Linda Vahdat

Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSEnNormal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy.nnnPATIENTS AND METHODSnUp to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy.nnnRESULTSnHigh-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered.nnnCONCLUSIONnThese results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.

The pharmacokinetics and pharmacodynamics of high-dose paclitaxel monotherapy (825 mg/m2 continuous infusion over 24 h) with hematopoietic support in women with metastatic breast cancer

Purpose: We evaluated the pharmacokinetics and pharmacodynamics of high-dose paclitaxel (HDP) monotherapy (825xa0mg/m2 continuous infusion over 24xa0h) with peripheral blood progenitor cell (PBPC) and G-CSF support in 17 women with metastatic breast cancer. Methods: Pharmacokinetic and pharmacodynamic data were collected in 17 women entered in a phase II trial of sequential HDP, and high-dose melphalan and cyclophosphamide/thiotepa/carboplatin. Results: The maximal plasma concentration (Cmax), area under the plasma concentration time curve (AUC), apparent clearance (Clapp), duration of plasma concentration above 0.05xa0µM (t>0.05xa0µM) for paclitaxel were (means±SD): 9.11±7.45xa0µM, 145±88xa0µM·h, 8.06±2.90xa0l/h per m2 and 82.4±31.2xa0h, respectively. There was a significant correlation between the plasma paclitaxel concentration at 1xa0h (r2=0.87), 12xa0h (r2=0.85)and 23xa0h (r2=0.92)and the AUC (P<0.0001). Duration of neutropenia was brief (median 3xa0days, range 0–5xa0days) and neutrophil recovery occurred earlier (median 6xa0days, range 0–7xa0days) than could be attributed to infused PBPC. Median nadir count for platelets was 66×109/l (range 13–160×109/l). Pharmacodynamic analysis showed no correlation between pharmacokinetic parameters (Cmax, AUC, t>0.05xa0µM) and time to neutropenic nadir, duration of neutropenia, platelet count nadir and grades of neuropathy or mucositis. In ten patients in whom detailed neurologic and nerve conduction studies were performed, linear regression analysis showed a significant correlation between pre- and post-HDP treatment total neuropathy scores (r2=0.46, P=0.03). Conclusions: HDP (825xa0mg/m2 continuous infusion over 24xa0h) did not appear to be myeloablative. The degree of neurotoxicity subsequent to HDP was associated with the degree of baseline neuropathy but was not predictable from pharmacokinetic parameters.

High-dose thiotepa and etoposide-based regimens with autologous hematopoietic support for high-risk or recurrent CNS tumors in children and adults

The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5u2009×u2009109/l was 11 days (range 8–37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10–37) than for PBPC (median 9.5 days, range 8–10). Platelet engraftment >50u2009×u2009109/l was 24 days (range 14–53 days) in children. In adults, platelet engraftment >20u2009×u2009109/l was 12 days (range 9–65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = −0.87, P = 0.009) and platelet engraftment (rho = −0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n = 4). Median time to tumor progression (TTP) was 7 months, with an overall median survival of 12 months. These TE-based BCNU or carboplatin three-drug combination HDC regimens are safe and tolerable with promising response rates in both children and older adults.

High-dose chemotherapy with autologous stem cell support for breast cancer

High‐dose chemotherapy is increasingly utilized for the treatment of metastatic and high‐risk breast cancer. Autologous Blood and Marrow Transplant Registry data reveal that a single high‐dose cycle of chemotherapy with stem cell support can produce high complete response rates, with 10% to 20% of patients disease‐free at 5 years. For patients with locally advanced disease, pooled results estimate 63% without relapse at 3 years for stage II and III disease and 42% for inflammatory breast cancer. New strategies to improve on these results include the incorporation of newly identified active drugs into established regimens and the use of multiple high‐dose cycles. Multicycle chemotherapy produces complete response rates ranging from 35% to 93% depending on the regimen. Additional strategies include the use of monoclonal antibodies, immunotherapy, and gene therapy for post‐transplant consolidation. The strongest predictor of longterm disease‐free survival in virtually all studies is a complete response prior to or following high‐dose chemotherapy. Randomized studies are now in the process of being completed in Europe and the United States with reporting scheduled over the next several years.

A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma

The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P‐glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over‐express P‐glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC).

Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15–20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m2), the second melphalan (180 mg/m2) and the third consisted of cyclophosphamide 6000 mg/m2 (1500 mg/m2/day × 4), thiotepa 500 mg/m2 (125 mg/m2/day × 4) and carboplatin 800 mg/m2 (200 mg/m2/day × 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1–43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.

A Phase I Study of High-dose BCNU, Etoposide and Escalating-dose Thiotepa (BTE) with Hematopoietic Progenitor Cell Support in Adults with Recurrent and High-risk Brain Tumors

This phase I dose-escalation study was performed to determine the tolerability of three-drug combination high-dose BCNU (B) (450 mg/m2), escalating-dose thiotepa (500–800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days in 22 adults with malignant primary brain tumors. Patients received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n=18) or both PBPC and marrow (n=4). The maximum tolerated dose of thiotepa with acceptable toxicity was determined as 800 mg/m2. The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included mucositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity (14%). Neurological toxicities occurred in 24% and included seizures (two patients) and encephalopathy (three patients). Encephalopathy was transient in two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) >0.5×109/l was 10 days (range 8–30 days). Platelet engraftment >20×109/l occurred after 11 days (range 9–65 days). In the eighteen patients supported solely with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho=−0.78, p=0.001) and platelet engraftment (rho=−0.76, p=0.002). Overall, 11% of evaluable patients (2/18) had a complete response to BTE. Median time to tumor progression (TTP) was 9 months, with an overall median survival of 17 months. BCNU (450 mg/m2), thiotepa (800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumors.

