Efficacy of Lapatinib in Patients with HER2-Negative Metastatic Breast Cancer and HER2-Positive Circulating Tumor Cells-The DETECT III Clinical Trial.

BACKGROUND: The phenotypes of tumor cells change during disease progression, but invasive rebiopsies of metastatic lesions are not always feasible. Here we aimed to determine whether initially HER2-negative metastatic breast cancer (MBC) patients with HER2-positive circulating tumor cells (CTCs) benefit from a HER2-targeted therapy. METHODS: The open-label, interventional randomized phase III clinical trial (EudraCT Number 2010-024238-46, CliniclTrials.gov Identifier: NCT01619111) recruited from March 2012 until September 2019 with a follow-up duration of 19.5 months. It was a multicenter clinical trial with 94 participating German study centers. A total of 2137 patients with HER2-negative MBC were screened for HER2-positive CTCs with a final modified intention-to-treat population of 101 patients. Eligible patients were randomized to standard therapy with or without lapatinib. Primary study endpoints included CTC clearance (no CTCs at the end of treatment) and secondary endpoints were progression-free survival, overall survival (OS), and safety. RESULTS: In both treatment arms CTC clearance at first follow-up visit-although not being significantly different for both arms at any time point-was significantly associated with improved OS (42.4 vs 14.1 months; P = 0.002). Patients treated additionally with lapatinib had a significantly improved OS over patients receiving standard treatment (20.5 vs 9.1 months, P = 0.009). CONCLUSIONS: DETECT III is the first clinical study indicating that phenotyping of CTCs might have clinical utility for stratification of MBC cancer patients to HER2-targeting therapies. The OS benefit could be related to lapatinib, but further studies are required to prove this clinical observation. ClinicalTrials.gov Registration Number: NCT01619111.

Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic colorectal cancer: Subgroup analysis of patients treated within the PanaMa trial (AIO KRK 0212).

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.

Fast and label-free automated detection of microsatellite status in early colon cancer using artificial intelligence integrated infrared imaging.

PURPOSE: Microsatellite instability (MSI) due to mismatch repair (MMR) defects accounts for 15-20% of colon cancers (CC). MSI testing is currently standard of care in CC with immunohistochemistry of the four MMR proteins representing the gold standard. Instead, label-free quantum cascade laser (QCL) based infrared (IR) imaging combined with artificial intelligence (AI) may classify MSI/microsatellite stability (MSS) in unstained tissue sections user-independently and tissue preserving. METHODS: Paraffin-embedded unstained tissue sections of early CC from patients participating in the multicentre AIO ColoPredict Plus (CPP) 2.0 registry were analysed after dividing into three groups (training, test, and validation). IR images of tissue sections using QCL-IR microscopes were classified by AI (convolutional neural networks [CNN]) using a two-step approach. The first CNN (modified U-Net) detected areas of cancer while the second CNN (VGG-Net) classified MSI/MSS. End-points were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). RESULTS: The cancer detection in the first step was based on 629 patients (train n = 273, test n = 138, and validation n = 218). Resulting classification AUROC was 1.0 for the validation dataset. The second step classifying MSI/MSS was performed on 547 patients (train n = 331, test n = 69, and validation n = 147) reaching AUROC and AUPRC of 0.9 and 0.74, respectively, for the validation cohort. CONCLUSION: Our novel label-free digital pathology approach accurately and rapidly classifies MSI vs. MSS. The tissue sections analysed were not processed leaving the sample unmodified for subsequent analyses. Our approach demonstrates an AI-based decision support tool potentially driving improved patient stratification and precision oncology in the future.

Depth of response of induction therapy and consecutive maintenance treatment in patients with RAS wild-type metastatic colorectal cancer: An analysis of the PanaMa trial (AIO KRK 0212).

BACKGROUND: In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. METHODS: Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (

Causes of mortality in elderly UICC stage III colon cancer (CC) patients--Tumor-related death and competing risks from the German AIO colorectal study group Colopredict Plus (CPP) registry.

