BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer.

BACKGROUND: Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. PATIENTS AND METHODS: The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. RESULTS: Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). CONCLUSION: The addition of sorafenib to gemcitabine does not improve PFS in APC patients.

Randomized study of early hospital discharge following autologous blood SCT: medical outcomes and hospital costs.

We report the first randomized study comparing early hospital discharge with standard hospital-based follow-up after high-dose chemotherapy (HDCT) and PBSCT. Patients aged 18-65 years, with an indication of PBSCT for non-leukemic malignant diseases were randomly assigned between two arms. Arm A consisted of early hospital discharge (HDCT during hospitalization, discharge at day 0, home stay with a caregiver, outpatient clinic follow-up). In arm B patients were followed up as inpatients. In total 131 patients were analyzed (66 in arm A and 65 in arm B). Patient characteristics and hematological reconstitution were comparable between the two groups. In arm A, 26 patients were actually discharged early. Patients in group A spent fewer days in hospital (11 vs 12 days, P=0.006). This strategy resulted in a 6% mean cost reduction per patient when compared with the conventional hospital-based group. The early discharge approach within the French health system, while safe and feasible, is highly dependent on social criteria (caregiver availability and home to hospital distance). It is almost always associated with conventional hospital readmission during the aplasia phase, and limits cost savings when considering the whole population of patients benefiting from HDCT in routine clinical practice.

Participants' uptake of clinical trial results: a randomised experiment.

BACKGROUND: Participants are showing great interest these days in obtaining the results of clinical trials. The aim of this study was to assess patients' uptake and understanding of the results of the trial in which they have participated and the impact of a letter offering patients the possibility of consulting the trial results on a specific website. METHODS: Breast cancer patients participating in a trial on the efficacy of Trastuzumab were randomly subdivided into an Internet group (who received the letter of invitation) and a control group (who did not receive it). Among 115 HER2-positive women from 21 centres, 107 (93%) answered a self-administered questionnaire. RESULTS: Most of the patients in both groups had access to the Internet (72.0%). The majority (97.2%) stated that receiving information about the trial results would be useful, and the oncologist was the most frequently preferred information provider. The Internet group's declared uptake of the trial results was only slightly higher (47.1% vs 33.9%; P=0.166); however, they understood the results significantly more accurately (18.8% vs 5.6%; P=0.039). INTERPRETATION: Although Internet was not the respondents' preferred source of information, the possibility of using this source slightly increased the uptake and understanding of the results.

Occult tumor cell contamination in patients with stage II/III breast cancer receiving sequential high-dose chemotherapy.

The purpose of this study was to evaluate the presence of micrometastatic cells in the apheresis products from patients with breast cancer, and also to determine if repeated infusion of contaminated products had any clinical impact. A total of 94 patients with high-risk breast cancer were enrolled in a prospective single center study to evaluate the use of dose-intensified chemotherapy (doxorubicine 75 mg/m(2) and cyclophosphamide 3000 or 6000 mg/m(2) for four cycles) with repeated (x 2) stem cell reinfusion. All women were monitored for the presence of metastatic cells in aphereses, collected after first course of intensive chemotherapy, and following additional mobilization with rhG-CSF. Epithelial cells were screened with monoclonal antibodies directed to cytokeratin. Eight of the 94 patients had detectable tumor cells in one or several aphereses collected after intensive chemotherapy; this was unrelated to other tumor characteristics, including size, histology, Scarff Bloom and Richardson (SBR) grading (presence or absence of hormone receptors). Hemato-poietic reconstitution was similar in the cells from these eight patients, and in the total patient population. Three of these eight patients relapsed. This study has confirmed that contamination of apheresis products remains a rare event, which does not seem to affect clinical evolution, even when reinfused into the patient.

Docetaxel and radiotherapy and pancreatic cancer.

