Multicenter evaluation of breast cancer patients' satisfaction and experience with oncology telemedicine visits during the COVID-19 pandemic.

INTRODUCTION: During the COVID-19 pandemic, teleconsultation was implemented in clinical practice to limit patient exposure to COVID-19 while monitoring their treatment and follow-up. We sought to examine the satisfaction of patients with breast cancer (BC) who underwent teleconsultations during this period. METHODS: Eighteen centres in France and Italy invited patients with BC who had at least one teleconsultation during the first wave of the COVID-19 pandemic to participate in a web-based survey that evaluated their satisfaction (EORTC OUT-PATSAT 35 and Telemedicine Satisfaction Questionnaire [TSQ] scores) with teleconsultation. RESULTS: Among the 1299 participants eligible for this analysis, 53% of participants were undergoing standard post-treatment follow-up while 22 and 17% were currently receiving active anticancer therapy for metastatic and localised cancers, respectively. The mean satisfaction scores were 77.4 and 73.3 for the EORTC OUT-PATSAT 35 and TSQ scores, respectively. In all, 52.6% of participants had low/no anxiety. Multivariable analysis showed that the EORTC OUT-PATSAT 35 score correlated to age, anxiety score and teleconsultation modality. The TSQ score correlated to disease status and anxiety score. CONCLUSION: Patients with BC were satisfied with oncology teleconsultations during the COVID-19 pandemic. Teleconsultation may be an acceptable alternative follow-up modality in specific circumstances.

Real-world safety and effectiveness of regorafenib in metastatic colorectal cancer: the French CORRELATE cohort.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66 years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand-foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3-7.6) and 2.8 months (95% CI: 2.6-3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab.

PURPOSE: The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders. METHODS: This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial. RESULTS: In the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10-7), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p<0·001). Patients with a SPECTRA Score >0·02 had a lower OS in the training cohort (p<0·0001), in the validation cohort (p<0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41). CONCLUSION: A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies. TRIAL REGISTRATION: Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

Importance: The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. Objective: To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. Design, Setting, and Participants: The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. Interventions: After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. Main Outcomes and Measures: The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Results: Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). Conclusion and Relevance: The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT02404935.

Predictive value of vascular endothelial growth factor polymorphisms for maintenance bevacizumab efficacy in metastatic colorectal cancer: an ancillary study of the PRODIGE 9 phase III trial.

Background: Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. Objective: We evaluated the impact of SNPs of VEGF-A, VEGF receptors (VEGFR-1, VEGFR-2), and hypoxia inducible factor-1α (HIF-1α) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). Patients and methods: We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). Results: In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype (n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7-17.1)] (p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1-42.8) versus 22.5 (95% CI: 18.6-24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2-11.3) versus 9.2 (95% CI: 8.71-10.1)], and duration of the first CFI [4.6 (95% CI: 1.6-13.3) versus 4.14 (95% CI: 0.5-29.0) months, p = 0.3]. Conclusion: Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.

Drastic Reduction of Turnaround Time After Implementation of a Fully Automated Assay for RAS-BRAF Mutations in Colorectal Cancer: A Pilot Prospective Study in Real-life Conditions.

In some situations, there is a need for rapid mutation tests for guiding clinical decisions and starting targeted therapies with minimal delays. In this study we evaluated the turnaround time before and after the implementation of a fully automated multiplex assay for KRAS and NRAS/BRAF mutation tests (Idylla™ platform, Biocartis) in metastatic colorectal cancer. The objective of this project was to compare the turnaround times in 2017-2018 with the fully automated multiplex assay to the 2016 results with previous methods. Centers with a number of tests for metastatic colorectal cancer > 100 yearly and a usual turnaround time ≥ 3 weeks for mutation detection were selected. Results of 505 KRAS tests and 369 NRAS/BRAF tests were transmitted by 10 centers. The mean turnaround time from test prescription to reception of results was reduced from 25.8 days in 2016 to 4.5 days in 2017-2018. In conclusion, this pilot project shows that the Idylla™ platform for testing KRAS and NRAS/BRAF mutations allows an optimized turnaround time from test prescription to reception of results.

