Visceral Leishmaniasis Masquerading as Drug-Induced Pancytopenia in Lung Cancer Patients.

Maintenance chemotherapy is a standard treatment in patients with non-progressive advance staged IV non-squamous non-small cell lung cancer after induction therapy. Here, we report the case of a 53-year-old man undergoing a maintenance monotherapy with pemetrexed who presented prolonged pancytopenia despite filgrastim injections. A bone marrow aspiration revealed a macrophage activation syndrome with Leishmania amastigotes. A Polymerase Chest Reaction testing confirmed the diagnosis of visceral leishmaniasis. Treatment with liposomal amphotericin B was started. Oncologists should bear in mind that visceral leishmaniasis in endemic areas can potentially induce severe and prolonged pancytopenia in immunosuppressed patients, during chemotherapy in particular.

Renal Immune-related Adverse Event of Pembrolizumab Masked by Pemetrexed.

A Japanese woman in her 60s developed a kidney injury 9 weeks after treatment with pemetrexed, carboplatin, and pembrolizumab for stage IV lung adenocarcinoma. A renal biopsy showed chronic tubulointerstitial damage with minimal focal interstitial inflammation, consistent with pemetrexed-induced nephropathy; thus, pemetrexed was withdrawn. However, the kidney injury continued to worsen. A repeated biopsy showed severe acute tubulointerstitial nephritis, suggestive of a pembrolizumab-induced immune-related adverse event (irAE). The worsening after pemetrexed discontinuation suggested that the irAE had already begun, as the first biopsy showed focal inflammation. This case suggests thatcombining immune checkpoints and chemotherapy requires considering concurrent drug-induced nephrotoxicity.

Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

A novel model to predict the risk of hematological toxicity in lung adenocarcinoma patients with pemetrexed plus platinum chemotherapy based on real-world data.

BACKGROUND: Pemetrexed plus platinum chemotherapy is the first-line treatment option for lung adenocarcinoma. However, hematological toxicity is major dose-limiting and even life-threatening. The ability to anticipate hematological toxicity is of great value for identifying potential chemotherapy beneficiaries with minimal toxicity and optimizing treatment. The study aimed to develop and validate a prediction model for hematologic toxicity based on real-world data. METHODS: Data from 1754 lung adenocarcinoma patients with pemetrexed plus platinum chemotherapy regimen as first-line therapy were used to establish and calibrate a risk model for hematological toxicity using multivariate and stepwise logistic regression analysis based on real-world data. The predictive performance of the model was tested in a validation cohort of 753 patients. An area under the curve (AUC) of the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis were used to assess the prediction model. RESULTS: 5 independent factors (platinum, pre-use vitamin B12, cycle of chemotherapy before hematological toxicity, Hb before first chemotherapy, and PLT before first chemotherapy) identified from multivariate and stepwise logistic regression analysis were included in the prediction model. The hematological toxicity prediction model achieved a sensitivity of 0.840 and a specificity of 0.822. The model showed good discrimination in both cohorts (an AUC of 0.904 and 0.902 for the derivation and validation cohort ROC) at the cut-off value of 0.591. The calibration curve showed good agreement between the actual observations and the predicted results. CONCLUSION: We developed a prediction model for hematologic toxicity with good discrimination and calibration capability in lung adenocarcinoma patients receiving a pemetrexed plus platinum chemotherapy regimen based on real-world data.

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. FUNDING: The Canadian Cancer Society and Merck & Co.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions.

BACKGROUND: Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed. METHODS: In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy. RESULTS: A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions. CONCLUSIONS: The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).

Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study.

BACKGROUND: Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy. METHODS: This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC. RESULTS: The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A]. CONCLUSION: The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed. TRIAL REGISTRATION: This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

Pemetrexed and Erlotinib as a Salvage Treatment in Patients With Metastatic Biliary Tract Cancer Who Failed Gemcitabine-containing Chemotherapy: A Phase II Single-arm Prospective Study.