BACKGROUND: Colon cancer (CC) is a disease of elderly patients (pts.) with a median age of 73 years (yrs.). Lack of data about the effects of adjuvant chemotherapy (ACT) is caused by underrepresentation of this clinically relevant cohort in interventional trials. We analyzed real-world data from the German CPP registry with regard to a possible benefit of ACT in elderly (70+ yrs.) versus younger pts. (50 to <70 yrs.) taking cause-specific deaths into account. METHODS: We analyzed the effect of age and ACT on overall survival (OS) and cause-specific death of stage III pts. using Cox regression. RESULTS: In total, 1558 pts. were analyzed and follow-up was 24.6 months. 62.6% of the elderly received ACT whereas 91.1% of younger pts. (p < 0.001). Oxaliplatin combinations were significantly less often given to older than younger pts. (38.8% vs. 88.9%; p < 0.001). Mean Charlson comorbidity score was significantly lower in pts. that received ACT (0.61) than in those without ACT (1.16; p < 0.001). ACT was an independent positive prognostic factor for cancer-related death in elderly pts. even in pts. 75+ yrs. No significant difference in the effect of ACT could be observed between age groups (interaction: cancer-specific death HR = 1.7948, p = 0.1079; death of other cause HR = 0.7384, p = 0.6705). CONCLUSION: ACT was an independent positive prognostic factor for OS. There may be a cohort of elderly with less co-morbidities who benefit from ACT.

High microsatellite instability (MSI-H) is associated with distinct clinical and molecular characteristics and an improved survival in early Colon cancer (CC); real world data from the AIO molecular registry Colopredict Plus.

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.

Randomised phase II trial of trofosfamide vs. doxorubicin in elderly patients with untreated metastatic soft-tissue sarcoma.

Doxorubicin represents the standard first-line treatment for metastatic soft-tissue sarcoma. We assessed the efficacy and safety of trofosfamide in elderly patients. In this controlled phase II trial, we randomly (1:2) assigned 120 previously untreated patients with soft-tissue sarcoma, older than 60 years, with an Eastern Cooperative Oncology Group score of 0-2, to receive either doxorubicin for 6 cycles (arm A) or oral trofosfamide (arm B). The primary end-point was a 6-month progression-free rate (PFR) in the experimental arm (clinical trial information: NCT00204568). Between August 2004 and October 2012, forty and 80 patients were randomly assigned to arm A and arm B, respectively, in 16 centres. The median age was 70 years (range, 60-89). The primary study end-point (6-month PFR) was exceeded, with 27.6% in arm B (95% confidence interval [CI], 18.0-39.1) and 35.9% in arm A: (95% CI, 21.2-52.8). Survival data in terms of progression-free survival were 4.3 months (95% CI, 2.2-6.3) and 2.8 months (95% CI, 1.7-3.6) and in terms of overall survival were 9.8 months (95% CI, 6.7-11.6) and 12.3 months (95% CI, 9.6-16.2), respectively. The number of serious adverse event (SAE) was 59% in arm A and 30.3% in arm B (p = 0.005). Trofosfamide caused more often dyspnoea and low-grade fatigue, whereas with doxorubicin, more often leukocytopenia, neutropenia and mucositis were seen. Discontinuation rates for reasons other than disease progression were 15.4% (arm A) vs. 7.9% (arm B). In an elderly population of patients, oral trofosfamide achieved the estimated primary end-point 6-month PFR and was associated with a favourable toxicity profile compared with doxorubicin.

EORTC-1203-GITCG - the "INNOVATION"-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group.

