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1.
Clin Genitourin Cancer ; 11(2): 128-33, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23332872

ABSTRACT

BACKGROUND: Because the response to treatment is limited, patients with metastatic renal cell carcinoma (mRCC) typically receive multiple treatments. Guidelines recommend everolimus for patients previously treated with tyrosine kinase inhibitors (TKI) sunitinib or sorafenib. This study evaluated the efficacy of TKI re-treatment in patients with disease progression after a TKI-everolimus sequence. PATIENTS AND METHODS: Data were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence. RESULTS: Thirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15, and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the disease-control rate (response plus stable disease) was 75%. The median PFS with each component of the TKI-everolimus-TKI sequence was 10.7 months (95% CI, 1.8-28.5 months), 8.9 months (95% CI, 1.7-34.6 months), and 8.2 months (95% CI, 5.2-11.9 months), respectively. The median overall survival from the start of everolimus was 29.1 months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this setting. CONCLUSIONS: Administration of a TKI-everolimus-TKI sequence may be associated with clinical benefit and should be prospectively investigated.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Pyrroles/therapeutic use , Sirolimus/analogs & derivatives , Adult , Aged , Benzimidazoles/therapeutic use , Carcinoma, Renal Cell/secondary , Disease-Free Survival , Everolimus , Female , France , Humans , Male , Middle Aged , Niacinamide/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Quinolones/therapeutic use , Salvage Therapy , Sirolimus/therapeutic use , Sorafenib , Sunitinib , TOR Serine-Threonine Kinases/antagonists & inhibitors , Treatment Failure , Treatment Outcome
2.
Eur J Cancer ; 48(8): 1141-6, 2012 May.
Article in English | MEDLINE | ID: mdl-22364733

ABSTRACT

BACKGROUND: Gemcitabine plus cisplatinum was shown to exert comparable activity and a different toxicity profile when compared to the methotrexate, vinblastine, doxorubicin, cisplatinum (MVAC) regimen in patients with advanced bladder cancer. Accelerated MVAC (aMVAC, the four drugs being administered every 2 weeks with granulocyte colony-stimulating factor (G-CSF)) is better tolerated than conventional MVAC, with a trend for improved activity. There is no standard of care after failure of gemcitabine-platinum (GP) chemotherapy. Our aim was to assess the activity and toxicity of accelerated MVAC as second-line treatment. METHODS: We reviewed data from patients previously treated with GP who had received aMVAC at two institutions at the time of disease progression. RESULTS: Forty-five patients received aMVAC after GP: 18 (40%) and 27 (60%) had received GP in the adjuvant and the metastatic settings, respectively. The median time to progression (TTP) after first-line GP was 9.3 months. The response rate for aMVAC was 61%, including 4/38 (10%) complete responses. Median time to progression and median overall survival (OS) were 5.8 and 14.2 months, respectively. Median TTP and OS were 9.6 and 16.5 months when GP was used in the adjuvant setting and 4.4 and 5.7 months when GP was used in the metastatic setting. Grade 3-4 toxicities were observed in 31 patients (69%), including four sepsis-related deaths. CONCLUSION: aMVAC exerts clinical activity after previous treatment with GP, especially when GP was used in the adjuvant setting. aMVAC should however be administered with caution due to toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Urinary Bladder Neoplasms/mortality , Vinblastine/administration & dosage , Vinblastine/adverse effects , Gemcitabine
3.
BMC Cancer ; 11: 72, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21324142

ABSTRACT

BACKGROUND: The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains debated. We analyzed the outcome of patients with non metastatic locally advanced primary GIST treated with IM within the prospective BFR14 phase III trial. METHODS: The database of the BFR14 trial was searched for patients with no metastasis at time of inclusion. Patients treated for recurrent disease were excluded. Twenty-five of 434 patients met these criteria. RESULTS: Fifteen of 25 patients (60%) had a partial response to IM. Nine of the 25 patients (36%) underwent surgical resection of their primary tumor after a median of 7.3 months of IM treatment (range 3.4-12.0). Per protocol patients received continuous IM treatment in the post resection period, in an adjuvant setting. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival (PFS) and overall survival (OS) for patients who underwent surgical resection versus those who did not (median not reached vs 23.6 months, p = 0.0318 for PFS and median not reached vs 42.2 months, p = 0.0217 for OS). In the group of patients who underwent resection followed by IM, the 3-year PFS and OS rates were 67% and 89% respectively CONCLUSIONS: Following neoadjuvant IM for non metastatic locally advanced GIST 9 of 25 patients (36%) were selected for resection of the primary tumor. OS and PFS figures were close to those of localised intermediate or high risk GIST (70% at 5 years) in the subgroup of operated patients, while the outcome of the non-operated subgroup was similar to that of metastatic GIST.


