Abstract: 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.
Abstract: Background: Survivin is involved in the regulation of cell division and survival, two key processes in cancer. The majority of studies on survivin in colorectal cancer (CRC) have focused on protein expression and less is known about the expression of survivin splicing variants or survivin gene polymorphisms in CRC. In the present study, the mRNA levels of the five known isoforms of survivin as well as survivin protein were assessed in matched normal and neoplastic colorectal tissue. Moreover, the 9386C/T and -31G/C polymorphisms were investigated.Methods: Quantitative RT-PCR was used to assess mRNA levels in fresh/frozen tissue samples. Protein levels were immunohistochemically evaluated on formalin-fixed paraffin-embedded tissue sections. Individuals were genotyped using real time PCR.Results: Expression of all 5 survivin splice variants as well as survivin protein was elevated in colorectal carcinomas compared to normal tissue. Specific splice variant expression differentially correlated with clinicopathological parameters. Furthermore, both snps correlated with splice variant levels or their ratios in colorectal carcinomas while the -31G/C snp may be related to CRC development and improved overall survival.Conclusion: Our results support a role of survivin in colorectal carcinogenesis while the -31G/C snp may constitute a marker of survival.
Abstract: Current evidence indicates that angiogenesis plays an important role in the pathogenesis of several malignancies, including breast cancer. Bevacizumab is a monoclonal antibody that targets the vascular endothelial growth factor (VEGF). Recent clinical data have demonstrated that the addition of bevacizumab to first-line chemotherapy improves the progression-free survival (PFS) of patients with advanced breast cancer. This review presents an update on the clinical studies evaluating the role of bevacizumab in combination with chemotherapy, as well as other agents, both in advanced and early disease. Moreover, although no definitive biomarkers have been identified so far, we provide current data regarding potentially useful predictive factors for treatment with bevacizumab. In addition, we review the suggested mechanisms that lead to resistance to VEGF targeted therapies and we present recent data with respect to the toxicity of bevacizumab.
Abstract: AIM: We sought to assess the effect of sunitinib and lapatinib applied either alone or in combination, on U87 and M059K glioma cells. METHODS: Both cell lines were cultured as recommended by the manufacturer. Sunitinib and lapatinib were applied, either separately or in combination, in the cultured cells after cell attachment at doses of 10 nM, 100 nM, 1 microM and 10 microM. To determine whether the agents affect the proliferation of glioma cells, the 3-[4,5-dimethylthiazol-2-yl]-2,5 dimethyltetrazolium bromide assay was used. Apoptosis was detected using annexin V/propidium iodide detection assay, migration assay was performed in 24-well microchemotaxis chambers. The release of MMPs into the culture medium of U87 and M059K cells was measured by zymography. RESULTS: Both agents, administered either alone or in combination, decreased cell proliferation in a dose-dependent manner 48 h after their application in both cell lines. The inhibition of their combination was statistically different than the inhibition of each agent alone. Apoptosis was increased and migration of U87 and M059K cells was inhibited either by each agent alone or their combination. MMPs levels remained unaffected by the application of both agents in U87 cells. However, MMP-9 and MMP-2 levels were decreased 48 h after treatment of M059K cells with sunitinib either alone or in combination with lapatinib. CONCLUSION: Sunitinib and/or lapatinib appear to exhibit significant effects on proliferation, apoptosis and migration of glioma cells. When applied alone, sunitinib appears to be a more potent inhibitor than lapatinib.
Abstract: Neoplastic meningitis from breast cancer has a dismal prognosis and short survival. Treatment is based on the intrathecal administration of chemotherapeutic agents, cranial or craniospinal radiotherapy, and systemic chemotherapy. In this report we describe the case of a woman with neoplastic meningitis from breast carcinoma who developed an excellent response to letrozole combined with intrathecal methotrexate, resulting in long-term survival of more than 36 months. Based on the findings of this case report, we suggest that addition of letrozole to the standard therapeutic approach may be beneficial for some patients.
Abstract: Patients with malignancies are often in a hypercoagulable status. The pathogenetic mechanisms of thrombotic events in malignancy are multifaceted and consist of release or expression of procoagulants by cancer cells, but also appearance of procoagulant action by normal host cells. Most importantly, current therapeutic modalities for cancer such as high dose chemotherapy and surgery represent a significant additional risk for serious or even fatal thromboembolic events. There is a wide spectrum of clinical manifestations of these events which encompass Trousseau's syndrome, deep venous thrombosis, marantic endocarditis, disseminated intravascular coagulation, thrombotic microangiopathy and arterial thrombosis. Cancer chemotherapy is most commonly associated with deep vein thrombosis but intracranial sinus vein thromboses and thrombotic microangiopathy may also occur. Our purpose is to review the relevant literature linked to the effect of chemotherapy and other cancer-related interventions on thromboembolic incidents.
