Thomas Makatsoris

Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature

Commonly used chemotherapeutic agents in oncology/hematology practice, causing toxic peripheral neuropathy, include taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. This review paper intends to put together and discuss the spectrum of chemotherapy-induced peripheral neuropathy (CIPN) characteristics so as to highlight areas of future research to pursue on the topic. Current knowledge shows that the pathogenesis of CIPN still remains elusive, mostly because there are several sites of involvement in the peripheral nervous system. In any case, it is acknowledged that the dorsal root ganglia of the primary sensory neurons are the most common neural targets of CIPN. Both the incidence and severity of CIPN are clinically under- and misreported, and it has been demonstrated that scoring CIPN with common toxicity scales is associated with significant inter-observer variability. Only a proportion of chemotherapy-treated patients develop treatment-emergent and persistent CIPN, and to date it has been impossible to predict high-and low-risk subjects even within groups who receive the same drug regimen. This issue has recently been investigated in the context of pharmacogenetic analyses, but these studies have not implemented a proper methodological approach and their results are inconsistent and not really clinically relevant. As such, a stringent approach has to be implemented to validate that information. Another open issue is that, at present, there is insufficient evidence to support the use of any of the already tested chemoprotective agents to prevent or limit CIPN. The results of comprehensive interventions, including clinical, neurophysiological, and pharmacogenetic approaches, are expected to produce a consistent advantage for both doctors and patients and thus allow the registration and analysis of reliable data on the true characteristics of CIPN, eventually leading to potential preventive and therapeutic interventions.

Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

BackgroundMore than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy.MethodsPreviously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA.ResultsOnly PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).ConclusionsBRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.

Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer

Aim. The current prospective study sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical and electrophysiological pattern. Patients and methods. Twenty-five adult patients scheduled to be treated with 12 courses of the oxaliplatin-based regimen, FOLFOX-4, for metastatic colon cancer participated in this study. Patients were clinically and electrophysiologically monitored at baseline and followed-up during chemotherapy. The severity of OXLIPN was summarized by means of a modified Total Neuropathy Score (TNS). Results. Evidence of OXLIPN was disclosed in 16 of the 25 patients (64%). The mean TNS values for patients manifesting some grade of OXLIPN were 13.9±5.8 (range 7–28). All longitudinal comparisons concerning the motor conduction parameters failed to reach significance. By contrast, comparisons of the median changes at baseline and each of the follow-up studies revealed significant decrease in all sensory action potentials examined. Conclusion. Our results indicate that the majority of patients treated with the FOLFOX-4 regimen would manifest an axonal, predominately sensory peripheral neuropathy, of mild to moderate severity.

Oxaliplatin-Induced Acute-Onset Thrombocytopenia, Hemorrhage and Hemolysis

Background: Oxaliplatin is a novel platinum derivative with established anti-tumor activity in colorectal cancer. Acute-onset hemolytic anemia and thrombocytopenia associated with this drug have rarely been reported and some of these cases have been severe or even fatal. Case Report: This case report describes a patient who developed fever, chills, abdominal and back pain as well as sudden-onset severe thrombocytopenia, upper gastrointestinal bleeding and hemolysis immediately after treatment with oxaliplatin for metastatic colorectal cancer. The reaction appeared during the 14th cycle of chemotherapy. Corticosteroids and antihistamines were administered together with platelet transfusions. Over the next 2 days platelet count improved and the syndrome abated. The patient was discharged 4 days later. Furthermore, the reaction was accompanied by a strongly positive Coombs test and increased TNF-α and IL-10 serum levels which returned to normal following anti-inflammatory drug administration. Conclusion: Physicians should be aware of the possibility of acute hematological emergencies following oxaliplatin administration.

XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis

BackgroundThe aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer.MethodsPatients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-β1 and VEGF-A were measured at baseline and during treatment.ResultsAmong 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3–4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS.ConclusionsThis trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. (Registration number: ACTRN12610000270011)

Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG) Study

BACKGROUND The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. METHODS Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. RESULTS High UBE2C mRNA expression was associated with poor DFS (Walds P = 0.003) and OS (Walds P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). CONCLUSIONS High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts.

Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression.

