Efficacy and quality of life for FOLFOX/bevacizumab +/- irinotecan in first-line metastatic colorectal cancer-final results of the AIO CHARTA trial.

BACKGROUND: FOLFOXIRI plus bevacizumab has demonstrated benefits for metastatic colorectal cancer (mCRC) patients. However, challenges arise in its clinical implementation due to expected side effects and a lack of stratification criteria. METHODS: The AIO "CHARTA" trial randomised mCRC patients into clinical Group 1 (potentially resectable), 2 (unresectable/risk of rapid progression), or 3 (asymptomatic). They received FOLFOX/bevacizumab +/- irinotecan. The primary endpoint was the 9-month progression-free survival rate (PFSR@9). Secondary endpoints included efficacy in stratified groups, QoL, PFS, OS, ORR, secondary resection rate, and toxicity. RESULTS: The addition of irinotecan to FOLFOX/bevacizumab increased PFSR@9 from 56 to 67%, meeting the primary endpoint. The objective response rate was 61% vs. 69% (P = 0.21) and median PFS was 10.3 vs. 12 months (HR 0.83; P = 0.17). The PFS was (11.4 vs. 12.9 months; HR 0.83; P = 0.46) in potentially resectable patients, with a secondary resection rate of 37% vs. 51%. Moreover, Group 3 (asymptomatic) patients had a PFS of 11.1 vs. 16.1 months (HR 0.6; P = 0.14). The addition of irinotecan did not diminish QoL. CONCLUSION: The CHARTA trial, along with other studies, confirms the efficacy and tolerability of FOLFOXIRI/bevacizumab as a first-line treatment for mCRC. Importantly, clinical stratification may lead to its implementation. TRIAL REGISTRATION: The trial was registered as NCT01321957.

Diagnosis and treatment of MPN in real life: exploratory and retrospective chart review including 960 MPN patients diagnosed with ET or MF in Germany.

PURPOSE: The WHO 2016 re-classification of myeloproliferative neoplasms resulted in a separation of essential thrombocythemia (ET) from the pre-fibrotic and fibrotic (overt) phases of primary myelofibrosis (MF). This study reports on a chart review conducted to evaluate the real life approach regarding clinical characteristics, diagnostic assessment, risk stratification and treatment decisions for MPN patients classified as ET or MF after implementation of the WHO 2016 classification. METHODS: In this retrospective chart review, 31 office-based hematologists/oncologists and primary care centers in Germany participated between April 2021 and May 2022. Physicians reported available data obtained from patient charts via paper-pencil based survey (secondary use of data). Patient features were evaluated using descriptive analysis, also including diagnostic assessment, therapeutic strategies and risk stratification. RESULTS: Data of 960 MPN patients diagnosed with essential thrombocythemia (ET) (n = 495) or myelofibrosis (MF) (n = 465) after implementation of the revised 2016 WHO classification of myeloid neoplasms was collected from the patient charts. While they met at least one minor WHO-criteria for primary myelofibrosis, 39.8% of those diagnosed with ET did not have histological BM testing at diagnosis. 63.4% of patients who were classified as having MF, however, did not obtain an early prognostic risk assessment. More than 50% of MF patients showed characteristics consistent with the pre-fibrotic phase, which was emphasized by the frequent use of cytoreductive therapy. Hydroxyurea was the most frequently used cytoreductive medication in 84.7% of ET and 53.1% of MF patients. While both ET and MF cohorts showed cardiovascular risk factors in more than 2/3 of the cases, the use of platelet inhibitors or anticoagulants varied between 56.8% in ET and 38.1% in MF patients. CONCLUSIONS: Improved histopathologic diagnostics, dynamic risk stratification including genetic risk factors for cases of suspected ET and MF are recommended for precise risk assessment and therapeutic stratification according to WHO criteria.

Nintedanib plus mFOLFOX6 as second-line treatment of metastatic, chemorefractory colorectal cancer: The randomised, placebo-controlled, phase II TRICC-C study (AIO-KRK-0111).

Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-3 and platelet-derived growth factor receptor-a/-b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC-C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC-C is a randomised controlled, double-blinded, phase II trial in mCRC patients that received a first-line non-oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1-d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty-three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32-1.30; P = .2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48-2.23; P = .9387; DCR: F + P: 50% vs F + N: 66,7%; P = .2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second-line therapy of mCRC.

Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD.

PURPOSE: The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer. METHODS: Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763). RESULTS: A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) v 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% v 37.3% and 23.4% v 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; P = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% v 65.5% (HR, 1.02) and OS of 73.5% v 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis. CONCLUSION: The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study).

