ABSTRACT
BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Adult , Aged , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Disease Progression , Docetaxel , Female , Fluorouracil/administration & dosage , Humans , Irinotecan , Male , Middle Aged , Taxoids/administration & dosageABSTRACT
BACKGROUND: The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. PATIENTS AND METHODS: We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). RESULTS: Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P<0.0001) and 19.5 versus 38.5 months (P<0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P<0.0001) and OS (P=0.001). CONCLUSION: The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.
Subject(s)
Bone Neoplasms/drug therapy , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Pyrroles/therapeutic use , Bone Neoplasms/secondary , Carcinoma, Renal Cell/pathology , Disease Progression , Disease-Free Survival , Female , Humans , Kidney Neoplasms/pathology , Male , Retrospective Studies , Sunitinib , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND: Xp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients. PATIENTS AND METHODS: Patients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified. Nuclear TFE3 positivity was confirmed by reviewing pathology slides. Responses according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Overall, 53 patients were identified; 23 had metastatic disease, and of these 21 had received targeted therapy (median age 34 years). Seven patients achieved an objective response. In first line, median PFS was 8.2 months [95% confidence interval (CI) 2.6-14.7 months] for sunitinib (n = 11) versus 2 months (95% CI 0.8-3.3 months) for cytokines (n = 9) (log-rank P = 0.003). Results for further treatment (second, third, or fourth line) were as follows: all three patients receiving sunitinib had a partial response (median PFS 11 months). Seven of eight patients receiving sorafenib had stable disease (median PFS 6 months). One patient receiving mTOR inhibitors had a partial response and six patients had stable disease. Median OS was 27 months with a 19 months median follow-up. CONCLUSION: In Xp11 translocation RCC, targeted therapy achieved objective responses and prolonged PFS similar to those reported for clear-cell RCC.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, X/genetics , Gene Fusion , Kidney Neoplasms/genetics , Translocation, Genetic/genetics , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Antiviral Agents/therapeutic use , Benzenesulfonates/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/secondary , Child , Child, Preschool , Everolimus , Female , Humans , Immunosuppressive Agents/therapeutic use , Indoles/therapeutic use , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Middle Aged , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/therapeutic use , Pyrroles/therapeutic use , Research Report , Retrospective Studies , Sirolimus/analogs & derivatives , Sirolimus/therapeutic use , Sorafenib , Sunitinib , Survival Rate , TOR Serine-Threonine Kinases/antagonists & inhibitors , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Young AdultABSTRACT
The authors report the case of a 44-year-old man in whom a poorly differentiated primary carcinoma of the head of the epididymis was discovered incidentally. Due to the rarity of this diagnosis, a comprehensive assessment was performed looking for a primary tumour, but without success. Despite early surgical resection, the patient developed lymph-node metastases. This exceptional tumour showed low sensitivity to chemotherapy. Malignant tumours of the epididymis are exceptional and require investigations to detect a primary tumour. Treatment is based on surgical resection, ideally via an inguinal incision, combined with chemotherapy adapted to the histological type.