PURPOSE: We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of weekly docetaxel delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Thirteen patients with histologically proven locally non-resectable advanced adenocarcinoma of the pancreas were enrolled in this study. Patients received 4 weekly doses of docetaxel by 1-hour intravenous (IV) infusion with 40 Gy of external beam radiation therapy during 4 weeks. Patients who were stabilized or in response, received 2 additional cycles of docetaxel with a 10 Gy boost of radiotherapy. Doses were escalated at 10 mg/m2 increments in successive cohorts of 3 new patients until MTD was observed. RESULTS: Four patients received docetaxel at 20 mg/m2/week, 3 at 25 mg/m2/week, 3 at 30 mg/m2/week, and 3 at 35 mg/m2/week. All patients, except 2, were given the treatment in its integrity. The most common toxicities were nausea, vomiting, asthenia, and abdominal pains. Except for 1 patient, all toxicity was reversible and did not exceed grade 3. Hematologic toxicity was mild and has not required treatment interruption. 28% of the patients had to be rehospitalized. A total of 73 cycles was administered with a mean of 4 cycles per patient (2-6). CONCLUSION: Even the MTD was not reached, dose escalation was stopped at 35 mg/m2/week. This dose is comparable to the ones previously published using docetaxel in combination with radiotherapy in other tumors. Three patients achieved stable disease and 1 patient an objective response. This combination of weekly docetaxel and radiotherapy shows a feasible and well-tolerated regimen, with, nonetheless, a significant rate of rehospitalization, for patients with locally advanced pancreatic cancer.

Phase I study of pegylated liposomal doxorubicin (Caelyx) in combination with carboplatin in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose of the combination of Carboplatin and Caelyx, a pegylated liposomal doxorubicin, with promising activities in various solid tumors. PATIENTS AND METHODS: Twenty-two patients with various advanced solid tumors were included. Three dose levels of Caelyx were explored: 30, 35 and 40 mg/m2 in association with a fixed dose of Carboplatin (AUC 5) every 3 weeks. Dose escalation followed a modified continuous reassessment method. RESULTS: Dose-limiting toxicities were almost exclusively hematological: 3 febrile neutropenia, 1 grade 4 neutropenia lasting more than 7 days and 2 grade 4 thrombopenia were observed. Grade 4 neutropenia and febrile neutropenia were observed in 20 and 10% of courses, respectively. The median interval between courses was 25 days after cycle 1 and 27-28 days after subsequent cycles. Palmar-plantar erythrodysesthesia, mucositis and other non hematological toxicities were mild and uncommon. One patient experienced a severe anaphylactic reaction immediately after Caelyx infusion. No clinical heart dysfunction was observed. Three patients responded to therapy including 2 clinical complete responses in relapsing ovarian cancer. CONCLUSION: The recommended dose for future studies is Caelyx 35 mg/m2 + Carboplatin AUC 5 every 3 or 4 weeks. Antitumor activity, especially in ovarian cancer, warrants further investigation in phase II studies.

Intensive sequential dose dense chemotherapy with stem cell support as first-line treatment in advanced ovarian carcinoma: a phase II study.

From August 1995 to December 1997, 15 patients with stage III-IV ovarian cancer were treated with outpatient intensive chemotherapy with G-CSF and stem cell support. The first cycle consisted of cyclophophamide IV 6 g/m(2); second, third, fourth and fifth paclitaxel 250 mg/m(2) and the sixth and seventh carboplatin AUC 18. CD34(+) cells were collected after the first cycle and reinfused after completion of cycles 6 and 7. Fourteen patients had stage IIIc and one patient had stage IV disease with liver metastases. All patients underwent laparotomy to maximize tumor debulking. This was optimal in eight patients and suboptimal in seven patients. Second-look surgery was performed in 14 patients. All patients had macroscopic complete responses and 10 patients had complete histologic response. Median follow-up was 48 months (range, 20 to 62). Twelve patients had further progression at a median of 27 months (range, 9 to 42) and nine are alive, three without evidence of disease progression. This pilot study shows that dose-dense chemotherapy with paclitaxel and carboplatin is associated with low toxicity and may improve the outcome of patients with poor prognosis ovarian cancer.

Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens.

The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m(2)) + cyclophosphamide (3000 mg/m(2)) every 21 days (group 1), doxorubicin (75 mg/m(2)) + cyclophosphamide (3000 mg/m(2)) every 15 days (group 2), and doxorubicin (75 mg/m(2)) + cyclophosphamide (6000 mg/m(2)) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC.

Quality of life of breast cancer patients receiving high-dose-intensity chemotherapy: impact of length of cycles.