Abstract: BACKGROUND: Effective anthracycline-free combinations need to be evaluated in metastatic breast cancer (MBC), due to the increased number of patients treated with anthracycline-based adjuvant chemotherapy. PATIENTS AND METHODS: Patients with MBC were randomized to paclitaxel and carboplatin (PCb) every 3 weeks or docetaxel and gemcitabine (GDoc) every 3 weeks or weekly paclitaxel (Pw). Trastuzumab was given to patients with HER-2 over-expressing tumors. The primary endpoint of the study was survival. Quality of life (QoL) and cost were assessed. RESULTS: Totally, 416 eligible patients entered the study. Median survival times were 29.9 months for PCb, 26.9 for GDoc and 41.0 for Pw (P = 0.037). According to multivariate analysis, adjuvant chemotherapy, >1 metastatic sites, lack of maintenance hormonal therapy, and worse performance status (PS) were significant adverse prognostic factors for survival, while Pw when compared to GDoc improved survival (P = 0.03), as well as when compared to PCb in the subgroup of patients with PS = 1 (P = 0.01, treatment by PS interaction P = 0.03). No significant differences in terms of time to progression were found. Severe myelotoxicity and mucositis were more frequent with GDoc, while severe neuropathy with PCb and Pw. QoL changes did not differ significantly between treatment groups, while cost analysis favored Pw. CONCLUSIONS: Pw appears to be the most preferable choice among the 3 anthracycline-free taxanes-based regimens tested in the present study.
Abstract: BACKGROUND: Erythropoietin corrects and prevents anemia and decreases the need for red blood cell (RBC) transfusions; its impact on quality of life (QOL) of cancer patients receiving chemotherapy is not clear. PATIENTS AND METHODS: 399 patients with solid tumors and Hb level of < or = 12 g/dl receiving chemotherapy were randomized to receive or not 10,000 IU epoetin-alpha thrice weekly. QOL was measured by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale and various subscales at baseline, at two months and at the end of the study. RESULTS: Changes in the average QOL scores were similar in the two groups. The improvement in Hb levels was significantly higher for the epoetin-alpha group, with a decrease in transfusion requirements compared to the control group. CONCLUSION: Epoetin-alpha does not improve QOL of patients with solid tumors receiving chemotherapy as assessed using FACT-An scale and various subscales, despite improving Hb levels and reducing transfusion requirements.
Abstract: BACKGROUND: Recent evidence suggests that estrogen signaling may be involved in the pathogenesis of non-small cell lung cancer (NSCLC). Aromatase is an enzyme complex that catalyses the final step in estrogen synthesis and is present in several tissues, including the lung. In the current study we investigated the activity of the aromatase inhibitor exemestane in human NSCLC cell lines H23 and A549. RESULTS: Aromatase expression was detected in both cell lines. H23 cells showed lower protein and mRNA levels of aromatase, compared to A549 cells. Exemestane decreased cell proliferation and increased apoptosis in both cell lines, 48 h after its application, with A549 exhibiting higher sensitivity than H23 cells. Aromatase protein and mRNA levels were not affected by exemestane in A549 cells, whereas an increase in both protein and mRNA levels was observed in H23 cells, 48 h after exemestane application. Moreover, an increase in cAMP levels was found in both cell lines, 15 min after the administration of exemestane. In addition, we studied the effect of exemestane on epidermal growth factor receptor (EGFR) localization and activation. Exemestane increased EGFR activation 15 min after its application in H23 cells. Furthermore, we demonstrated a translocation of EGFR from cell membrane, 24 h after the addition of exemestane in H23 cells. No changes in EGFR activation or localization were observed in A549 cells. CONCLUSION: Our findings suggest an antiproliferative effect of exemestane on NSCLC cell lines. Exemestane may be more effective in cells with higher aromatase levels. Further studies are needed to assess the activity of exemestane in NSCLC.
Abstract: The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity. The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80 mg/m(2) intravenously (IV), LV 200 mg/m(2) and 5FU 450 mg/m(2) bolus (arm A) versus LV 200 mg/m(2) and 5FU 450 mg/m(2) IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU. There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm. IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.
Abstract: The primary aim of this study was to assess whether epoetin alpha (Ea) would improve cognitive performance in a group of anaemic cancer patients receiving chemotherapy. The secondary aim was to confirm the positive impact of Ea on haematological parameters, and quality of life (QOL). Fifty patients with solid tumours and haemoglobin (Hb) <11.0 g/dL received Ea 40,000 units once weekly for 12 weeks and were administered the Mini-Mental State Examination and the European Organization for Research and Treatment of Cancer (QLQ-C30) questionnaire prior to Ea therapy and at study completion. No clinically significant alterations were observed on cognitive function during Ea treatment. Changes in cognitive function were unrelated to Hb change and there were no significant differences in cognitive performance between Ea responders and non-responders. The analyses revealed clinically significant improvements in Hb levels, physical and role function, and clinically meaningful reductions in fatigue. Hb changes were significantly associated with the magnitude of improvement in QOL parameters. The lack of a clinical benefit in cognition observed in this study during Ea treatment may redirect the focus of research from enhancing to maintaining cognitive function, since stability in cognitive performance through time may be as well clinically important.
