Treatment of an unresectable cardiac angiosarcoma using paclitaxel and image guided radiotherapy: Case report and literature review.

Primary cardiac angiosarcomas (PCAs) are rare tumors that are typically found in the right atrium between the third and the fifth decade of life. While surgical removal of the tumor combined with adjuvant chemotherapy and/or radiotherapy is the treatment of choice, most of the patients present with unresectable tumors and metastatic disease carrying a dismal prognosis with a median survival of less than 1 year. Doxorubicin and ifosfamide based chemotherapy combined with radiotherapy is currently employed in these patients, but no standardized treatment algorithms exist. In this report, we present the management of a patient with an unresectable PCA treated using weekly paclitaxel (120 mg) combined with radiotherapy (60 Gy in 30 fractions) delivered by a helical TomoTherapy system. Follow-up imaging studies showed a remarkable tumor regression which allowed for surgical excision of the tumor 10 months post treatment. Histopathological examination of the resected mass showed no viable tumor cell. On the latest follow-up study, 12 months post treatment, no sign of disease progression (local or distant) was found, and the patient is in good clinical condition.

Prophylaxis of cancer-associated venous thromboembolism with low-molecular-weight heparin-tinzaparin: Real world evidence.

Thromboprophylaxis, as a preventive measure for cancer-associated thrombosis (CAT), may be beneficial for patients with active cancer and high-risk for thrombosis. The present post hoc analysis include a total of 407 patients enrolled in the Greek Management of Thrombosis study, who received thromboprophylaxis with tinzaparin. The objectives of the present analysis were: i) To obtain sufficient evidence for the administration of prophylaxis in patients with active cancer, irrespective of Khorana risk assessment model score; ii) to identify the selection criteria for both dose and duration of tinzaparin; and iii) to evaluate the efficacy and safety of tinzaparin administered for CAT prophylaxis. The main tumor types for the patients included in the present study were as follows: Lung (25.1%), pancreatic (14.3%), breast (9.1%), stomach (8.4%), colorectal (7.9%) and ovarian (7.6%). Furthermore, metastatic disease was observed in 69.5% of the patients. High thrombotic burden agents (HTBAs) were administered to 66.3% of the patients, and 17.4% received erythropoietin. A total of 43.7% of the patients exhibited a Khorana score <2. The results of the present study demonstrated that both the presence of metastatic disease and the use of HTBAs seemed to influence oncologists' decisions for the use of thromboprophylaxis in patients with active cancer, regardless of Khorana score. Tinzaparin, in dose expressed in the standard notation for heparins, i.e., anti-Xa factor international units (Anti-Xa IU), was administered at an intermediate dose (InterD; 8,000-12,000 Anti-Xa IU; once daily) to 52.4% of patients, while the remaining patients received a prophylactic dose (ProD; ≤4,500 Anti-Xa IU; once daily). The average duration of thromoprophylaxis was 5 months. Furthermore, a total of 14 (3.4%) thrombotic events and 6 (1.5%) minor bleeding events were recorded. A total of four thrombotic events were observed following an InterD treatment of tinzaparin, while 10 thrombotic events were observed following ProD treatment. The present study also demonstrated that an InterD of tinzaparin was administered more frequently to patients with a body mass index >30 kg/m2, a history of smoking and a history of metastatic disease, along with administration of erythropoietin. InterD tinzaparin treatment was found to be potentially more efficacious and without safety concerns. The present study is a registered clinical trial (ClinicalTrials.gov code, NCT03292107; registration date, September 25, 2017).

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma.

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

Observational Study of Clinical Practice in Patients with Pancreatic Adenocarcinoma in Greece.

