Phase I study of intraperitoneal irinotecan combined with palliative systemic chemotherapy in patients with colorectal peritoneal metastases.

BACKGROUND: Patients with colorectal peritoneal metastases who are not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) owing to extensive peritoneal disease have a poor prognosis. It was hypothesized that these patients may benefit from the addition of intraperitoneal irinotecan to standard palliative systemic chemotherapy. METHODS: This was a classical 3 + 3 phase I dose-escalation trial in patients with colorectal peritoneal metastases who were not eligible for CRS-HIPEC. Intraperitoneal irinotecan was administered every 2 weeks, concomitantly with systemic FOLFOX (5-fluorouracil, folinic acid, oxaliplatin)-bevacizumab. The primary objective was to determine the maximum tolerated dose and dose-limiting toxicities. Secondary objectives were to elucidate the systemic and intraperitoneal pharmacokinetics, safety profile, and efficacy. RESULTS: Eighteen patients were treated. No dose-limiting toxicities were observed with 50 mg (4 patients) and 75 mg (9 patients) intraperitoneal irinotecan. Two dose-limiting toxicities occurred with 100 mg irinotecan among five patients. The maximum tolerated dose of intraperitoneal irinotecan was established to be 75 mg, and it was well tolerated. Intraperitoneal exposure to SN-38 (active metabolite of irinotecan) was high compared with systemic exposure (median intraperitoneal area under the curve (AUC) to systemic AUC ratio 4.6). Thirteen patients had a partial radiological response and five had stable disease. Four patients showed a complete response during post-treatment diagnostic laparoscopy. Five patients underwent salvage resection or CRS-HIPEC. Median overall survival was 23.9 months. CONCLUSION: Administration of 75 mg intraperitoneal irinotecan concomitantly with systemic FOLFOX-bevacizumab was safe and well tolerated. Intraperitoneal SN-38 exposure was high and prolonged. As oncological outcomes were promising, intraperitoneal administration of irinotecan may be a good alternative to other, more invasive and costly treatment options. A phase II study is currently accruing.

Patients with extensive colorectal peritoneal metastases who are not eligible for surgery and heated intraperitoneal chemotherapy have poor survival. The authors tried to improve the survival of these patients by adding intraperitoneal (inside the abdominal cavity) chemotherapy to standard palliative chemotherapy which is administered into the bloodstream. In this trial, irinotecan (a type of chemotherapy) was administered into the abdomen of patients with extensive colorectal peritoneal metastases. The authors investigated which dose could be administered safely in combination with standard palliative chemotherapy. They also looked into toxicity, safety, benefit, and movement of the drug in the body. Eighteen patients were treated in this study. The maximum tolerated dose of intraperitoneal irinotecan was 75 mg. It was well tolerated and could be administered safely. The intra-abdominal amount of irinotecan was high, whereas the amount of irinotecan in the blood remained low. The benefits of intra-abdominal irinotecan were promising. Because of this, a new study has been started to further investigate this new combination chemotherapy for colorectal cancer.

Design and statistics of pharmacokinetic drug-drug, herb-drug, and food-drug interaction studies in oncology patients.

Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed.

Treatment and Implications of Vascular Endothelial Growth Factor Inhibitor-Induced Blood Pressure Rise: A Clinical Cohort Study.

Background Anti-cancer vascular endothelial growth factor inhibitors (VEGFI) frequently induce a rise in blood pressure (BP). The most effective treatment of this BP rise is currently unknown, and risk factors and its association with survival remain inconclusive. Methods and Results Baseline characteristics and BP readings were retrospectively collected from oncology patients who received oral VEGFI treatment (sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, or cabozantinib). Risk factors for a clinically relevant BP rise (increase of ≥20 mm Hg in systolic BP or ≥10 mm Hg in diastolic BP) were investigated via logistic regression (relative), efficacy of antihypertensives via unpaired t-tests, and association of BP rise with survival via Cox regression analysis. In total, 162 (47%) of 343 included patients developed a clinically relevant BP rise ≥7 days after VEGFI treatment initiation. Both calcium channel blockers and renin-angiotensin system inhibitors effectively reduced systolic BP (-24.1 and -18.2 mm Hg, respectively) and diastolic BP (-12.0 and -11.0 mm Hg, respectively). Pazopanib therapy (odds ratio, 2.71 [95% CI, 1.35-5.42; P=0.005], compared with sorafenib) and estimated glomerular filtration rate <60 mL/min per 1.73 m2 (OR, 1.75 [95% CI, 0.99-3.18, P=0.054]) were risk factors for a BP rise, whereas a baseline BP ≥140/90 mm Hg associated with a lower risk (OR, 0.39 [95% CI, 0.25-0.62, P<0.001]). Only for renal cell carcinoma, BP rise was associated with a substantially improved median overall survival compared with no BP rise: 45.4 versus 20.3 months, respectively, P=0.003. Conclusions The type of VEGFI, baseline BP, and baseline estimated glomerular filtration rate determine the VEGFI-induced BP rise. Both calcium channel blockers and renin-angiotensin system inhibitors are effective antihypertensive treatments. Particularly in patients with renal cell carcinoma, a BP rise is associated with improved overall survival.

