Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.

BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial.

BACKGROUND: Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody-drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. PATIENTS AND METHODS: We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2-) HR+/HER2- mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%-45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7-12.7), median PFS was 5.5 months (95% CI 3.6-7.6), and median OS was 12 months (95% CI 9.0-18.2). CONCLUSIONS: SG shows encouraging activity in patients with pretreated HR+/HER2- mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). TRIAL REGISTRATION: ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552.

Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer.

BACKGROUND: Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative. PATIENTS AND METHODS: Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer. RESULTS: At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%). CONCLUSIONS: GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS: This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS: Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Employment after a breast cancer diagnosis: a qualitative study of ethnically diverse urban women.

Employment status is related to treatment recovery and quality of life in breast cancer survivors, yet little is known about return to work in immigrant and minority survivors. We conducted an exploratory qualitative study using ethnically cohesive focus groups of urban breast cancer survivors who were African-American, African-Caribbean, Chinese, Filipina, Latina, or non-Latina white. We audio- and video-recorded, transcribed, and thematically coded the focus group discussions and we analyzed the coded transcripts within and across ethnic groups. Seven major themes emerged related to the participants' work experiences after diagnosis: normalcy, acceptance, identity, appearance, privacy, lack of flexibility at work, and employer support. Maintaining a sense of normalcy was cited as a benefit of working by survivors in each group. Acceptance of the cancer diagnosis was most common in the Chinese group and in participants who had a family history of breast cancer; those who described this attitude were likely to continue working throughout the treatment period. Appearance was important among all but the Chinese group and was related to privacy, which many thought was necessary to derive the benefit of normalcy at work. Employer support included schedule flexibility, medical confidentiality, and help maintaining a normal work environment, which was particularly important to our study sample. Overall, we found few differences between the different ethnic groups in our study. These results have important implications for the provision of support services to and clinical management of employed women with breast cancer, as well as for further large-scale research in disparities and employment outcomes.

Treatment of metastatic breast cancer: second line and beyond.

Increasing use of standard chemotherapy, especially anthracycline- and taxane-based therapies, in early-stage breast cancer has led to a corresponding increase in heavily pretreated and/or treatment-resistant cases of metastatic breast cancer (MBC). Thus, second and later lines of MBC therapy frequently involve the clinically challenging picture of progressive disease and limited treatment options. While several prognostic factors have been identified to aid treatment selection in MBC patients, treatment is palliative and aimed at prolonging survival, controlling symptoms, and maximizing patients' quality of life. No globally accepted standard exists for meeting these goals, and treatment patterns vary according to region. The list of available agents for the treatment of MBC is increasing with newer chemotherapeutic agents and molecular-targeted therapies. Within recent years, several single-agent and combination chemotherapy regimens have been shown to improve progression-free survival and reduce symptoms of disease in clinical studies in patients with resistant and/or heavily pretreated MBC. However, at present, the demonstrated benefits of these medical interventions have usually not included extension of overall survival times. It is hoped that in the near future, ongoing refinements to treatment approaches used in second-line settings and beyond will allow meaningful improvements in symptom control and survival in MBC.

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary.

BACKGROUND: Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer. METHODS: Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients. RESULTS: Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer. CONCLUSION: Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205.

BACKGROUND: Fulvestrant produces a clinical benefit rate (CBR) of approximately 45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib-fulvestrant combination in HR-positive MBC. PATIENTS AND METHODS: Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1-21 every 28 days. The primary end point was CBR. RESULTS: The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%). CONCLUSIONS: The target CBR of 70% for the tipifarnib-fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer.

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.

Kinetics of amoxicillin and clavulanate degradation alone and in combination in aqueous solution under frozen conditions.

Kinetics of the reactions of amoxicillin sodium and potassium clavulanate alone and in combination were investigated in the frozen state at selected pH values of 2.0, 4.6 and 7.0. Extrapolation of the rate constant values to the frozen state from the liquid state data indicated marked acceleration of the rates of amoxicillin and clavulanate degradation for the pH values investigated. The highest acceleration in rate recorded was 15.0-fold for clavulanate and the lowest value was 4.6-fold for amoxicillin at -7.3 degrees C in the hydrochloric acid system. The rate constant values obtained were interpreted in terms of the concentration model [Pincock, R.E., Kiovsky, T.E., 1966. Kinetics of reactions in frozen solution. J. Chem. Educ. 43, 358-360], phase-temperature relationship of the solutes, buffer catalysis, pH change and polymerization reactions. A kinetic model was deduced for the hydrochloric acid system providing adequate explanation of the experimental results. A large stabilizing effect of sodium chloride used for maintaining constant ionic strength (micro=0.5) was evident in this system. The shelf-life of amoxicillin was increased from 2.2 to 58.7h at -7.3 degrees C when sodium chloride was included in the hydrochloric acid system.

Rapid administration of multiple cycles of high-dose myelosuppressive chemotherapy in patients with metastatic breast cancer.