Abstract: INTRODUCTION: Taxane/platinum combinations exhibit synergistic cytotoxicity and activity against a broad range of solid tumours. We sought to optimise the regimen as a suitable outpatient palliative treatment for cancer of unknown primary (CUP). PATIENTS AND METHODS: Eligible CUP patients with adenocarcinoma or poorly differentiated carcinoma, performance status of 0-2, adequate organ function and assessable disease were treated with docetaxel 75 mg/m(2) and carboplatin at an area under the concentration time-curve (AUC) of 5, both as 30-minute intravenous infusions, every three weeks. Patients with isolated axillary adenopathy, squamous cell cervical or inguinal adenopathy and PSA or germ-cell serum tumour markers were excluded. RESULTS: Forty-seven patients entered the trial, 24 with predominantly nodal disease or non-mucinous peritoneal carcinomatosis (favourable risk) and 23 with visceral metastases (unfavourable risk). A median of 6 cycles of chemotherapy were administered, with relative dose intensities of both drugs >90%. Response rates were 32% (46% in favourable risk, 17% in unfavourable), comparable to the activity of paclitaxel/platinum regimes, though complete remissions were seen only in favourable risk patients. Granulocyte-colony stimulating factor support was used in a third of treatment cycles. Toxicity was mild and manageable, with grade 3-4 neutropenia in 26% of patients, febrile neutropenia in 7% and severe non-hematologic side-effects in less than 8% of patients. No toxic deaths or severe neurotoxicity were seen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 16.2 months respectively. Survival was driven mainly by favourable-risk patients (22.6 months), as those with visceral metastases had a poor median survival of only 5.3 months. Good performance status and low-volume disease predicted for superior outcome, while docetaxel relative dose-intensity was a positive prognosticator only in favourable-risk patients. CONCLUSIONS: One-hour docetaxel/carboplatin is a convenient, safe and effective outpatient palliative treatment for CUP patients, providing meaningful survival prolongation only in favourable-risk patients. Insights in the molecular biology of CUP are needed for the development of targeted therapeutic manipulations of malignant resistance and progression.
Abstract: The combination of gemcitabine and gefitinib was evaluated in advanced pancreatic cancer. Totally, 53 patients were treated with a 7 week cycle of gemcitabine (1,000 mg/m(2) given weekly) followed by six 4 week cycles of gemcitabine given on days 1, 8 and 15. Gefitinib 250 mg was administered daily. Responses were seen in 6, and stabilization of the disease in 12 patients. The main toxicity was myelotoxicity (92%). The 6-month progression-free survival (PFS) was 30%. Median PFS was 4.1 months and median survival 7.3 months with a 1 year survival rate of 27%. The above combination demonstrated promising activity in advanced pancreatic cancer.
Abstract: BACKGROUND: A number of studies have shown that absence of myelotoxicity during chemotherapy is associated with worse outcome for various types of cancer, including carcinoma of the breast. The aim of this study was to determine whether myelosuppression in patients being treated with chemotherapy for advanced breast cancer has an impact on their prognosis. PATIENTS AND METHODS: A retrospective review was conducted of a series of 475 patients with advanced breast cancer enrolled in two randomised trials, who received first-line chemotherapy. The impact of severe (grade 3 or 4) hematological toxicity on survival and time to disease progression was assessed. RESULTS: When severe myelotoxicity was evaluated as a whole, a significant negative association for time to disease progression and a trend for a worse survival were demonstrated. In multivariate analysis, hematological toxicity retained its significance as an independent negative prognostic factor for time to disease progression. CONCLUSION: Our findings do not confirm the results of previous studies which have demonstrated a better outcome for patients experiencing hematological toxicity during treatment.
Abstract: The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT-PCR). The overall concordance between kRT-PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.
Abstract: PURPOSE: Treatment options in patients with recurrent non-small cell lung cancer (NSCLC) remain limited as a result of poor activity of most agents after failure of platinum-based therapy. In the present phase I-II study, we evaluated the feasibility and efficacy of bi-weekly gemcitabine (GEM) + irinotecan (CPT-11) in patients with relapsed NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, WHO-performance status (PS) </= 2, prior taxane/platinum-based chemotherapy were eligible. Chemotherapy was administered in a dose-escalated fashion in subgroups of 3-6 patients until dose-limiting toxicity (DLT) was encountered as follows: CPT-11 150 or 180 mg/m(2) followed by GEM 1,200-1,800 mg/m(2), both on days 1 + 15, recycled every 28 days in four dose levels (DLs). RESULTS: Forty-nine patients entered the phase I and II part of the study (phase I: 12-phase II: 37 + 3 at DL-3), and 40 patients were evaluable for a response in phase II and all for toxicity: median age, 61 years (range 36-74); PS, 1 (0-2); gender, 43 males/6 females-histologies; adenocarcinoma, 25; squamous, 20; large cell, 4. Metastatic sites included lymph nodes, 38; bone, 5; liver, 4; brain, 3; lung nodules, 14; adrenals, 13; other, 3. All patients had prior taxane + platinum-based treatment, and 42 patients had prior docetaxel-ifosfamide-cisplatin/or-carboplatin regimens. DLT was observed at DL-4 and included 2/3 cases with grade 3 diarrhea-1/3 of these with febrile neutropenia. The recommended DL for phase II evaluation was DL3: GEM, 1,500 + CPT-11-180 mg/m(2). Objective responses in phase II were PR, 6/40 [15%; 95% confidence interval (CI), 5-31%]; stable disease, 16/40 (40%; 95% CI, 21-53%); and progressive disease, 18/40 (45%; 95% CI, 28.5-62.5%). The median time-to-progression was 4 months (range 1-12) and median survival 7 months (range 1.5-42 +), while 1-year survival was 20%. Grade 3/4 neutropenia was seen in 18% of patients (6% grade 4) and 6% incidence of febrile neutropenia. No Grade 3/4 thrombocytopenia were seen, grade 3 diarrhea in 6% of patients and grade 2 in 15% of patients, while other grade 3 non-hematologic toxicities were never encountered. CONCLUSIONS: Bi-weekly GEM + CPT-11 is active and well tolerated in patients with advanced NSCLC failing prior taxane + platinum regimens, and represents an effective and convenient combination to apply in the palliative treatment of relapsed NSCLC particularly after failure of first-line docetaxel + platinum-based regimens.