Feasibility of therapeutic drug monitoring of sorafenib in patients with liver or thyroid cancer.

INTRODUCTION: Sorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. METHODS: We included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough was below the target of 3750 ng/mL and toxicity was manageable. RESULTS: A total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough above the target or caused excessive toxicity. CONCLUSIONS: TDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.

The influence of green tea extract on nintedanib's bioavailability in patients with pulmonary fibrosis.

Nintedanib is an oral small-molecule kinase inhibitor and first-line treatment for idiopathic pulmonary fibrosis. Nintedanib is a substrate of the drug efflux transporter ABCB1. Green tea flavonoids --especially epigallocatechin gallate (EGCG)-- are potent ABCB1 modulators. We investigated if concomitant administration of green tea extract (GTE) could result in a clinically relevant herb-drug interaction. Patients were randomized between A-B and B-A, with A being nintedanib alone and B nintedanib with GTE. Both periods lasted 7 days, in which nintedanib was administered twice daily directly after a meal. In period B, patients additionally received capsules with GTE (500 mg BID, >60% EGCG). Pharmacokinetic sampling for 12 h was performed at day 7 of each period. Primary endpoint was change in geometric mean for the area under the curve (AUC0-12 h). A linear mixed model was used to analyse AUCs and maximal concentration (Cmax). In 26 included patients, the nintedanib AUC0-12 h was 21% lower (95% CI -29% to -12%; P < 0.001) in period B (with GTE) compared to period A. Cmax did not differ significantly between periods; - 14% (95% CI -29% to +4%; P = 0.12). The detrimental effect was predominant in patients with the ABCB1 3435 C>T wild type variant. No differences in toxicities were observed. Exposure to nintedanib decreased with 21% when administered 60 min after GTC for only 7 days. This is a statistically significant interaction which could potentially impair treatment efficacy. Before patients and physicians should definitely be warned to avoid this combination, prospective clinical validation of an exposure-response relationship is necessary.

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer.

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

Influence of green tea consumption on endoxifen steady-state concentration in breast cancer patients treated with tamoxifen.

BACKGROUND: Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most commonly used dietary supplements among breast cancer patients. EGCG may alter the metabolism of tamoxifen. Therefore, the aim of this study was to investigate the influence of green tea supplements on the pharmacokinetics of endoxifen; the most relevant active metabolite of tamoxifen. METHODS: In this single-center, randomized cross-over trial, effects of green tea capsules on endoxifen levels were evaluated. Patients treated with tamoxifen for at least 3 months were eligible for this study. After inclusion, patients were consecutively treated with tamoxifen monotherapy for 28 days and in combination with green tea supplements (1 g twice daily; containing 300 mg EGCG) for 14 days (or vice versa). Blood samples were collected on the last day of monotherapy or combination therapy. Area under the curve (AUC0-24h), maximum concentration (Cmax) and minimum concentration (Ctrough) were obtained from individual plasma concentration-time curves. RESULTS: No difference was found in geometric mean endoxifen AUC0-24h in the period with green tea versus tamoxifen monotherapy (- 0.4%; 95% CI - 8.6 to 8.5%; p = 0.92). Furthermore, no differences in Cmax (- 2.8%; - 10.6 to 5.6%; p = 0.47) nor Ctrough (1.2%; - 7.3 to 10.5%; p = 0.77) were found. Moreover, no severe toxicity was reported during the whole study period. CONCLUSIONS: This study demonstrated the absence of a pharmacokinetic interaction between green tea supplements and tamoxifen. Therefore, the use of green tea by patients with tamoxifen does not have to be discouraged.

Clinical implications of food-drug interactions with small-molecule kinase inhibitors.

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.

The influence of single-nucleotide polymorphisms on overall survival and toxicity in cabazitaxel-treated patients with metastatic castration-resistant prostate cancer.

