Angelos Koutras

Docetaxel and Cisplatin With Granulocyte Colony-Stimulating Factor (G-CSF) Versus MVAC With G-CSF in Advanced Urothelial Carcinoma: A Multicenter, Randomized, Phase III Study From the Hellenic Cooperative Oncology Group

PURPOSE The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. PATIENTS AND METHODS Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status < or = 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. RESULT Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P =.017), median time to progression (TTP; 9.4 v 6.1 months; P =.003) and median survival (14.2 v 9.3 months; P =.026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P =.005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P =.089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P =.006), thrombocytopenia (5.7% v 0.9%; P =.046), and neutropenic sepsis (11.6% v 3.8%; P =.001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. CONCLUSION MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.

Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial

Background: The authors conducted a pilot, randomized, open label with blind assessment, controlled trial to determine whether vitamin E supplementation has a neuroprotective effect in chemotherapy-induced peripheral nerve damage. Methods: Thirty-one patients with cancer treated with six courses of cumulative cisplatin, paclitaxel, or their combination regimens were randomly assigned in two groups and followed by neurologic examination and electrophysiologic study. Patients assigned in Group I (n = 16) received oral vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its cessation were compared to patients of Group II (n = 15), who received no supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified peripheral neuropathy score. Results: The incidence of neurotoxicity differed between the two groups, occurring in 4/16 (25%) patients assigned in the vitamin E supplementation group and in 11/15 (73.3%) patients assigned in the control group (p = 0.019). Mean peripheral neuropathy scores were 3.4 ± 6.3 for patients of Group I and 11.5 ± 10.6 for patients of Group II (p = 0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of control patients, RR = 0.34, 95% CI = 0.14 to 0.84. Conclusion: Vitamin E supplementation in cancer patients may have an important neuroprotective effect.

Prospective assessment of emotional distress, cognitive function, and quality of life in patients with cancer treated with chemotherapy

The current study sought to delineate prospectively the rates and clinical course of emotional distress, cognitive impairment, and quality of life (QOL) in chemotherapy‐naive patients with cancer and to consider the determinants of global QOL.

Efficacy of oxcarbazepine for prophylaxis against cumulative oxaliplatin-induced neuropathy

We conducted a randomized, open-label, controlled trial to assess the efficacy of oxcarbazepine for prophylaxis against oxaliplatin-induced peripheral neuropathy (OxIN). Thirty-two patients with colon cancer received 12 courses of the FOLFOX-4 regimen and were randomly assigned to receive oxcarbazepine (600 mg BID) or chemotherapy without oxcarbazepine. The incidence of OxIN was strikingly decreased in patients receiving oxcarbazepine (31.2% vs 75%). Oxcarbazepine may prevent OxIN symptoms. Further larger placebo-controlled trials are warranted to confirm our results.

Information needs and awareness of diagnosis in patients with cancer receiving chemotherapy: a report from Greece

This study assessed the information needs of Greek cancer patients and examined whether awareness of diagnosis had any impact on patients. One hundred patients were interviewed about overall and specific information needs, satisfaction, emotional distress, and quality of life. Patients exhibited a great desire for information overall. The need to have more information was high especially regarding the aftermath of chemotherapy, prognosis, how chemotherapy worked, and diagnosis. Patients were more satisfied with care but less satisfied with the information received. Only 37% knew they had cancer, especially the younger, the better educated, and those with breast cancer. Awareness was not related to satisfaction, emotional distress, or quality of life. Our findings suggest that Greek cancer patients need more factual information about their condition and management. Greek oncologists may feel freer to inform their patients about the diagnosis and other issues following their judgement, rather than employing the policy of concealing the truth.

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.

The upgraded role of HER3 and HER4 receptors in breast cancer

The human epidermal growth factor receptor (HER) family comprises four homologous members. The activation of these receptors affects essential tumorigenic processes and plays a crucial role in the pathogenesis of breast cancer. Among HER family members, EGFR and HER2 are the most studied. However, accumulating data provide evidence for the significance of HER3 and HER4 alterations in breast carcinogenesis. The combination of HER2 and HER3 receptors may be critical in breast cancer growth and progression. Moreover, HER3 may provide a route for resistance to agents targeting EGFR or HER2. Although a number of studies have demonstrated that HER3 overexpression is associated with poor prognosis in patients with breast cancer, other studies have indicated that HER3 overexpression may be a positive prognostic factor. With respect to HER4 receptor, the existing evidence suggests that HER4 signalling promotes differentiation and growth inhibition of breast cancer cells. In addition, HER4 is more consistently related with a favourable prognosis in breast cancer. HER4 has multiple different activities in the breast, and many of these functions are mediated by a soluble HER4 intracellular domain. In addition, loss of HER4 expression may represent a marker for resistance to tamoxifen. Because of the functional interdependency among the HER receptors, it is possible that the effect on cell proliferation and tumor growth depends on receptor trans-signalling. Therefore, clarifying how and the extent to which these different signalling pathways interact in breast carcinogenesis, may lead to additional therapeutic opportunities. This review presents an update on the role of HER3 and HER4 receptors in breast cancer. Moreover, we provide current data relating to the prognostic significance of these receptors, as well as their impact on the activity of HER-targeting therapies in patients with breast cancer.

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.

Peripheral neuropathy induced by administration of cisplatin- and paclitaxel-based chemotherapy. Could it be predicted?

GoalThe goal of this study was to investigate the potential role of clinical and electrophysiological signs of chemotherapy-induced neurotoxicity (CIPN) in predicting the final outcome of CIPN.Patients and methodsWe prospectively studied 46 cancer patients treated with paclitaxel, cisplatin, or their combination-containing regimens for a nonmyeloid malignancy. The clinical evaluation of neuropathy was based on the modified Neurological Symptom and Neurological Disability Scores. Neurophysiological examination was also carried out. The battery of clinical and electrophysiological tests was repeated at the third and sixth courses of chemotherapy and up to 3 months after its cessation. Results of the clinical and electrophysiological study were summarized by means of a modified peripheral neuropathy (PNP) score.ResultsPatients were divided according to the PNP scores obtained at follow-ups into those with better outcome (group 1, PNP <14, n=19) and those with worse outcome (group 2, PNP >15, n=27). In each patient and before the maximum severity of CIPN had been reached, the incidence of clinical and electrophysiological variables was determined and compared between groups. After univariate analysis two variables from the clinical evaluation and one from the neurophysiological evaluation were related to higher severity of CIPN and thus with worse outcome. Multivariate regression analysis defined only one of them, namely, the decrease sural a-SAP >50% of the baseline value, as being the sole, significant predictor of worse neurological outcome.ConclusionOur study indicates that a precise clinical evaluation combined with a detailed electrophysiological evaluation could predict the final neurological outcome of the cisplatin- or/and paclitaxel-based chemotherapy.

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)