Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel-5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin-cyclophosphamide (EC) and locoregional treatment in IBC patients. PATIENTS AND METHODS: PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m(2) and C 4000 mg/m(2) every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m(2), day 1 and 5FU 750 mg/m(2)/day continuous infusion, days 1-5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). RESULTS: Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4-60.3] in arm A and 60.5 months (95% CI 58.3-61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9-64.7) in arm A and 55.5% (95% CI 44.3-65.3) in arm B [hazard ratio (HR) = 0.94 (0.61-1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1-78.8) in arm A and 70% (95% CI 58.8-78.7) in arm B [HR = 0.93 (0.55-1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. CONCLUSION: The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. CLINICAL TRIAL NUMBER: ClinicalTrials.gov identifier: NCT02324088.

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.

A phase II trial of high-dose chemotherapy (HDCT) supported by hematopoietic stem-cell transplantation (HSCT) in germ-cell tumors (GCTs) patients failing cisplatin-based chemotherapy: the Multicentric TAXIF II study.

BACKGROUND: High-dose chemotherapy (HDCT) is an effective salvage treatment of germ-cell tumors (GCTs) patients. In the first salvage setting, 30%-70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT. PATIENTS AND METHODS: This phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy. Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy, nonseminomatous GCT in relapse after first or second lines, partial remission after first line, primary mediastinal GCT in first relapse. Patients received two cycles combining Epirubicin and Paclitaxel (Epi-Tax), followed by three consecutive HDCT, one using a Paclitaxel/Thiotepa (Thio-Tax) association and two using the 5-day Ifosfamide-Carboplatin-Etoposide regimen. The main objective was to determine the complete response rate. RESULTS: Forty-five patients were included between September 2004 and December 2007: 44 received the first HDCT cycle, 39 two HDCT cycles, 29 could receive the whole protocol. Sixteen patients did not receive the entire protocol, including eight (17.7%) for toxic side-effects. Two patients (4.4%) died of toxicities, and 17 (37.7%) of disease progression. With a median follow-up time of 26 months (range, 4-51), the final overall response rate was 48.8% (including a complete response rate of 15.5% and a partial response/negative serum markers rate of 26.6%) in an intent-to-treat analysis. The median progression-free survival (PFS) and overall survival (OS) times were 22 months [95% confidence interval (CI) 2-not reached] and 32 months (95% CI 4-49), respectively. The 2-year PFS was a plateau setup at 50% (95% CI 32-67) and the 2-year OS was 66% (95% CI 44-81). CONCLUSION: The TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy. The toxic death rate remained acceptable in the field of HDCT regimens. TRIAL REGISTRATION NUMBER: NCT00231582.

Use of liposomal doxorubicin-cyclophosphamide combination in breast cancer patients with brain metastases: a monocentric retrospective study.

Brain metastases (BM) can affect up to 45 % of a high-risk breast cancer (BC) population. Liposomal doxorubicin (LD)-based chemotherapy has demonstrated efficacy in the treatment of BC and LD crosses the blood-brain barrier. The aim of this retrospective study is to evaluate the efficacy of the LD-cyclophosphamide (CTX) combination in BM related to BC. Patients diagnosed with BM related to BC and treated with the LD-CTX combination were eligible. BM objective response rate (BM-ORR), BM disease control rate (BM-DCR), BM progression-free survival, overall survival (OS) and safety were analyzed. 29 patients were eligible. The median time from metastatic diagnosis to brain involvement was 12 months. BM was more frequently observed in HER2+ patients. On average, three courses of chemotherapy were administered without grade 3-4 limiting adverse events. After three cycles, BM-ORR and BM-DCR were 41.4 and 58.6 % respectively versus 50 and 62.5 % when no prior radiotherapy was administered. From BM diagnosis, OS was 23 months. A high BM-ORR is observed with the LD-CTX combination in patients with BM related to BC. This is an attractive therapeutic option for these patients, especially when no prior whole brain radiotherapy has been administered.

Generic learning skills in academically-at-risk medical students: a development programme bridges the gap.

BACKGROUND: Widening access to medical students from diverse educational backgrounds is a global educational mandate. The impact, on students' generic learning skills profiles, of development programmes designed for students at risk of attrition is unknown. AIMS: This study investigated the impact of a 12-month Intervention Programme (IP) on the generic learning skills profile of academically-at-risk students who, after failing at the end of the first semester, completed the IP before entering the second semester of a conventional medical training programme. METHODS: This prospective study surveyed medical students admitted in 2009 and 2010, on entry and on completion of first year, on their reported practice and confidence in information handling, managing own learning, technical and numeracy, computer, organisational and presentation skills. RESULTS: Of 414 first year students, 80 (19%) entered the IP. Levels of practice and confidence for five of the six skills categories were significantly poorer at entry for IP students compared to conventional stream students. In four categories these differences were no longer statistically significant after students had completed the IP; 62 IP students (77.5%) progressed to second year. CONCLUSIONS: A 12-month development programme, the IP, effectively addressed generic learning skills deficiencies present in academically-at-risk students entering medical school.