This study was designed to measure treatment side-effects and quality of life (QL) of 47 nonmetastatic breast cancer patients subjected to a dose-intensity increase while receiving a sequential high dose chemotherapy (doxorubicin+cyclophosphamide - 4 cycles). The dose-intensity increase was obtained by shortening the length of cycles from 21 to 14 days. Treatment side-effects were self-assessed in terms of frequency and associated distress in cycles 1 and 3 by using a specific side-effect self-report questionnaire (19 items). Multidimensional QL measurement was performed at inclusion and before the start of cycles 2 and 4, by using the EORTC QLQ-C30. Pain was evaluated by patients on a visual analogue scale at the same times as QL evaluation. Patients' self-ratings indicated that the total number of symptoms, the number of symptoms rated by patients as quite or very distressing, and symptom frequency were comparable whatever the length of cycle. Overall, although underestimating most patients' symptoms, physicians' reports provided similar results. However, analysis of multidimensional QL showed that, in comparison to standard administration of 4 cycles of 21 days, there was a more significant deterioration of the QLQ-C30 global QL score ( P=0.01) at the second cycle of chemotherapy and of the physical functioning score ( P=0.02) at the fourth cycle when the cycle length was reduced. This study, although limited by a small patient cohort, has shown that shortening cycles to increase dose intensity had relatively few consequences on adverse treatment effects but a highly negative impact on patients' quality of life.

Phase II study of a combination of cisplatin, all-trans-retinoic acid and interferon-alpha in squamous cell carcinoma: clinical results and pharmacokinetics.

UNLABELLED: Preclinical and clinical data suggest a certain antitumor efficacy for combination of retinoids, cytokines and cytotoxic compounds. PATIENTS AND METHODS: Between November 1994 and October 1996, 38 patients with advanced squamous cell carcinoma were enrolled in a phase II study to investigate an association of low-dose all-trans-retinoic acid (tRA) (40 mg/m2/day, 84 days), interferon-alpha (IFN-alpha) (6.10(6) UI/day, 84 days s.c.) and cisplatin (40 mg/m2/day, day 1, 28 and 56, i.v.). A Pharmacokinetic evaluation was performed on 12 patients. RESULTS: The incidence of grade 3/4 hematologic toxicities was moderate (< 20%). Extra hematological toxicities were frequent but easily manageable and not life threatening. However, treatment delivery was poor since only 6 patients (16%) received full therapy. Seven objective responses were observed (21%), suggesting some degree of synergism between tRA, IFN-alpha and cisplatin. Interestingly, continuous tRA treatment in combination with IFN-alpha and cisplatin did not induce a significant decrease in plasma levels, as had been previously described. CONCLUSIONS: Regarding the short median response duration and the frequency of toxic events, this regimen should no longer be recommended in pretreated patients with advanced disease. However, the consistent response rate reported here may warrant further investigation in an early setting.

Outpatient sequential high dose alkylation with stem cell support for patients with advanced breast cancer: a phase I-II study.

We evaluated the feasibility of administering, in an out-patient setting, a sequential high dose alkylating regimen with hematopoietic growth factor (HGF) and stem cell support to patients with advanced breast cancer. Peripheral blood stem cells (PBSC) were previously collected after chemotherapy and HGF. Two consecutive cycles of alkylating agents were planned: Thiotepa (T) then, 15 days later, BCNU (B). Three dose levels of each agent were administered in cohorts of consecutive patients: 400, 500 and 600 mg/m2 respectively. HGF and reinfusion of PBSC followed both cycles. Toxicity and response were evaluated according to the WHO recommendations. From April 1996 to August 1988, 30 women were enrolled: 8 in the first, 12 in the second and 10 in the third dose level. In all cases, B was administered after T with a median delay of 25 days because of grade 3/4 hematological toxicity. 4 patients did not receive B because of previous lung radiotherapy, persistent tricytopenia or insufficient PBSC collection. 19 patients with measurable lesions were considered for response. The objective response rate was 48% (11% CR, 37% PR). We recommended T and B at a dose of 600 mg/m2 to conduct a phase II study in metastatic breast cancer and even to administer B before T.

Patient participation in medical decision-making: a French study in adjuvant radio-chemotherapy for early breast cancer.

BACKGROUND: Shared decision-making is increasingly advocated as an ideal model. However, very few studies have tested the feasibility of giving patients the opportunity to participate in the choice of treatment. PATIENTS AND METHODS: Women, with non-metastatic breast cancer, eligible for non-intensified adjuvant chemotherapy attending our hospital were proposed two administrations of chemotherapy and radiotherapy: a sequential and a concomitant one. Two patient-questionnaires were used to elicit motivations for their choice and their degree of comfort with the process of decision-making and one questionnaire to test physicians' ability to predict patients' choice. RESULTS: Participation rate in the study was 75.3% (n = 64). Majority (64%) of patients chose the concomitant treatment. Multivariate analysis revealed that patients with a lower level of education, who discussed the choice with social circle, and who most feared side-effects were more likely to choose the sequential treatment. Physicians were able to predict patients' choice in 66% of cases. 89% of patients declared that they were fully satisfied with having participated in the choice of treatment and 79% supported shared decision-making. CONCLUSIONS: Results are in favour of promoting active participation of cancer-patients in medical decision-making. The adequate degree of such participation remains however to be elicited and tested for therapeutic choices implying more difficult trade-offs between quantity and quality of life.

