Christoph Salat

Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study

BACKGROUND The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. METHODS Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (> or = 5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. FINDINGS 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20-67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41-0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6-26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54-0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45-0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. INTERPRETATION To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location. FUNDING Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).

Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive and Triple-Negative Primary Breast Cancers

PURPOSE Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. PATIENTS AND METHODS GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. RESULTS Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rates ≥ 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2-positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P < .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P < .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P < .001). CONCLUSION Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC.

Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial

BACKGROUND Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. METHODS Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. FINDINGS 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. INTERPRETATION The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. FUNDING GlaxoSmithKline, Roche, and Teva.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer—results at the time of surgery

BACKGROUND Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. PATIENTS AND METHODS Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)→T(dd)→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). RESULTS Pathological complete response (pCR) rate (breast) was higher with E(dd)→T(dd)→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)→T(dd)→CMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). CONCLUSION Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis.

BACKGROUND The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. PATIENTS AND METHODS A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). CONCLUSION Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial.

Objective:To evaluate the effect of intravenous IgMA-enriched immunoglobulin (ivIGMA) therapy on mortality in neutropenic patients with hematologic malignancies and sepsis syndrome or septic shock. Design:Multiple-center, prospective randomized, controlled study. Setting:Six university hospitals in Germany. Patients:Patients were 211 neutropenic patients with sepsis syndrome or septic shock after chemotherapy for severe hematologic disorders between 1992 and 1999. Interventions:Patients received 1300 mL of ivIGMA (7.8 g IgM, 7.8 g IgA, and 49.4 g IgG) infused intravenously within a period of 72 hrs or human albumin according to the same schedule as ivIGMA. Measurements and Main Results:All-cause mortality at 28 days, sepsis-related mortality at 28 days, all-cause mortality at 60 days, mortality from septic shock, and mortality from microbiologically proven Gram-negative sepsis and septic shock were recorded. Immunoglobulin had no benefit over human albumin. The 28-day mortality rate was 26.2% and 28.2% in the ivIGMA and control patients, respectively (difference, 2.0% [95% confidence interval, −10.2 to 14.2 percentage points]). Likewise, the 60-day mortality rate did not differ between both arms (29.6% vs. 34.7% in the ivIGMA and control patients, respectively). Mortality rates in patients with sepsis syndrome (17.1% vs. 16.7%) and septic shock (51.9% vs. 54.8%) were also found to be similar between both groups. Conclusions:Intravenous ivIGMA had no beneficial effects in neutropenic patients with hematologic malignancies and sepsis syndrome and septic shock.

Abstract S2-04: Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto)

Introduction Addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy has shown to improve pathological complete response (pCR; ypT0 ypN0) rates in patients with triple-negative breast cancer in two large phase II studies (GeparSixto: von Minckwitz et al. Lancet Oncol 2014; CALGB 40603: Sikov et al. J Clin Oncol 2015). Participants of the GeparSixto study with triple-negative tumors showed an improvement of pCR rate from 36.9 to 53.2% by the addition of carboplatin (p=0.005); however, no statistically significant difference in pCR rate was observed in the HER2-positive subgroup (36.8 vs 32.8%, respectively). A greater benefit with carboplatin was observed in patients with BRCA mutations or a high homologous recombination deficiency (HRD score) in the tumor (pCR rate of 30% compared to 10% for patients without HRD). So far, it is unknown whether these effects on pCR translate into a survival benefit for the patients. We here report an early survival analysis of the GeparSixto study. Patients and Methods In the GeparSixto trial (NCT01426880), patients were treated for 18 weeks with paclitaxel 80mg/m2 q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m2 q1w. Patients with TNBC (N=315) received concurrently bevacizumab 15mg/kg i.v. q2w until surgery. Patients with HER2+ disease (N=273) received concurrently trastuzumab 6(8)mg/kg q3w and lapatinib 750mg daily. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2.0 q1w vs no carboplatin, stratified by subtype (HER2+ vs TNBC). Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients. Primary objective was pCR rate (ypT0 ypN0). Loco-regional invasive recurrence free survival (LRRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) were secondary objectives. Results 595 patients were recruited (8/2011 - 12/2012) in 51 German centers. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. So far, 82 events have been reported after a median of 28 months follow-up. Analysis of updated events by treatment arm in the full study population as well as in the TNBC and HRD subgroups will be presented. Conclusion Even if the GeparSixto study was not powered to show carboplatin effects on survival, the expected results will help to assess the overall benefit of carboplatin in TNBC and the power of pCR to predict for DFS and OS. Citation Format: von Minckwitz G, Loibl S, Schneeweiss A, Salat CT, Rezai M, Zahm D-M, Klare P, Blohmer J-U, Tesch H, Khandan F, Fasching PA, Jakisch C, Nekljudova V, Untch M. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-04.

