Combining gemcitabine, cisplatin, and ifosfamide (GIP) is active in patients with relapsed metastatic germ-cell tumors (GCT): a prospective multicenter GETUG phase II trial.

BACKGROUND: The standard treatment of patients with metastatic germ-cell tumor (GCT) relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing three-drug regimen, which usually yields a complete response (CR) rate <50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study. PATIENTS AND METHODS: The GIP regimen consisted in gemcitabine 1000 mg/m(2) day 1 and 5, ifosfamide 1200 mg/m(2)/day day 1-5, cisplatin 20 mg/m(2)/day day 1-5, and granulocyte colony-stimulating factor 263 µg/day day 7-15, repeated every 3 weeks for four cycles. Eligibility criteria were that patients had favorable prognostic factors to conventional-dose salvage chemotherapy including a testis primary tumor and a previous CR to first-line chemotherapy for metastatic disease. The primary end point was the CR rate and a two-stage Simon design was used. RESULTS: Thirty-seven patients were accrued and 29 (78%) achieved a favorable response, including a CR in 20 (54%) and a partial response with normalization of tumor markers (PRm-) in 9 (24%). With a median follow-up of 53 months (13-81), the 2-year overall survival rate is 73% (57%-84%) and the continuous progression-free survival rate is 51% (35%-66%). Myelosuppression was the main toxicity including febrile neutropenia in 8 (22%) patients and 18 (50%) cases required platelet infusion. No grade 3 and 4 peripheral neurotoxicity or renal toxicity occurred. Two patients died of treatment-related toxicity, one of them with cancer progression. CONCLUSION: In a multicenter context, four cycles of the GIP regimen achieved a high CR rate in patients with relapsed testicular GCT. The GIP regimen avoided severe neurotoxicity and yielded a high survival rate. CLINICAL TRIAL NUMBER: NCT00127049.

Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma?

BACKGROUND: As most patients with retroperitoneal sarcomas (RPS) die of local recurrence, front-line aggressive surgery (FAS) has been developed, and it seems to achieve better local control. The aim of this study was to evaluate conformal postoperative radiotherapy (PORT) in patients who had enlarged surgery. PATIENTS AND METHODS: Between 1994 and 2008, 110 patients with primary RPS mainly operated by FAS were analysed. Sixty-two patients underwent surgery and no PORT (group S), and 48 received surgery and PORT (group S + R). The median age was 52. Most patients had 3D conformal PORT (81%) with a median dose of 50 Gy. RESULTS: Comparing results at 5 years in the S and the S + R group, the cumulative rate of local failure was, respectively, 36% and 22% (NS); relapse-free survival was 47% and 60% (P = 0.02), and overall survival was, respectively, 77% and 71% (NS). CONCLUSION: Even if patients with adjuvant PORT were at higher risk of recurrence, there was a trend for radiotherapy (RT) to decrease the local relapse rate and improve recurrence-free survival. This study confirms that adjuvant conformal RT should be evaluated in a randomized trial, the control arm being FAS. Adjuvant RT in the preoperative setting is being evaluated in an EORTC trial.

A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas.

BACKGROUND: Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay). METHODS: Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch according to the manufacturer's protocol and ISET by studying cytomorphology and immunolabelling with anti-cytokeratin or lineage-specific antibodies. RESULTS: Concordant results were obtained in 55% (11 out of 20) of the patients with breast cancer, in 60% (12 out of 20) of the patients with prostate cancer and in only 20% (4 out of 20) of lung cancer patients. CONCLUSION: Our results highlight important discrepancies between the numbers of CTC enumerated by both techniques. These differences depend mostly on the tumour type. These results suggest that technologies limiting CTC capture to EpCAM-positive cells, may present important limitations, especially in patients with metastatic lung carcinoma.

Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). PATIENTS AND METHODS: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. RESULTS: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). CONCLUSION: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castration-resistant prostate cancer.