BACKGROUND/AIM: No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the efficacy and safety of a pemetrexed and erlotinib combination in patients with BTC previously treated with gemcitabine. PATIENTS AND METHODS: This phase II, open-label, single-arm study enrolled patients with BTC who had previously failed gemcitabine-based first-line chemotherapy. Patients were treated with pemetrexed as a 500 mg/m2 intravenous infusion on day 1 for three weeks and erlotinib 100 mg daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR). RESULTS: The study enrolled 20 patients with BTC, including 12 (60%) with intrahepatic cholangiocarcinoma (IHCC), 3 (15%) with extrahepatic cholangiocarcinoma (EHCC), and 5 (25%) with gallbladder cancer (GBC). The ORR was 5%, and the disease control rate (DCR) was 55%. As of the cutoff point of March 31, 2023, the median progression-free survival (PFS) was 2.3 months [95% confidence interval (CI)=0.00-4.74] and the median overall survival (OS) was 5.6 months (95%CI=2.28-8.87). Patients with EHCC showed longer PFS and OS compared to patients with IHCC or GBC, but the differences were not significant. A baseline CEA greater than the upper normal limit was the only significant prognostic factor for a worse OS rate. The only treatment-related adverse event (TRAE) with severity grade ≥3 was anemia (5%). CONCLUSION: Salvage chemotherapy with pemetrexed plus erlotinib was well-tolerated and showed marginal clinical activity in BTC patients after failure to gemcitabine-based chemotherapy.

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration-induced nephropathy.

AIMS: Long-term administration of pemetrexed (PEM) in patients with lung cancer can cause renal damage, leading to treatment discontinuation. Previous reports have suggested that specific single nucleotide polymorphisms (SNPs) in the folylpolyglutamate synthase (FPGS) gene affect therapeutic efficacy; however, whether the FPGS SNPs affect renal function is unclear. Identifying SNPs related to renal damage during PEM administration may help predict the decrease in renal function caused by PEM. METHODS: We retrospectively examined age, sex, body weight, total administered PEM, combined platinum, estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) levels before and after PEM administration in patients with non-small cell lung cancer and searched for the alleles of FPGS SNPs (rs1544105 and rs10106) using DNA extracted from whole blood samples of patients. RESULTS: Renal function decreased after PEM administration in 26 cases overall. The SCr and eGFR indices showed decreased renal function irrespective of concomitant cisplatin use. Based on promoter activity and miRNA binding predictions, rs1544105-C and rs10106-T were hypothesized to increase FPGS expression. Single SNP analyses showed no significant differences in renal function between groups with and without each SNP. Multiple regression analysis revealed that the most significant factors for decreased renal function were sex on SCr and the number of SNPs on eGFR. In subgroup analyses, the patients with rs10106-T showed a decline in renal function in the older group. CONCLUSIONS: The number of FPGS SNPs may contribute to PEM-induced renal impairment. Detecting FPGS SNPs may help predict PEM-induced renal damage.

Using the neutrophil-to-lymphocyte ratio to predict the outcome of individuals with nonsquamous non-small cell lung cancer receiving pembrolizumab plus platinum and pemetrexed.

BACKGROUND: Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb-Plt-PEM) in nonsquamous non-small cell lung cancer (non-sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non-sq NSCLC. METHODS: We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non-sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan-Meier method were used to compare progression-free survival (PFS) and overall survival (OS). RESULTS: The response rate was 51.2% (95% CI: 44.9-57.5%). The median PFS and OS after beginning Pemb-Plt-PEM were 8.8 (95% CI: 7.0-11.9) months and 23.6 (95% CI: 18.7-28.6) months, respectively. The NLR independently predicted the efficacy of Pemb-Plt-PEM-the PFS and OS were more prolonged in individuals with NLR <5 than in those with NLR ≥5 (PFS: 12.8 vs. 5.3 months, p = 0.0002; OS: 29.4 vs. 12.0 months, p < 0.0001). BMI predicted the treatment response-individuals with BMI ≥22.0 kg/m2 had longer OS than did those with BMI < 22.0 kg/m2 (OS: 28.4 vs. 18.4 months, p = 0.0086). CONCLUSIONS: The NLR significantly predicted PFS and OS, whereas BMI predicted OS, in individuals who initially received Pemb-Plt-PEM for non-sq NSCLC. These factors might be prognosis predictors in non-sq NSCLC.

[Efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors combined with chemotherapy as first-line treatment for epidermal growth factor receptor-mutant advanced non-small cell lung cancer].

