Opinion statement
Pancreatic cancer is increasing in incidence in the USA. This disease disproportionately affects older adults, and as the percentage of adults > 65 years old increases with the ...aging of the baby boomers, the prevalence is expected to rise over the coming decade. These patients are often more susceptible to disease-related symptoms and have less ability to withstand both cancer and treatment-related side effects. Therefore, it is imperative that treating physicians thoughtfully consider their recommended treatment approach towards this vulnerable patient population. This review focuses on the current state of research of older adults with pancreatic adenocarcinoma, highlighting deficiencies in the representation of this patient population in clinical trials. It is vital that the treating physicians take a nuanced approach towards therapy of localized and metastatic disease in geriatric patients. A one size fits all treatment algorithm is no longer appropriate in any cancer patient, let alone the elders who are particularly vulnerable to developing treatment-related toxicities. To help guide therapy decisions, it is important to perform a comprehensive geriatric assessment which may uncover unexpected frailty and lead to a change in the recommended treatment approach. In this way, we can support older adults during therapy for this aggressive malignancy and provide optimal care.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study ...evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.
In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed.
Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% 95% CI 26·5–45·4) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 60% of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 12%), arthralgia (nine 6%), stomatitis (eight 5%), hyponatraemia (eight 5%), abdominal pain (seven 5%), and fatigue (seven 5%). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven 5%), pyrexia (seven 5%), cholangitis (five 3%), and pleural effusion (five 3%). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 42%); no deaths were deemed to be treatment related.
These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
Incyte Corporation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Opinion statement
The need for evidence-based data in the rapidly growing group of older patients is vast and more elderly-specific studies are desperately needed, for which there is clear demand ...from both patients and providers. Notably, many of the studies discussed in this review included unplanned subset analyses based on age and/or were not originally stratified by age; therefore, these data, particularly overall survival data, need to be interpreted with some caution as they may not be statistically valid based on the initial trial design and statistical plan. As we await data from ongoing elderly-specific trials, our recommendation for managing older patients with CRC should include geriatric screening tools (e.g., CSGA, VES-13, G8, CARG, CRASH) to help guide treatment adjustments for improved tolerability without sacrificing efficacy. For patients with a positive screen for significant geriatric concerns, a full geriatric assessment is recommended to guide treatment approach and supportive care. Prior data support the use of all approved medications for CRC in older adults who are fit; however, treatment breaks and dose attenuation with potential escalation are reasonable options for these patients. Ultimately, management decisions in the care of older adults with mCRC must be made through shared decision-making with the patient with consideration for the patient’s functional status, comorbidities, goals of care, social support, as well as potential toxicities and possible effect on QoL.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. ctDNA can comprise up to 10% of a patient's cfDNA ...depending on their tumor type and burden. The short half-life of ctDNA ensures that its detection captures tumor burden in real-time and offers a non-invasive method of repeatedly evaluating the genomic profile of a patient's tumor. A challenge in ctDNA detection includes clonal hematopoiesis of indeterminate potential (CHIP), which can be distinguished from tumor variants using a paired whole-blood control. Most assays for ctDNA quantification rely on measurements of somatic variant allele frequency (VAF), which is a mutation-dependent method. Patients with certain types of solid tumors, including colorectal cancer (CRC), can have levels of cfDNA 50 times higher than healthy patients. ctDNA undergoes a precipitous drop shortly after tumor resection and therapy, and rising levels can foreshadow radiologic recurrence on the order of months. The amount of tumor bulk required for ctDNA detection is lower than that for computed tomography (CT) scan detection, with ctDNA detection preceding radiologic recurrence in many cases. cfDNA/ctDNA can be used for tumor molecular profiling to identify resistance mutations when tumor biopsy is not available, to detect minimal residual disease (MRD), to monitor therapy response, and for the detection of tumor relapse. Although ctDNA is not yet implemented in clinical practice, studies are ongoing to define the appropriate way to use it as a tool in the clinic. In this review article, we examine the general aspects of ctDNA, its status as a biomarker, and its role in the management of early (II-III) and late (IV; mCRC) stage colorectal cancer (CRC).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination ...with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (
n
= 16).
Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously ...treated metastatic G3NENs.
Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint.
Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related.
Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered.
NCT02939651 (10/20/2016).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Limited tools exist to predict the risk of chemotherapy toxicity in older adults with early-stage breast cancer.
Patients of age ≥ 65 years with stage I-III breast cancer from 16 institutions treated ...with neoadjuvant or adjuvant chemotherapy were prospectively evaluated for geriatric and clinical features predictive of grade 3-5 chemotherapy toxicity. Logistic regression with best-subsets selection was used to identify and incorporate independent predictors of toxicity into a model with weighted variable scoring. Model performance was evaluated using area under the ROC curve (AUC) and goodness-of-fit statistics. The model was internally and externally validated.