BACKGROUND: During the last decade, significant improvement was made in systemic therapy of pancreatic adenocarcinoma (PAC). The impact of this progress in everyday clinical practice has not been fully described yet. The aim of the study was to investigate the pattern followed by Greek Medical Oncologists regarding the treatment of patients with PAC. METHODS: This observational, noninterventional multicenter study recorded clinical data from the files of 200 active patients (alive and under treatment or follow-up) for a two-year period (November 2015 until November 2017) from 20 oncology centers around Greece. RESULTS: In total, 51 (25.5%) patients underwent radical surgical resection of PAC, and 40 (78.4%) of them received adjuvant and 1 (2.0%) neoadjuvant chemotherapy. The median time to recurrence was 7.9 months, and median overall survival (OS), 20.2 months. First-line chemotherapy was administered to 193 (96.5%) patients. The majority of patients were treated with the combination of nab-paclitaxel-gemcitabine (NPG), 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or gemcitabine monotherapy. Of them, 39.5% responded to the treatment. Median OS and PFS were 14.1 months and 7.0 months, respectively. Second-line treatment was administered to 112 patients. The majority received NPG, FOLFIRINOX/capecitabine, oxaliplatin, irinotecan (CAPOXIRI), or 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (CAPOX). Median OS with second-line treatment was 8.6 months, and median PFS, 5.5 months. The most common chemotherapy sequences were NPG as first-line followed by FOLFIRINOX/CAPOXIRI as second-line, NPG followed by FOLFOX/CAPOX, NPG followed by other regimens, and FOLFIRINOX/CAPOXIRI followed by NPG. CONCLUSION: This study described the significant improvement in prognosis of PAC patients receiving palliative chemotherapy and the relatively high rate of receipt of second-line chemotherapy, according to real-world data. However, due to the nonrandomized nature of the study, any comparison between different chemotherapy regimens should be regarded with caution.

Real-World Data on Thromboprophylaxis in Active Cancer Patients: Where Are We? Are We Getting There?

Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the second leading cause of death in these patients but it can be preventable with thromboprophylaxis. Patients and Methods: An observational, prospective, multicenter study aiming to record CAT management in clinical practice was conducted by the Hellenic Society of Medical Oncology (HeSMO). Results: A total of 426 active cancer patients (mean age 65.3 years, mean BMI: 26.1 kg/m2) who received thromboprophylaxis, were included from 18 oncology units. Tumor types were lung 25.1%, pancreas 13.9%, breast 8.7%, stomach 8.5%, ovarian 7.8%, and others 36%, while 69% had metastases. A total of 71% had a Khorana score ≤2 and 61% received High Thrombotic Risk Chemotherapy Agents (HTRCAs, e.g., platinum). For thromboprophylaxis patients received mainly Low Molecular Weight Heparins (LMWHs), on higher than prophylactic doses in 50% of cases. Overall, 16 (3.8%) thrombotic events and 6 (1.4%) bleeding events were recorded. Notably, patients on higher doses of LMWHs compared to patients who received standard prophylactic doses had 70% lower odds to develop thrombotic events (OR: 0.3, 95% CI: 0.10-1.0, p = 0.04). Conclusion: CAT is an important issue in oncology. Along with the Khorana score, factors as metastasis and use of HTRCAs should also be taken into consideration. Thromboprophylaxis for active cancer patients with LMWHs, even on higher doses is safe and efficient.

Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative.

Background: We evaluated the association between pathogenic mutations and overall survival (OS) in patients with cancer referred to Hellenic Cooperative Oncology Group-affiliated Departments. Patients and methods: Patients referred from 12/1980 to 1/2017 had molecular testing (for research) of archival tumor tissue collected at the time of first diagnosis (non-metastatic, 81%; metastatic, 19%). Tumor-specific gene panels (16-101 genes) were used to identify pathogenic mutations in clinically relevant genes. NGS genotyping was performed at the Laboratory of Molecular Oncology, Aristotle University of Thessaloniki. Annotation of mutations was performed at MD Anderson Cancer Center. Results: We analyzed 3,084 patients (median age, 57 years; men, 22%) with sequencing data. Overall, 1,775 (58% of 3,084) patients had pathogenic mutations. The median follow-up was 7.52 years (95% CI, 7.39-7.61). In patients with non-metastatic tumors, after stratification by tumor type, increasing age, higher grade, and histology other than adenocarcinoma were associated with shorter OS. OS was also shorter in patients with pathogenic TP53 (HR=1.36; p<0.001), MLL3 (HR=1.64; p=0.005), and BRCA1 (HR=1.46; p=0.047) mutations compared to wild-type genes. In multivariate analyses, independent prognostic factors predicting shorter OS were pathogenic mutations in TP53 (HR=1.37, p=0.002) and MLL3 (HR=1.50, p=0.027); increasing age (HR=1.02, p<0.001); and increasing grade (HR=1.46, p<0.001). In patients with metastatic cancer, older age and higher grade were associated with shorter OS and maintained their independent prognostic significance (increasing age, HR=1.03, p<0.001 and higher grade, HR=1.73, p<0.001). Conclusions: Analysis of molecular data reveals prognostic biomarkers, regardless of tissue or organ of origin to improve patient management.