Objective: To observe the clinical efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with chemotherapy as first-line treatment for EGFR mutant advanced non-small cell lung cancer (NSCLC). Methods: It was a retrospective, single-arm real-world study and a total of 39 patients with stage ⅢB to Ⅳ EGFR mutant NSCLC diagnosed in Cancer Hospital of Chinese Academy of Medical Sciences from July 2018 to December 2020 were collected. There were 16 males and 23 females, the age ranged from 25 to 73 years, with a median age of 53 years. All patients received EGFR-TKIs synchronously combined with pemetrexed and platinum-containing chemotherapy for 4-6 cycles as first-line treatment, followed by EGFR-TKI monotherapy with or without pemetrexed maintenance therapy. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse reactions were evaluated. Median follow-up time was 18.6 months (95%CI: 16.2-21.0 months). The Kaplan-Meier method was used for survival analysis. Results: The ORR was 61.5% (24/39), the DCR was 94.9% (37/39) and the median PFS was 16.4 months (95%CI: 12.1-20.7 months). The main adverse reactions were liver function injury (59.0%, 23/39), myelosuppression (43.6%, 17/39), skin reaction (25.6%, 10/39), gastrointestinal reaction (17.9%, 7/39), fatigue (12.8%, 5/39) and kidney injury (5.1%, 2/39). Most of the patients had grade 1-2 adverse reactions, and the rate of grade 3 adverse events were 12.8%(5/39), which were effectively alleviated after symptomatic support treatment, no grade 4 serious adverse events occurred. Conclusion: EGFR-TKIs synchronously combined with chemotherapy followed by EGFR-TKI monotherapy with or without pemetrexed maintenance therapy has a certain therapeutic effect and fairly good safety, which can prolong PFS in patients with EGFR mutated advanced NSCLC.

Predictive factors associated with pemetrexed acute toxicity.

PURPOSE: Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. METHODS: This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. RESULTS: Seventy-four patients were included in this study (median age: 67 years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). CONCLUSION: To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

ATP-binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum-based doublet chemotherapy. The association of ABCB1 (C1236 T, C3435 T, and G2677 T/A), ABCC1 (G3173 A and G2168 A),ABCC2 (G4544 A), and ABCG2 (C421 A) polymorphisms with chemotherapy-induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous (GA) genotype for ABCC1 G3173 A had an increased risk of developing leukopenia (odds ratio [OR] = 1.88, p = 0.04) and anemia (adjusted odds ratio [AOR] = 2.70, p = 0.03). For ABCC2 G4544 A polymorphism, patients harboring one copy of the mutant (GA) allele showed an increased risk of developing anemia (OR = 4.24, p = 0.03). After adjusting with various confounding factors, the heterozygous (GA) genotype showed a 5.63-fold increased risk of developing anemia (AOR = 5.63, p = 0.03). The ABCB1 G2677 A (OR = 0.37, p = 0.008) and ABCC1 G3173 A (OR = 0.54, p = 0.04) polymorphism showed a lower incidence of developing nephrotoxicity. In ABCG2 C421 A polymorphism, patients harboring heterozygous (CA) genotype had a lower incidence of having diarrhea (OR = 0.25, p = 0.04). An increased risk of having diarrhea was observed in the heterozygous genotype (GA) for ABCC1 G3173 A polymorphism (AOR = 2.78, p = 0.04). An increased risk of liver injury was found in the patients carrying heterozygous genotype of the ABCC1 G3173 A (OR = 2.06, p = 0.02) and ABCB1 C1236 T (OR = 1.85, p = 0.01). This study demonstrates the role of polymorphic variations in ABCB1, ABCC1, ABCC2, and ABCG2 in predicting hematological, nephrotoxicity, gastrointestinal, and hepatotoxicity.

Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof-of-concept study.

PURPOSE: Pemetrexed is a cytotoxic drug used for the treatment of lung cancer and mesothelioma. The use of a low test dosing of cytotoxic drugs may aid in dose individualization without causing harm. The aim of this proof-of-concept study was to assess if the pharmacokinetics (PKs) of a test dose could predict the PKs of a therapeutic pemetrexed dose. METHODS: Ten patients received both a low test dose (100 µg) and a therapeutic dose of pemetrexed after which plasma concentrations pemetrexed were measured. PK analysis was performed by means of nonlinear mixed-effects modelling. The predictive performances of test dose clearance and renal function towards a therapeutic dose were assessed. RESULTS: The PKs of a pemetrexed test dose were best described by a one-compartment model with linear elimination. A high variability in the administered dose was observed for the test dose, but not for the therapeutic dose. A statistically significant correlation between test dose clearance and therapeutic dose clearance was observed (Spearman's rho: 0.758, P = 0.02). The predictive performance of test dose clearance was worse than renal function: mean predictive error (+95% confidence interval [CI]) 53.9% (50.1-57.6%) vs 19.4% (12.4-26.4%) and normalized root-mean square error (+95% CI) 57.8% (30.5-85.1%) vs 25.7% (20.3-31.0%). CONCLUSION: We show that test dosing of pemetrexed is feasible, but there seems no added value for a low test dosing in the dose individualization of pemetrexed.