BACKGROUND: In patients with bone metastases from castration-resistant prostate cancer (CRPC) not pretreated with a bisphosphonate elevated N-telopeptide of type I collagen (uNTx), a marker of bone resorption, predicts skeletal-related events (SRE). The aim of this study was to assess the prognostic value of uNTx for overall survival (OS) and the incidence of SRE in patients with bone metastases from CRPC receiving zoledronic acid. METHODS: From 2004 to 2007, 94 patients with bone metastases from CRPC receiving zoledronic acid for at least 2 months were screened for uNTx. RESULTS: Median age was 66 years (range 46-88). Median serum prostate-specific antigen (PSA) was 66 ng/ml (0-3984) and median uNTx was 19 nmol/mM creatinine (3-489). During follow-up, 38 patients (40%) experienced an SRE. Median OS was 20 months [95% (CI) confidence interval 15-24). In the multivariate analysis, elevated uNTx [hazard ratio (HR) 2.2 (95% CI 1.2-4.0)], serum PSA [HR 2.8 (95% CI 1.6-5.1)], and ECOG performance status were the only independent prognostic factors for OS. Median OS was 12 months (10-16) and 25 months (21-34) in patients with uNTx > or =20 nmol/mM creatinine and in those with uNTx <20 nmol/mM creatinine, respectively. CONCLUSION: An elevated uNTx level is an independent prognostic factor for OS in patients with bone metastases from CRPC receiving a bisphosphonate.

p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-alpha and melphalan.

BACKGROUND: Recombinant tumor necrosis factor-alpha (TNF-alpha) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-alpha and loss of p53 function contributes to the resistance of tumour cells to TNF-alpha. The relationship between p53 status and response to TNF-alpha and melphalan in patients undergoing ILP is unknown. PATIENTS AND METHODS: We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters. RESULTS: P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-alpha and melphalan showed significantly higher levels of p53-mutated protein. CONCLUSIONS: Our results might be a clue to a role of p53 protein status in TNF-alpha and melphalan response in clinical use.

Ultra-pressure liquid chromatography-electrospray tandem mass spectrometry for multiresidue determination of pesticides in water.

A multiresidue analysis method has been developed for the determination of pesticides in water by ultra-performance liquid chromatography (UPLC) combined with tandem mass spectrometry (MS/MS). The selected pesticides represent a broad range of polarity and volatility [benzoylcyclohexanedione (mesotrione and sulcotrione); chloroacetamide (acetochlor, alachlor, dimethenamide, and metolachlor); phenoxyacetic acid (2,4-D and MCPA); phenoxypropionic (dichloprop and mecoprop); phenylurea (chlortoluron, diuron, isoproturon, linuron, and metoxuron); sulfonylurea (foramsulfuron, iodosulfuron, and nicolsulfuron); triazine (atrazine, cyanazine, desethylatrazine (DEA), desisopropylatrazine (DIA), simazine, and terbutylazine)]. The analytes were extracted using solid-phase extraction (SPE). The separation was carried out on an acquity UPLC BEH C18 column (1.7 microm, 50 mm x 1 mm ID) using a gradient elution profile and mobile phase consisting of 0.1% formic acid in water and acetonitrile. The pesticides were detected with a tandem mass spectrometer after being ionised positively or negatively (depending on the molecule) using an electrospray ionisation (ESI) source. To achieve the suitable extraction conditions for sample preparation, several parameters affecting the efficiency of SPE such as the nature of the sorbent and the eluent, extractant volume and pH were studied. The best recovery was obtained by the extraction with an Oasis HLB cartridge and 3 mL of a solution of acetonitrile/dichloromethane (1:1, v/v) at pH 2. The average recoveries of the pesticides in different samples ranged from 82 to 109%. The weight least squares (WLS) linear regression was used to calculate the limits of detection and quantification (LOD and LOQ) because the dispersion was heteroskedastic. All the pesticides could be correctly quantified at a concentration level of 50 ng L(-1) and most of them could be detected at a concentration inferior or equal to 8 ng L(-1). Efficiency and robustness of this method were evaluated by the analysis of several samples of real natural water.