Abstract: The current prospective study sought to trace the incidence and severity of cisplatin plus paclitaxel (DDP+P)-induced neuropathy and to determine its clinical and electrophysiological pattern. Furthermore, it was attempted to describe its evolution by following up the course of peripheral neuropathy (PN) during chemotherapy as well as 3 months after its discontinuation. Thirteen adult patients scheduled to be treated with six courses of cumulative DDP+P-based regimens for a non-myeloid malignancy participated in this study. These patients were clinically and electrophysiologically monitored at baseline, during chemotherapy and 3 months after its discontinuation. The severity of PN was summarized by means of a modified PN score. Evidence of PN was disclosed in nine of the 13 patients (69.2%). The mean PN score for patients that manifested some grade of PN was 17.3 +/- 6.1 (range 9-28). All longitudinal comparisons concerning the motor conduction velocities (MCV) variables failed to reach significance. By contrast, comparisons of the mean changes at baseline and each of the follow-up studies revealed a significant decrease in all sensory action potentials examined. The follow-up evaluation performed 3 months after the discontinuation of chemotherapy showed that the DDP+P-induced neuropathy persists and progresses over time. Our results indicate that the majority of patients treated with a DDP+P-based regimen at full dose intensities would manifest an axonal, predominately sensory PN, of mild to moderate severity, which would persist for several months after the discontinuation of chemotherapy.
Abstract: 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.
Abstract: Cholangiocarcinoma is one of the most aggressive malignancies. Patients with advanced or metastatic disease have a particularly dismal prognosis. The role of chemotherapy remains a matter of debate. A number of recent trials have shown that capecitabine in combination with other agents seems to be active as first-line treatment in advanced biliary cancer. Clinical data regarding the activity of capecitabine in pretreated patients are limited. In this report we describe a patient with previously treated, metastatic cholangiocarcinoma who developed stabilization of the disease for 7 months following chemotherapy with capecitabine. The patient had previously received 2 lines of chemotherapy. Capecitabine was tolerated fairly well without serious adverse events. We consider this observation to be important given the absence of active, non-surgical treatments in unresectable tumors.
Abstract: The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU)/leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m(2) intravenously (i.v.), followed by LV 200 mg/m(2) (i.v.) and 5-FU 450 mg/m(2) as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatment-related deaths. The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.
Abstract: BACKGROUND: Sunitinib (SU011248; Sutent) is a new small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases (RTKs), with established antitumor activity in renal cancer. In the current report, we describe a patient with a solitary brain metastasis from renal cell carcinoma who achieved partial response of the cerebral lesion following treatment with sunitinib. To the best of our knowledge, this is the first report of sunitinib activity in brain metastases from kidney cancer. A limited number of publications support the hypothesis that small tyrosine kinase inhibitors may cross the blood-brain barrier. Although the role of sunitinib in advanced renal carcinoma has been evaluated through prospective trials, the efficacy of the drug in patients with brain metastases has not been explored, since patients with cerebral lesions were excluded in those studies. Thus, we believe that accumulating evidence from personal experience or limited reports could be useful. Moreover, in our case, sunitinib was found to be safe, leading to considerable shrinkage of the brain metastasis without any serious adverse events or central nervous system toxicities. We consider this observation to be important, given the absence of data regarding the activity of the drug in this particular clinical setting.
Abstract: Vinorelbine and mitoxantrone have both been demonstrated to have significant antitumor activity in patients with breast cancer. The aim of this study was to evaluate the efficacy and safety of the combination as second or third line treatment in patients with metastatic breast cancer (MBC). Fifty-one previously treated patients with MBC were enrolled from October 2001 to May 2004 and 48 were eligible for evaluation. Median age was 59 years (range 33-82) and ECOG performance status was < or =2. Distant sites of metastasis were as follows: liver 64%, bone 49%, lung 36%, lymph nodes 6%, skin 4%, brain 2% and other sites 6%. All patients received vinorelbine 20 mg/m(2), D1+8 and mitoxantrone 10 mg/m(2) D8 every 21 days for 6 cycles. All eligible patients were analyzed for toxicity and response. Two patients (4%) achieved complete response and 12 (25.5%) partial response. The objective overall response rate was 29.5% (95% confidence interval [CI] 17 - 45), 9 (19%) patients had stable disease, 17 (36%) had progressive disease and 7 (15%) were non-evaluable. After a median follow up of 18 months, overall survival was 13 months (range 0.8 - 38+) and median time to disease progression was 5 months (range 1 - 32). A total of 280 cycles was delivered. The relative dose intensities of mitoxantrone and vinorelbine were 79% and 77%, respectively. Toxicities (grade III-IV) were as follows: leukopenia 18 (38%), neutropenia 21 (45%), thrombocytopenia 1 (2%), anemia 4 (8.5%), alopecia 2 (4%) and constipation 1 (2%). Febrile neutropenia was recorded in one patient. There were no treatment related deaths. The combination of mitoxantrone and vinorelbine is an effective regimen with manageable toxicity in pretreated patients with advanced breast cancer.