Subject(s)
Carcinoma , Epididymis , Genital Neoplasms, Male , Adult , Carcinoma/diagnosis , Genital Neoplasms, Male/diagnosis , Humans , MaleABSTRACT
Sunitinib, a multitargeted tyrosine-kinase inhibitor, extends survival of patients with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumours. Between October 2005 and March 2007, we retrospectively reviewed blood glucose level variations associated with sunitinib therapy in patients treated for mRCC. Nineteen of the patients had type II diabetes. All 19 patients had a decrease in blood glucose level (mean 1.77 mmol l(-1)) after 4 weeks of treatment. This was followed by re-elevation in the 2-week rest period. After two cycles of sunitinib administration, two patients had stopped blood glucose-lowering drugs whereas five other patients had normalised their blood glucose level. On the basis of pre-clinical data, we hypothesise that several mechanisms could be involved in this process, such as capillary regression of pancreatic islets, IGF-1 modulation through HIF1-alpha or NF-kappaB activation. In addition, a decrease of glucose uptake in the context of concomitant gastrointestinal toxicity cannot be excluded. Glycaemic control should be carefully evaluated in diabetic patients treated with sunitinib, and routine monitoring is warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Blood Glucose/analysis , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Pyrroles/therapeutic use , Adult , Aged , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/secondary , Female , Humans , Indoles/pharmacology , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/physiology , Kidney Neoplasms/blood , Kidney Neoplasms/pathology , Male , Middle Aged , NF-kappa B/physiology , Pyrroles/pharmacology , Retrospective Studies , SunitinibABSTRACT
BACKGROUND: The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter. METHODS: This nationwide observational survey was carried out in France from 18 January to 2 February 2005 among representative samples of 773 women aged between 40 and 75 years and 600 general practitioners (GPs). Information collected included socio-demographic characteristics, attitude towards cancer screening and actual experience of cancer screening, as well as GPs' practice regarding screening. The precision of the results is +/- 4.3% for a 95% confidence interval. RESULTS: Among the 507 participating women aged between 50 and 74 years, 92.5% (469/507) had undergone at least one mammography: 54.6% (256/469) underwent this test on their own initiative and 44.6% (209/469) of women performed it in the framework of a systematic screening plan. Most women participating in the systematic screening (89.0% i.e. 186/209) had a mammography within the last dating from less than 2 years versus 73.8% (189/256) of those who performed it outside the screening program (Chi(2) test; p<0.01). Interestingly, 422 women (61.9% i.e. 422/682 women aged between 40-75 years with at least one mammography) had performed a mammography before the recommended age for screening. There was a significant correlation (p = 0.009) between the existence of a first mammography before 50 years of age and subsequent screening on women's own initiative (54.6% of 469 screened women). Main reasons for not performing the screening test every second year (77 women aged between 50-74 years) included: feeling unconcerned and/or unmotivated (p = 0.0001), no cancer anxiety (p = 0.020) and no recommendation by the GP (p = 0.015); Of the 600 participating GPs, 68.6% (412/600) systematically recommended a mammography to their patients. GPs' perceptions of the reasons for women's avoidance of the screening test were unwillingness to be aware of mammography results (44.4% - 266/600) and the belief that mammography was painful (52.5% - 315/600). CONCLUSION: The main result of the EDIFICE survey is the high rate of women's attendance at mammography screening. The EDIFICE survey pointed out that systematic and organized screening played a major role in the regularity of screening tests for breast cancer every second year. GPs and gynaecologist are key actors in heightening public awareness.
Subject(s)
Breast Neoplasms/diagnosis , Mass Screening/methods , Adult , Aged , Attitude to Health , Female , France , Gynecology/methods , Humans , Mammography/methods , Medical Oncology/methods , Middle Aged , Multivariate Analysis , Odds Ratio , Tissue DistributionABSTRACT
Ten percent of patients with kidney cancer have associated vena cava thrombus, which is associated with a high operative morbidity. Up to now, no medical treatment has allowed regression of vena cava tumour thrombus. The authors report the case of a 62-year-old patient with left kidney cancer associated with vena cava tumour thrombus. After surgical resection, the patient relapsed in the form of vena cava thrombus associated with right renal vein thrombus, responsible for renal insufficiency requiring dialysis. Sorafenib therapy allowed regression of the vena cava thrombus, suspension of haemodialysis and local disease control with a follow-up of one year. This case report justifies a review of the place of anti-angiogenic therapy in the treatment of kidney cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzenesulfonates/therapeutic use , Carcinoma, Renal Cell/complications , Kidney Neoplasms/complications , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Renal Veins , Venae Cavae , Venous Thrombosis/drug therapy , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Follow-Up Studies , Humans , Kidney/pathology , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Magnetic Resonance Imaging , Male , Middle Aged , Nephrectomy , Niacinamide/analogs & derivatives , Phenylurea Compounds , Receptors, Vascular Endothelial Growth Factor , Sorafenib , Time Factors , Treatment Outcome , Venous Thrombosis/diagnosisABSTRACT
A 73-year-old man presented with renal cell carcinoma of the left kidney. Despite the absence of metastases, primary nephrectomy was not performed immediately due to the large tumour volume and the presence of large lymph node extension. The patient was treated with sunitinib for 10 months. Computed tomography at the end of treatment showed a significant reduction of the size of the tumour and the volume of lymph node extension. Radical nephrectomy was then performed. On histological evaluation, the primary renal tumour and, to a lesser degree, the lymph nodes were predominantly necrotic.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Pyrroles/therapeutic use , Aged , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/surgery , Chemotherapy, Adjuvant , Humans , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/surgery , Lymph Node Excision , Male , Nephrectomy , Sunitinib , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Hormone-refractory prostate cancer is an advanced stage of the metastatic disease; it has a poor prognosis and a short median survival, about 9 to 18 months. The current article is based on a literature review regarding the prognostic factors and medical treatments, with a focus on recent advances in chemotherapy. With the use of docetaxel that increases the median survival of this disease and improves the symptoms, new clinical protocols have been developed, with promising results; these protocols propose a combination with calcitriol or antiangiogenic agents. Supportive care is also an important part of the treatment due to the high level of bone involvement and its consequences. Such recent advances constitute a real progress in the management of prostate cancer, namely the pharmacological combinations with a promising efficacy and little toxicity.