Management of Cancer-associated Thrombosis (CAT): Symptomatic or Incidental.

BACKGROUND: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines. PATIENTS AND METHODS: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months. RESULTS: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m2), trauma history, renal insufficiency and bevacizumab use. CONCLUSION: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning.

Clinical feasibility of NGS liquid biopsy analysis in NSCLC patients.

BACKGROUND: Analysis of circulating tumor nucleic acids in plasma of Non-Small Cell Lung Cancer (NSCLC) patients is the most widespread and documented form of "liquid biopsy" and provides real-time information on the molecular profile of the tumor without an invasive tissue biopsy. METHODS: Liquid biopsy analysis was requested by the referral physician in 121 NSCLC patients at diagnosis and was performed using a sensitive Next Generation Sequencing assay. Additionally, a comparative analysis of NSCLC patients at relapse following EGFR Tyrosine Kinase Inhibitor (TKIs) treatment was performed in 50 patients by both the cobas and NGS platforms. RESULTS: At least one mutation was identified in almost 49% of the cases by the NGS approach in NSCLC patients analyzed at diagnosis. In 36 cases with paired tissue available a high concordance of 86.11% was observed for clinically relevant mutations, with a Positive Predictive Value (PPV) of 88.89%. Furthermore, a concordance rate of 82% between cobas and the NGS approach for the EGFR sensitizing mutations (in exons 18, 19, 21) was observed in patients with acquired resistance to EGFR TKIs, while this concordance was 94% for the p.T790M mutation, with NGS being able to detect this mutation in three 3 additional patients. CONCLUSIONS: This study indicates the feasibility of circulating tumor nucleic acids (ctNA) analysis as a tumor biopsy surrogate in clinical practice for NSCLC personalized treatment decision making. The use of new sensitive NGS techniques can reliably detect tumor-derived mutations in liquid biopsy and provide clinically relevant information both before and after targeted treatment in patients with NSCLC. Thus, it could aid physicians in treatment decision making in clinical practice.

Prognostic implications of mismatch repair deficiency in patients with nonmetastatic colorectal and endometrial cancer.

BACKGROUND: The clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR deficiency in patients with stage I-III colorectal and endometrial cancer. METHODS: Patients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)'s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS). RESULTS: From May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ2, p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021). CONCLUSIONS: DMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy.

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer.

BACKGROUND: We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). METHODS: In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high - low; 412 informative). The primary outcome measure was disease-free survival (DFS). RESULTS: We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively). CONCLUSION: In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

Gemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study.

BACKGROUND: The prognosis of patients with advanced pancreatic cancer is dismal, and there is a need for novel and effective treatments. OBJECTIVES: Tο determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a novel gemcitabine (G) and temsirolimus (T) combination (phase I) and estimate the 6-month progression-free survival (PFS) in patients treated with the T + G combination (phase II). PATIENTS AND METHODS: Eligible patients with histologically confirmed inoperable or metastatic pancreatic carcinoma (MPC) were entered into the trial. G was given bi-weekly and T weekly in a 4-week cycle. The first dose level was set at G 800 mg/m2 and T 10 mg. G was escalated in increments of 200 mg/m2 and T in increments of 5 mg until DLT was reached, and the recommended dose was used for the phase II part. RESULTS: Thirty patients were enrolled in the phase I component at the pre-planned six dose levels; one bilirubin DLT of grade III occurred at the first dose level. The MTD was established as the approved doses of both drugs. Fifty-five patients were entered into the phase II component. Median relative dose intensities administered in the first cycle were 0.75 for T and 0.99 for G. Grade 3-4 hematological toxicities were recorded in 87.3% of patients. The most common non-hematological adverse events were metabolic disorders (81.8%) followed by gastrointestinal disorders (63.6%). Median PFS was 2.69 months (95% CI 1.74-4.95) and median OS was 4.95 months (95% CI 3.54-6.85), while the 6-month PFS rate was 30.9%. CONCLUSIONS: Combination of G and T is feasible in patients with locally advanced or MPC with manageable side effects, but lacks clinical efficacy. The study was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12611000643976).

Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping.

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.

Nab-paclitaxel as second-line treatment in advanced gastric cancer: a multicenter phase II study of the Hellenic Oncology Research Group.

BACKGROUND: This study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma. METHODS: Thirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days). RESULTS: Partial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22). CONCLUSION: Nab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation.

Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group.

BACKGROUND: Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer. METHODS: Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m-2 followed by four cycles of docetaxel 75 mg m-2 (sequential regimen) or six cycles of epirubicin 75 mg m-2 plus docetaxel 75 mg m-2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ⩽2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990-2.556; P=0.055). Toxicity included grade 2-4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths. CONCLUSIONS: Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease.

Lessons from the past: Long-term safety and survival outcomes of a prematurely terminated randomized controlled trial on prophylactic vs. hemoglobin-based administration of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia.

Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients WHO had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)-based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration FOR CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels <12 mg/dl at baseline and 47.9% received ESA prophylactically (1:1 randomization). The major tumor types included colorectal (36.0%), breast (20.6%), non-prostate genitourinary (11.0%) and lung CANCER (8.4%). After a median follow-up of 85.4 months, 358 patients had relapsed and 380 had succumbed to the disease. Patients in the prophylactic ESA group (GROUP A; experimental arm), as compared with those in the Hb-based group (GROUP B; iron supplementation alone), exhibited A significantly more prominent increase in median Hb levels, particularly in the subset of patients with non-metastatic disease (two-sided P<0.01) among patients receiving chemotherapy for advanced cancer, those who received ESAs prophylactically exhibited a lower incidence of CIA (all grades: P=0.014, grades 3-4: P=0.034) and fatigue (all grades: P<0.001, grades 3-4: P=0.055), but a higher rate of a composite outcome encompassing all thrombosis-related events (all grades: P=0.043, grades 3-4: P=0.099). These differences were less prominent in the group of patients who received adjuvant treatment. There were no significant differences in overall mortality and relapse/progression rates between the two groups. therefore, prophylactic, compared with Hb-based, administration of ESAs for CIA in patients with solid tumors, was found to be associated with a significantly lower incidence of anemia and fatigue, but with a marginally higher rate of thrombosis-related adverse events, particularly in patients receiving first-line chemotherapy for advanced cancer.

The use of granulocyte colony stimulating factor (G-CSF) and management of chemotherapy delivery during adjuvant treatment for early-stage breast cancer--further observations from the IMPACT solid study.

OBJECTIVE: To investigate the use and impact of granulocyte colony-stimulating factors (G-CSF) on chemotherapy delivery and neutropenia management in breast cancer in a clinical practice setting. METHODS: IMPACT Solid was an international, prospective observational study in patients with a physician-assessed febrile neutropenia (FN) risk of ≥20%. This analysis focused on stages I-III breast cancer patients who received a standard chemotherapy regimen for which the FN risk was published. Chemotherapy delivery and neutropenia-related outcomes were reported according to the FN risk of the regimen and intent of G-CSF use. RESULTS: 690 patients received a standard chemotherapy regimen; 483 received the textbook dose/schedule with a majority of these regimens (84%) having a FN risk ≥10%. Patients receiving a regimen with a FN risk ≥10% were younger with better performance status than those receiving a regimen with a FN risk <10%. Patients who received higher-risk regimens were more likely to receive G-CSF primary prophylaxis (48% vs 22%), complete their planned chemotherapy (97% vs 88%) and achieve relative dose intensity ≥85% (93% vs 86%) than those receiving lower-risk regimens. Most first FN events (56%) occurred in cycles not supported with G-CSF primary prophylaxis. CONCLUSION: Physicians generally recommend standard adjuvant chemotherapy regimens and were more likely to follow G-CSF guidelines for younger, good performance status patients in the curative setting, and often modify standard regimens in more compromised patients. However, G-CSF support is not optimal, indicated by G-CSF primary prophylaxis use in <50% of high-risk patients and observation of FN without G-CSF support.