Production of ex vivo expanded hematopoietic cells and progenitors in a closed bioreactor, starting with a small volume marrow collection: A feasibility study in patients with poor-risk breast cancer and receiving high-doses of cyclophosphamide.

We report a clinical pilot study conducted in 6 women with poor-prognosis breast cancer. The goal was to evaluate the feasibility and safety of producing hematopoietic progenitors and cells from a small marrow sample, for clinical use after high-dose cyclophosphamide. A small volume marrow collection was obtained, using local anesthesia and conscious sedation, before the first of two chemotherapy cycles. Cells were cryopreserved, and later thawed to inoculate two Aastrom Biosciences Inc Replicell bioreactors, on time to reinfuse ex vivo expanded cells after the second chemotherapy cycle. Patients recovered neutrophils and platelets at similar times after the first and second chemotherapy cycles, and showed comparable clinical events. This pilot study prepares future randomized trials, designed to evaluate clinical benefits associated with the use of ex vivo expanded cells in the setting of multicycle high-dose chemotherapy.

Concomitant chemoradiotherapy for patients with nonmetastatic breast carcinoma: side effects, quality of life, and organization.

BACKGROUND: This study was designed to investigate the personal experience of patients with nonmetastatic breast carcinoma who were treated with the concurrent administration of radiotherapy and chemotherapy in terms of side effects and quality of life (QL). METHODS: One hundred nine patients with nonmetastatic breast carcinoma, recruited between May 1995 and February 1997, were included in a protocol combining chemotherapy with mitoxantrone and cyclophosphamide, administered intravenously in 4 cycles of 21 days, and concomitant radiotherapy. Side effects of treatment and its impact on patients' daily lives were measured using ad hoc questionnaires; QL was measured by the European Organization for Research and Treatment of Cancer QLQ-C30 QL questionnaire, and pain was measured by a visual analogue scale (VAS). RESULTS: All patients agreed to participate. The mean number of chemotherapy and radiotherapy symptoms per cycle were: 7.2+/-2.5 and 2.4+/-1.8, respectively. Chemotherapy symptoms generally were more frequent and distressing than those of radiotherapy. The average pain score reported on the VAS by patients during treatment was 3.0+/-2.0. Multidimensional QL assessment showed that treatment mainly affects physical functioning and global QL. Multivariate analysis showed that the main determinants of QL at the end of treatment were fatigue, pain, and loss of appetite experienced during treatment. Moreover, 62.8% of patients required specific help for transportation to the hospital and/or home upkeep. CONCLUSIONS: The concurrent administration of chemotherapy and radiotherapy deteriorates patients' QL but in a proportion similar to sequential administration while presenting the advantage of a shorter duration of treatment. However, increased fatigue, pain, and loss of appetite as well as difficulties in patients' daily lives have to be taken into account in therapeutic decision-making analysis.

The role of autologous hematopoietic progenitor and cell reinfusion for intensive chemotherapy in women with poor-prognosis breast cancer. Clinical studies with ex-vivo expanded cells produced with the Aastrom Replicell technology.

In recent years, we have initiated two clinical studies, to evaluate the usefulness of ex-vivo expanded cells in patients with breast cancer who receive sequential high-dose chemotherapy. Ex-vivo expanded cells were produced from autologous cryopreserved bone marrow nucleated cells, using a biomedical device. The Aastrom Replicell system cultures cells in animal serum-replete medium, with a combination of flt3-L, PIXY321 and Epo, for 12 days. The initial pilot trial was set up to establish the feasibility and safety of the technique: 6 patients completed the study. An ongoing randomized study searches to establish whether ex-vivo expanded cells provide a clinical benefit.

Patients who are receiving concomitant medications should not systematically be excluded from phase I studies.