Cardiac toxicity with capecitabine, vinorelbine and trastuzumab therapy: case report and review of fluoropyrimidine-related cardiotoxicity.

A 45-year-old woman presented with a metastatic breast carcinoma and was treated with capecitabine, oral vinorelbine and trastuzumab combination therapy. The initial echocardiogram and the ECG were considered normal. She began treatment with 3-weekly cycles of the combination therapy. After the fourth dose of capecitabine, she presented with severe chest and arm pain, which was responsive to nitroglycerine spray. ECG at admission demonstrated tachycardia with ST-segment elevation suggesting ischemia. The clinical symptoms returned to baseline after a few hours and within 24 h the ECG showed inverted T in leads V3-V6. Cardiac ultrasonography revealed hypokinesia in the left ventricle without segmentary hypokinesia, with mildly reduced global systolic function, which normalized 1 week later. Two weeks later, she was rechallenged with capecitabine. After the fourth dose, the patient developed chest pain. ECG showed infero-apico-lateral injury, which normalized after administration of nitrates, nicorandil and verapamil and discontinuation of capecitabine. This case suggests that capecitabine can lead to the cardiotoxicity characteristic of other fluoropyrimidines. Therefore, it is important to inform patients about the risk of angina-like chest pain, to stop treatment immediately if symptoms occur, and to monitor the patient in hospital. Fluoropyrimidine rechallenge should be avoided because of the risk of ischemic event or sudden death.

Results of PONDx, a prospective multicenter study of the Oncotype DX® breast cancer assay: Real-life utilization and decision impact in French clinical practice.

Adjuvant chemotherapy shows clear benefits in HER2-positive and triple-negative breast cancer (BC). Its benefits are less universal in BCs expressing hormone receptors. The 21-gene Oncotype DX® Breast Recurrence Score test was designed for HR+, HER2- early-stage BC before decision on adjuvant chemotherapy. Its validity and utility was demonstrated prospectively across multiple studies. The observational study PONDx characterized the use of Oncotype DX® Breast in routine practice in France and evaluated its decision impact. Of 882 ER-positive BC patients (67% postmenopausal), most (79%) had N0/Nmic node involvement, grade 2 tumors (68%), tumor size 1-5 cm (88%), and ductal histology (78%). BCs with histopathologically elevated recurrence risk included grade 3: 18%; N1: 21%; Ki67 > 20%: 31%. Recurrence Score results by prognostic category were: <18: 54%, 18-30: 36%; >30: 10%. Compared to recommendations before individual availability of the score, results prompted net absolute reductions in chemotherapy recommendations of 36% (total population), and 29% (grade 3 and/or Ki67 > 20% histologies). Decisions reflected prognostic implications: in the Recurrence Score <18 category, 95% of patients received recommendations of hormonal therapy only, in the >30 category, 97.5% were recommended additional chemotherapy; 95% followed the final recommendations of their physicians. The Recurrence Score provides independent predictive and prognostic information in ER + N0/N1 early BC, including high-risk subgroups. PONDx further characterizes the population where the test is beneficial in real-life use and fits current clinical needs. Oncotype DX® Breast enables relevant net reductions in chemotherapy use, sparing patients from serious toxicities. Its therapeutic implications are highly accepted by physicians and patients.

Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9).

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderly metastatic colorectal cancer patients.

