Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Healthcare utilisation in patients with breast cancer or non-Hodgkin lymphoma who experienced febrile neutropenia in the Netherlands: a retrospective matched control study using the PHARMO database.

Few data have been published on healthcare resource utilisation associated with chemotherapy-induced febrile neutropenia (FN) in Europe. Using the PHARMO record linkage system, we identified incident adult patients with a primary hospital discharge diagnosis of breast cancer (BC) or non-Hodgkin lymphoma (NHL) from 1998 to 2008. Patients who experienced FN were matched 1:2 non-FN reference patients. Of 1033 BC patients, 80 (8%) had FN and were matched with 160 reference patients; and of 486 NHL patients, 95 (20%) had FN and 89 were matched with 178 reference patients. Significantly more FN patients were hospitalised for any cause than reference patients: BC, 81% vs. 24% (OR 12.6; 95% CI 5.7-27.8); NHL, 82% vs. 44% (OR 6.7; 95% CI 3.3-13.9). Median length of all-cause hospitalisation stay was higher for FN patients: BC, 4.0 vs. 1.0 days; NHL, 8.5 vs. 1.8 days. The median (interquartile range) number of medication treatments was higher for FN patients: BC, 5.5 (4.0-7.5) vs. 2.0 (2.0-4.0); NHL, 8.0 (5.0-11.0) vs. 3.0 (2.0-4.0). In conclusion, FN in patients with BC or NHL had increased healthcare utilisation compared with non-FN patients; thus, efforts to reduce FN are warranted to reduce cost and improve outcomes.

Pharmacokinetics of panitumumab in a patient with liver dysfunction: a case report.

PURPOSE: Panitumumab is used for the treatment for metastatic RAS wild-type colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment has not been investigated, and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction. METHODS: A heavily pretreated KRAS wild-type mCRC patient with liver disease Child-Pugh class B was treated with 2-weekly intravenous panitumumab (6 mg/kg). The patient received 2 doses of 490 mg i.v. panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected, and panitumumab concentrations were determined using a validated immunoassay. Pharmacokinetic parameters after the first dose, including dose-normalized AUC from time zero-day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal noncompartmental methods. Data were compared to historical data from a population with adequate liver function, as reported by Stephenson (Clin Colorectal Cancer, 8:29-37, 2009). Values within the range of the mean ±1 standard deviation (SD) were considered not deviant. RESULTS: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 µg day/mL (Stephenson's cohort 1: 744 ± 195 µg day/mL). Estimated T1/2 was 3.58 days (5.28 ± 1.90 days), and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ±1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment; particularly, no diarrhea and skin toxicity were noticed. CONCLUSIONS: The pharmacokinetics of panitumumab in this patient suffering from metastatic colorectal cancer with liver dysfunction Child-Pugh class B was similar compared to patients with adequate liver function. Moreover, no substantial toxicity was detected. The here-presented data may help clinical decision making in real-life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS wild-type mCRC and hepatic dysfunction, without the need for any dose adjustments.

Panitumumab monotherapy as a second-line treatment in metastasised colorectal cancer: a single centre experience.

AIMS: To report our clinical experience of panitumumab monotherapy as a second-line treatment for patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: This retrospective, descriptive study included a series of consecutive patients receiving panitumumab monotherapy (6 mg/kg 2 weekly) at a single centre in the Netherlands between June 2009 and November 2011. All patients had wild-type KRAS tumours, had progressed during first-line fluoropyrimidine-based therapy and were not candidates for, or refused, standard second-line therapy (usually irinotecan in the Netherlands). Prophylactic medication was given for epidermal growth factor receptor inhibitor-associated skin toxicities. RESULTS: Thirty-one patients were treated during this period. The most commonly administered first-line mCRC regimen was capecitabine/oxaliplatin/bevacizumab (18/31 patients; 58.1%). Patients received a mean of 7.9 (range 1-18) panitumumab cycles. The median progression-free survival was 3.4 (95% confidence interval 2.4, 4.4) months. The median overall survival estimates were 11.4 (95% confidence interval 1.2, 21.6) months from the initiation of panitumumab monotherapy. Ten patients experienced partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST; objective response rate: 32.3%); disease was controlled (objective response or stable disease) in 15 patients (48.4%). Carcinoembryonic antigen (CEA) responses (two consecutive ≥10% decreases from baseline) occurred in 11/29 patients (37.9%); all of whom had >50% decreases in CEA levels. All patients with an objective response at week 12 had CEA reductions at weeks 6 and 12. The only adverse events were grade 1/2 skin toxicities (61.3%) and gastrointestinal complaints (6.5%); three other patients (9.7%) experienced both skin and gastrointestinal complaints. CONCLUSION: Panitumumab monotherapy seems to be a safe and active second-line treatment for patients with wild-type KRAS mCRC, with activity in line with that seen for irinotecan monotherapy, but with less toxicity. CEA may provide a useful early indicator of response to panitumumab.

Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review.

Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.

Renal function as a predictor of irinotecan-induced neutropenia.

Although approximately half of the administered dose of irinotecan is recovered in urine, scarce data are available on the association of renal function with irinotecan pharmacokinetics and toxicity. Here, these relationships are investigated in 187 patients treated with irinotecan in a three-weekly schedule. No significant effects on irinotecan pharmacokinetics were found in these patients. However, in 131 patients treated with the registered dose, categorized renal function was related to hematological toxicity. The incidence of grade 3-4 neutropenia decreased as function of creatinine clearance, particularly in nonsmoking patients (P < 0.01). Patients with slower creatinine clearance (35-66 ml/min) had a four-times higher risk of grade 3-4 neutropenia (58% vs. 14%; P < 0.001). This study suggests that pretreatment renal function values are associated with irinotecan-induced neutropenia. A confirmatory analysis is warranted to determine whether measures of renal function should be incorporated in future attempts toward individualized treatment with irinotecan.

Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity.

BACKGROUND: Recently, case reports of patients treated with imatinib (imatinib mesylate; Gleevec; Glivec) indicated that this tyrosine kinase inhibitor may induce cardiomyopathy. Consequently, careful cardiac monitoring was advocated for clinical studies. The purpose of this study was to prospectively evaluate whether imatinib (Gleevec) induces early, subclinical, cardiac toxicity. PATIENTS AND METHODS: History and physical examination were carried out with special attention for symptoms of heart failure. Additionally, assessments of serial plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) and serum cardiac troponin T (cTnT) measurement before and 1 and 3 months after the start of imatinib treatment (400-800 mg daily) were done in patients with advanced and/or metastatic gastrointestinal stromal tumours (GIST). RESULTS: A total of 55 GIST patients were enrolled. Only one patient, with a normal pretreatment NT-proBNP, showed an increase in NT-proBNP to above age-specific normal values during imatinib treatment and developed symptomatic heart failure due to pre-existent cardiac valvular disease. cTnT levels remained stable. CONCLUSIONS: In our study population, imatinib treatment for GIST was not associated with an increase in plasma NT-proBNP levels, indicating that the risk of subclinical cardiac toxicity is limited with the use of this agent. These results do not support the current strategy to standard cardiac monitoring in all patients. This may be restricted to GIST patients with a history of cardiac disease.

Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein.

Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

Limited potential of hepatic arterial infusion of irinotecan.

Intravenously administered irinotecan has gained an important place in the struggle against metastatic and/or irresectable colorectal cancer. In patients with irresectable metastases confined to the liver, hepatic arterial infusion (HAI) of this anti-cancer agent has considered to be an option. Partly based on conducted phase I- and II-studies, here we conclude that irinotecan as single agent HAI therapy has limited potential compared to intravenous administration. From a pharmacokinetic-pharmacodynamic point of view, in particular the long half-life of the active metabolite, SN-38, its use is limited as well. In our view, future clinical implementation of irinotecan as HAI chemotherapy is unrealistic.

The acute phase response in the rodent.

In the rodent, the general response to acute inflammation and tissue damage is characterized by a complex rearrangement in the pattern of concentrations of proteins in the plasma leading to an increase in the sedimentation rate of erythrocytes, an increase in leukocyte concentration in the bloodstream, and a decrease in the hematocrit. Body temperature changes only slightly or not at all. The reasons for the change in plasma concentrations of proteins are changes in their rates of synthesis in the liver. Degradation of plasma proteins is not affected. The details of the acute phase response evolved in the interaction of species with their environment. Therefore, it is not surprising to find differences in the details of the acute phase response among species. For example, alpha 2-macroglobulin is a strongly positive acute phase reactant in the rat, but not in the mouse; C-reactive protein is a strongly positive acute phase protein in the mouse, but is not found in the rat. An inducible acute phase cysteine proteinase inhibitor system, which has evolved from a primordial kininogen gene, has been observed so far only in the rat. The changes in the synthesis rates of acute phase proteins during inflammation are closely reflected by corresponding changes in intracellular mRNA levels. In the liver, the capacity to induce the acute phase pattern of synthesis and secretion of plasma proteins probably develops around birth. Changes in mRNA levels are brought about by changes in transcription rates or by changes in mRNA stability. Kinetics of mRNA changes during the acute phase response differ for individual proteins. The main signal compound for eliciting the acute phase response in liver seems to be interleukin-6/interferon-beta 2/hepatocyte stimulating factor, whereas interleukin-1 leads to typical acute phase changes in mRNA levels only for alpha 1-acid glycoprotein, albumin, and transthyretin. Plasma protein genes are expressed in various extrahepatic tissues, such as the choroid plexus, the yolk sac, the placenta, the seminal vesicles, and other sites. All these tissues are involved in maintaining protein homeostasis in associated extracellular compartments by synthesis and secretion of proteins. Synthesis and secretion of plasma proteins in paracompartmental organs other than the liver is not influenced by the acute phase stimuli.