Scrubbing intensification for sulphur and ammonia compounds removal.

Operating conditions were optimised in a new compact scrubber in order to remove odorous sulphur (H(2)S and CH(3)SH) and ammonia compounds. The influence of the superficial gas and liquid velocities, pH, contactor length, inlet concentrations (sulphur compounds, ammonia, chlorine), and the mixing effects was characterised. Whereas abatement increased with velocities, pH and the chlorine concentration, an increase of inlet CH(3)SH concentration drove to a worse efficiency of process. Moreover, the contactor length and the presence of another pollutant in the gas phase only played a role on the methylmercaptan removal. Finally, the reactive consumptions were estimated at the outlet of the reactor. The chlorination by-product quantification permitted to understand the under-stoichiometry.

Differential time to positivity of central and peripheral blood cultures is inaccurate for the diagnosis of Staphylococcus aureus long-term catheter-related sepsis.

OBJECTIVES: Differential time to positivity of cultures of blood drawn simultaneously from central venous catheter and peripheral sites is widely used to diagnose catheter-related bloodstream infections without removing the catheter. However, the accuracy of this technique for some pathogens, such as Staphylococcus aureus, is debated in routine practice. METHODS: In a 320-bed reference cancer centre, the charts of patients with at least one blood culture positive for S. aureus among paired blood cultures drawn over a six-year period were studied retrospectively. Microbiological data were extracted from the prospectively compiled database of the microbiology unit. Data concerning the 149 patients included were reviewed retrospectively by independent physicians blinded to the absolute and differential times to positivity, in order to establish or refute the diagnosis of catheter-related sepsis. Due to missing data, 48 charts were excluded, so 101 cases were actually analysed. The diagnosis was established in 62 cases, refuted in 15 cases and inconclusive in the remaining 24 cases. RESULTS: For the 64 patients with both central and peripheral positive blood cultures, the differential positivity time was significantly greater for patients with catheter-related bloodstream infections due to S. aureus (P<0.02). However, because of the high number of false-negative cases, the classic cut-off limit of 120 min showed 100% specificity but only 42% sensitivity for the diagnosis of catheter-related bloodstream infection due to S. aureus. CONCLUSIONS: These results strongly suggest that despite its high specificity, the differential time to positivity may not be reliable to rule out catheter-related bloodstream infection due to S. aureus.

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases.

BACKGROUND: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. METHODS: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. RESULTS: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. CONCLUSIONS: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy.

Cost-minimization analysis of prophylactic granulocyte colony-stimulating factor after induction chemotherapy in children with non-Hodgkin's lymphoma.

BACKGROUND: Colony-stimulating factors promote the proliferation of certain bone marrow cell populations. The primary objective of treating patients with these factors prophylactically following chemotherapy is to reduce the risk of infection, thereby minimizing the need for hospitalization and parenteral antibiotics. The use of colony-stimulating factors in children is widespread, despite the absence of conclusive supportive data and the high cost of these drugs. Consequently, the cost-benefit ratio of using prophylactic colony-stimulating factors is an important issue in cancer therapy. METHODS: During the period from January 1994 through June 1996, 149 afebrile children with newly diagnosed non-Hodgkin's lymphoma were randomly assigned either to receive granulocyte colony-stimulating factor (G-CSF) (lenograstim; 5 microg/kg body weight per day subcutaneously) or not to receive it (the control) at the end of the first two courses of induction chemotherapy with cyclophosphamide, vincristine, prednisone, doxorubicin, and methotrexate. A cost-minimization analysis was performed to assess the cost of chemotherapy in each group and to quantify how much could be economized by prescribing G-CSF. RESULTS: The total cost for induction chemotherapy was $29,765 in the G-CSF-treated group and $30,774 in the control group, indicating that the treatment strategy with G-CSF was slightly less expensive than the strategy without G-CSF (mean difference = $1009; 95% confidence interval = -$1474 to $3492). CONCLUSION: Treatment with G-CSF following chemotherapy in children with non-Hodgkin's lymphoma--previously shown to be of limited clinical benefit--also does not appear to reduce the costs of chemotherapy.

Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients.

We report the results observed in a large, randomized study that compared the effects of radiotherapy alone (the standard therapy) with those of a combination of radiotherapy and chemotherapy in nonresectable squamous cell and large-cell lung carcinoma. The radiation dose was 65 Gy in each group, and chemotherapy included vindesine, cyclophosphamide, cisplatin, and lomustine. In this study, 177 patients received radiotherapy alone (group A), and 176 patients received the combined treatment (group B). The 2-year survival rate was 14% in group A and 21% in group B (P = .08). The distant metastasis rate was significantly lower in group B (P less than .001). Local control was poor in both groups (17% and 15%, respectively) and remained the major problem.

[Role and perspectives of sentinel node biopsy in head and neck tumors]. / Place et perspectives du ganglion sentinelle dans les tumeurs des voies aérodigestives supérieures.

PURPOSE: To evaluate the accuracy of sentinel node biopsy for assessing the neck status for those patients with squamous cell carcinoma T1T2N0 of oral cavity. PATIENTS AND METHODS: 55 patients were included in a prospective study between 2000 and 2003. 53 underwent a sentinel node biopsy (SNB) followed by an elective neck dissection (END). Pathological examination with stepped serial sectioning and immunohistochemistry of sentinel node (SN) has been compared with routine pathology examination of remaining END nodes. RESULTS: 12 patients had a positive SN. No false negative was found. Patient follow up on, at less of 3 years, did not show any node recurrence for those patients with negative SN. After that study, 44 patients had a SNB without END. 7 patients had a positive SN. Follow up showed a node recurrence for 3 patients. In two of these, pathological reexamination showed a micrometastase in SN. SN failure rate is less than 3% for those 99 patients. CONCLUSION: SNB is a liable procedure. Failure rate is the same as in END. We plan to use this procedure in orophyngeal tumors where it could be possible to reduce irradiation fields and treatment sequels for those patients with negative SN.

New compact scrubber for odour removal in wastewater treatment plants.

This work presents the performances of a new odour scrubber. The reactor is packed with a new structure which enables co-current operations at high gas velocities. Energy consumption and removal efficiency of sulphur compounds by oxidative alkaline scrubbing were studied. The influence of both superficial gas (U(SG)) and liquid (U(SL)) velocities, ranging from 5.6 to 28 m.s(-1) and 0.016 to 0.055 m.s(-1) respectively, were quantified. Thus, the range of 0.5 to 5 liquid-to-gas mass ratio (L/G) was studied. A comparison has been made with a previous study on static mixers (SM) and with classical random packed towers (PT). It has been shown that superficial liquid and gas velocities have a significant influence on these parameters. Hydrogen sulphide (H2S) abatement reached values up to 99%. As concerns methylmercaptan (CH3SH), the maximal removal efficiency was 87%. As a result, if well scaled-up, our reactor can be a small single stage efficient apparatus for the elimination of low concentrations of sulphur compounds as H2S and CH3SH in high flow rates of polluted gas effluents.

Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial.