AIM: Several predictors of metastatic colorectal cancer (mCRC) outcomes have been described. Specific geriatric characteristics could be of interest to determine prognosis. METHOD: Elderly patients (75+) with previously untreated mCRC were randomly assigned to receive infusional 5-fluorouracil-based chemotherapy, either alone (FU) or in combination with irinotecan (IRI). Geriatric evaluations were included as an optional procedure. The predictive value of geriatric parameters was determined for the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: From June 2003 to May 2010, the FFCD 2001-02 randomised trial enrolled 282 patients. A baseline geriatric evaluation was done in 123 patients; 62 allocated to the FU arm and 61 to the IRI arm. The baseline Charlson index was ≤1 in 75%, Mini-Mental State Examination was ≤27/30 in 31%, Geriatric Depression Scale was >2 in 10% and Instrumental Activities of Daily Living (IADL) was impaired in 34% of the patients. Multivariate analyses revealed that no geriatric parameter was predictive for ORR or PFS. Normal IADL was independently associated with better OS. The benefit of doublet chemotherapy on PFS differed in subgroups of patients ≤80 years, with unresected primary tumour, leucocytes >11,000 mm3 and carcinoembryonic antigen >2N. There was a trend towards better OS in patients with normal IADL. CONCLUSION: The autonomy score was an independent predictor for OS. A trend toward a better efficacy of doublet chemotherapy in some subgroups of patients was reported and should be further explored.

Logistic regression model of the clinical response to 5-fluorouracil based chemotherapy for metastatic colorectal cancer patients.

Several genes have been involved in drug resistance but none are currently used in the drug decision process. To address this problem, mRNA levels were measured for the 5-fluorouracil metabolism-related genes, thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumor samples of 40 patients with synchronous metastatic colon cancer by quantitative RT-PCR. Drug response and overall survival were also obtained for each patient. A logistic regression model was defined to calculate a response predicting score (RPS) with gene expression levels. This RPS split responders from nonresponders as, at the best statistical threshold (0.35), the area of receiver operating characteristic (ROC) curve established with this method was 0.82 and sensitivity and specificity were respectively 100% and 65.4%. Furthermore patients with scores above 0.35 tended to have better overall survival than those with a score less than 0.35 (p = 0.09).

Thrombotic complications of implanted central venous access devices: prospective evaluation.

Implanted venous access devices (IVAD) are routinely used in oncologic patients. Thrombotic complication is a source of morbidity. During one year 246 patients with different solid neoplastic diseases received IVAD for chemotherapy administration. Two hundred forty-nine IVAD were placed percutaneously or by surgical cutdown. IVAD were flushed immediately after implantation with 3-5 mL of heparinized saline (100 U/mL). No monthly flush was required. A prospective evaluation of thrombotic complications was realised. in event of catheter dysfunction and/or clinical symptoms of phlebitis, a catheter opacification and/or a Doppler ultrasonography were performed. Twenty-three catheter dysfunctions were noted, corresponding to 13 catheter occlusions. Twelve patients presented clinical symptoms of phlebitis. Eleven venous thrombosis were diagnosed in this group; 10 by echo-Doppler and one by scanography. A unvaried statistic analysis using Fisher's test was performed to detect risk factors. Two factors were identified: the position of catheter tip above T4 (p < 0.001) and mediastinal or cervical lymph nodes larger than 6 cm (p < 0.001). The first increased the risk of catheter occlusion and the second increased the risk of phlebitis.

Lymph node assessment with (18)F-FDG-PET and MRI in uterine cervical cancer.

BACKGROUND: To assess pelvic (P) and/or paraaortic (PA) lymph node (LN) involvement in patients with primary stage IA-IVA cervical cancer, (18)F-fluorodeoxyglucose (FDG)-PET, and MRI were compared with histological results. MATERIALS AND METHODS: Forty patients were prospectively evaluated. Twenty-eight patients underwent radio-chemotherapy (RT-CT) after initial staging and lymph node dissection (LND). RESULTS: PLN metastases were present in 6/31 patients. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) and accuracy in detecting PLN metastases were 67%, 84%, 50%, 91% and 81%, with MRI, and 33%, 92%, 50%, 85% and 81%, with FDG-PET. PALN metastases were present in 5/27 patients. Sensitivity, specificity, PPV, NPV and accuracy were 60%, 73%, 33%, 89% and 70% with MRI and 100%, 77%, 50%, 100% and 81% with FDG-PET in detecting PALN metastasis. CONCLUSION: FDG-PET is less accurate than MRI for PLN, but more accurate for PALN; FDG-PET cannot replace PA surgical procedures, but could guide them.

Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer.

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I |0.25|; P < 0.01). I

Validation of patient's self-reported social functioning as an independent prognostic factor for survival in metastatic colorectal cancer patients: results of an international study by the Chronotherapy Group of the European Organisation for Research and Treatment of Cancer.

PURPOSE: A recent study identified a prognostic model for survival in metastatic colorectal cancer patients which included WBC count, alkaline phosphatase (AP), number of metastatic sites, and patients' self-reported social functioning. The aim of this research is to validate this model on data from an independent sample. PATIENTS AND METHODS: This validation study is based on a prospective randomized controlled trial in patients with metastatic colorectal cancer conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Chronotherapy Group. Overall, 564 patients in 10 countries were enrolled. For the purpose of this independent validation, patients with health-related quality of life (HRQOL) baseline data were analyzed. HRQOL was assessed using the EORTC Quality of Life Questionnaire C30 (QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. RESULTS: The previous model with an additional adjustment, by stratification for sex, was replicated and its parameters were confirmed to independently predict survival: WBC count with an hazard ratio (HR) of 1.31 (95% CI, 1.021 to 1.698; P = .034); AP with an HR of 1.53 (95% CI, 1.188 to 1.979; P = .001); number of sites involved with an HR of 1.90 (95% CI, 1.531 to 2.364; P < .0001); and patients' self-reported social functioning with an HR of 0.94 (95% CI, 0.905 to 0.976; P = .001). The latter translates into a 6% increase in the likelihood of an earlier death for every 10-point decrease in the social functioning scale of the EORTC QLQ-C30. CONCLUSION: This study provides confirmatory evidence of the independent prognostic value of patients' self-reported social functioning in patients with advanced colorectal cancer.

A randomized multicenter study of optimal circadian time of vinorelbine combined with chronomodulated 5-fluorouracil in pretreated metastatic breast cancer patients: EORTC trial 05971.

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m(2)/d on D1 and D6 and chronomodulated 5-fluorouracil of 850 mg/m(2) from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m(2)/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3-4 (G3-4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3-4 neutropenia was observed at 21:00 h with a non-significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3-4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3-4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time-finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time-finding design may be used to identify the best time of chemotherapy administration.

Gemcitabine, ifosfamide, and cisplatin combination (GIP) in treatment of patients with locally advanced or metastatic nonsmall cell lung cancer: results of a phase II study.

OBJECTIVES: We have carried out a phase II study to evaluate the efficacy and the toxicity associated with the combination of gemcitabine, ifosfamide, and cisplatin (GIP) in chemotherapy-naive patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Each cycle consisted of treatment with ifosfamide (3000 mg/m2) and gemcitabine (1500 mg/m2) on day 1, followed by cisplatin (100 mg/m2) and gemcitabine (1500 mg/m2) on day 15. Each treatment cycle was repeated every 28 days. A maximum of 6 cycles were administered. RESULTS: Sixty NSCLC patients (23 stage III and 37 stage IV) were entered in this study. The median survival for all patients is 9 months (stage III: 12.3 months; stage IV: 7.5 months). The overall survival at 1 and 2 years is 38% and 17%, respectively (52% and 30% for stage III; 30% and 8% for stage IV). The median time to progression is 6.3 months (stage III: 8.8 months; stage IV: 3.6 months). Progression free survival at 1 and 2 years for all patients is 22% and 8%. The response rate is 56% for patients with stage III disease and 27% for patients with stage IV disease. Among the grade 3/4 toxicities, hematological toxicity was the most frequent (59% of patients) followed by gastrointestinal toxicity (nausea/vomiting) in 21% of patients. CONCLUSION: The GIP combination yields an efficacy, in terms of response and survival, comparable to that reported with other triplet combination treatments for local advanced or metastatic NSCLC, with an acceptable toxicity profile.

Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group.

PURPOSE: In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. PATIENTS AND METHODS: For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. RESULTS: Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. CONCLUSION: Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.

A quantitative RT-PCR method to determine topoisomerase I mRNA levels in human tissue samples.

DNA topoisomerase I (Topo I) is involved in DNA replication, transcription, recombination and repair. Clinical interest has focused on Topo I as it is the molecular target of camptothecin (CPT), used in first and second lines of treatment for different cancer types. Furthermore, it is well demonstrated that the patients who best responded to CPT-based chemotherapy were generally those with the greatest tumoral Topo I expression and/or activity. We developed a sensitive, simple and reproducible method to measure Topo I mRNA expression in human cancer samples. Experiments were performed in two steps. First, we checked the accuracy of the reverse transcription-polymerase chain reaction (RT-PCR) method by testing intra- and interassay reproducibility of Topo I and G6PDH gene amplification in different cell types. We observed that crossing-points (Cps) were different, depending on the cell type, dilution or cDNA concentration, but that the intra- and interassay Cp standard deviation (SD) never exceeded 0.77% and 1.39% for Topo I amplification, or 1.63% and 2.9% for G6PDH amplification, respectively. Secondly, we used our method to measure Topo I mRNA levels in primary tumor samples obtained from 27 patients with advanced colorectal cancer and 10 patients with pharyngeal/laryngeal cancer. The accuracy of G6PDH as a housekeeping gene was tested by analyzing its correlation with the mRNA level of a second housekeeping gene, porphobilinogen deaminase (PBG-D) in the tumoral samples. We found that the normalized Topo I/G6PDH mRNA ratios were significantly correlated with that of Topo I/PBGD in colorectal tumors (r(2)=0.47, p=0.02) but not in pharyngeal/laryngeal tumors (r(2)=0.35, p=0.3). Neither ratio showed any significant association with clinicopathological parameters, such as gender, age, tumor size, or grade and lymph node status. We believe that RT-PCR is a reliable and highly reproducible technique. However, the choice of the reference gene is an important point and must be defined based on the samples studied.

Docetaxel plus 5-fluorouracil in locally recurrent and/or metastatic squamous cell carcinoma of the head and neck: a phase II multicenter study.

This phase II study evaluated docetaxel-5-fluorouracil (5-FU) in locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients were divided into 2 cohorts--those previously treated with chemotherapy and those nonpretreated--that received docetaxel 75 mg/m2 (day 1) plus 5-FU 1,000 mg/m2/day (days 1-5 every 3 weeks). Of 63 patients entered, 20 (31.7%) were pretreated and 43 (68.3%) were nonpretreated. Fifty-nine patients (93.7%) had received prior radiotherapy. After inclusion of 20 patients, the 5-FU dose was reduced to 750 mg/m2/day due to unacceptable toxicity. The overall response rate (ORR) was 20.6% on radiologic review (22.2%, investigator assessment). Pretreated patients achieved an ORR of 25.0% versus 18.6% for nonpretreated patients. This unexpected finding was partly attributed to differences in patient characteristics between the groups. Overall major grade 3 to 4 toxicities comprised neutropenia (66.6%), febrile neutropenia (31.7%), and mucositis (31.7%). Grade 3 to 4 toxicities were lower at the reduced 5-FU dose (750 mg/m2/day): Febrile neutropenia declined from 40.0% to 27.9%; mucositis declined from 55.0% to 20.9%. Three treatment-related deaths occurred (2 with 5-FU 750 mg/m2/day, 1 with 5-FU 1,000 mg/m2/day). Docetaxel-5-FU appears active in locally recurrent and/or metastatic SCCHN with acceptable toxicity at the dose of 5-FU 750 mg/m2.