Effect of recombinant interleukin-1 on mRNA levels in rat liver.

Levels of rat liver mRNA for the plasma proteins albumin, apolipoprotein E, transthyretin, transferrin, alpha 1-acid glycoprotein, major acute-phase alpha 1-protein, and the beta-chain of fibrinogen were measured after intraperitoneal injection of interleukin-1 alpha (IL-1). A maximum response of mRNA levels for most of the plasma proteins studied was reached between 6 and 10 h after injection of IL-1. The results suggest that at the dosage used, IL-1 alone does not elicit a typical acute-phase response of the plasma protein-synthesizing system of the liver.

Messenger RNA levels of plasma proteins following fasting.

1. The effect of fasting on hepatic mRNA levels of seven plasma proteins was examined in the rat. 2. The levels of mRNA were measured directly in cytoplasmic extracts by hybridization to specific 32P-labelled cDNA probes. 3. Following a 48 h period of fasting, the mRNA levels of apolipoprotein E, apolipoprotein A-IV, albumin, transferrin, and transthyretin decreased by 15-30%, while apolipoprotein A-II decreased by 78% compared with non-fasted control rats. The mRNA for apolipoprotein A-I increased by 33%. 4. These findings suggest that mRNA levels in the liver following fasting are regulated independently and variations in these levels may be due to differences in transcription rates or mRNA stability.

Messenger RNA levels of plasma proteins in rat liver during protein depletion and refeeding.

The levels of mRNA for albumin, transferrin, transthyretin, the beta-chain of fibrinogen and apolipoprotein E in livers from rats during protein depletion and refeeding were measured by hybridization to specific cDNA probes. A period of protein depletion of 3 d resulted in a 30-40% decrease in mRNA levels for all five proteins. These levels were further decreased by only 15-20% after additional protein depletion for 6 d. There was no noticeable change in mRNA levels within 4 h of refeeding by gavage with a casein hydrolysate suspension supplemented with L-tryptophan and L-arginine. Upon refeeding a 30% protein diet, mRNA levels returned to normal after 3 d. The work presented here suggests that changes observed in the protein synthetic rate following protein depletion and repletion are due to changes in mRNA levels altered as a consequence of the availability of dietary protein.

Levels of messenger ribonucleic acids for plasma proteins in rat liver during acute experimental inflammation.

The levels of mRNA for plasma proteins and for metallothionein in rat liver during the acute-phase response were studied by hybridization to specific cDNA probes. The mRNA for alpha 2-macroglobulin, the beta-chain of fibrinogen, alpha 1-acid glycoprotein (so-called acute-phase reactants) reached a maximum level between 18 and 36 h after inducing an acute inflammation. The level of mRNA for metallothionein-I peaked earlier, after 12 h. The mRNA for transferrin showed a delayed increase with a broad maximum for its relative level after 36-60 h. The mRNA levels for albumin and alpha 2u-globulin (so-called negative acute-phase reactants) decreased, reaching a minimum of 25% of the normal level after 36 h (albumin) and after 72 h (alpha 2u-globulin). The ratios of the rates of incorporation of leucine into the proteins over the levels of their mRNA in liver changed only a little, indicating that the rates of synthesis of plasma proteins in the liver are regulated at the mRNA level during the acute-phase response to inflammation.

Synthesis of rat apolipoprotein E by Escherichia coli infected with recombinant bacteriophage.

A cDNA library was constructed from rat liver polyadenylated RNA using the expression vector lambda gt11-Amp3. Several clones expressing antigenic determinants for rat apolipoprotein E were identified. The cDNA insert in one clone was further characterized and found to have a sufficient length (1120 base pairs) to code for full length apolipoprotein E. Restriction mapping and nucleotide sequencing showed the clone to contain the coding region for apolipoprotein E flanked by about 120 nucleotides at the 3'-side and by about 64 nucleotides on the 5'-side. One of the proteins produced by the clone was found to be a prokaryotic/eukaryotic hybrid protein reacting with antibodies to both bacterial beta-galactosidase and rat apolipoprotein E.