Abstract: AIM: A randomized, open label with blind assessment, controlled trial was performed to assess efficacy and adverse-event profile of vitamin E, given as supplementation for prophylaxis against cisplatin-induced peripheral neuropathy (CIPN). PATIENTS AND METHODS: A total of 30 patients scheduled to receive six courses of cumulative cisplatin-based regimens were randomly allocated to treatment and control groups and were then studied by means of neurological examination and electrophysiological study. Patients assigned to group I (n=14) orally received 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=16), who received no vitamin E supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified Peripheral Neuropathy (PNP) score. RESULTS: The incidence of neurotoxicity differed significantly between groups, occurring in 3/14 (21.4%) of patients assigned to the vitamin E supplementation group and in 11/16 (68.5%) of controls (p=0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of controls, RR=2.51, 95% C.I.=1.16-5.47. Mean PNP scores were 4.99+/-1.33 for patients of group I and 10.47+/-10.62 for controls, (p=0.023). None of the adverse events or deaths occurred, were judged as likely to be related to the vitamin E supplementation. CONCLUSION: Vitamin E effectively and safely protects patients with cancer from occurrence of cisplatin neurotoxicity.
Abstract: BACKGROUND: There has been limited research examining the efficacy of providing written information to cancer patients in southern and eastern European countries. This study investigated the impact of a booklet about chemotherapy on patient satisfaction, quality of life (QoL) and emotional distress, and assessed booklet use. PATIENTS AND METHODS: A total of 145 Greek cancer outpatients prior to commencing chemotherapy completed a questionnaire and were randomized to receive (n = 72) or not receive (n = 73) the booklet. All patients completed the second questionnaire before the following cycle of chemotherapy. RESULTS: Baseline characteristics were well balanced between the two groups. Experimental group patients reported being significantly more satisfied with the information received and care overall than those in the control group, felt significantly more and better informed, and perceived the information received as being clearer and detailed. The intervention produced no benefits in terms of anxiety, depression or QoL. The booklet was read by almost all patients and to a great extent by significant others. The majority considered the booklet useful to read and helpful in recalling chemotherapy-related information. CONCLUSIONS: The current results provide further evidence on the efficacy of information-giving interventions in societies where disclosure of information to cancer patients still remains controversial.
Abstract: The expressions ofp27Kip1 (p27) and p21waf1 (p21) cyclin-dependent kinase inhibitors and p53 were examined in a series of 170 node-negative breast carcinomas (NNBCs) to evaluate their prognostic significance. Low nuclear (p27TN) and cytoplasmic (p27TC) p27 expressions were noted in 66% and 81% of NNBCs, respectively. p21 and p53 overexpressions were detected in 56% and 26%, respectively. Low p27TN was significantly associated with high grade (p=0.001), age < or = 50 years (p=0.01), negative hormone receptors (p<0.001), low p27TC (p<0.001) and p53 overexpression (p=0.02). Low p27TC was associated with negative hormone receptors (p<0.001). p53 overexpression was associated with high grade (p<0.001) and negative hormone receptors (p<0.001). p21 overexpression, although not correlated with the examined parameters, was associated with increased disease-free survival in univariate analysis. In multivariate analysis, p27TN, p27TC, p21 and p53 were not associated with disease-free survival or overall survival. These findings argue against the prognostic value of p27, p21 and p53 in NNBC.
Abstract: BACKGROUND: The toxicity of platinum-based combinations represents a common problem for patients with advanced urothelial carcinoma. The authors previously reported encouraging efficacy for the combination of carboplatin and gemcitabine in patients considered to be unfit for cisplatin-based treatment. The objective of the current multicenter Phase II study was to evaluate the safety and efficacy of the combination of gemcitabine and carboplatin as first-line treatment in unselected patients with advanced urothelial carcinoma. METHODS: Patients with previously untreated, bidimensionally measurable, inoperable or metastatic urothelial carcinoma were treated with carboplatin, area under the concentration curve of 5 (Day 1) and gemcitabine at a dose of 1000 mg/m(2) (Days 1 and 8), every 21 days for a total of 6 cycles. RESULTS: Sixty patients (49 men and 11 women, with a median age of 69 yrs) were enrolled in the current study. Intent-to-treat analysis demonstrated an objective response rate (ORR) of 38.4% (95% confidence interval [95% CI], 26-51.8%) (11.7% complete responses and 26.7% partial responses). The median time to disease progression was 7.6 months (95% CI, 4.5-10.7 mos) and the median overall survival was 16.3 months (95% CI, 12-20.6 mos). The median survival was comparable to that reported for the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) according to the Memorial Sloan-Kettering Cancer Center prognostic model for patients with similar baseline prognostic features. Grade 3 or 4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) included anemia (18%), thrombocytopenia (23%), and neutropenia (52%), with 7 episodes of febrile neutropenia (11%) reported. Nonhematologic toxicity was rare. One toxic death occurred during the study. CONCLUSIONS: The combination of gemcitabine and carboplatin appears to have considerable activity as the first-line treatment of unselected patients with advanced urothelial carcinoma with manageable toxicity, and deserves further evaluation in this setting.