High-dose Therapy for Breast Cancer☆

The high incidence of breast cancer in young women, and the unfavorable prognosis for those who present with a high number of lymph nodes involved with cancer, has encouraged the development and evaluation of new treatment strategies. The use of dose intensification is supported by laboratory and clinical models. In this review article, the use of dose intensification supported by hemopoietic growth factors, and also by hemopoietic stem cells, is discussed. The results of published studies of high-dose chemotherapy in Stage II, III, and IV breast cancer are discussed and summarized, including those randomized comparisons with more conventional therapy. Improvements in supportive care continue to reduce the risks from neutropenia and thrombocytopenia, and these and other toxicities are likely to decrease as side-effects are anticipated and experience increases.

Disease-Free Survival According to the Use of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy

INTRODUCTIONnThe purpose of the study was to determine predictors of recurrence for patients treated with neoadjuvant chemotherapy (NAC) and mastectomy according to the use of postmastectomy radiation therapy (PMRT).nnnPATIENTS AND METHODSnAn analysis of 161 clinically staged T1 to T3/N0 to N3 patients treated with NAC and mastectomy with and without PMRT at our institution from 2003 to 2010 was conducted. The Kaplan-Meier product limit method was used to estimate survival and time to recurrence rates and the log-rank test was used to compare groups. A Cox proportional hazard regression analysis was carried out for time to recurrence, radiation therapy, and their interaction in the model.nnnRESULTSnThe median follow-up period was 48 months and 18 patients developed a recurrence. The 5-year recurrence rate and overall survival was 16.1% (95% confidence interval [CI], 9.6%-26.3%) and 93.6% (95% CI, 88.2%-97.0%), respectively. Patients who underwent PMRT had a decreased risk of recurrence compared with patients who did not (hazard ratio [HR], 0.25; 95% CI, 0.097-0.661; P < .005). The 5-year disease-free survival (DFS) rate for those who received PMRT was 91.3% (95% CI, 82.8%-95.7%) and 64.8% (95% CI, 37.8%-82.4%) for those who did not (P = .0126). Among all clinicopathologic factors examined, pathologic T stage (ypT) and pathological N stage (ypN) significantly correlated with the risk of recurrence (P < .05). Patients with any pathological nodal disease had an increased risk of recurrence compared with patients who were pathologically node-negative (HR, 7.196; 95% CI, 2.05-25.264; P < .002).nnnCONCLUSIONnPatients treated with NAC and mastectomy, but without PMRT had a higher risk recurrence with increasing ypT and ypN stages. PMRT might increase DFS.

CD34+ Cell Dose Requirements for Rapid Engraftment in a Sequential High-Dose Chemotherapy Regimen of Paclitaxel, Melphalan, and Cyclophosphamide, Thiotepa, and Carboplatin (CTCb) with PBPC Support in Metastatic Breast Cancer

Sequential high-dose chemotherapy may increase the threshold dose of CD34+ cells necessary for rapid and successful hematologic recovery. There are limited data regarding the pharmacodynamics and threshold CD34+ cell dose required for engraftment following high-dose paclitaxel. To determine the dose of CD34+ PBPC sufficient for rapid engraftment, 65 women with metastatic breast cancer undergoing a sequential high-dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin (CTCb) chemotherapy regimen were evaluated. The intertreatment interval was a median of 27 days. Paclitaxel was escalated from 400 to 825 mg/m2, infused continuously (CI) over 24 h on day -4 with PBPC reinfusion on day 0. Following marrow recovery, 90 mg/m2/day of melphalan was given over 30 min on days -2 and -1, with PBPC reinfusion on day 0. On recovery, patients received CTCb on days -7 to -3, with PBPC reinfusion on day 0. G-CSF was administered after each cycle until WBCC recovery. For paclitaxel, an ANC >0.5 x 10(9)/L occurred at a median of 6 days (range 0-7 days) after PBPC reinfusion. The median nadir platelet count was 63 x 10(9)/L (range 6 x 10(9)/L-176 x 10(9)/L). Eight patients (12%) had platelet nadir <20 x 10(9)/L, and all recovered their counts to >20 x 10(9)/L on day 7. There was no clinical difference in days to engraftment between women receiving <2 or > or =2 x 10(6) CD34+ PBPC/kg following paclitaxel. All patients recovered neutrophil and platelet counts within 7 days after reinfusion of > or =1 x 10(6) CD34+ cells/kg and G-CSF. The data suggest that a paclitaxel dose of 825 mg/m2 is not myeloablative. For melphalan, median days to ANC >0.5 x 10(9)/L was 10 days (range 9-15), and platelet recovery to >20 x 10(9)/L was 13 days (range 0-28) after PBPC reinfusion. Median time to engraftment was more rapid in patients receiving > or =2 x 10(6) CD34+/kg versus <2 x 10(6)CD34+/kg, for both neutrophils (11 days versus 10 days, p = 0.05) and platelets (14 days versus 12 days, p < 0.01). Ninety-eight percent of patients infused with > or =2 x 10(6) CD34+/kg engrafted within 21 days. Following CTCb in this sequential regimen, a dose of > or =2 x 10(6) CD34+ cells/kg provided for significantly more rapid neutrophil engraftment than <2 x 10(6) CD34+ cells/kg (9 days versus 10 days,p = 0.01), but a dose > or =3 X 10(6) CD34+ cells/kg is necessary for reliable, rapid, and sustained neutrophil and platelet engraftment by day 21.