Subject(s)
Androgen Antagonists/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms , Taxoids/therapeutic use , Adult , Aged , Androgen Antagonists/administration & dosage , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/administration & dosage , Bone Density Conservation Agents/therapeutic use , Calcitriol/administration & dosage , Calcitriol/therapeutic use , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Combined Modality Therapy , Diphosphonates/therapeutic use , Docetaxel , Humans , Male , Prognosis , Prostatic Neoplasms/blood , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Randomized Controlled Trials as Topic , Risk Factors , Taxoids/administration & dosage , Time Factors , Vitamins/administration & dosage , Vitamins/therapeutic useABSTRACT
BACKGROUND: Cisplatin (cis-diamminedichloroplatinum) is one of the most active agents against a broad range of malignancies, including ovarian cancer. Cisplatin resistance appears to be associated with several molecular alterations, including overexpression of metallothionein, a metal-binding protein. In the present study, we attempted to take advantage of metallothionein overexpression to overcome cisplatin resistance. METHODS: Using a virus-free system (liposomes), we sought to express the suicide gene, thymidine kinase (TK), driven by the promoter of the human metallothionein IIa (hMTIIa) gene using the pMT-TK plasmid. We used cisplatin-resistant human ovarian carcinoma cells as a model. RESULTS: We first analyzed metallothionein expression using a ribonuclease protection assay. In comparison to parental cells, the cisplatin-resistant cells were found to have increased expression of metallothionein messenger RNA (mRNA). Metallothionein overexpression in these cells was not associated with an increased copy number of the hMTIIa gene or with different transfection efficiencies. Furthermore, we showed by reverse transcription-polymerase chain reaction analysis that transfection of the pMT-TK plasmid results in a 56-fold higher expression of thymidine kinase mRNA in cisplatin-resistant cells compared with parental cells, consistent with increased metallothionein promoter-mediated transactivation in the cisplatin-resistant cells. Transfection of resistant cells with pMT-TK or a control plasmid (pCD3-TK) resulted in a marked sensitization to ganciclovir, with a 50% cell growth-inhibitory concentration (IC(50)) of 20 microg/mL and 9 microg/mL, respectively. Transfections of the cisplatin-sensitive cells resulted in no sensitization to ganciclovir with pMT-TK (IC(50) 200 microg/mL) and a high sensitization with pCD3-TK (IC(50) = 6 microg/mL). CONCLUSION: These studies suggest that pMT-TK gene therapy may provide an alternative treatment for cisplatin-refractory ovarian tumors.
Subject(s)
Cisplatin/pharmacology , Genetic Therapy , Metallothionein/genetics , Ovarian Neoplasms/genetics , Promoter Regions, Genetic , Thymidine Kinase/genetics , Drug Resistance, Neoplasm , Female , Ganciclovir/pharmacology , Humans , Liposomes/administration & dosage , Prodrugs/metabolism , RNA, Messenger/analysis , Simplexvirus/enzymology , Thymidine Kinase/metabolism , Transcriptional Activation , Transfection , Tumor Cells, CulturedABSTRACT
Lung cancer is the first cause of choroidal metastasis in man. Generally, its discovery is made at end-stage of the disease. It can be uncommonly the presenting sign as in our case. We report a case of a 28-year-old patient with no prior medical history. He presented with visual decrease and metamorphopsia that lead to the diagnosis of a metastatic adenocarcinoma of the lung (bone, liver, choroid, nodles). Chemotherapy permitted to improve visual acuity, in parallel with disappearance of choroidal metatasis. Discovery of choroidal tumor should evoke in first line metastasis. Chemotherapy can improve visual acuity and the quality of life.