PURPOSE: To determine the feasibility and safety of a rapidly cycled sequence of high-dose myelosuppressive chemotherapy courses. PATIENTS AND METHODS: Seventeen patients with metastatic breast cancer were treated with two courses of cyclophosphamide (CPA; 3.0 g/m2) supported by granulocyte colony-stimulating factor (G-CSF). Following the first CPA treatment, peripheral-blood leukaphereses commenced when the leukocyte count recovered to 1.0 x 10(9)/L. After hematologic recovery from the second dose of CPA, patients were treated with carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and CPA 5.0 g/m2 administered over 3 days. The peripheral-blood progenitors (PBPs) were reinfused 3 days later, and G-CSF was recommenced. RESULTS: All patients received the three courses. The median interval between treatments was 14 days (range, 13 to 21). Sixteen of the 34 courses of CPA resulted in admissions for fever. Following the third course, neutrophil counts recovered to 0.5 x 10(9)/L at a median of 9 days (range, 8 to 18) after PBP reinfusion and platelets recovered to 50 x 10(9)/L at a median of 12 days (range, 9 to 102). There were no treatment-related deaths. Flow-cytometric analysis was performed on the leukapheresis collections of eight patients. Seven patients with at least 2.0 x 10(6) CD34+ CD33- cells per kilogram body weight exhibited prompt hematologic recovery. One patient with 0.03 x 10(6) CD34+ CD33- cells was still cytopenic on day 21, and required reinfusion of her back-up marrow. Among seven patients with measurable or assessable disease, there were two complete responses (CRs) and four partial responses (PRs). CONCLUSION: These preliminary results suggest that multiple, rapidly cycled courses of high-dose myelosuppressive chemotherapy can be administered. PBPs, harvested during the G-CSF-augmented rebound from CPA-induced cytopenia, produce rapid hematologic recovery in patients undergoing high-dose chemotherapy (HDC). Further follow-up will be necessary to assess the efficacy of this specific regimen in the treatment of metastatic breast cancer.

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.

PURPOSE: Normal 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. PATIENTS AND METHODS: Up 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. RESULTS: High-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. CONCLUSION: These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.

Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer.

PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma.

In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30-50 mg/m2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400-850 mg/m2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.

Therapy-related myelodysplastic syndrome after autologous stem cell transplantation for breast cancer.

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) are serious complications of chemotherapy and radiotherapy for cancer. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may be associated with an increased incidence of these complications. The frequency of t-MDS/AML after ASCT for breast cancer is uncertain. We reviewed our database of 379 consecutive breast cancer ASCT patients treated with alkylator-based chemotherapy, followed for a median of 1.52 years (range 0-8.97), with a median survival of 6.16 years. Three patients have developed tMDS/AML. The probability of developing this complication at 5 years is 0.032 in our series. We have used pathologic, cytogenetic and molecular methods to evaluate which portions of therapy may have predisposed to the development of this complication. Cytogenetic abnormalities were not found in the stem cell harvests of these patients by metaphase analysis or by fluorescence in situ hybridization (FISH). One patient demonstrated a clonal X chromosome inactivation pattern in her stem cell harvest, indicating pre-transplant chemotherapy may have been responsible for the development of her leukemia. As two of our patients developed this complication at greater than 4 years post-transplant, the number of cases may increase with longer follow-up. While the incidence appears to be low, further prospective and retrospective analysis will be necessary to determine which portions of therapy predispose to the development of t-MDS/AML in patients undergoing ASCT for treatment of breast cancer.

Rapidly cycled courses of high-dose alkylating agents supported by filgrastim and peripheral blood progenitor cells in patients with metastatic breast cancer.

Our purpose was to determine the feasibility of a regimen of multiple, rapidly cycled courses of high-dose alkylating agents, including paired courses of escalating doses of thiotepa, supported by peripheral blood progenitor cells and filgrastim, in patients with responding stage IV breast cancer. The regimen consisted of two courses of cyclophosphamide (3.0 g/m2/course) followed by two courses of thiotepa (500-700 mg/m2/course). All courses were supported by filgrastim. Leukaphereses were performed after each cyclophosphamide course to harvest peripheral blood progenitors (PBPs) for use as rescue following thiotepa administration. The planned interval for all courses was 14 days. Forty-two patients were enrolled. Thirty-eight received all four courses, and four did not receive the second thiotepa cycle due to poor PBP mobilization. The maximum dose of thiotepa that was administered was 700 mg/m2 x 2. At this dose, one patient developed encephalopathy, which resolved over several weeks. The median number of days to an absolute neutrophil count of 0.5 x 10(9)/liter after PBP reinfusion for cycles 1 and 2 of thiotepa were 9 (range, 7-16) and 9 (range, 8-13) days, respectively. The corresponding values for platelet recovery to >20 x 10(9)/liter were 11 (range, 8-39) and 12 (range, 10-28) days, respectively. There were no treatment-related deaths. Hospitalization was required following 28 of 84 cyclophosphamide courses and 76 of 80 thiotepa courses. Four patients developed grade III-IV mucositis. The median interval between courses of treatment was 15 (range, 13-29) days. Of 19 patients who entered the protocol with measurable disease in partial response from prior therapy, 8 (42%) achieved complete response following the high-dose therapy. Nine (21%) of 42 remain progression free at a median follow-up of 28 (range, 20-32) months. Therefore, we concluded that the administration of multiple, rapidly cycled courses of high-dose alkylating agents is feasible.

Phase I trial of sequential high-dose chemotherapy with escalating dose 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 with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.

Reduction of paclitaxel-induced peripheral neuropathy with glutamine.

PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.

Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study.

AIMS: The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel. MATERIALS AND METHODS: In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment. RESULTS: Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups. CONCLUSIONS: In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.