This retrospective study was designed to evaluate possible relationships between the number and types of concomitant medications administered to patients on the first day of therapy in phase I trials and demographic characteristics, outcome measures and toxicities. Concomitant medications received by 690 patients enrolled on 28 phase I trials between August 1985 and January 1996 were grouped into 31 categories based on the American Hospital Formulary Service 1993. These patients received 1650 cycles of treatment with investigational agents (median 2 cycles per patient). Median duration on-study was 49 days (range 1-776 days). Clinical response rate (complete, partial, minor) was 3.8%. Only three toxic deaths occurred (0.4%). Nearly all patients (90.9%) received at least one concomitant medication on the first day of therapy. The number of concomitant medications directly correlated with poor performance status (rSp = 0.27, p < 0.0001) and indirectly with duration on-study (rSp = -0.18, p < 0.0001). The dose of the investigational agent administered during the first course of therapy was not related to concomitant medications on the first day of therapy. Most importantly, no relationships were observed between concomitant medications and either toxicities or clinical response to therapy. We conclude that patients who are receiving concomitant medications should not systematically be excluded from phase I studies.

Benefits of granulocyte-colony-stimulating factor after stem cell transfusion in intensive sequential chemotherapy for breast cancer.

The aim of this study was to evaluate the clinical and economic benefit of filgrastim given with intensive sequential chemotherapy. Women with poor-prognosis breast cancer received four cycles of high-dose cyclophosphamide (3 g/m2) and doxorubicin (75 mg/m2), followed by filgrastim 5 microg/kg/dy, stem cell collection after the cycle 1, and stem cell infusion after cycle 3 and cycle 4. The first cohort received filgrastim after the fourth cycle but the second cohort did not.Thirty three patients were included in the first cohort and 13 in the second. The results indicate that the duration of grade IV neutropenia was shorter in the group given filgrastim as was the median time to recover an absolute neutrophil count (ANC) > 1.0 x 10(9)/L. The rate and duration of the rehospitalizations were higher in the group not receiving filgrastim. We found that costs such as drugs and hospitalizations were significantly higher (p = 0.032 and p = 0.049) in the non-filgrastim-treated group. Using ANC > 1.0 x 10(9)/L as an intermediary efficiency criterion it was more cost effective to give filgrastim. It can be concluded from this study that filgrastim can decrease the duration of grade IV neutropenia in patients receiving intensive sequential chemotherapy. This, in turn, reduces the cost of hospitalization. However, in our study, this reduction of neutropenia did not have any impact on further therapy.

High-dose sequential chemotherapy with stem cell support for non-metastatic breast cancer.

The importance of dose-intensity has been suggested in breast cancer. The aim of this study was to evaluate the feasibility of a high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells. Twenty-five patients with non-metastatic breast cancer received four cycles of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2) at 3 week intervals. Apheresis was performed after the first cycle and if necessary after the second cycle. Stem cells were reinfused after the third and fourth cycles. G-CSF was started on day 3 of each cycle (5 microg/kg/day) and was stopped the day before the last apheresis or when absolute neutrophil count was above 0.5 x 10(9)/l. Median received dose-intensity was respectively 25 mg/m2/week (range 22-26) and 1000 mg/m2/week (range 904-1065) for doxorubicin and cyclophosphamide. Grade IV thrombocytopenia occurred in 8% of cycles. Two patients needed platelets and 12 red cell transfusion. Fifteen patients were readmitted for a median duration of 4 days (range 1-7). We have established a safe, outpatient, high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells which can be submitted for comparison with the current standards.

[Adjuvant chemotherapy with mitoxantrone, cyclophosphamide and 5-fluorouracil in breast neoplasms: therapeutic life]. / Chimiothérapie adjuvant par mitoxantrone, cyclophosphamide et 5 fluro-uracile dans les cancers du sein: vécu thérapeutique.

The chemotherapy side-effects are insufficiently documented while they strongly condition patients' quality of life. The aim of the study was to assess by means of a self-administered questionnaire the somatic symptoms experienced by breast cancer patients during their NCF (mitoxantrone + cyclophosphamide + 5-fluorouracil) chemotherapy and to demonstrate the interest of this self-report by comparing the frequency of side-effects assessed by the patients to that noted by the physicians in medical records. The study was carried out among 44 patients receiving their chemotherapy + radiotherapy at the Paoli-Calmettes Institute (marseille) between July 1994 and May 1995. The questionnaire comprized of 17 symptoms evaluated in terms of frequency, duration/severity and distress. The most frequent symptoms are: hair loss and nausea (75%), hot flush (57%), lack of appetite and headache (46%) associated with distress in 67 to 100% of cases. Their frequency was underestimated by the physicians in medical records. This study showed a large discordance patient-physician in the assessment of chemotherapy side-effects. The type of tool presented in this study could complement the usual scales of toxicity that do not provide an estimation of true patients' experience.