PURPOSE: A multicentric randomized study that compared patients who received intrahepatic arterial infusion (HAI) to a group of patients who did not receive HAI (control group) was performed for unresectable hepatic metastases from primary colorectal carcinoma. PATIENTS AND METHODS: One hundred sixty-six patients were assigned randomly to HAI of floxuridine (5 fluoro-2'deoxyuridine [FUDR]) 0.3 mg/kg/d for 14 days every 4 weeks or to the control group; this latter group, depending on the investigator's choice, was either under observation or received systemic fluorouracil (5-FU). The same regimen of systemic 5-FU also was administered to the HAI group in the event of extrahepatic progression. No crossover from the control group to the HAI group was permitted. The mean duration of follow-up was 54 months (range, 31 to 72), and 163 patients were analyzed. RESULTS: A significant improvement was observed in the survival rate for the 81 patients assigned to HAI group (P less than .02) with a 1-year survival rate of 64% versus 44% in the control group (82 patients). The 2-year survival rate was 23% versus 13%. The median survival was 15 months versus 11 months for the HAI group and the control group, respectively. Survival was better for patients with a less than 30% liver involvement, and for those treated in more specialized centers. The hepatotoxic effects of HAI were observed in 47 patients (chemical hepatitis [n = 28], and biliary sclerosis [n = 19]). The 1-year rate of sclerosing cholangitis was equal to 25%. Gastrointestinal toxicity was infrequent and consisted of gastritis or diarrhea. CONCLUSIONS: Therapy with HAI of FUDR improves the survival of patients with liver metastases over colorectal carcinoma. However, the methods that are used to diminish the toxicity of HAI and efficient systemic chemotherapy, such as a combination of 5-FU and leucovorin, are required to prevent extrahepatic metastases.

Granulocyte colony-stimulating factor in induction treatment of children with non-Hodgkin's lymphoma: a randomized study of the French Society of Pediatric Oncology.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF-) prophylactic G-CSF, 5 microg/kg/d, from day 7 until an absolute neutrophil count > or = 500/microL was sustained over 48 hours, after two consecutive induction courses of cyclophosphamide 1.5 or 3 g/m(2), vincristine 2 mg/m(2), prednisone 60 mg/m(2)/d x 5, doxorubicin 60 mg/m(2), high-dose methotrexate 3 or 8 g/m(2), and intrathecal injections (COPAD[M]) on protocols LMB89, LMT89, and HM91 of the French Society of Pediatric Oncology. RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF-. Although duration of neutropenia less than 500/microL was 3 days shorter in G-CSF+ patients (P = 10(-4)), incidence of febrile neutropenia (89% v. 93% in the first course, 88% v. 88% in the second course), durations of hospitalization and antimicrobial therapy, percentages of infections, mucositis, and transfusions were not significantly different. Although the percentage of G-CSF+ patients commencing the following course on day 21 was significantly higher (84% v 68% after the first and 57% v. 38% after the second course; P <.05), the median delay between the two courses was only 1 day less in G-CSF+ patients (median delay after first COPAD(M), 19 v. 20 days, P =.01; after second, 21 v. 22 days, P = not significant). Remission and survival rates were similar in both arms. CONCLUSION: This study demonstrates that G-CSF did not decrease treatment-related morbidity, nor increase the dose-intensity in children undergoing COPAD(M) induction chemotherapy for NHL.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.

PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.

Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study.

Patients who are cured from head and neck carcinomas remain at high risk for developing a second primary in the head and neck area. It is now clear that retinoids exert a prophylactic action on the development of epithelial cancers when tested on laboratory animals and on human premalignant lesions. They are now used in the chemoprevention of epithelial cancers in randomised trials evaluating their efficacy. We prospectively studied 316 patients who developed squamous cell carcinoma of the head and neck, classified as T1/T2, N0/N1 < or 3 cm, M0 according to the UICC TNM classification. Patients were randomly assigned to receive orally, either etretinate (a loading dose of 50 mg/day for the first month, followed by a dose of 25 mg/day in the following months) or a placebo for 24 months. Adjuvant treatment began no later than 15 days after surgery and/or the initiation of radiotherapy. The 5-year survival rate and disease-free survival rate are similar in the two groups. There are no significant differences regarding either local, regional and distant relapses. After a median follow-up of 41 months (range 0-81), 28 patients in the etretinate group and 29 in the placebo group developed a second cancer with, respectively, 12 and 13 in the head and neck region. Adjuvant treatment was definitively discontinued mainly due to toxicity in 33% of patients in the etretinate group versus 23% in the placebo group (P < 0.05). Etretinate, a second-generation retinoid, does not prevent second primary tumours in patients who have been treated for squamous cell carcinoma of the oral cavity and oropharynx.