[Evaluation of the management of metastatic renal cell carcinoma in the era of targeted therapies. retrospective clinical study over six years]. / Évaluation de la prise en charge du cancer du rein métastatique à l'ère des thérapies ciblées. Étude clinique rétrospective sur six ans.

OBJECTIVE: To evaluate the outcomes following targeted therapies in the management of metastatic renal cell carcinoma (mRCC), through the study of overall survival (OS) and progression-free (PFS). PATIENTS AND METHODS: We retrospectively included 78 patients treated with targeted therapies for mRCC at the Paul Papin Cancer Institute from 2004 to 2009. Overall survival (OS), progression free survival (PFS), response to treatment, occurrence of grade III and IV side effects, were analyzed following first and second line treatments. RESULTS: Median follow-up was 33 months [5-236], and 41 patients died (52.6%). Median OS was 36 months [95% CI 29-43]. The median PFS was 14 months [95% CI 6.71-21.29] for sunitinib, 38 months [95% CI 11.41-64.59] for bevacizumab with interferon (IFN), and 8 months [95% CI 0-17.03] for IFN alone. A partial reduction, stabilization or increase in tumor size was observed for 19.2%, 47.4% and 25.6% of cases. A second line treatment was given for 53 patients. They received either sunitinib (n=20, 37.8%), bevacizumab with IFN (n=7, 13.2%), sorafenib (n=17, 32.2%), temsirolimus (n=3, 5.6%) or other molecules (n=6 11.2%). Grade III or IV side effects were observed for 14.1%, 28.3% and 18.2% of the patients following first, second and third line treatment, respectively. CONCLUSION: Outcomes of targeted therapies in our center upheld the literature data. These therapies allow a benefit survival versus immunotherapy, with sometimes large side-effect.

First-line bevacizumab-containing therapy for breast cancer: results in patients aged≥70 years treated in the ATHENA study.

BACKGROUND: There are limited data on treatment outcomes in the growing population of elderly patients with locally recurrent/metastatic breast cancer (LR/mBC). To gain information on first-line bevacizumab combined with chemotherapy in the elderly, we analyzed data from the ATHENA trial in routine oncology practice. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor-2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We carried out a subgroup analysis of safety and efficacy in patients aged≥70 years. Possible correlations between tolerability and baseline comorbidities or Eastern Cooperative Oncology Group status were explored. RESULTS: Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older than in younger patients (grade≥3 hypertension: 6.9% versus 4.2%, respectively; grade≥3 proteinuria: 4.0% versus 1.5%, respectively). Grade≥3 arterial/venous thromboembolism occurred in 2.9% versus 3.3%, respectively. Further analysis revealed no relationship between baseline presence and severity of hypertension and risk of developing hypertension during bevacizumab-containing therapy. Median time to progression was 10.4 months in patients aged≥70 years. CONCLUSIONS: These findings suggest that bevacizumab-containing therapy is tolerable and active in patients aged≥70 years. Hypertension was more common than in younger patients but was manageable. We find no evidence precluding the use of bevacizumab in older patients, including those with hypertension, although age may influence chemotherapy choice.

High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

BACKGROUND: A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy. METHODS: Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 mg m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. RESULTS: In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%). CONCLUSION: Sequential dose-dense FEC 100 followed by docetaxel 100 mg m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.

Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy.

BACKGROUND: We investigated whether circulating tumor cells (CTCs) and circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy combined with bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: In a French substudy of the MO19391 trial, CTC and CEC counts (CellSearch system) at baseline and changes after two cycles of treatment were correlated with time to progression (TtP). RESULTS: CTC and CEC levels were not correlated in the 67 patients included. At baseline, CTC positivity was a significant prognostic marker for TtP at a threshold of 3 CTC/7.5 ml (P < 0.05) but not at 5 CTC/7.5 ml (P = 0.09). Baseline CEC levels (median 17 CEC/4 ml, range 1-769) were associated with age > or =45 years (P = 0.01), elevated lactate dehydrogenase (P < 0.01) and not with TtP at any threshold. Changes of CTC count during treatment were not a surrogate of TtP, with any of the model tested (threshold based or relative decrease in percent). However, increase in CEC count was associated with improved TtP, at the threshold of 20 CEC/4 ml (P < 0.01). CONCLUSION: Bevacizumab combined with first-line chemotherapy may modify the predictive value of CTC during treatment possibly due to impaired tumor cells intravasation through vessels endothelium. Variations in CEC levels appear to be a promising early surrogate marker of TtP under antiangiogenic treatment.

