The optimal first‐line palliative systemic treatment strategy for metastatic esophagogastric cancer is not well defined. The aim of our study was to explore real‐world use of first‐line systemic ...treatment in esophagogastric cancer and assess the effect of treatment strategy on overall survival (OS), time to failure (TTF) of first‐line treatment and toxicity. We selected synchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010–2016) from the nationwide Netherlands Cancer Registry (n = 2,204). Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy, and trastuzumab‐containing regimens. Data on OS were available for all patients, on TTF for patients diagnosed from 2010 to 2015 (n = 1,700), and on toxicity for patients diagnosed from 2010 to 2014 (n = 1,221). OS and TTF were analyzed using multivariable Cox regression, with adjustment for relevant tumor and patient characteristics. Up to 45 different systemic treatment regimens were found to be administered, with a median TTF of 4.6 and OS of 7.5 months. Most patients (45%) were treated with doublet chemotherapy; 34% received triplets, 10% monotherapy and 10% a trastuzumab‐containing regimen. The highest median OS was found in patients receiving a trastuzumab‐containing regimen (11.9 months). Triplet chemotherapy showed equal survival rates compared to doublets (OS: HR 0.92, 95%CI 0.83–1.02; TTF: HR 0.92, 95%CI 0.82–1.04) but significantly more grade 3–5 toxicity than doublets (33% vs. 21%, respectively). In conclusion, heterogeneity of first‐line palliative systemic treatment in metastatic esophagogastric cancer patients is striking. Based on our data, doublet chemotherapy is the preferred treatment strategy because of similar survival and less toxicity compared to triplets.
What's new?
Metastatic esophagogastric cancer can't be cured, but palliative therapy can improve patients’ quality of life and survival. However, there's no consensus regarding the optimal first‐line palliative systemic therapy for metastatic esophagogastric cancer. Here, the authors evaluated real‐world use of first‐line systemic treatments. The retrospective study included a cohort of 2,204 metastatic patients and found 45 different treatment regimens administered. Patients that received doublet and triplet chemotherapy had similar survival, with triplet patients experiencing higher toxicity. Monotherapy produced significantly worse overall survival and only modest reduction in toxicity. These findings support doublet therapy as the optimal first‐line treatment strategy.
Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour ...types (soft-tissue sarcomas STS, ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer NSCLC, gastric/esophageal cancer and transitional cell carcinoma TCC).
During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.
A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio HR: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval CI: 1.4–4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3–1.6) for placebo (HR = 0.64, 95% CI: 0.38–1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6–4.2) months for brivanib and 2.0 months (95% CI: 1.2–2.7) for placebo (HR: 0.56, 95% CI: 0.26–1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6–4.2) and was 2.0 months (95% CI: 1.2–2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25–1.17; p = 0.11).
Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.
•We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas STS, ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer, gastric/esophageal cancer and transitional cell carcinoma).•In 53 randomised patients with STS and fibroblast growth factor (FGF) 2–positive tumours, the median progression-free survival was 2.8 for brivanib and was 1.4 months for placebo (hazard ratio: 0.58, p = 0.08).•Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile.•FGF2 expression (per protocol) is not a predictive biomarker of the efficacy of brivanib.
