malignancy. Two patients receiving immune checkpoint inhibitors had a satisfying outcome, signifying that the PD‐L1 expression and amplification can be a possible predictive marker of clinical response. This study highlights the possible prospects of biomarkers that can be used for patient selection in clinical trials involving treatments with novel targeted therapies based on these molecular aberrations.
AbstractTreatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)—the number of somatic mutations per DNA megabase (Mb)—has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next‐generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole‐exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression‐free survival in patients with non‐small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response.Implications for Practice.Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next‐generation sequencing‐based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole‐exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI‐based therapies.
AbstractTreatment options for women with recurrent ovarian cancer who have received two or more prior lines of chemotherapy have recently expanded with the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals of the poly(ADP‐ribose) polymerase (PARP) inhibitor rucaparib. As more oncologists begin to use rucaparib and other PARP inhibitors as part of routine clinical practice, awareness of possible side effects and how to adequately manage toxicities is crucial. In this review, we summarize the safety and tolerability of rucaparib reported in an integrated safety analysis that supported the FDA's initial approval of rucaparib in the treatment setting. Additionally, drawing on clinical data and our personal experience with rucaparib, we provide our recommendations on the management of common side effects observed with rucaparib, including anemia, blood creatinine elevations, alanine aminotransferase and aspartate aminotransferase elevations, thrombocytopenia, gastrointestinal‐related events (e.g., nausea, vomiting), and asthenia and fatigue. These side effects, many of which appear to be class effects of PARP inhibitors, are often self‐limiting and can be managed with adequate interventions such as treatment interruption and/or dose reduction and the use of supportive therapies. Supportive therapies may include blood transfusions for patients with anemia, prophylactic medications to prevent nausea and vomiting, or behavioral interventions to mitigate fatigue. Understanding and appropriate management of potential side effects associated with rucaparib may allow patients with ovarian cancer to continue to benefit from rucaparib treatment.Implications for Practice.Rucaparib was recently approved in the U.S. and European Union for use as treatment or maintenance for recurrent ovarian cancer. This review focuses on the safety and tolerability of rucaparib in the treatment setting. Similar side effects are observed in the maintenance setting. Drawing on the authors’ clinical experience with rucaparib, rucaparib prescribing information, and published supportive cancer care guidelines, this review discusses how to optimally manage common rucaparib‐associated side effects in patients with advanced ovarian cancer in the real‐world oncology setting. Adequate management of such side effects is crucial for allowing patients with ovarian cancer to remain on treatment to receive optimal efficacy benefit.
AbstractVenous thromboembolism (VTE) frequently occurs in patients with cancer, and particularly those with pancreatic ductal adenocarcinoma (PDAC). Therapeutic anticoagulation with either low‐molecular‐weight heparin or a direct oral anticoagulant is clearly beneficial in patients who develop a VTE. However, whether thromboprophylaxis improves patient outcomes remains unclear. Studies assessing this risk show a 10%–25% risk of VTE, with reduction to 5%–10% with thromboprophylaxis but no impact on survival. To aid in the risk stratification of patients, several tools have been developed to identify those at highest risk for a VTE event. However, the clinical application of these risk stratification models has been limited, and most patients, even those at the highest risk, will never have a VTE event. New oral anticoagulants have greatly improved the feasibility of prophylaxis but do show increased risk of bleeding in patients with the underlying gastrointestinal dysfunction frequently found in patients with pancreatic cancer. Recently, several completed clinical trials shed new light on this complicated risk versus benefit decision. Here, we present this recent evidence and discuss important considerations for the clinician in determining whether to initiate thromboprophylaxis in patients with PDAC.Implications for Practice.Given the high risk of venous thromboembolism in patients with pancreatic adenocarcinoma (PDAC), whether to initiate prophylactic anticoagulation is a complex clinical decision. This review discusses recent evidence regarding the risk stratification and treatment options for thromboprophylaxis in patients with PDAC, with the goal of providing practicing clinicians with updates on recent developments in the field. This article also highlights important considerations for individualizing the treatment approach for a given patient given the lack of general consensus of uniform recommendations for this patient population.
AbstractBackground.Bevacizumab, a VEGF‐A inhibitor, in combination with chemotherapy, has proven to increase progression‐free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin‐2 (Ang‐2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF‐A and Ang‐2, suggesting that the dual VEGF‐A and Ang‐2 blocker vanucizumab (RO5520985 or RG‐7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX‐6 (folinic acid (leucovorin), fluorouracil (5‐FU) and oxaliplatin) versus bevacizumab/mFOLFOX‐6 for first‐line mCRC.Patients and Methods.All patients received mFOLFOX‐6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator‐assessed PFS.Results.One hundred eighty‐nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang‐2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm.Conclusion.Vanucizumab/mFOLFOX‐6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX‐6. Our results suggest that Ang‐2 is not a relevant therapeutic target in first‐line mCRC.Implications for Practice.This randomized phase II study demonstrates that additional angiopoietin‐2 (Ang‐2) inhibition does not result in superior benefit over anti–VEGF‐A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang‐2 is not a relevant therapeutic target in the clinical setting of treatment‐naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF‐A and Ang‐2 inhibitor vanucizumab was discontinued.