Utilization of Systemic Chemotherapy in Advanced Urothelial Cancer: A Retrospective Collaborative Study by the Hellenic Genitourinary Cancer Group (HGUCG).

BACKGROUND: Advanced urothelial cancer (AUCa) is associated with poor long-term survival. Two major concerns are related to nonexposure to cisplatin-based chemotherapy and poor outcome after relapse. Our purpose was to record patterns of practice in AUCa in Greece, focusing on first-line treatment and management of relapsed disease. METHODS: Patients with AUCa treated from 2011 to 2013 were included in the analysis. Fitness for cisplatin was assessed by recently established criteria. RESULTS: Of 327 patients treated with first-line chemotherapy, 179 (55%) did not receive cisplatin. Criteria for unfitness for cisplatin were: Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2, 21%; creatinine clearance ≤ 60 mL/min, 55%; hearing impairment, 8%; neuropathy, 1%; and cardiac failure, 5%. Forty-six patients (27%) did not fulfill any criterion for unfitness for cisplatin. The main reasons for these deviations were comorbidities (28%) and advanced age (32%). Seventy-four (68%) of 109 patients who experienced a relapse received second-line chemotherapy. The most frequent reason for not offering second-line chemotherapy was poor PS or limited life expectancy (66%). CONCLUSION: In line with international data, approximately 50% of Greek patients with AUCa do not receive cisplatin-based chemotherapy, although 27% of them were suitable for such treatment. In addition, about one third of patients with relapse did not receive second-line chemotherapy because of poor PS or short life expectancy. Enforcing criteria for fitness for cisplatin and earlier diagnosis of relapse represent 2 targets for improvement in current treatment practice for AUCa.

Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study.

BACKGROUND: The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer. METHODS: Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors. RESULTS: PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified. CONCLUSIONS: The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.

Immune response gene expression in colorectal cancer carries distinct prognostic implications according to tissue, stage and site: a prospective retrospective translational study in the context of a hellenic cooperative oncology group randomised trial.

BACKGROUND: Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study. PATIENTS AND METHODS: Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa. RESULTS: Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC. CONCLUSIONS: In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression. TRIAL REGISTRATION: ANZCTR.org.au ACTRN12610000509066.

Impact of tumor angiogenic profile on the outcome of patients with metastatic breast carcinoma treated with weekly docetaxel. A Hellenic Cooperative Oncology Group (HeCOG) study.

BACKGROUND: Metronomic taxane administration has putative antiangiogenic properties. Herein, we examined the baseline tumor angiogenic profile of patients with metastatic breast carcinoma (MBC) in a prospective-retrospective translational research study. The interplay between the angiogenic factors expressed in the tumors and their prognostic value in MBC were investigated. PATIENTS AND METHODS: Tumor tissues from patients with MBC treated with weekly docetaxel (n=159) were examined by immunohistochemistry for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, VEGFR-3 and osteopontin (OPN) and by mRNA analysis for expression of VEGF-A, VEGFxxxa, VEGFxxxb, VEGF-C, thrombospondin-1 (THBS-1), hypoxia-inducible factor-1α (HIF-1α) and von Hippel-Lindau (VHL) genes. Associations between these parameters and outcome were statistically analyzed. RESULTS: Statistically significant correlations were identified between almost all biomarkers examined in continuous form, particularly at the mRNA level: VEGF-A with VEGFxxxa (rho=0.70); VEGF-C with VEGFxxxa, VEGFxxxb and VHL (rho=0.51, 0.60 and 0.44 respectively); HIF-1α with VEGF-C and THBS1 (rho= 0.48 and 0.45). High VEGF-A mRNA was associated with worse survival (p=0.0279) and marginally with progression free survival (PFS). Intratumoral co-expression of VEGFR-1 and VEGFR-2 proteins was associated with more favorable survival (p=0.0337). In multivariate analysis, only high VEGF-A mRNA levels retained their prognostic role for worse PFS and survival (PFS: HR=2.34, 95% CI=1.25-4.40, p=0.0080; survival: HR=3.15, 95% CI=1.48-6.72, p=0.0029). CONCLUSIONS: In MBC, this study confirms the adverse prognostic effect of high intratumoral VEGF-A mRNA and reveals the combined VEGFR-1/VEGFR-2 protein expression as a potentially favorable prognosticator, which merits further evaluation in larger studies.