Data on treatment and survival of patients with advanced unresectable esophageal squamous cell carcinoma (ESCC) from Western populations are limited. Here we describe treatment and survival in ...patients with advanced unresectable ESCC: patients with cT4b disease without metastases (cT4b), metastases limited to the supraclavicular lymph nodes (SCLNM) or distant metastatic ESCC at the population level. All patients with unresectable (cT4b) or synchronous metastatic ESCC at primary diagnosis (2015‐2018) or patients with metachronous metastases after primary non‐metastatic diagnosis in 2015‐2016 were selected from the Netherlands Cancer Registry. Fifteen percent of patients had cT4b disease (n = 146), 12% SCLNM (n = 118) and 72% distant metastases (n = 681). Median overall survival (OS) time was 6.3, 11.2, and 4.4 months in patients with cT4b, SCLNM, and distant metastases, respectively (P < .001). Multivariable Cox regression showed that patients with cT4b (hazard ratio 1.44, 95% CI 1.04‐1.99) and patients with distant metastases (hazard ratio 1.42, 95% CI 1.12‐1.80) had a worse survival time compared with patients with SCLNM. Among patients who received chemoradiotherapy and/or underwent resection (primary tumor and/or metastases), median OS was 11.9, 16.1, and 14.0 months in patients with cT4b, SCLNM, and distant metastases, respectively (P = .76). Patients with SCLNM had a better survival time compared with patients with cT4b and patients with distant metastases. Survival of patients with advanced unresectable ESCC in clinical practice was poor, even in patients treated with curative intent.
Patients with metastases limited to the supraclavicular lymph nodes had a better survival time compared with patients with a cT4b tumor (without metastases) and patients with distant metastases. Survival of patients with advanced unresectable ESCC in clinical practice was poor, even in patients treated with curative intent.
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are both deadly cancers and they share many biological features besides their close anatomical location. One of the main ...histological features is neurotropism, which results in frequent perineural invasion. The underlying mechanism of cancer cells favoring growth by and through the nerve fibers is not fully understood. In this review, we provide knowledge of these cancers with frequent perineural invasion. We discuss nerve fiber crosstalk with the main different components of the tumor microenvironment (TME), the immune cells, and the fibroblasts. Also, we discuss the crosstalk between the nerve fibers and the cancer. We highlight the shared signaling pathways of the mechanisms behind perineural invasion in PDAC and CCA. Hereby we have focussed on signaling neurotransmitters and neuropeptides which may be a target for future therapies. Furthermore, we have summarized retrospective results of the previous literature about nerve fibers in PDAC and CCA patients. We provide our point of view in the potential for nerve fibers to be used as powerful biomarker for prognosis, as a tool to stratify patients for therapy or as a target in a (combination) therapy. Taking the presence of nerves into account can potentially change the field of personalized care in these neurotropic cancers.
Aims
Olaparib, a potent oral poly(ADP‐ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or ...moderate hepatic impairment to provide dosing recommendations.
Methods
This Phase I open‐label study assessed the PK, safety and tolerability of single doses of olaparib 300‐mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child–Pugh class A) or moderate (MoHI; Child–Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long‐term safety assessment.
Results
Thirty‐one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least‐squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected.
Conclusion
Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.
Background
Brown adipose tissue (BAT) has been primarily researched as a potential target for mitigating obesity. However, the physiological significance of BAT in relation to cachexia remains poorly ...understood. The objective of this study was to investigate the putative contribution of BAT on different components of energy metabolism in emphysematous chronic obstructive pulmonary disease (COPD) patients.
Methods
Twenty COPD patients (mean ± SD age 62 ± 6, 50% female, median range BMI 22.4 15.1–32.5 kg/m2 and 85% low FFMI) were studied. Basal metabolic rate (BMR) was assessed by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water and physical activity by triaxial accelerometry. BMR was adjusted for fat‐free mass (FFM) as assessed by deuterium dilution. Analysis of BAT and WAT was conducted in a subset of ten patients and six age‐matched, gender‐matched and BMI‐matched healthy controls. BAT glucose uptake was assessed by means of cold‐stimulated integrated 18FFDG positron‐emission tomography and magnetic resonance imaging. WAT was collected from subcutaneous abdominal biopsies to analyse metabolic and inflammatory gene expression levels. Lung function was assessed by spirometry and body plethysmography and systemic inflammation by high sensitivity C‐reactive protein.