[Renal cell carcinoma: which criteria to define antiangiogenic treatment failure? A case report]. / Cancer du rein: quels sont les critères pour juger de l'échec d'un traitement anti-angiogénique? A propos d'un cas.

Failure criteria of antiangiogenic treatment that must make envisage a change of molecule are still difficult to define. Concerning the evaluation of the response, if the RECIST criteria seem to be limited, several other tools of evaluation (clinical, radiological or biological tools) can be interesting. It is the case of contrast-enhanced ultra-sonography, but a precise definition of functional parameters should be defined and a standardization of the technique is necessary. Side effects do not translate necessarily a treatment failure. They must be estimated by taking into account the frequency of some of symptoms. Asthenia is noticed in more than 50% of the patients ; it is however necessary to exclude another aetiology, in particular iatrogenic hypothyroidism.

Weekly combination of topotecan and gemcitabine in early recurrent ovarian cancer patients: a French multicenter phase II study.

OBJECTIVES: The aim of this phase II study was to assess the benefits of a weekly administration of topotecan and gemcitabine in patients with ovarian carcinoma having relapsed after platinum/taxane-based first-line chemotherapy. METHODS: Seventy-seven patients with progression of disease /=2 cycles administered). The only major severe toxicity was neutropenia grades 3 (17%) and 4 (6%). Approximately 60% of the patients received the complete schedule of treatment, dose interruptions/delays being mainly due to moderate thrombocytopenia or neutropenia. The objective response rate was 14%, the values for patients having relapsed within 6 (n=30) and 6-12 (n=36) months being 7% and 20%, respectively. Median durations of response were 4.9 and 6.4 months and clinical benefit rates including stabilizations reached 63% and 69% in patients having relapsed within 6 or 6-12 months, respectively. Corresponding median overall survival was 7.5 and 15.6 months. Symptoms and pain were reduced in 64% and 39% of the patients concerned, respectively. CONCLUSION: In early relapse ovarian cancer, weekly combination of gemcitabine and topotecan has a modest objective response rate. However, a high proportion of patients experienced stable disease and symptom control leading to acceptable quality of life.

First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with untreated metastatic renal cell carcinoma (mRCC), progression-free survival (PFS) was longer with bevacizumab + interferon (IFN)-alpha than IFN + placebo (AVOREN trial). In this hypothesis-generating study, subgroup analysis was carried out to determine the effect of IFN dose reduction. PATIENTS AND METHODS: A total of 649 patients received IFN 9 MIU s.c. three times weekly plus bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity. Differences between treatment arms in PFS, response rate and tolerability were analysed in the reduced-dose group. RESULTS: IFN dose was reduced in 131 patients in the bevacizumab + IFN arm and 97 patients in the IFN + placebo arm during the trial. PFS rates in the bevacizumab + reduced-dose IFN group were comparable with the total population (Kaplan-Meier estimates of event-free rate at 1 year: 0.524 versus 0.427). Bevacizumab + reduced-dose IFN was well tolerated, with substantial decreases in the rate of adverse events following dose reduction. CONCLUSION: This retrospective subgroup analysis suggests that the dose of IFN can be reduced to manage side-effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.

Oral vinorelbine/paclitaxel combination treatment of metastatic breast cancer: a phase I study.

PURPOSE: Intravenous (i.v.) vinorelbine (VRL) generally given on days 1 and 8 of an every three-week cycle in combination with paclitaxel (PTX) is an effective option for the treatment of metastatic breast cancer (MBC). In an effort to improve both patient and chemotherapy unit convenience, oral VRL was used at equivalent doses of i.v. VRL. PATIENTS AND METHODS: The maximal tolerated dose (MTD) was determined during the first cycle of oral VRL given on days 1 and 8 or 15 and PTX infused over 3 h on day 1 every 3 weeks, maximum of 6 cycles. The dose of oral VRL was escalated from 60 to 80 mg/m2 in 10 mg/m2 increments. Paclitaxel was administered at 110 and then 135 mg/m2. The combination regimen was given as first-line chemotherapy of MBC. Three to six patients per cohort were treated. RESULTS: Twenty-two patients were treated in the first four cohorts (oral VRL/PTX): 60/110, 70/110, 80/110 and 80/135. In cohort 4, seven patients were treated, one patient being non-evaluable for MTD, three of them presented a dose-limiting toxicity (DLT) consisting of febrile neutropenia and neutropenic infection. Therefore 80/135 was the MTD. Because 36% of oral VRL administrations on day 8 were delayed to day 15 at 80/110, two additional cohorts were tested: in cohort 5, oral VRL 60 mg/m2 on days 1 and 15 and PTX 135 mg/m2 on day 1 and in cohort 6, oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1, every 3 weeks. In cohort 5, six out of eight patients had DLTs: omission of oral VRL on day 15 for five patients, grade 4 neutropenia>7 days for another one. Therefore the recommended dose (RD) for further clinical testing was oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1 of an every 3-week cycle. Two of the three evaluable patients treated at the RD had a partial response. The pharmacokinetics of VRL and PTX is being analysed and will be further presented in a separate publication. CONCLUSIONS: This phase I study has determined the doses of oral VRL and PTX to be used in combination for the benefit of the patient and of the chemotherapy unit in term of nurse's workload. The recommended regimen of oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1 given every 3 weeks will be further tested in phase II.

