Guy Cantin

A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial

We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.

A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors.

Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 μg/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), β-thromboglobulin (β-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin–antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 ± 0.32 U/ml to 1.83 ± 0.69 U/ml; P < 0.001), in vwf activity (from 1.04 ± 0.34 u/ml to 1.78 ± 0.50 u/ml; P < 0.001) and in fviii:c (from 1.12 ± 0.37 u/ml to 1.73 ± 0.57 u/ml; P < 0.001) after g-csf. of note, four donors with low baseline vwf had a two- to three-fold increase after receiving g-csf. g-csf had no impact on the platelet count, β-tg, pf-4, gmp-140 or pac-1. the final% of platelet aggregation decreased from 73 ± 22% to 37 ± 26% after g-csf (P < 0.001). we found a significant decrease in aptt after g-csf (29.9 ± 3.1 s to 28.3 ± 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.

Comparison of Serious Adverse Events Between the Original and a Generic Docetaxel in Breast Cancer Patients

Background: Generic formulations are not necessarily identical to the original in terms of efficacy and adverse events. Generic docetaxel has been available in Canada since 2011. Objective: To compare the occurrence of grade III to IV adverse events between original docetaxel and a generic formulation in breast cancer patients. Methods: A consecutive series of 400 patients were assessed retrospectively: 200 who received the original docetaxel and 200 who received a generic formulation. Patients who received both formulations or received their chemotherapy outside our center were excluded. The primary outcome was the occurrence of grade III to IV adverse events related to docetaxel (febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and death). Results: Three hundred-sixty-four patients were available for analysis (182/group). The use of a granulocyte colony-stimulating factor (G-CSF) was more frequent in the generic group (44.5% vs 28.8%), as well as treatment discontinuation (26.4% vs 14.8%). The occurrence of grade III to IV febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and docetaxel-related deaths were similar between the 2 formulations. However, grade IV febrile neutropenia was more frequent with the generic formulation (78.8% vs 56.3%). Limitations were the retrospective nature of the study and the variety of chemotherapy regimens. Conclusion: Adverse events occurrence was similar between the 2 formulations. However, febrile neutropenia was more serious with generic docetaxel, despite increased G-CSF use. Results suggest that the studied generic formulation may be safe, but more caution during treatments might be warranted, especially concerning febrile neutropenia events.

Hematopoietic engraftment from a minimal number of apheresis procedures after mobilization of peripheral blood stem cells with chemotherapy and rhG-CSF

In a cohort of 13 patients, peripheral blood stem cells (PBSC) were harvested by apheresis after mobilization with chemotherapy and rhG-CSF. Nine patients who had excellent mobilization were transplanted with PBSC concentrates from a minimal number of apheresis procedures (mean of 1.5, range = 1-3). During collection, the number of circulating progenitors was on average 50 times higher than those observed at the steady state in the peripheral blood of healthy unstimulated individuals. The mean number of CFU-GM/kg reinfused per patient was 28.1 x 10(4) (range = 18.0-50 x 10(4)). The use of rhG-CSF, at either 1 or 5 micrograms/kg/day, resulted in a significantly greater yield of CFU-GM per mononuclear cells than that observed previously in a comparable group of patients receiving chemotherapy alone. Prompt and durable engraftment occurred after myeloablative chemotherapy. The average duration of absolute neutropenia was 9 days. Transfusion requirements were low with an average of four packed red cell units and two platelet transfusions per patient. The shortest follow-up is 5 months and the longest is 20+ months. The convenience of this new approach to support myeloablative therapy offers new possibilities for the administration of a higher dose-intensity of chemotherapeutic agents. A limited number of apheresis procedures timely harvested will improve the cost effectiveness of transplant programs.

Evaluation of Factors Associated with Recruitment in Breast Cancer Clinical Trials in a Specialized Breast Cancer Centre.

Background: Recruitment of patients (pts) in cancer clinical trials has been reported to be between 3-5%. Very few data come from Canada. Methods: The objective was to measure the recruitment and its associated characteristics in breast cancer clinical trials for non-metastatic breast cancer pts. This was a retrospective cohort study at the Centre des Maladies du Sein Deschenes-Fabia, a specialized breast cancer centre in Quebec City, Canada. Clinical trials opened between 2004 and 2008 were used. For each protocol, main criteria were used to define the population under study (e.g. triple negative breast cancer). Charts were identified from our database and reviewed in decreasing chronological order of diagnosis. Staging, hormone receptors status and Her2 status were available from the database. All charts were reviewed to assess eligibility criteria (inclusion and exclusion criteria). Also, information was sought in the notes about whether or not the protocol has been proposed to the pt, if the pt accepted and if not, reason(s) for refusal. Protocol and physicians characteristics were collected. Results: A total of 9 protocols were studied and 244 charts identified (relates to 704 pt-protocols because one pt could be assessed for more than one protocol if applicable). Eligibility could not be assessed for 19% (n=138) pt-protocols. Among all pt-protocols, 74.4% met all the eligibility criteria. There was a note in the chart, about protocol being proposed to a potentially eligible pt, in 13.8% of the pt-protocols. Overall, 9.7% of pt-protocols were recruited. Among patients who had a protocol offered, 74.2% accepted. Data on characteristics associated with recruitment will be presented at the meeting. Conclusion: Enrollment in clinical trials in a specialized breast cancer centre is slightly higher than the 3-5% generally reported but still low. Interventions should focus on finding ways to offer a clinical trial when available to every suitable eligible patient. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5122.

Two different schedules for integrating filgrastim as adjuvant therapy in the treatment of patients with advanced stage Hodgkin's lymphoma receiving MOPP/ABV hybrid chemotherapy

Purpose: Management of advanced-stage Hodgkins disease with a MOPP/ABV hybrid regimen (mechlorethamine, vincristine, procarbazine, prednisone, Adriamycin, bleomycin and vinblastine) has yielded a high complete response rate (75–85%). However, myelosuppression can limit delivery of treatment. Filgrastim has been shown to reduce chemotherapy-related neutropenia and allow for on-time administration of planned doses of chemotherapeutic agents. The objective of this study was to find the best way to integrate filgrastim with the MOPP/ABV hybrid regimen. Methods: Enrolled in this study were 24 patients (aged 18–52 years) with newly diagnosed, histologically documented Hodgkins disease. In schedule I, patients received filgrastim (5 μg/kg s.c. daily) beginning on day 9, 24 h after administration of ABV. In schedule II, patients received filgrastim concomitantly with procarbazine on days 2–7 (starting 24 h after day-1 MOPP administration and stopping 24 h before ABV administration) as well as after ABV beginning on day 9. Filgrastim after ABV administration was administered until two consecutive ANC readings of 10 × 109/l were achieved. Results: All patients were able to complete all six cycles of therapy. There was a trend to fewer dose reductions in schedule II (0.76%) as compared to schedule I (4.2%) with a P-value of 0.077 (chi-squared test). Specifically, 11.6% of MOPP courses and 5.5% of ABV courses were dose-reduced in schedule I versus 1.7% and 1.4%, respectively, in schedule II. Conclusion: In conclusion, filgrastim was effective in supporting the delivery of the MOPP/ABV chemotherapy. Concomitant administration of filgrastim with procarbazine (days 2–7) appears to be safe and allows the maximum dose intensity of this therapy.