UNLABELLED The CXCL13-CXCR5 is a chemokine axis that is activated in some breast cancers. A total of 321 tissue blocks from a group of patients who received adjuvant, dose-dense chemotherapy for high-risk early breast cancer were examined. Activation of this axis was found to be associated with determinants of poor prognosis but also with improved outcome in the human epidermal growth factor receptor 2 overexpressing subpopulation. BACKGROUND Chemokines are important in cell migration and are thought to play a key role in metastasis. We explored the prognostic significance of C-X-C ligand-motif (CXCL) 12, CXCL13, and receptor (CXCR) 5 on disease-free survival (DFS) and overall survival (OS) in early breast cancer. METHODS A total of 595 patients with high risk, [corrected] early breast cancer were treated in a 2-arm trial (HE10/97) with dose-dense sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without paclitaxel. RNA was extracted from 321 formalin-fixed paraffin-embedded primary tumor tissue samples and quantitative reverse-transcriptase polymerase chain reaction was used to assess messenger RNA (mRNA) expression of CXCL12, CXCL13, and CXCR5; estrogen receptor; progesterone receptor (PgR); microtubule-associated protein tau and human epidermal growth factor receptor 2 (HER2). RESULTS CXCL13 and CXCR5 were found to be negatively associated with estrogen receptor and microtubule-associated protein tau mRNA expression and with dense lymphocytic infiltration, and were positively associated with nuclear grade. Only CXCL13 was positively associated with HER2. Multivariate analysis revealed an association between high CXCL13 mRNA expression and improved DFS (hazard ratio [HR] 0.48 [95% CI, 0.25-0.90]; Wald, P = .023) but not OS; whereas high CXCL12 expression was significantly associated with increased OS (HR 0.53 [95% CI, 0.33-0.85]; Wald, P = .009). In the HER2 mRNA overexpressing subgroup, high CXCL13 mRNA expression was associated with improved DFS (P < .001), whereas high CXCR5 was associated with increased DFS and OS (P = .004 and P = .049, respectively). CONCLUSIONS The CXCL13-CXCR5 axis is associated with classic determinants of poor prognosis, such as high grade, hormone receptor negativity, and axillary node involvement. Interestingly, this chemokine axis seems to be strongly associated with improved outcome in patients with HER2(+) disease.

The potential role of TGFbeta1, TGFbeta2 and TGFbeta3 protein expression in colorectal carcinomas. Correlation with classic histopathologic factors and patient survival.