AbstractBackground.Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first‐line chemotherapy in metastatic esophagogastric cancer.Materials and Methods.Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5‐fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14‐day cycle. The primary endpoint was 6‐month progression‐free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS.Results.Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single‐center phase II study (NCT01913639). The most common grade 3–4 treatment‐related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6‐month PFS was 53% (95% confidence interval [CI], 38%–71%), the objective response rate was 54% (95% CI, 37%–70%), and the disease control rate was 77% (95% CI, 67%–94%). Next‐generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum‐based chemotherapy.Conclusion.Regorafenib (one week on–one week off schedule) is well tolerated in combination with first‐line FOLFOX but does not improve 6‐month PFS relative to historical control.Implications for Practice.Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first‐line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD‐1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.
AbstractBackground.Polypharmacy (PP) and potentially inappropriate medications (PIM) are highly prevalent in older adults with cancer. This study systematically reviews the associations of PP and/or PIM with outcomes and, through a meta‐analysis, obtains estimates of postoperative outcomes associated with PP in this population.Materials and Methods.We searched PubMed, Embase, Web of Science, and Cochrane Register of Clinical Trials using standardized terms for concepts of PP, PIM, and cancer. Eligible studies included cohort studies, cross‐sectional studies, meta‐analyses, and clinical trials which examined outcomes associated with PP and/or PIM and included older adults with cancer. A random effects model included studies in which definitions of PP were consistent to examine the association of PP with postoperative complications.Results.Forty‐seven articles met the inclusion criteria. PP was defined as five or more medications in 57% of the studies. Commonly examined outcomes included chemotherapy toxicities, postoperative complications, functional decline, hospitalization, and overall survival. PP was associated with chemotherapy toxicities (4/9 studies), falls (3/3 studies), functional decline (3/3 studies), and overall survival (2/11 studies). A meta‐analysis of four studies indicated an association between PP (≥5 medications) and postoperative complications (overall odds ratio, 1.3; 95% confidence interval [1.3–2.8]). PIM was associated with adverse outcomes in 3 of 11 studies.Conclusion.PP is associated with postoperative complications, chemotherapy toxicities, and physical and functional decline. Only three studies showed an association between PIM and outcomes. However, because of inconsistent definitions, heterogeneous populations, and variable study designs, these associations should be further investigated in prospective studies.Implications for Practice.Polypharmacy and potentially inappropriate medications (PIM) are prevalent in older adults with cancer. This systematic review summarizes the associations of polypharmacy and PIM with health outcomes in older patients with cancer. Polypharmacy and PIM have been associated with postoperative complications, frailty, falls, medication nonadherence, chemotherapy toxicity, and mortality. These findings emphasize the prognostic importance of careful medication review and identification of PIM by oncology teams. They also underscore the need to develop and test interventions to address polypharmacy and PIM in older patients with cancer, with the goal of improving outcomes in these patients.
AbstractLessons Learned.Perioperative capecitabine and oxaliplatin (CapeOx) therapy showed favorable efficacy with sufficient pathological response. Small sample size limited the statistical power of this result.Perioperative CapeOx therapy showed good feasibility.Further studies with larger sample size are required to validate this novel approach.Background.D2 gastrectomy followed by adjuvant S‐1 is the standard therapy for patients (pts) with stage III gastric cancer (GC) in Japan; however, the outcome is not satisfactory. We examined the efficacy of perioperative capecitabine and oxaliplatin (CapeOx) in pts with GC.Methods.The eligibility criteria included confirmed clinical T3(SS)/T4a(SE) N1‐3 M0 GC according to the Japanese Classification (JCGC; 3rd English Edition). Three cycles of neoadjuvant CapeOx (NAC; capecitabine, 2,000 mg/m2 for 14 days; oxaliplatin, 130 mg/m2 on day 1, every 3 weeks) were administered, followed by five cycles of adjuvant CapeOx (AC) after D2 gastrectomy. The primary endpoint was the pathological response rate (pRR) according to the JCGC (≥grade 1b).Results.Thirty‐seven pts were enrolled on CapeOx. An R0 resection rate of 78.4% (n = 29) and a pRR of 54.1% (n = 20, p = .058; 90% confidence interval [CI], 39.4–68.2) were demonstrated. Among 27 pts who initiated AC, 21 (63.6%) completed the treatment. Grade 3–4 toxicities during NAC included neutropenia (8%), thrombocytopenia (8%), and anorexia (8%) and during AC included neutropenia (37%), diarrhea (4%), and anorexia (4%).Conclusion.Perioperative CapeOx showed good feasibility and favorable efficacy with sufficient pathological response, although statistical significance at .058 did not reach the commonly accepted cutoff of .05. The data obtained using this novel approach warrant further investigations.