Abstract: PURPOSE: The current setting tested the hypothesis that advanced age would be strongly associated with increased incidence and severity of chemotherapy-induced peripheral neuropathy (CIPN). PATIENTS AND METHODS: We prospectively studied 35 cancer patients treated with paclitaxel or cisplatin-based regimens for lung or breast cancer. All patients underwent a detailed clinical and electrophysiological evaluation for screening of CIPN at baseline, at the third, the sixth course of chemotherapy and up to 3 months after its cessation. Means of a modified Peripheral Neuropathy (PNP) score summarized the results of the clinical and electrophysiological study. RESULTS: Patients were divided according to their age in two groups (mean age difference, p=0.000) to those younger than 65 years (group I, n=18) and those older or equal than 65 years (group II, n=17). According to the clinical, neurological and electrophysiological variables of each patient, the incidence and severity of CIPN was determined and then compared between groups. The incidence of neurotoxicity was similar (p=0.869) between group I (9/18 patients, 50%) and group II (8/17 patients, 52.9%). Likewise, according to the mean PNP scores, the severity of CIPN was similar between age groups (p=0.897). The between-age-groups comparison of electrophysiological data revealed no significant differences in any of the motor or sensory conduction parameters examined. CONCLUSION: Our study indicates that elderly cancer patients do not have greater risk of CIPN, whilst advanced age was not associated with worst severity of CIPN.
Abstract: PURPOSE: To assess the safety and efficacy of a 3-day schedule of cisplatin and topotecan in patients with recurrent small-cell lung cancer (SCLC). METHODS: Thirty-four relapsed patients were treated with cisplatin 20 mg/m2 and topotecan 0.9 mg/m2, both given on days 1-3 every 3 weeks, in a phase II study. RESULTS: Complete response (CR) was achieved in two patients (6%), partial response (PR) in 4 (12%), stable disease in 6 (18%) and progressive disease in 14 (41%). Eight patients (23%) were non-evaluable for response. Among 21 sensitive patients, 2 (9.5%) achieved CR and 3 (14%) PR. Among 13 refractory patients, none achieved CR and only 1 (8%) PR. Median survival was 6.5 months for all patients, 7.8 for sensitive and 6.2 for refractory. Median time to progression (TTP) was 4.4 months for all patients, 5.9 for sensitive and 3.2 for refractory. Grade 3-4 toxicities included anemia (15%), thrombocytopenia (15%), neutropenia (42%), nausea/vomiting (3%), and alopecia (6%). No toxic death occurred. CONCLUSIONS: This 3-day schedule was well tolerated, produced modest response rates but good survival and TTP both in sensitive and refractory patients with relapsed SCLC.
Abstract: BACKGROUND: Capecitabine is a tumor-activated oral fluoropyrimidine with established antitumor activity in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature. CASE REPORT: This is a report of two patients who developed capecitabine-induced severe hypertriglyceridemia, together with an increase in total cholesterol levels. The first patient developed hyperlipidemia during long-term capecitabine treatment in combination with trastuzumab for metastatic breast carcinoma (triglycerides: from 219 mgldl to 1409 mg/dl, 543% increase; cholesterol: from 239 mg/dl to 363 mg/dl, 52% increase). The second patient developed abnormalities in the lipid profile after the second cycle of chemotherapy with capecitabine and oxaliplatin for metastatic colorectal cancer (triglycerides: from 101 mg/dl to 1510 mg/dl, 1395% increase; cholesterol: from 203 mg/dl to 310 mgldl, 52% increase). An analysis of the possible underlying pathogeneic mechanisms is provided. CONCLUSION: Physicians should be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia, following treatment with capecitabine.
Abstract: 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.
Abstract: A randomized, controlled trial was performed to assess the efficacy and safety of vitamin E supplementation for prophylaxis against paclitaxel-induced peripheral neuropathy (PIPN). Thirty-two patients undergoing six courses of paclitaxel-based chemotherapy were randomly assigned to receive either chemotherapy with vitamin E (300 mg twice a day, Group I) or chemotherapy without vitamin E supplementation (Group II). A detailed neurological examination and electrophysiological study was performed during and 3 months after chemotherapy. The severity of PIPN was summarized by means of a modified Peripheral Neuropathy (PNP) score. The incidence of neurotoxicity differed significantly between groups, occurring in 3/16 (18.7%) patients assigned to the vitamin E supplementation group and in 10/16 (62.5%) controls (P=0.03). The relative risk (RR) of developing PIPN was significantly higher in controls than in vitamin E group patients (RR=0.3, 95% confidence interval (CI)=0.1-0.9). Mean PNP scores were 2.25+/-5.1 (range 0-15) for patients in Group I and 11+/-11.63 (range 0-32) for those in Group II (P=0.01). Vitamin E supplementation was well tolerated and showed an excellent safety profile. This study shows that vitamin E effectively and safely protects patients with cancer from the occurrence of paclitaxel-induced peripheral nerve damage. A double-blind, placebo-controlled trial is needed to confirm these results.