Subject(s)
Clinical Trials, Phase III as Topic , Gastrointestinal Stromal Tumors/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Benzamides , Combined Modality Therapy , Disease Progression , Female , Follow-Up Studies , Gastrointestinal Stromal Tumors/mortality , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/surgery , Humans , Imatinib Mesylate , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Piperazines/adverse effects , Pyrimidines/adverse effects
4.
Cancer Chemother Pharmacol ; 67(1): 49-56, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20204365

ABSTRACT

BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 ± 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 ± 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Fluorouracil/therapeutic use , Head and Neck Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Dihydrouracil Dehydrogenase (NADP)/genetics , Dose-Response Relationship, Drug , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Head and Neck Neoplasms/enzymology , Humans , Male , Middle Aged , Pharmacogenetics , Prospective Studies , Retrospective Studies , Severity of Illness Index , Treatment Outcome
5.
J Clin Oncol ; 28(1): 160-5, 2010 Jan 01.
Article in English | MEDLINE | ID: mdl-19933910

ABSTRACT

PURPOSE Anticipating toxicities with gemcitabine is an ongoing story, and deregulation in cytidine deaminase (CDA) could be associated with increased risk of developing early severe toxicities on drug exposure. PATIENTS AND METHODS A simple test to evaluate CDA phenotypic status was first validated in an animal model investigating relationships between CDA activity and gemcitabine-related toxicities. Next, relevance of this test as a marker for toxicities was retrospectively tested in a first subset of 64 adult patients treated with gemcitabine alone, then it was tested in a larger group of 130 patients who received gemcitabine either alone or combined with other drugs and in 20 children. Additionally, search for the 435 T>C, 208 G>A and 79 A>C mutations on the CDA gene was performed. Results In mice, CDA deficiency impacted on gemcitabine pharmacokinetics and had subsequent lethal toxicities. In human, 12% of adult patients experienced early severe toxicities after gemcitabine administration. A significant difference in CDA activities was observed between patients with and without toxicities (1.2 +/- 0.8 U/mg v 4 +/- 2.6 U/mg; P < .01). Conversely, no genotype-to-phenotype relationships were found. Of note, the patients who displayed particularly reduced CDA activity all experienced strong toxicities. Gemcitabine was well tolerated in children, and no CDA deficiency was evidenced. CONCLUSION Our data suggest that CDA functional testing could be a simple and easy marker to discriminate adult patients at risk of developing severe toxicities with gemcitabine. Particularly, this study demonstrates that CDA deficiency, found in 7% of adult patients, is associated with a maximum risk of developing early severe toxicities with gemcitabine.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Cytidine Deaminase/blood , Deoxycytidine/analogs & derivatives , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Biomarkers , Child , Child, Preschool , Deoxycytidine/adverse effects , Female , Humans , Male , Mice , Gemcitabine
6.
Cancer Chemother Pharmacol ; 63(6): 1177-80, 2009 May.
Article in English | MEDLINE | ID: mdl-19107485

ABSTRACT

We report here the case of a 19-year-old female patient who suffered from extremely severe toxicities (G4 mucitis, fever, diarrhea, alteration of general state) while undergoing low-dose capecitabine treatment for her metastatic corticosurrenaloma. The severe toxicities stopped as soon as treatment was suspended. Interestingly, this patient was not deficient in DPD, a pharmacogenetic syndrome usually associated with increased risk of developing severe/lethal toxicities in patients undergoing fluoropyrimidine therapy, and she had been treated previously with 5-FU with a good tolerance. We then hypothesized that cytidine deaminase (CDA) extensive phenotype could be responsible for the severe toxicities observed with capecitabine. CDA is affected by genetic polymorphism, with subsequent acquisition of either deficient or extensive metabolizer profile. Phenotypic investigations confirmed that CDA activity in this patient was +180% higher than the ones usually recorded in the general population. This strongly suggests that the extensive activation of triple-prodrug capecitabine could have occurred in this patient, resulting in overexposure to 5-FU and its cytotoxic metabolites eventually. This case report suggest for the first time that severe toxicities with a capecitabine-containing protocol could be, at least in part, linked with an extensive-CDA syndrome. The case reported here suggests therefore that besides DPD, screening for CDA activity could be of interest to ensure a better safety in the handling of oral capecitabine at the bedside.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Cytidine Deaminase/metabolism , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Adrenal Cortex Neoplasms/drug therapy , Adrenal Cortex Neoplasms/enzymology , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacokinetics , Antimetabolites, Antineoplastic/therapeutic use , Capecitabine , Cytidine Deaminase/genetics , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/pharmacokinetics , Deoxycytidine/therapeutic use , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/pharmacokinetics , Fluorouracil/therapeutic use , Humans , Metabolic Clearance Rate , Polymorphism, Genetic , Young Adult
7.
Pharmacogenet Genomics ; 17(10): 841-4, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17885621

ABSTRACT

Gemcitabine is an antimetabolite drug used in the treatment of various solid tumours, including lung, pancreatic or gynaecological cancers. Innovative combinational strategies (e.g. gemcitabine+capecitabine or gemcitabine+oxaliplatin) make gemcitabine an extensively prescribed drug now. Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. Besides, we showed here that our cost-effective and simple phenotypic approach should enable, in the future, the detection of deficient patients at risk upon gemcitabine administration.


Subject(s)
Cytidine Deaminase/genetics , Deoxycytidine/analogs & derivatives , Down-Regulation/drug effects , Aged , Cytidine Deaminase/blood , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Fatal Outcome , Female , Humans , Phenotype , Polymorphism, Single Nucleotide/genetics , Reference Values , Gemcitabine
8.
Ther Drug Monit ; 28(5): 678-85, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17038885

ABSTRACT

Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Dihydropyrimidine Dehydrogenase Deficiency , Drug Monitoring/methods , Fluorouracil/adverse effects , Neoplasms/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/therapeutic use , Chromatography, High Pressure Liquid , Dihydrouracil Dehydrogenase (NADP)/genetics , Female , Fluorouracil/blood , Fluorouracil/therapeutic use , Humans , Male , Middle Aged , Neoplasms/enzymology , Neoplasms/mortality , Phenotype , Retrospective Studies
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