Abstract S1-06: Increased tumor-associated lymphocytes predict benefit from addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer in the GeparSixto trial (GBG 66)

Background: We have recently described a significantly increased pCR rate in triple-negative breast cancer with addition of carboplatin to a non-pegylated liposomal doxorubicin/taxane (MC) combination in the neoadjuvant Geparsixto study (von Minckwitz et al, ASCO, 2013). Here we report the results of prospective biomarker analyses performed in Geparsixto. Methods: Geparsixto investigates the effect of adding carboplatin to MC for the treatment of patients with HER2+ve and triple-negative (TN) primary BC. All HER2+ve patients received trastuzumab and lapatinib, all TN patients received bevacizumab. As part of the central pathology assessment, we prospectively evaluated tumor-associated lymphocytes (TILs) in 580 core biopsies. We used the parameters stromal lymphocytes (strLy) and lymphocyte-predominant breast cancer (LPBC, ≥60%TILs) as previously described (Denkert et al, JCO, 2010). In addition, Ki67 (n = 588) was measured by immunohistochemistry and p53 mutations in Exons 5-8 (n = 444) were evaluated by Sanger sequencing. Pathological complete remission (pCR) was defined as ypT0ypN0. Results: 24.7% of the 588 patients had a LPBC. These patients had an increased pCR rate of 60.3%, compared to 35.8% for the non-LPBC tumors (p Ki67>20% was associated with an increased pCR rate of 46.6%, compared to 27% in tumors with lower proliferation (p Conclusion: Our results show that the interaction with host immune response is relevant for response to chemotherapy, this effect is particularly strong with the addition of carboplatin. Tumor-associated lymphocytes as a continuous parameter as well as LPBC as a tumor subgroup are predictive for response to neoadjuvant chemotherapy. In particular with regard to the relevant toxicity of the MC+carboplatin combination, the integration of immunological biomarkers would be helpful to identify the patients with the highest benefit from the addition of carboplatin. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-06.

Platelet flow cytometric findings in patients undergoing conditioning therapy for allogeneic hematopoietic stem cell transplantation

The conditioning regimen preceding hematopoietic stem cell transplantation (HSCT) causes a rapid decrease in the platelet count and signs of disseminated intravascular coagulation, possibly indicating platelet activation. As impacts during the conditioning regimen may predict later transplantation-associated complications, we investigated changes in platelet membrane glycoproteins (GP) and the liberation of microparticles. Platelet receptors and granules of 49 patients undergoing HSCT were evaluated by flow cytometric analysis before and after the different phases of the conditioning regimen [chemotherapy, total body irradiation (TBI), therapy with antithymocyte globulin (ATG)] and final transplantation. Following chemotherapy a high surface expression of CD62P, a low mepacrine staining, and a reduced surface expression of CD42b (part of the GP Ib/V/IX complex) were found, indicating an irreversible activation of platelets. In addition, elevated levels of circulating microparticles were observed, which may reinforce the thrombosis risk in these patients. Treatment with ATG leads to an elevated surface expression of PAC-1 epitopes, which are neoepitopes appearing after activation of GP IIb/IIIa. However, a significant degranulation was not detectable, which may be the consequence of inhibitory influences on platelets during ATG-induced cytokine release syndrome. TBI and transplantation itself had no influence on platelets. This study was able to demonstrate activating effects on platelets by certain phases of the conditioning regimen in patients receiving HSCT. Chemotherapy, in particular, leads to a strong and irreversible platelet activation and a generation of microparticles, which may cause an increased thrombosis risk. Our findings underline the impact of platelets on the pathogenesis of hemostatic complications during HSCT.

Factor XIII activity levels in patients with allogeneic haematopoietic stem cell transplantation and acute graft‐versus‐host disease of the gut

Summary. Severe graft‐versus‐host disease (GvHD) of the gut clinically resembles Crohns disease and ulcerative colitis. As low plasma levels of factor XIII (FXIII) have been described in chronic inflammatory bowel disease (CIBD) and as beneficial effects of FXIII concentrates in CIBD have been reported, we studied the FXIII plasma activity levels in patients undergoing allogeneic stem cell transplantation (SCT). In 20 of 22 patients with an uncomplicated course of SCT, FXIII stayed within the normal range (median 102 iu/dl, range 74–122), but was significantly reduced with the lowest FXIII levels on d 0 and 7 (d 0: median 83 iu/dl, range 55–165, d 7: median 83, range 70–101). In 20 of 22 patients with histologically proven GvHD of the gut, FXIII levels far below the normal range were observed (median 50, range 21–87) with a strong correlation between FXIII activity levels and degree of GvHD (r = −0·908; P < 0·001). We conclude that FXIII is consumed in patients with GvHD of the gut. As FXIII plays a a crucial role in haemostasis and wound healing, a study on the potential benefit of FXIII substitution in patients with severe GvHD of the gut might be rewarding.