AbstractCabozantinib treatment prolonged progression‐free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number. NCT01835158.
AbstractGeriatric assessment (GA) is used in oncology to identify deficits in older patients with cancer that may affect treatment choice. We examine GA in 550 patients with early breast cancer, including both younger (<65 years) and older women (aged 65 years or older), to assess the potential value of this tool in younger, presumed “healthier” patients. Although older women have more GA‐identified deficits overall, younger patients are more anxious. Suboptimal physical function was problematic across the age spectrum. GA domains can identify major deficits in younger patients beyond those likely to be uncovered in routine investigation.
AbstractBackground.Studies have demonstrated worse breast cancer‐specific mortality with older age, despite an increasing risk of dying from other causes due to comorbidity (competing mortality). However, findings on the association between older age and recurrence risk are inconsistent. The aim of this study was to assess incidences of locoregional and distant recurrence by age, taking competing mortality into account.Materials and Methods.Patients surgically treated for nonmetastasized breast cancer between 2003 and 2009 were selected from The Netherlands Cancer Registry. Cumulative incidences of recurrence were calculated considering death without distant recurrence as competing event. Fine and Gray analyses were performed to characterize the impact of age (70–74 [reference group], 75–79, and ≥80 years) on recurrence risk.Results.A total of 18,419 patients were included. Nine‐year cumulative incidences of locoregional recurrence were 2.5%, 3.1%, and 2.9% in patients aged 70–74, 75–79, and ≥80 years, and 9‐year cumulative incidences of distant recurrence were 10.9%, 15.9%, and 12.7%, respectively. After adjustment for tumor and treatment characteristics, age was not associated with locoregional recurrence risk. For distant recurrence, patients aged 75–79 years remained at higher risk after adjustment for tumor and treatment characteristics (75–79 years subdistribution hazard ratio [sHR], 1.25; 95% confidence interval [CI], 1.11–1.41; ≥80 years sHR, 1.03; 95% CI, 0.91–1.17).Conclusion.Patients aged 75–79 years had a higher risk of distant recurrence than patients aged 70–74 years, despite the higher competing mortality. Individualizing treatment by using prediction tools that include competing mortality could improve outcome for older patients with breast cancer.Implications for Practice.In this population‐based study of 18,419 surgically treated patients aged 70 years or older, patients aged 75–79 years were at higher risk of distant recurrence than were patients aged 70–74 years. This finding suggests that patients in this age category are undertreated. In contrast, it was also demonstrated that the risk of dying without a recurrence strongly increases with age, and patients with a high competing mortality risk are easily overtreated. To identify older patients who may benefit from more treatment, clinicians should therefore take competing mortality risk into account. Prediction tools could facilitate this and thereby improve treatment strategy.
AbstractBackground.Nivolumab has shown a survival benefit compared with docetaxel as second‐line treatment for patients with previously treated advanced squamous non‐small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program.Patients and Methods.Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information.Results.The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any‐grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment‐related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment‐related deaths.Conclusion.To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real‐world setting are consistent with those obtained in clinical trials.Implications for Practice.Nivolumab is approved in the U.S. and Europe for the treatment of advanced non‐small cell lung cancer (NSCLC) after failure of prior platinum‐based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real‐world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.
AbstractBackground.Canada has an established publicly funded health care system with a complex drug approval and funding process. After proof of efficacy (POE; key publication/presentation) and before becoming publicly accessible, each drug undergoes a Health Canada approval process, a health technology assessment (HTA), a pricing negotiation, and finally individual provincial funding agreements. We quantified potential life‐years lost during this process.Methods.We analyzed drugs for advanced lung, breast, and colorectal cancer that underwent the HTA process between 2011 and 2016. Life‐years lost were calculated by multiplying documented improvement in progression‐free and overall survival, number of eligible patients, and time from POE to first public funding. For conservative calculation, we assumed all eligible patients in Canada had access at the time of first public funding, whereas in reality provinces fund at different time points.Results.We analyzed 21 drugs. Of these, 15 have been funded publicly. The time from POE to first public funding ranged from 14.0 to 99.2 months (median 26.6 months). Total overall life‐years lost from POE to first public funding were 39,067 (lung 32,367; breast 6,691). Progression‐free life‐years lost from POE to first public funding were 48,037 (lung 9,139, breast 15,827, colorectal 23,071).Conclusion.The number of potential life‐years lost during the drug regulatory and funding process in Canada is substantial, largely driven by delays to funding of colorectal cancer drugs. Recognizing that interprovincial differences exist and that eligible patients may not all receive a given drug, if even a fraction does so, the impact of delays remains substantive. Collaborative national initiatives are required to address this major barrier to treatment access.Implications for Practice.Patients may spend lengthy periods of time awaiting access to new and effective cancer drugs. Patients with private drug insurance or personal funds or who reside in certain Canadian provinces may obtain some drugs sooner than others, potentially creating a two‐tiered access system. The cancer drug access and public funding system must be expedited to improve equity.
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