Purpose:This study investigates the expression of tumor growth factors TGFβ1, TGFβ2 and TGFβ3 in tissue material from patients with colorectal carcinoma and evaluates their correlation with known prognostic markers and patient survival.Patients and Methods:The study included 124 patients with colorectal carcinoma. According to the TNM classification of malignant tumors, 26 tumors were identified as being stage I, 30 stage II, 48 stage III, and 20 stage IV, whereas 106 tumors were low-grade and 18 high-grade malignancies. On paraffin sections, the streptavidin-biotin technique using antibodies against TGFβ1, TGFβ2 and TGFβ3 was applied. Morphological and immunohistochemical results were correlated with clinicopathologic parameters.Results:TGFβ1 protein was expressed in 88 out of 124 (71%) carcinomas, whereas TGFβ2 and TGFβ3 proteins were detected in all tumors examined. Normal colonic mucosal epithelial cells expressed TGFβ2 (significantly less as compared to neoplastic cells; p < 0.01) and TGFβ3 (p > 0.05 compared to neoplastic cells), but not TGFβ1. Statistical analysis revealed a higher expression of TGFβ1 in low-grade carcinomas (p = 0.009) and a higher presence of TGFβ2 in advanced tumors (p = 0.008). TGFβ1 expression was related with increased disease-free and overall survival (p < 0.05 each). The presence of TGFβ2 was correlated with worse prognosis (p < 0.05). Cox analysis revealed that besides tumor grade and stage, TGFβ1 expression constituted an independent prognostic factor.Conclusion:This study shows that in adenocarcinomas of the colon, there is a differential expression of TGFβ1, TGFβ2 and TGF3. TGFβ1 may be implicated in the pathogenesis of these tumors, since it is expressed only in neoplastic but not in normal cells. TGFβ1 is related with an increased disease-free and overall survival and constitutes an independent prognostic factor. In advanced stages, TGFβ2 seems to be involved in tumor progression and is related with worse prognosis.Ziel:Diese Studie untersuchte die Expression der Tumorwachstumsfaktoren TGFβ1, TGFβ2 and TGFβ3 in Gewebeproben von Patienten mit kolorektalen Karzinomen und prüfte ihre Korrelation mit bekannten prognostischen Markern und mit dem Überleben der Patienten.Patienten und Methodik:Die Studie umfasste 124 Patienten mit kolorektalen Karzinomen. Nach der TNM-Klassifikation wurden 26 Tumoren als Stadium I, 30 als Stadium II, 48 als Stadium III und 20 als Stadium IV eingeordnet, während 106 Tumoren Low-Grade- und 18 High-Grade-Malignome waren. Paraffinschnittpräparate wurden nach der Streptavidin-Biotin-Methode mit Antikörpern gegen TGFβ1, TGFβ2 und TGFβ3 behandelt. Die morphologischen und immunhistochemischen Befunde wurden mit klinisch-pathologischen Parametern korreliert.Ergebnisse:TGFβ1 wurde in 88 von 124 (71%) Karzinomen exprimiert, während TGFβ2 und TGFβ3 in allen untersuchten Tumoren gefunden wurden. Normale Epithelzellen der Dickdarmschleimhaut exprimierten TGFβ2 (signifikant weniger verglichen mit neoplastischen Zellen; p < 0,01) und TGFβ3 (p > 0,05 verglichen mit neoplastischen Zellen), aber kein TGFβ1. Die statistische Analyse ergab stärkere TGFβ1-Expression in Low-Grade-Karzinomen (p = 0,009) und eine verstärkte Präsenz von TGF2 in fortgeschrittenen Tumoren (p = 0,008). Die TGFβ1-Expression korrelierte mit verlängertem krankheitsfreien und Gesamtüberleben (jeweils p < 0,05). Das Vorliegen von TGFβ2 korrelierte mit schlechterer Prognose (p < 0,05). Die Cox-Analyse ergab, dass neben Tumorgrad und -stadium die TGFβ1-Expression einen unabhängigen prognostischen Faktor darstellte.Schlussfolgerung:Diese Studie zeigt für Adenokarzinome des Kolons und Rektums Unterschiede in der Expression von TGFβ1, TGFβ2 und TGFβ3. TGFβ1 könnte in der Pathogenese dieser Tumoren eine Rolle spielen, da es nur in neoplastischen, nicht aber in normalen Zellen exprimiert wird. TGFβ1 geht mit verlängertem krankheitsfreien und Gesamtüberleben einher und ist ein unabhängiger prognostischer Faktor. In fortgeschrittenen Stadien scheint TGFβ2 für die Tumorprogression relevant zu sein und ist mit einer schlechteren Prognose verbunden.

A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study

BackgroundPlatinum-based combinations are the standard second-line treatment for platinum-sensitive ovarian cancer (OC). This randomized phase II study was undertaken in order to compare the combination of carboplatin and pegylated liposomal doxorubicin (LD) with carboplatin and paclitaxel (CP) in this setting.MethodsPatients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21) or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28).ResultsA total of 189 eligible patients (CP 96, CLD 93), with a median age of 63 years, median Performance Status (PS) 0 and a median platinum free interval (PFI) of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016). The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23%) and there was no statistical difference in time-to-progression (TTP) or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454). No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%). More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016), skin toxicity and Palmar-plantar erythrodysesthesia (PPE) grade 1-2 (38% versus 9%, P< 0.001), while grade 3 neurotoxicity and alopecia were higher in CP (7% versus 0%, P = 0.029, 20% versus 5%, P = 0.003). PS and PFI were independent prognostic factors for TTP and OS.ConclusionsThe combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients.Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12609000436279

Induction chemotherapy with cisplatin, epirubicin, and paclitaxel (CEP), followed by concomitant radiotherapy and weekly paclitaxel for the management of locally advanced nasopharyngeal carcinoma. A Hellenic Cooperative Oncology Group phase II study.

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.