Abstract: Gemcitabine and mitoxantrone have both shown significant antitumor activity in patients with breast cancer. The aim of this study was to evaluate the efficacy and safety of this combination as second or third-line treatment in patients with metastatic breast cancer (MBC). Forty-six previously treated patients with MBC were enrolled from June 2000 to November 2002. Mean age was 56 years and ECOG performance status was < or =2. All patients received mitoxantrone 10 mg/m2, D8 and gemcitabine 1000 mg/m2, D1+8 every 21 days for 6 cycles. There were no complete responders. Objective response was observed in 12 patients (26%), 15 (33%) patients had stable disease, 15 (33%) had progressive disease and 4 (9%) were non-evaluable. At median follow-up of 27.8 months, overall survival was 13.3 months (range 0.6-33.8+) and the median time to disease progression (TTP) was 4.4 months (range 0.2-33.8). Toxicities (grade 3-4) were as follows: leukopenia 18 (39%), neutropenia 19 (41%), thrombocytopenia 4 (8.5%), anemia 6 (13%) and alopecia 1 (2%). Febrile neutropenia was recorded in 2 (4%) patients. There were no treatment related deaths. The authors conclude that the combination of mitoxantrone and gemcitabine is an effective regimen in pretreated patients with metastatic breast cancer. Toxicity was manageable.
Abstract: Teratomas with malignant transformation occur in a small proportion of patients with metastatic germ cell tumors treated with platinum-based chemotherapy. Chondrosarcoma has rarely been reported as a component of the second non-germ cell malignancy. We report the case of a 37-year-old man who developed a chondrosarcoma in a recurrent retroperitoneal mass after chemotherapy for testicular germ cell tumor. Malignant transformation of the retroperitoneal teratomatous mass occurred in the absence of any symptoms or clinical signs, elevation in serum tumor markers, or the presence of atypical elements in previously resected specimens, suggesting the need for close radiographic follow-up of these patients.
Abstract: 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.
Abstract: PURPOSE: In the present phase II study we evaluated the docetaxel-ifosfamide-carboplatin (DICb) combination in the outpatient setting in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC (stages IIIB/IV), WHO performance status (PS) <2, and no prior chemotherapy were eligible. Chemotherapy drug doses were: docetaxel: 80 mg/m2, ifosfamide: 3.5 g/m2, and carboplatin at a target area under the curve of 5 (based on Calvert's formula), all on day 1, followed by prophylactic G-CSF. RESULTS: Fourty patients were entered and all are evaluable for response and toxicity: median age: 64 (48-72); PS: 1 (0-1); gender: 29 males/11 females; stages: IIIB: 13 (33%), IV: 27 (67%). Metastatic sites at diagnosis included: lymph nodes: 25; bone: 7; liver: 4; brain: 5; lung nodules: 13; adrenals: 6. Responses were as follows: 22/40 [55%; 95% confidence interval (CI), 54-81%] evaluable patients responded: 4 complete responses, 18 partial responses, 11 had stable disease, and 7 had progressive disease. The median response duration was 7 months (range 2-14 months), median time to progression 9 months (range 2-18 months) and median overall survival 11 months (range 3-46+ months). 1-year survival was 47.5%. Grade 3/4 toxicities included: neutropenia 28/40, with 12 developing grade 4 and 12% febrile neutropenia, thrombocytopenia grade 3: 3/40 and grade 4: 1/40, no grade 3 neuropathy, grade 1 CNS toxicity in 3, no renal toxicity, 8 grade 2 diarrhea and 4 grade 3 vomiting. CONCLUSION: In the present phase II study the DICb combination yielded important activity and good tolerability in advanced NSCLC.
Abstract: GOAL: The 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 METHODS: We 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. RESULTS: Patients 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. CONCLUSION: Our 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.