BACKGROUND: 10-20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperative CT for localized HER2+ GC. METHODS: This is a prospective, randomized, open-label, phase II trial. HER2 status from patients with resectable GC (UICC TNM7 tumor stage Ib-III) will be centrally determined. Two hundred and-fifteen patients from 52 sites in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms: 1. Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator's choice in Europe, and cisplatin/capecitabine in Asia. 2. Experimental arm 1: CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery. 3. Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1. Adjuvant treatment with T or T + P will continue for 17 cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P. DISCUSSION: Depending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC. TRIAL REGISTRATION: This article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: NCT02205047 ; EudraCT: 2014-000722-38.

Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice.

BACKGROUND: Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. PATIENTS AND METHODS: A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. RESULTS: The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. CONCLUSION: Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.

Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. METHODS: For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m(2), day 1) plus either bendamustine (90 mg/m(2), days 1 and 2) or fludarabine (25 mg/m(2), days 1-3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0-2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m(2) every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing). FINDINGS: Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0·76 (95% CI 0·68-0·84) and 0·48 (0·39-0·58) with fludarabine plus rituximab (non-inferiority p<0·0001). At a median follow-up of 96 months (IQR 73·2-112·9), median progression-free survival with bendamustine plus rituximab was 34·2 months (95% CI 23·5-52·7) and 11·7 months (8·0-16·1) with fludarabine plus rituximab (hazard ratio [HR] 0·54 [95% CI 0·38-0·72], log-rank test p<0·0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections. INTERPRETATION: In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. FUNDING: Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).

Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group.

PURPOSE: Weekly administration of topotecan (Tw) is less toxic and widely considered a better treatment option than conventional 5-day therapy (Tc) in women with platinum-resistant recurrent ovarian cancer. We conducted a randomized phase II trial (TOWER [Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer]) to better define the ratio between benefits and risks with either treatment approach. PATIENTS AND METHODS: Patients were randomly assigned to two independent two-stage protocols of Tw (4 mg/m(2)/wk administered on days 1, 8, and 15) or Tc (1.25 mg/m(2)/d on days 1 to 5). We evaluated risk ratios (RRs) for the primary end point of clinical benefit (complete response, partial response, and stable disease), the duration of progression-free survival (PFS) and overall survival (OS), associated hazard ratios (HRs), and RRs of toxicity with 95% CIs. RESULTS: In total, 194 patients were randomly assigned at 54 centers to Tw (n = 97) or Tc (n = 97). Clinical benefit was observed in 36 of 76 (47%; 95% CI, 36% to 59%) Tw and 46 of 80 (58%; 95% CI, 46% to 68%) Tc patients (RR, 1.21; 95% CI, 0.90 to 1.64; P = .205). Patients in the Tw group had a slightly shorter PFS (HR, 1.29; 95% CI, 0.96 to 1.76) but similar OS (HR, 1.04; 95% CI, 0.74 to 1.45) compared with Tc. Tw was associated with significantly lower risks of anemia (RR, 0.35; 95% CI, 0.16 to 0.79), neutropenia (RR, 0.38; 95% CI, 0.23 to 0.65), and thrombocytopenia (RR, 0.23; 95% CI, 0.09 to 0.57). CONCLUSION: With regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.

A combination of cytomorphology, cytogenetic analysis, fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction for establishing clonality in cases of persisting hypereosinophilia.

To evaluate the frequency of clonal abnormalities in patients with unexplained persisting eosinophilia we analyzed 40 patients (27 males, 13 females) using cytomorphology, cytogenetic analysis, interphase fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR). Cytogenetic analysis revealed clonal abnormalities in five patients (four of whom were males) including t(8;9)(p21;p24), ins(9;4)(q34;q12q31), del(6)(q24), and trisomy 8 (n=2). RT-PCR confirmed a PCM1-JAK2 fusion underlying the t(8;9). FISH analysis suggested a rearrangement involving PDGFRA in the ins(9;4). A FIP1L1-PDGFRA fusion gene was identified in four male patients by interphase FISH and RT-PCR. These methods in combination demonstrated clonality in 8/40 patients (20%) with a male predominance (6/8; 75%).