OBJECTIVE: Azacitidine (Vidaza® ) is the standard treatment for patients with higher-risk myelodysplastic syndromes (MDS) not eligible for allogeneic stem cell transplantation. In the noninterventional study PIAZA, we evaluated the effectiveness and safety of azacitidine treatment in 149 patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) in routine clinical practice. METHOD: Patients were treated according to physician's discretion. Besides evaluation of safety and effectiveness, impact of covariates on progression-free survival (PFS) was assessed. RESULTS: Median age of patients was 75 years. 61.1% of patients were diagnosed with MDS, 31.5% with AML and 7.4% with CMML. Patients were treated with azacitidine for a median of seven cycles. Median PFS was 10.9 months. Median OS was 14.1 months. Two-year survival rate was 28.9%. 45.9% of patients showed CR or PR. Stable and progressive disease were observed in 37.2% and 8% of patients, respectively. Transfusion independence was reported in 64 of 89 patients. Eastern cooperative oncology group (ECOG) performance status (PS) and red blood cell (RBC) transfusion before azacitidine therapy were identified as predictive factors for PFS. CONCLUSION: In conclusion, we estimated the duration of PFS in a real-world setting and identified ECOG PS and RBC transfusion as predictive factors for PFS. The safety of azacitidine showed a similar profile as demonstrated in the pivotal clinical trials.

AIO LQ-0110: a randomized phase II trial comparing oral doxycycline versus local administration of erythromycin as preemptive treatment strategies of panitumumab-mediated skin toxicity in patients with metastatic colorectal cancer.

BACKGROUND: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. PATIENTS AND METHODS: In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). RESULTS: In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm (P = n.s.). However, as per WoMo score significantly more patients in the erythromycin arm developed moderate or severe skin toxicity at earlier time points. Skin related and overall quality of life was comparable between both arms. CONCLUSIONS: Based on this data erythromycin cannot be regarded as an alternative to doxycycline as prevention of EGFR-related skin toxicity.

Neoadjuvant Chemotherapy with Docetaxel, Carboplatin and Weekly Trastuzumab Is Active in HER2-Positive Early Breast Cancer: Results after a Median Follow-Up of over 4 Years.

INTRODUCTION: Most patients with HER2-positive breast cancer receive chemotherapy and trastuzumab. Data from adjuvant trials have shown that the combination of docetaxel, carboplatin and weekly trastuzumab (TCH) is well tolerated and as effective as anthracycline-containing regimes. Previous investigations on neoadjuvant treatment with taxanes, platinum salts and trastuzumab showed pathological complete remission (pCR) rates between 43.3 and 76%. To date, the longest published follow-up in this indication is 3 years. Here we present 4-year follow-up data for a cohort of 78 patients treated with neoadjuvant TCH. METHODS: Between 2009 and 2014 we treated 78 patients with operable HER2-positive breast cancer with a neoadjuvant schedule of docetaxel (75 mg/m2) and carboplatin (AUC 6) every 3 weeks (q3w) and trastuzumab (4 mg/kg loading dose then 2 mg/kg) q1w. Lymph node involvement was verified by sentinel lymph node or core-cut biopsy. Patients were diagnosed at a mean age of 55.5 years; 65.4% had hormone receptor-positive tumors, 34.6% presented with grade 3 disease and 51.3% of patients were node positive. Patients were monitored every 2 cycles by ultrasound. After 6 cycles of chemotherapy all patients had surgery. Axillary dissection was performed in case of positive lymph node status prior to TCH. After surgery, trastuzumab was continued q3w up to 1 year. RESULTS: No grade III/IV toxicities occurred and no case of congestive heart failure was observed. Neither dose modifications nor dose delays were necessary. 34 of the 78 patients (43.6%) achieved a pCR, 27 of the 40 node-positive patients (67.5%) experienced nodal conversion. After a median follow up of 48.5 months the disease-free survival (DFS) was 84.6%, the distant disease-free survival (DDFS) was 87.2% and the overall survival (OS) was 91%. Only T stage and nodal status at baseline were found to be significantly associated with survival estimates. CONCLUSION: The anthracycline-free regimen TCH is effective and safe in the neoadjuvant therapy of HER2-positive breast cancer, yielding DFS, DDFS and OS probabilities comparable to the results of adjuvant trials. Our data support the use of TCH as a neoadjuvant therapy regimen for patients with HER2-positive breast cancer. They also strongly encourage the use of taxanes and platinum salts as the chemotherapy backbone in studies investigating dual blockade with trastuzumab and pertuzumab in the neoadjuvant setting.

Sequential chemotherapies for advanced gastric cancer: a retrospective analysis of 111 patients.

BACKGROUND: The role of second-line chemotherapy in advanced gastric cancer is not yet fully established. PATIENTS AND METHODS: We analysed 111 patients with advanced gastric cancer treated at the University Hospital Heidelberg (51) and the private oncology practice Bottrop/Dorsten (60) between 2001 and 2011, comparing the outcome of patients with first-line chemotherapy and those who received second-line chemotherapy. RESULTS: Thirty-six patients were treated with one chemotherapy regimen, 75 patients received at least two different chemotherapies. Patients who received one chemotherapy regimen were older (median age 69 years) and had a shorter overall survival (6 months) than patients receiving sequential chemotherapies [median age 61 years, p = 0.009, overall survival 14 months (2-42), p = 0.001]. Under second-line chemotherapy, partial response was observed in 25 patients (33%) and stable disease for ≥3 months in 26 patients (35%). Patients treated before 2005 had a slightly better overall survival than patients treated in or after 2005. Survival was not influenced by the treatment centre (primary or tertiary), but was influenced by former surgery. CONCLUSION: The prognosis of advanced gastric cancer is still poor. Selected patients may benefit from individualized salvage chemotherapy after failure of first-line chemotherapy.