Subject(s)
Adenocarcinoma/secondary , Choroid Neoplasms/secondary , Lung Neoplasms , Adenocarcinoma/drug therapy , Adult , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Choroid Neoplasms/diagnosis , Choroid Neoplasms/diagnostic imaging , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Docetaxel , Fluorescein Angiography , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/drug therapy , Male , Quality of Life , Radiography, Thoracic , Taxoids/administration & dosage , Taxoids/therapeutic use , Ultrasonography , Vision Disorders/etiology , Visual AcuityABSTRACT
BACKGROUND: Inhibitors of epidermal growth factor receptors (EGFR) constitute a new alternative treatment for patients presenting certain advanced stage solid cancers (bowel, breast, ovary). Adverse cutaneous effects of these drugs are now starting to be described. OBSERVATIONS: Our study involved 2 men and 2 women with no previous history of acne included in a treatment protocol comprising EGFR inhibitors. Mean age was 52 years. The primary cancers were breast, ovary, bowel and unidentified. The EGFR inhibitors used were gefitinib (ZD1839) (2 cases), carnetinib (Cl1033) and cetuximab (IMC-C225). Skin lesions appeared after 7 days and included erythematous papules and follicular pustules of the face, back and upper chest. No comedons were seen, and there were no nodules or cysts. The severity of the rash resulted in discontinuation of treatment in 2 patients with complete disappearance of skin lesions in both cases. In one patient, reduction of the dosage of gefitinib (IMC-C225) led to gradual resolution of the rash. Histological examination of papules and pustules concluded on an acute suppurative folliculitis. Smears and cultures ofa nasal lesion and pustules revealed coagulase-positive Staphylococcus aureus in 2 patients. Combined doxycycline 100 mg daily and benzoyl peroxide was prescribed for 3 months and a favourable outcome was achieved after a mean 2 weeks. DISCUSSION: EGFR inhibitors act by inhibiting mechanisms oftumour proliferation in certain cancers at advanced stages or refractory to other treatments. Our findings in these four patients are similar to the published cases in terms of rapid onset of monomorphous, papulopustular, follicular eruption without comedons. Rapid response to cyclines and benzoyl peroxide is also reported in literature. This treatment must be instituted rapidly and patients must be informed about the cutaneous side-effects of EGFR inhibitors before the start of therapy. The pathophysiology of these eruptions is still unknown. Skin signs are probably due to interaction with EGFR functions, including overexpression of EGFR in keratinocytes and hair follicles.
Subject(s)
Antineoplastic Agents/adverse effects , Drug Eruptions/etiology , ErbB Receptors/antagonists & inhibitors , Adult , Antineoplastic Agents/administration & dosage , Female , Folliculitis/chemically induced , Humans , Male , Middle Aged , Neoplasms/drug therapy , Retrospective StudiesABSTRACT
Gene therapy using the herpes simplex virus thymidine kinase gene (HSV-TK) is a promising new approach for the treatment of gliomas, a tumor type with a poor prognosis. To limit the toxic effects of this procedure, it is desirable to restrict expression of the HSV-TK gene to the target cells. This can be accomplished by use of the promoter of the glial fibrillary acidic protein gene, an intermediate filament protein expressed primarily in astrocytes. A plasmid containing the HSV-TK gene, driven by the human glial fibrillary acidic protein promoter gfa2, was lipofected into glioma cell lines and into an ovarian cancer cell line. Treatment with ganciclovir showed efficient killing of glioma cells, with no effect on the ovarian cells. Thus, the gfa2 promoter is a promising candidate for directing expression of toxic genes to gliomas.