PURPOSE: Cabazitaxel, used in patients with metastatic castration-resistant prostate cancer (mCRPC), is associated with adverse events which may require dose reductions or discontinuation of treatment. We investigated the potential association of single-nucleotide polymorphisms (SNPs) in genes encoding drug transporters and drug-metabolizing enzymes with cabazitaxel toxicity, overall survival (OS) and pharmacokinetics (PK). METHODS: A total of 128 cabazitaxel-treated mCRPC patients, of whom prospectively collected data on toxicity and OS were available and 24 mCRPC patients with available cabazitaxel PK measurements, were genotyped using genomic DNA obtained from EDTA blood. The SLCO1B1 (388A > G; *1B; rs2306283 and 521 T > C; *5; rs4149056 and haplotype SLCO1B1*15), SLCO1B3 (334 T > G; rs4149117), CYP3A4 (*22; rs35599367), CYP3A5 (*3; rs776746), ABCB1 (3435C > T; rs1045642), and TUBB1 (57 + 87A > C; rs463312) SNPs were tested for their association with clinical and PK parameters by univariate/multivariate logistic regression, log-rank test, or Kruskal-Wallis test. RESULTS: The SLCO1B1*15 haplotype was significantly associated with a lower incidence of leukopenia and neutropenia (p = 0.020 and p = 0.028, respectively). Patients harboring a homozygous variant for SLCO1B1*1B experienced higher rate ≥ grade 3 (p = 0.042). None of the SNPs were associated with pharmacokinetics or OS. CONCLUSIONS: In this study, SLCO1B1 (SLCO1B1*15 and SLCO1B1*1B) was associated with cabazitaxel-induced adverse events in mCRPC patients. As the associations were opposite to previous studies in other drugs and contradicted an underlying pharmacokinetic rationale, these findings are likely to be false-positive and would ideally be validated with even larger (pharmacokinetic) cohorts.

Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma.

Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P < 0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P < 0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10.

Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence.

BACKGROUND AND OBJECTIVE: Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation. METHODS: We performed studies in male FVB-mice aged 8-12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration-time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times. RESULTS: Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14-27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (C trough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (C trough-1 p.m. 66.0 ng/mL; C trough-6 p.m. 58.9 ng/mL; C trough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times. CONCLUSIONS: Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower C trough values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.

Sorafenib induced thyroiditis in two patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib is a multi-targeted tyrosine kinase inhibitor licensed for the treatment of hepatocellular carcinoma and renal cell carcinoma. Thyroid function test abnormalities have been reported for different tyrosine kinase inhibitors, but only limited data on thyroid function test abnormalities related to sorafenib are available, demonstrating the occurrence of hypothyroidism in patients treated with sorafenib. SUMMARY: We describe two patients who developed temporary hyperthyroidism during the course of sorafenib treatment, which was followed by overt and subclinical hypothyroidism, respectively. Thyroid ultrasonography showed an atrophic thyroid gland in patient 1 , and signs of thyroiditis in patient 2 . Detailed reassessment of thyroid volumes on routinely performed computerized tomography scans showed a gradual decrease in thyroid volume during sorafenib treatment in one patient, suggesting progressive thyroid destruction. CONCLUSION: This case report describes in detail and for the first time two cases of sorafenib-induced thyroiditis. We assume that this sorafenib-induced destructive thyroiditis is an important cause of sorafenib-induced hypothyroidism.

Lifestyle habits as a contributor to anti-cancer treatment failure.

Lifestyle may have serious consequences for cancer treatment outcome, which is a fact that both physicians and patients are often not explicitly aware of, thereby unwillingly exposing the patient to possible danger. In certain cases, patient behaviour can lead to potentially life-threatening adverse events, whilst in other cases the clinical benefit of anti-cancer therapy can be diminished. In this review, we focus on the role of certain habits (like cigarette smoking, alcohol use and the use of complementary and alternative medicine) and discuss the effects they may have on anti-cancer medication. Also patient compliance to prescribed anti-cancer drugs is a factor frequently overlooked if treatment does not follow the expectations, which gains importance with the increasingly frequent prescription of oral anti-cancer agents.

Medicinal cannabis in oncology.

In The Netherlands, since September 2003, a legal medicinal cannabis product, constituting the whole range of cannabinoids, is available for clinical research, drug development strategies, and on prescription for patients. To date, this policy, initiated by the Dutch Government, has not yet led to the desired outcome; the amount of initiated clinical research is less than expected and only a minority of patients resorts to the legal product. This review aims to discuss the background for the introduction of legal medicinal cannabis in The Netherlands, the past years of Dutch clinical experience in oncology practice, possible reasons underlying the current outcome, and future perspectives.

Complementary and alternative medicine during cancer treatment: beyond innocence.

Nowadays, complementary and alternative medicine (CAM) is popular all over the world. Billions of dollars are spent in this booming business. For several reasons, young, female, educated, and higher socioeconomic class cancer patients, in particular, have shown interest in these agents. Unfortunately, besides direct (and sometimes serious) side effects, several CAM ingredients are capable of interfering with the metabolism of concurrently used drugs, which may render the therapeutic outcome of the subscribed drug unpredictable. In the case of anticancer drugs, with their usually narrow therapeutic window, this may have dramatic consequences and can lead to unacceptable toxicities in some cases or decreased therapeutic activity in others. Therefore, cancer patients should be warned for these possible interactions and be advised to discuss CAM use openly with their treating physician. The general concept that natural products are harmless should thus be changed into a more realistic and responsible attitude. A tightened legislation and regulation (including Internet advertising and sales) could play a crucial role in this awareness process. This should finally enable safe exploration of the potential advantageous aspects of CAM, while living with cancer.

Effects of St. John's wort on irinotecan metabolism.

St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7 micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.