In 473 patients (283 in development and 190 in validation cohort), 46% developed grade 3-5 chemotherapy toxicities. Eight independent predictors were identified (each assigned weighted points): anthracycline use (1 point), stage II or III (3 points), planned treatment duration > 3 months (4 points), abnormal liver function (3 points), low hemoglobin (3 points), falls (4 points), limited walking (3 points), and lack of social support (3 points). We calculated risk scores for each patient and defined three risk groups: low (0-5 points), intermediate (6-11 points), or high (≥ 12 points). In the development cohort, the rates of grade 3-5 chemotherapy toxicity for these three groups were 19%, 54%, and 87%, respectively (
< .01). In the validation cohort, the corresponding toxicity rates were 27%, 45%, and 76%. The AUC was 0.75 (95% CI, 0.70 to 0.81) in the development cohort and 0.69 (95% CI, 0.62 to 0.77) in the validation cohort. Risk groups were also associated with hospitalizations and reduced dose intensity (
< .01).
The Cancer and Aging Research Group-Breast Cancer (CARG-BC) score was developed and validated to predict grade 3-5 chemotherapy toxicity in older adults with early-stage breast cancer.
Approximately one third of patients diagnosed with early-stage colon cancer will present with lymph node involvement (stage III) and about one quarter with transmural bowel wall invasion but negative ...lymph nodes (stage II). Adjuvant chemotherapy targets micrometastatic disease to improve disease-free (DFS) and overall survival (OS). While beneficial for stage III patients, the role of adjuvant chemotherapy is unestablished in stage II disease. This likely relates to the improved outcome of these patients, and the difficulties in developing studies with sufficient power to document benefit in this patient population. However, recent investigation also suggests that molecular differences may exist between stage II and III cancers and within stage II patients. Validated pathologic prognostic markers are useful at identifying stage II patients at high risk for recurrence for whom the benefit from adjuvant chemotherapy may be greater. Such high-risk features include higher T stage (T4 v T3), suboptimal lymph node retrieval, presence of lymphovascular invasion, bowel obstruction, or bowel perforation, and poorly differentiated histology. However, for the majority of patients who do not carry any of these adverse features and are classified as "average-risk" stage II patients, the benefit of adjuvant chemotherapy remains unproven. Emerging understanding of the underlying biology of stage II colon cancer has identified molecular markers that may change this paradigm and improve our risk assessment and treatment choices for stage II disease. Assessment of microsatellite stability (MSI), which serves as a marker for DNA mismatch repair (MMR) system function, has emerged as a useful tool for risk stratification of patients with stage II colon cancer. Patients with high frequency of MSI have been shown to have increased OS and limited benefit from 5-fluorouracil (5-FU)-based chemotherapy. Additional research is necessary to clearly define the most appropriate way to use this marker and others in routine clinical practice.
Introduction
Positive cytology from peritoneal washings obtained prior to potential resection of pancreatic cancer is associated with grim prognosis, equivalent to M1 disease. We examine our ...experience with pancreatic cancer patients who underwent pre-resection lavage in an attempt to predict who would have malignant cells on peritoneal cytology.
Methods
We conducted a retrospective review of patients undergoing pancreatectomy for pancreatic adenocarcinoma at a tertiary care institution from 1995 to 2019 and had pre-resection lavage performed. Demographic and clinicopathologic data were collected. Logistic regression models were used to identify predictors of positive cytology.
Results
Three hundred ninety-nine patients underwent pancreatic resection and had lavage performed. Forty-three (10.8%) had positive peritoneal cytology. Those with positive cytology had higher median Ca19-9 value than those with negative cytology at diagnosis (368.5 vs 200 U/mL,
p
= 0.007) and after neoadjuvant therapy (100.3 vs 43 U/mL,
p
= 0.013). After controlling for preoperative therapy received, an initial Ca19-9 greater than 1220 U/mL (OR 2.72, 95% CI 1.07–6.89,
p
= 0.035), locally advanced disease (OR 4.86, 95% CI 1.31–18.09,
p
= 0.018), and BMI ≥ 25 kg/m
2
(OR 2.67, 95% CI 1.04–6.97,
p
= 0.042) were associated with positive cytology in multivariate logistic regression model. The associated ROC curve had an AUC of 0.7507, suggesting adequate discrimination of those with positive peritoneal cytology.
Conclusion
Diagnostic laparoscopy remains an important adjunct to the workup, diagnosis, and staging of pancreatic adenocarcinoma. Patients with locally advanced disease, significantly elevated serum Ca19-9 at diagnosis, and BMI ≥ 25 kg/m
2
may be at higher risk for positive peritoneal cytology, regardless of whether neoadjuvant therapy is administered.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti-angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy.
This phase ...I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy 5-1,500 mg every 3 weeks (Q3W) or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed.
We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer prolonged grade 3 edema-associated adverse events (AE) occurred. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively.
Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued.
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