Gerasimos Aravantinos

Oral estramustine and oral etoposide for hormone-refractory prostate cancer

OBJECTIVES Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC). METHODS Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression. RESULTS Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival. CONCLUSIONS We conclude that the combination of estramustine and etoposide is an active and well-tolerated oral regimen in HRPC.

Treatment of Pancreatic Cancer With Docetaxel and Granulocyte Colony-Stimulating Factor: A Multicenter Phase II Study

PURPOSE To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer. PATIENTS AND METHODS Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m(2)) and granulocyte colony-stimulating factor (150 microg/m(2)/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease. RESULTS One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients. CONCLUSION Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.

Docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer: a Hellenic Cooperative Oncology Group Phase II study.

Abstract A phase II study was conducted to evaluate the activity and toxicity profile of the combination of docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer (ABC). Thirty-nine eligible patients with a median performance status of I (range, 0–2) were enrolled in the study. Treatment consisted of docetaxel 75 mg/m2 in a 1-hr infusion on day 1 preceded by gemcitabine 1000 mg/m2 over 30 min on days 1 and 8. One hundred eighty-one treatment cycles were administered, 113 (62.4%) of them at full dose. Relative dose intensity of gemcitabine and of docetaxel was 0.73 and 0.85, respectively. More common grade 3–4 toxicities included neutropenia (49%), anemia (10%), fatigue (10%), nausea/vomiting (8%), and alopecia (77%). Seven patients were hospitalized for febrile neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was required in 90% of patients. Overall, 14 patients (36%) responded, 3 (7.5%) of them completely. Median duration of response was 10.3 months (range, 4.6–17.5+). Median time to progression was 7 months (range, 0.2–17.5+) and median survival 12.7 months (range, 2-–20.5+). In conclusion, the combination of docetaxel and gemcitabine, as used in the present study, has moderate activity in anthracycline-resistant ABC. Future studies should incorporate prophylactic administration of G-CSF to reduce the incidence of febrile neutropenia and maintain dose intensity.

Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review

As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in development, as potential treatment options for patients with advanced disease. Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor, has gained European Medicines Agency approval for the front-line treatment of advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in combination with carboplatin and paclitaxel, and for the treatment of first recurrence of platinum-sensitive ovarian cancer in combination with carboplatin and gemcitabine. We conducted a systematic literature review to identify available efficacy and safety data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development. We analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab. We also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib. Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA). The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data. Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer. Further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit. Data from phase III trials of newer anti-angiogenic agents in ovarian cancer are awaited.

Gemcitabine versus Gemcitabine–Carboplatin for Patients with Advanced Non-small Cell Lung Cancer and a Performance Status of 2: A Prospective Randomized Phase II Study of the Hellenic Cooperative Oncology Group

Background: The purpose of this study was to evaluate gemcitabine–carboplatin (GCb) versus single-agent gemcitabine (G) in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2. The primary endpoint was clinical benefit. Patients and Methods: Patients were randomly assigned to either 1250 mg/m2 of G (arm A) or 1250 mg/m2 of G plus carboplatin area under the curve of 3 (arm B). Both treatments were given on days 1 and 14 and were repeated every 28 days for up to four cycles. Results: Among the 90 eligible patients (47 in arm A and 43 in arm B), in arm A, two (4%) had partial responses (95% CI, 0.52%–14.5%) and 10 (21%) had stable disease (95% CI, 10.7%–35.7%). In arm B, six (14%) had partial responses (95% CI, 5.3%–27.9%) and nine (21%) had stable disease (95% CI, 10%–36%) (p = 0.14). No significant difference was found in terms of clinical benefit between the two treatment groups after two cycles of treatment or at the end of chemotherapy. Furthermore, no association was found between clinical benefit and response to treatment (p > 0.05). Median survival was 4.8 months (95% CI, 2.45–7.25) for arm A and 6.7 months (95% CI, 2.47–10.8) for arm B (p = 0.49). Neutropenia (p = 0.007) and thrombocytopenia (p < 0.001) were more common in group B. Nevertheless, no significant differences were found in terms of severe toxicities (p > 0.05 in all cases). Conclusion: No significant difference was found in terms of clinical benefit in patients with NSCLC and PS 2 who received single-agent G or GCb. Nevertheless, GCb caused more toxicity, particularly neutropenia and thrombocytopenia.