Subject(s)
Astrocytes/metabolism , Genetic Therapy , Glioma/therapy , Simplexvirus/enzymology , Thymidine Kinase/genetics , Ganciclovir/pharmacology , Glial Fibrillary Acidic Protein/analysis , Glial Fibrillary Acidic Protein/genetics , Glioma/pathology , Humans , Promoter Regions, Genetic , Tumor Cells, CulturedABSTRACT
PURPOSE: To evaluate the activity and the toxicity of the combination of cisplatin (CDDP)/recombinant interleukin-2 (rIL-2) and interferon alfa-2a (IFN alpha) in disseminated malignant melanoma (DMM). PATIENTS AND METHODS: Between December 1990 and March 1992, 39 patients with biopsy-proven metastatic malignant melanoma (MM), bidimensionally measurable lesions and an Eastern Cooperative Oncology Group (ECOG) performance status < or = 2 entered this protocol. Seventy-nine percent had received previous chemotherapy including platinum complex (15%) and alpha interferon (44%). They received CDDP (100 mg/m2 on day 0) followed by IL-2 18.10(6) IU/m2/d continuous intravenous (IV) infusion from day 3 to day 6 and from day 17 to day 21. The cycle was repeated on day 28. Subcutaneous IFN alpha 9.10(6) IU three times weekly was administered throughout the treatment period. From day 66 or 94, patients were administered a maintenance cycle with CDDP 100 mg/m2, subcutaneous IL-2 5.10(6) IU/m2/d from day 15 to day 19 and from day 22 to day 26 and IFN alpha 9.10(6) IU three times weekly repeated every 5 weeks (maximum four cycles). RESULTS: Among 39 assessable patients, five patients achieved complete responses (CRs). Sixteen patients had partial responses (PRs). The overall objective response rate was 53.8%. The number of metastatic sites was the only response-predictive factor. Toxicity was manageable in a routine patient setting and there was no life-threatening toxicity. CONCLUSION: These results seem to indicate a possible synergy between CDDP/rIL-2 and IFN alpha in MM.
Subject(s)
Cisplatin/therapeutic use , Interferon-alpha/therapeutic use , Interleukin-2/therapeutic use , Melanoma/therapy , Adult , Aged , Combined Modality Therapy/adverse effects , Female , Humans , Immunotherapy/methods , Interferon alpha-2 , Male , Melanoma/drug therapy , Melanoma/secondary , Middle Aged , Recombinant Proteins , Remission Induction , Treatment OutcomeABSTRACT
PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m(2). All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h.m(2). The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m(2). CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m(2) every 3 weeks in patients previously treated with chemotherapy.
Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/analogs & derivatives , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Neoplasms/drug therapy , Neoplasms/metabolism , Adult , Aged , Antineoplastic Agents, Phytogenic/blood , Camptothecin/blood , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Nausea/chemically induced , Neoplasms/blood , Neutropenia/chemically induced , Topoisomerase I Inhibitors , Vomiting/chemically inducedABSTRACT
PURPOSE: To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/irinotecan (OC) combination. PATIENTS AND METHODS: Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m(2) followed by a 400-mg/m(2) 5-FU bolus injection, then a 600-mg/m(2) continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m(2) on day 1) and oxaliplatin (85 mg/m(2) on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2) every 3 weeks. RESULTS: In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred. CONCLUSION: The every-3-weeks OC combination is safe and active in advanced 5-FU-resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Colonic Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Adult , Aged , Camptothecin/administration & dosage , Chemotherapy, Adjuvant , Colonic Neoplasms/mortality , Colonic Neoplasms/secondary , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Humans , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Rectal Neoplasms/mortality , Rectal Neoplasms/secondary , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Delayed emesis following chemotherapy in cancer patients remains an important challenge for treatment and contributes to poor quality of life and treatment compliance. OBJECTIVES: To compare the efficacy and tolerability of associations of metopimazine and ondansetron with methylprednisolone for the prevention of delayed chemotherapy-induced nausea and emesis. METHODS: A randomised, open-label, observational, cross-over design was used to compare two treatment strategies following two consecutive sessions of chemotherapy separated by at least 1 week. Patients were randomised to treatment with sublingual metopimazine (15 mg tid) or ondansetron lyophilisate (8 mg bid) for 5 days. All patients received oral methylprednisolone (48 mg). Patients reported episodes of nausea and emesis in a diary, and completed the Functional Living Index Emesis quality of life questionnaire. Adverse events were also evaluated. RESULTS: Ninety-nine patients were included in the study, 79.5% of whom were women, with a mean age of 52.7 years. Breast cancer was the most common individual cancer and most patients were receiving combinations of cytotoxic drugs. Treatment was successful at preventing delayed emesis in 73.6% of patients during treatment with the metopimazine-methylprednisolone association and 57.5% during the ondansetron-methylprednisolone association. Analysis of discordant pairs revealed a significant benefit in favour of the methopimazine-methylprednisolone association (p = 0.006). No significant difference was observed between treatments for the overall quality of life score. The incidence of gastrointestinal disorders, particularly constipation, was significantly higher during ondansetron-methylprednisolone treatment (p = 0.0112). CONCLUSION: Methopimazine is an effective and well-tolerated alternative to setrons for the treatment of delayed nausea and emesis in patients undergoing chemotherapy.