Results
Mean TDEE was 2209 ± 394 kcal/day, and mean BMR was 1449 ± 214 kcal/day corresponding to 120% of predicted. FFM‐adjusted BMR did not correlate with lung function or C‐reactive protein. Upon cooling, energy expenditure increased, resulting in a non‐shivering thermogenesis of (median range) 20.1% 3.3–41.3 in patients and controls. Mean BAT glucose uptake was comparable between COPD and controls (1.5 0.1–6.2 vs. 1.1 0.7–3.9). In addition, no correlation was found between BMR adjusted for FFM and BAT activity or between cold‐induced non‐shivering energy expenditure and BAT activity. Gene expression levels of the brown adipocyte or beige markers were also comparable between the groups. No (serious) adverse events were reported.
Conclusions
Although COPD patients were hypermetabolic at rest, no correlation was found between BMR or TDEE and BAT activity. Furthermore, both BAT activity and gene expression levels of the brown adipocyte or beige markers were comparable between COPD patients and controls.
No standard treatment is available for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin (GEMCIS). The objective of this study was to evaluate safety and ...anti-tumour activity of fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) as salvage treatment in patients with previously treated advanced BTC.
In this two-stage phase 2 study, patients with advanced BTC who had disease progression or unacceptable toxicity after ≥3 cycles of GEMCIS were eligible. Primary endpoints were safety and efficacy (defined as objective response rate, ORR). In stage one, ten patients were treated with FOLFIRINOX every 2 weeks. In stage two, an additional 20 patients were enrolled at a starting dose as defined in stage one, provided that in stage ≥1 objective response or ≥2 stable diseases were observed and ≤3 patients had serious adverse events (SAEs) within the first 6 weeks of treatment. Secondary endpoints were progression-free survival (PFS) and overall survival (OS).
Forty patients were screened for eligibility and 30 patients were enrolled. In stage one, one patient had a partial response and five patients had stable disease. One patient had a SAE during the first 6 weeks of treatment, and five patients required a dose reduction due to adverse events. The most common grade 3-4 adverse events in stage one were neutropaenia, mucositis and diarrhoea. Stage two was initiated with FOLFIRINOX in an adapted dose. In stage two, grade 3-4 neutropaenia, diarrhoea, nausea and vomiting were the most common adverse events. The ORR, median PFS and OS in all patients were 10%, 6.2 and 10.7 months, respectively.
In patients with advanced BTC who progressed after or were intolerant to GEMCIS, FOLFIRINOX can be administered safely and could be considered as an option for salvage treatment in these patients.
ClinicalTrials.gov Identifier NCT02456714.
The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC‐4 trial. Real‐world data on the effectiveness of ...gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015‐2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8‐40.7) for GEMCAP and 22.1 months (95% CI 20.6‐25.0) for GEM (HR: 0.71, 95% CI 0.56‐0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57‐0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.
What's new?
The benefit of treating pancreatic ductal adenocarcinoma (PDAC) with a combination of gemcitabine plus capecitabine (vs gemcitabine alone) was previously shown in a carefully controlled clinical trial. But does this approach work as well in the real world? In this study, the authors found that the answer is yes—patients had significantly better overall survival (OS) with the combined therapy than with gemcitabine alone. These results may aid in the selection of adjuvant chemotherapy for patients who are not eligible for modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin).
Abstract Purpose The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA -mutated ovarian cancer, is mediated by ...cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. Methods Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0–t and Cmax fell within the bioequivalence range of 0.80–1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). Findings In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33–1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44–2.97). Mean CL/F and Vz /F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24–0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11–0.16). CL/F and Vz /F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. Implications Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).
Background
Addition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment ...and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients.
Methods
Data of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010–2016 that received palliative systemic treatment (
n
= 2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test.
Results
HER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (
P
< 0.01). Median OS increased from 6.9 (2010–2013) to 7.9 months (2014–2016;
P
< 0.05). Between the hospitals, the proportion of tested patients varied between 29–100%, and was higher in high-volume hospitals (
P
< 0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months;
P
< 0.05).
Conclusion
Increased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.
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