Palliative chemotherapy in elderly patients with common metastatic malignancies: A Hellenic Cooperative Oncology Group registry analysis of management, outcome and clinical benefit predictors

INTRODUCTION Cancer in the elderly is a common health issue in developed societies. We sought to present epidemiology, management and outcome data on fit elderly patients with common metastatic cancers and to identify predictors of clinical benefit from palliative chemotherapy. METHODS All patients aged >65 years who were diagnosed with metastatic breast, colorectal or non-small cell lung carcinomas and managed with palliative chemotherapy in the context of Hellenic Cooperative Oncology Group (HeCOG) clinical trials or protocols were eligible for electronic data retrieval and analysis. Common eligibility criteria included adequate performance status (ECOG 0-3), organ function and absence of severe co-morbidity forbidding cytotoxic chemotherapy. RESULTS One thousand three hundred and seventy-two fit patients (PS 0-1 in 73%) with a median age of 70 years diagnosed with metastatic breast (n=250), colorectal (n=621) or lung cancer (n=501) received chemotherapy from 1991 until 2006. Most patients received modern full-dose chemotherapy regimens including platinum, taxanes, anthracyclines, fluoropyrimidines, oxaliplatin or irinotecan. Mild to moderate co-morbidity was present in 35%. At a median follow-up of 3 years, objective responses were seen in 41% of patients with breast cancer, 25% with colorectal cancer and 31% with lung cancer, while median survival was 21, 16 and 9.4 months, respectively. Grade 3 or 4 toxicity was seen in a quarter of patients, the most common being neutropenia (14%), diarrhoea (6%), neurotoxicity (4%), fatigue, nausea and febrile neutropenia (each 2%). In multivariate analysis, diagnosis of colorectal or lung cancer, metastases in multiple organ sites, presence of liver/brain/peritoneal deposits, impaired PS and low baseline serum albumin levels were prognostic factors for adverse outcome. The same factors excluding metastatic sites and with the addition of anemia predicted for resistance to chemotherapy. Toxicity was more likely in females with low serum albumin and renal dysfunction. A six-variable geriatric assessment for palliation (GAP) score that included tumour type, sites of metastatic dissemination, impaired PS, low serum albumin and anemia classified elderly patients to groups with low, intermediate and high risk for disease progression and death (relative risks of 1.59 and 2.50 for resistance to therapy and 1.87 and 3.12 for death in the intermediate and high-risk groups). CONCLUSIONS Our data indicate that relatively fit elderly patients with advanced cancer safely tolerate modern chemotherapy and enjoy disease control in a manner comparable to younger patients. Our GAP score, if further validated, offers promise for geriatric application in combination to comprehensive geriatric assessment tools for the optimisation of palliative therapy on an individualised basis.

Oxaliplatin for Pretreated Patients with Advanced or Metastatic Pancreatic Cancer: A Multicenter Phase II Study

A phase II study was designed to evaluate the efficacy and safety of oxaliplatin as second-line treatment in patients with locally advanced or metastatic pancreatic cancer. Eighteen patients with advanced pancreatic cancer previously treated with gemcitabine-based chemotherapy, received oxaliplatin 130 mg/m2 i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. No objective response was observed among the 18 treated patients. Three (16.7%) patients had stable disease for > 2 months. A clinical benefit response was observed in five (27.7%) patients. Toxicity was mild. Oxaliplatin as second-line treatment for patients with unresectable pancreatic cancer is well tolerated and associated with improvement of tumor-related symptoms despite its failure to induce objective responses. LOHP merits further investigation in combination with other drugs as palliative treatment of pretreated patients with advanced pancreatic cancer.

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.

HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy.

BackgroundHER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.MethodsIn a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).ResultsHER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.ConclusionsThis study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12611000506998.

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