Subject(s)
Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Isonipecotic Acids/therapeutic use , Methylprednisolone/therapeutic use , Ondansetron/therapeutic use , Vomiting/drug therapy , Adult , Aged , Antiemetics/adverse effects , Antineoplastic Agents/therapeutic use , Cross-Over Studies , Drug Therapy, Combination , Female , Humans , Isonipecotic Acids/adverse effects , Male , Methylprednisolone/adverse effects , Middle Aged , Nausea/drug therapy , Nausea/etiology , Neoplasms/drug therapy , Ondansetron/adverse effects , Quality of Life , Surveys and Questionnaires , Vomiting/etiologyABSTRACT
BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Isoquinolines/pharmacokinetics , Neoplasms/metabolism , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Biological Availability , Female , Half-Life , Hematologic Tests , Humans , Infusions, Intravenous , Isoquinolines/adverse effects , Isoquinolines/pharmacology , Male , Maximum Tolerated Dose , Middle Aged , Molecular Structure , Neoplasms/drug therapyABSTRACT
We report virus-free transfer of a "suicide" gene into tumoral cells. The system can be used in vitro or in vivo to induce tumor cell death. A plasmid carrying the herpes simplex virus thymidine kinase (HSV-TK) gene with its 5'- and 3'-flanking regions was used both alone and in liposomes to transduce B16 cells. In vitro, a 5-day treatment with ganciclovir after transfection with the HSV-TK gene in liposomes induced a significant lysis of B16 melanoma cells as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. The efficacy of transfection was determined using liposomes harboring the beta-galactosidase reporter gene and was around 10%. Thus, the cytotoxicity observed resulted presumably from a large bystander effect. In vivo, direct transfer of the TK DNA into established B16 melanoma tumors in C57B6 mice followed by i.p. ganciclovir treatment induced a 50% reduction of tumor weight after 8 days and an increased necrosis. Despite the use of the nonspecific strong TK promoter, no necrosis was detected in normal tissues surrounding the tumor or elsewhere. Thus, this system of tumor transfection, which does not involve any viral vector, is safe and straightforward and seems to be suitable for testing in clinical trials.
Subject(s)
Ganciclovir/therapeutic use , Genetic Therapy , Melanoma, Experimental/therapy , Simplexvirus/enzymology , Thymidine Kinase/genetics , Animals , Cell Death , Gene Transfer Techniques , Liposomes , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Plasmids , Tumor Cells, CulturedABSTRACT
The involvement of interleukin (IL-) 6 in malignant disease has been investigated in a variety of different malignancies. To evaluate whether serum IL-6 is a useful disease marker in metastatic malignant melanoma (MMM), we studied the time course of endogenous IL-6 secretion in 41 patients treated with cisplatinum, IL-2, and IFN-alpha. Furthermore, the relationship of endogenous IL-6 concentrations to the tumor burden and/or the clinical response was also evaluated. The baseline serum IL-6 levels were significantly higher in patients with MMM than in the control group (P = 0.002). When tumor burden was taken into consideration, we found that IL-6 levels were higher in patients with high tumor burden than in patients with low tumor burden. During treatment in the whole patient population, a higher serum IL-6 level was observed in nonresponding as compared to responding patients at days 7 (P = 0.0005), 21 (P = 0.002), and 35 (P = 0.009). The follow-up of serum IL-6 in patients with MMM according to the tumor burden and clinical response demonstrated that: (a) IL-6 levels were significantly higher at days 7 and 21 in patients with high tumor burden as compared to those with low tumor burden; and (b) IL-6 levels remain significantly higher in nonresponding patients as compared to responding patients regardless of the tumor burden. From these results, we can conclude that endogenous IL-6 may play a role in the failure of IL-2 therapy in such patients, since the very early IL-6 increase is correlated with the tumor mass and nonresponse to biochemotherapy. Therefore, it seems that the early detection of endogenous IL-6 may represent valuable information for monitoring the response to biochemotherapy in patients with MMM.