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A 54-year-old patient with primary cerebral lymphoma was treated with two 4-weekly cycles of high-dose intravenous cytarabine (12 g/m2) and methotrexate (3 g/m2). The administration of the first course proceeded without notable complications. Before the administration of methotrexate in the second cycle blood cell counts and chemistry showed no abnormalities except for slightly increased alkaline phosphatase and gamma-glutamyl-transpeptidase levels which was attributed to diphantoin comedication. The patient developed symptoms of acute renal failure 7 h after methotrexate infusion which resulted in a very high serum methotrexate level (39.84 micromol/l) at 20 h after infusion. Rescue therapy was intensified: the leucovorin dosage was increased (1,200 mg continuous i.v. infusion every 24 h) and combined with thymidine rescue therapy (8 g/m2 per day continuous i.v. infusion every 24 h). Urine alkalinization was increased and diphantoin therapy was stopped. Leucovorin eye drops and mouth washes were started 5 days after methotrexate administration to prevent conjunctivitis and mucositis as a result of high methotrexate levels (>2.4 micromol/l). In spite of the fact that serum methotrexate levels remained persistently higher than 0.1 micromol/l for 12 days, the patient experienced no further short-term systemic toxicity except for anaemia (grade 3 according to NCI Common Toxicity Criteria). After day 12 intensified rescue therapy and the frequency of alkalinization were decreased to standard procedures and stopped on day 19. It is concluded that i.v. administration with high-dose methotrexate can result in unpredictable acute toxicity. In our patient, acute methotrexate toxicity was treated successfully by intensification of classical leucovorin rescue therapy in combination with thymidine infusion. In addition, leucovorin mouth washes and eye drops may have prevented mucositis and conjunctivitis, respectively. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the influence of body mass index (BMI) on the tolerability and effectiveness of full-weight-based paclitaxel chemotherapy in early breast cancer patients., Methods: Early-stage breast cancer patients who received (neo)adjuvant weekly paclitaxel 80 mg/m 2 chemotherapy were included in this retrospective study. Patients were divided into three groups based on their BMI: lean, overweight, and obese. Logistic regression was used to assess for association between BMI with administered relative dose intensity (RDI) < 85%. The occurrence of treatment modifications and the pathological response on neoadjuvant chemotherapy were compared between BMI categories., Results: Four hundred (400) patients were included in this study; 200 (50%) lean, 125 (31%) overweight, and 75 (19%) obese patients. The adjusted odds ratio to receive RDI < 85% for BMI was 1.02 (p value, .263). Treatment modifications occurred in 115 (58%), 82 (66%), and 52 (69%) patients in the respective BMI categories (p value = .132). Peripheral neuropathy was observed in 79 (40%), 58 (46%), and 41 (55%) patients in the lean, overweight, and obese group (p value = .069), whereas hematologic toxicity was observed in 31 (16%), 10 (8%), and 4 (5%) patients (p value = .025). Pathological complete response was observed in 22 (17%), 11 (14%), and 6 (13%) patients in the respective BMI categories (p value = .799)., Conclusion: BMI did not significantly influence the tolerability and effectiveness of full-weight-based paclitaxel chemotherapy. Therefore, the results of this study align with current guideline recommendations of using full-weight-based paclitaxel chemotherapy in obese patients., (© 2022. The Author(s).)

Background: Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients., Methods: Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed based on BSA, was chosen as a control cohort. A total of two combined scores were used: capecitabine-specific toxicity (diarrhea, National Cancer Institute Common Toxicity Criteria grade ⩾3, hand-foot syndrome ⩾2, or neutropenia ⩾2), and clinically relevant events due to toxicity, that is, hospital admission, dose reduction, or discontinuation. Per treatment regimen, patients were divided into three BSA groups based on BSA quartiles corrected for sex. Toxicity scores were compared by a Chi-square test between cohorts, and within cohorts using BSA groups. Progression-free survival (PFS) was estimated by the Kaplan-Meier method., Results: A total of 2319 patients were included (fixed dosed, n = 1126 and BSA-based dose, n  = 1193). Overall, four regimens were evaluated: capecitabine-radiotherapy ( n = 1178), capecitabine-oxaliplatin ( n = 519), capecitabine triplet ( n = 181) and capecitabine monotherapy ( n = 441). The incidence of capecitabine-specific toxicity and clinically relevant events was comparable between fixed-dose and BSA-dosed patients, while a small difference (7.1%) in absolute dose was found. Both cohorts showed only a higher incidence of both toxicity scores in the lowest BSA group of the capecitabine-radiotherapy group ( p < 0.05). Subgroups of the fixed-dose cohort analyzed for PFS, showed no differences between BSA groups., Conclusions: Fixed-dose capecitabine is as comparably well tolerated and effective as BSA-based dosing and could be considered as a reasonable alternative for BSA-based dosing., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study., Methods: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5'-UTR VNTR and TYMS 3'-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q<0.050 (corresponding to P<0.010)., Results: Uracil was superior to the dihydrouracil/uracil ratio as a predictor of severe toxicity. High pretreatment uracil concentrations (>16 ng ml -1 ) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P<0.0001), toxicity-related hospitalisation (OR 16.9, P<0.0001), as well as fatal treatment-related toxicity (OR 44.8, P=0.001). None of the DPYD variants alone, or TYMS variants alone, were associated with severe toxicity., Conclusions: High pretreatment uracil concentration was strongly predictive of severe, including fatal, fluoropyrimidine-associated toxicity, and is a highly promising phenotypic marker to identify patients at risk of severe fluoropyrimidine-associated toxicity.