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.

Post-operative sequential high-dose chemotherapy with haematopoietic stem cell support as front-line treatment in advanced ovarian cancer: a phase II multicentre study.

In spite of multimodal management including aggressive surgery and chemotherapy, the prognosis of advanced ovarian cancer (AOC) remains poor. Multicycle high-dose chemotherapy (HDC) with haematopoietic stem cell (HSC) support has been shown to be a promising procedure in various cancers including AOC. We conducted a phase II multicentre study to evaluate feasibility, toxicity and efficacy of post-operative front-line sequential HDC with HSC support in AOC. Thirty four patients with stage IIIC/IV received a post-operative sequential combination of high-dose cyclophosphamide/epirubicin (D1, D21) with HSC harvesting, high-dose carboplatin (D42, D98) followed by HSC infusion, and dose-dense paclitaxel (D63, D77, D119, D133). Rh-G-CSF (filgrastim) was administered following all cycles. Primary endpoint was pathological complete response rate (pCR). Thirty patients received at least 7 of the scheduled 8 cycles. Haematological toxicity was significant but manageable. Grade 3/4 extra-haematopoietic toxicities were relatively uncommon and reversible. No toxicity-related death was observed. The observed pCR was 37% and did not reach the initial endpoint. Post-operative front-line sequential HDC in AOC is feasible and safe in a multicentre setting. The observed pCR does not support a clear advantage over conventional treatment. This approach remains an experimental strategy to further optimise and validate.

Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage.

PURPOSE: Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU. PATIENTS AND METHODS: Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m(2) was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH(2)), were measured before treatment, and the ratio of UH(2) to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH(2) to U and 5-FU metabolic outcome and tolerance. RESULTS: The UH(2)-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r =.58), (2) 5-FU plasma clearance (r =.639), and (3) individual optimal therapeutic 5-FU dose (r =.65). Toxic side effects were observed only in patients with initial UH(2)-U ratios of less than 1.8. No adverse effects were noted in patients with UH(2)-U ratios of greater than 2.25. CONCLUSION: The UH(2)-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).

Tumor parameters, clinical and pathological responses, medical management, and survival through time on 710 operable breast cancers.

The aim of the current study is an analysis of tumor parameters, clinical and pathological responses, medical management, and survival on 710 operable breast cancer patients who received neoadjuvant chemotherapy from 1982 to 2004 and were grouped into four successive periods according to diagnosis date: (1) 1982-1989; (2) 1990-1994; (3) 1995-1999; and (4) 2000-2004. Patients were treated by different neoadjuvant chemotherapies combinations: AVCF/M, TNCF, NEM, NET, TAXOTERE, FEC 50, 75, 100, FAC 50, and TAXOTERE-TNCF, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1-9). After primary chemotherapy, patients underwent a surgery and a radiotherapy. In case of significant residual disease, some patients received additional courses of chemotherapy. In addition, menopausal patients with hormonal receptor-positive tumors received tamoxifen for 5 yr. Clinical factors had some remarkable variations with time. The median age of the patients was 49.5 yr (range, 26-81). The size of the tumor was significantly greater from 1995; conversely, clinical lymph-node involvement was lower in period 4 than in the first period. The percentage of invasive ductal carcinoma and of SBR III tumors increased about 20% from 1982-1989 to 2000-2004. The number of positive hormonal receptors increased from 38.3% in period 1 to 74% in period 4. The clinical response rate improved recently from before 1990. The pathological response rate was greater in periods 2 and 3 than in periods 1 and 4. An adjuvant hormonotherapy became progressively more frequently given (44.7 for period 1 and 73.3% for period 4). Finally, no significant difference was found when we compared overall and disease-free survival through the four periods. It appears that the progressive increase of tumor burden was compensated by more effective treatments.