Purpose: Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing., Patients and Methods: Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses., Results: A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs., Conclusion: DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving., (© 2015 by American Society of Clinical Oncology.)

Capecitabine, 5-fluorouracil and tegafur form the group called the fluoropyrimidines, which is one of the most frequently prescribed group of anti-cancer drugs for the treatment of (metastatic) colorectal, gastric and breast cancer. The primary enzyme responsible for the inactivation of the fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD). Consequently, patients with an inborn partial DPD deficiency, induced, for example by the polymorphism DPYD*2A, are highly prone to severe, potentially lethal toxicity following a standard dose of fluoropyrimidines. In this article, based on three representative case reports and our prospective study in patients with cancer, we demonstrate the clinical value of prospective screening for DPD deficiency in patients being treated with fluoropyrimidine-based anti-cancer therapy. The results show that upfront genotyping for DPYD*2A followed by a fluoropyrimidine dose reduction of 50% (on average) in patients heterozygous polymorphic for DPYD*2A, significantly reduces the incidence of severe to potentially lethal toxicity compared to historical control patients given full-dose therapy.

Lemierre's syndrome is a potentially fatal disease that usually presents with oropharyngeal infection, followed by sepsis, thrombosis of the internal jugular vein and septic emboli. Most cases are caused by the Gram-negative, anaerobic Fusobacterium necrophorum. We present two patients with an atypical presentation of Lemierre's syndrome and a review. These cases illustrate that a positive blood culture for F. necrophorum, even without the presence of clinical symptoms pointing towards thrombosis of the internal jugular vein, justifies further radiological testing for thrombophlebitis of the internal jugular vein.

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel., Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling., Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (-25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified., Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

Background: The exact incidence of venous thromboembolism (VTE) in cancer patients is unknown, partly because of confounding factors. Prophylactic treatment is warranted in surgical patients with cancer because of a high incidence of VTE. We performed a retrospective study to evaluate if the same applies for cancer patients treated with chemotherapy., Methods: The medical records of 206 consecutive patients with malignancy, treated with chemotherapy, were identified. The kind of malignancy and chemotherapeutic treatment were recorded, as was the date of treatment. The records were reviewed for other risk factors for VTE, and were searched for proved deep venous thrombosis or pulmonary embolism., Results: Of those 206 patients, 15 (7.3%) had proved VTE during or within 3 months after chemotherapeutic treatment. The annual incidence was 10.9%. The incidence of VTE was specifically high in the 39 patients treated with a combination of fluorouracil and leucovorin calcium because of colorectal cancer (6 [15%] of the patients were affected). The occurrence of VTE in the latter group of patients was not influenced by factors such as surgery, central venous catheters, or tumor load., Conclusions: The annual incidence of VTE in patients treated with chemotherapy was high, specifically in patients with colorectal cancer treated with fluorouracil-leucovorin. If these observations are confirmed, trials to evaluate the use of prophylactic anticoagulant treatment should be conducted.

A young patient developed Hodgkin's disease 11 years after surgical, chemotherapeutic and radiation treatment for stage IIIA embryonal carcinoma of the testis. The importance is stressed of establishing a tissue diagnosis when there is an unexpected course of the disease.

Cure of high grade malignant gliomas is seldom possible with surgery and adjuvant radiotherapy as first line treatment, so many trials have been carried out with adjuvant chemotherapy. During the last decade, clinical studies with immunotherapy in recurrent gliomas have been added to the therapeutic regimens. We made an extensive search of the literature on chemotherapy and immunotherapy of high grade malignant gliomas up to 1 January 1990. The median survival time (MST) of surgery and adjuvant radiation is about 35 weeks. Adjuvant single-agent chemotherapy extends the MST by some 15 weeks. Combination-agent chemotherapy did not achieve better results than single agents. Of the cytotoxic agents, the nitrosureas have been most extensively tested. Immunotherapy is in an early stage of clinical testing: however, very recent trials show promising results, especially those which make use of monoclonal antibodies for targeting therapeutics. In the future a combination of chemotherapy and immunotherapy might offer a better outcome in this malignancy.