Abstract: BACKGROUND: Irinotecan (IRI) and oxaliplatin (OXA) are effective in the treatment of colorectal cancer. Previously untreated patients with advanced colorectal carcinoma (CRC) were randomly assigned to receive IRI plus leucovorin (LV)/5-fluorouracil (5-FU), or OXA plus LV/5-FU in order to compare the response rates, time-to-tumor progression, overall survival rates, and toxicity profiles of these two agents. MATERIALS AND METHODS: From January 1999 to February 2002, 295 patients were randomized to receive either IRI/LV/5-FU or OXA/LV/5-FU. The treatment schedules consisted of weekly IRI 70 mg/m(2) or OXA 45 mg/m(2) plus LV 200 mg/m(2) followed immediately by intravenous bolus 5-FU 450 mg/m(2) for 6 weeks, followed by a 2-week rest period. Treatment was continued for up to four cycles or until disease progression, unacceptable toxicity or patient refusal. RESULTS: There were no significant differences between the study arms in the overall response rate (33% with IRI/LV/5-FU versus 32% with OXA/LV/5-FU based on responses demonstrated on a single evaluation; 23% with IRI/LV/5-FU versus 22.3% with OXA/LV/5-FU based on responses confirmed according to WHO criteria) median time to progression (8.9 versus 7.6 months), and median overall survival (17.6 versus 17.4 months). Toxicity profiles (grades 3 and 4) were similar in the IRI and OXA arms (diarrhea 12.3% and 9.8%, neutropenia 8.2% and 4.9%, and febrile neutropenia 1.4% and 1.4%, respectively), with the exception of grade 3 sensory neuropathy, which almost exclusively occurred in the OXA arm (0% versus 5.6%; P=0.003, Fisher's exact test). CONCLUSION: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA-LV/5-FU.
Abstract: The current study aimed to assess the viability of sympathetic sudomotor fibers in cancer patients treated with cisplatin or paclitaxel-based chemotherapy and to ascertain whether this method could contribute to the diagnostic sensitivity of conventional techniques. Sympathetic skin response (SSR) from the hand and sole of 23 cancer patients (nine females and 14 males, mean age 62.4 +/- 10.5 years) was recorded unilaterally before and after chemotherapy with six courses of cumulative cisplatin or paclitaxel containing regimens. Clinical and electrophysiological data were also collected and correlated with the SSR results. Twenty-three healthy subjects served as controls. SSR abnormalities were only present in patients with evidence of peripheral neuropathy assessed by conventional nerve conduction techniques. Three patients had absent SSR in the upper limb whilst six patients had absent SSR both in the upper and lower limbs. In the upper limb, the mean SSR latency was not significantly altered through time (P = 0.086). In the lower limb the mean delay from baseline to follow-up was significantly changed (P = 0.029). In patients, the mean SSR latency was significantly prolonged compared with controls in both upper limb (P = 0.001) and lower limb (P = 0.000). SSR abnormalities were strongly related to sensory conduction abnormalities as detected by conventional techniques (r = 0.39, P = 0.004). Our results showed that SSR does not seem to add to the diagnostic sensitivity of conventional techniques in chemotherapy-induced neuropathy. However, its role in the disclosure of small fibers neuropathy abnormalities is worth considering. Further studies are warranted to address this important issue.
Abstract: OBJECTIVE: The current study intended to determine the incidence, severity and reversibility of paclitaxel plus carboplatin (CP)-induced peripheral neuropathy (CPPN) and to describe its clinical and electrophysiological features. PATIENTS AND METHODS: We prospectively studied 21 adult patients scheduled to be treated with 6 courses of cumulative carboplatin plus paclitaxel (CP) regimens for a non-myeloid malignancy. They were followed-up by neurological examination and electrophysiological study during chemotherapy and 3 months after its discontinuation. The severity of neurotoxicity was assessed by means of a modified peripheral neuropathy (PNP) score. RESULTS: Evidence of CPPN was recorded in 14 of the 21 patients (66.6 %). The sensory symptoms were present in the lower limbs first and then involved the upper limbs. No statistical significance, concerning the changes from baseline to subsequent mean scores in all motor conduction parameters examined,was revealed. By contrast, comparisons of the mean changes at baseline and each of the follow-up studies showed significant decrease in all sensory action potentials examined. The mean PNP scores for patients that manifested some grade of neurotoxicity were 17.9 +/- 9.8. The followup data 3 months after the discontinuation of chemotherapy showed that the CP-induced neuropathy was at least partially reversed. CONCLUSIONS: CP-induced neuropathy was symmetrical, distal and predominantly sensory in character, though minor to moderate motor signs were only evident in severely affected patients. Reversibility of CP-induced neuropathy was partially observed after the suspension of chemotherapy.
Abstract: 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.
Abstract: The purpose of the present study was to investigate the prognostic role of severe hypoxemia on admission as an independent risk factor of pulmonary complications and mortality in patients with acute pancreatitis. Pulmonary complications were studied in 166 previously healthy patients with acute pancreatitis. Forty-eight patients (28.9%) developed one or more pulmonary complications, including pleural effusion, atelectasis, pulmonary consolidations, and acute respiratory distress syndrome (ARDS). Pulmonary consolidations (odds ratio = 7.25) and, especially, ARDS (odds ratio = 22.9) were significantly associated with severe baseline hypoxemia (PaO2, <60 mm Hg). Mortality was mainly related to severity of disease (odds ratio = 46.45), while hypoxemia was also found to be an independent risk factor of poor outcome (odds ratio = 9.56). It seems that, in patients with acute pancreatitis, severe hypoxemia on admission may be an early predictive marker of pulmonary complications, especially ARDS, and, independently of severity score, it may also be a marker of poor outcome.
Abstract: 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-alpha 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.
Abstract: BACKGROUND: 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. METHODS: Patients who consented to participate were administered the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, the Mini-Mental State Examination (MMSE), and the Hospital Anxiety and Depression Scale before and at the end of treatment (EOT). RESULTS: Of the 102 patients initially assessed, 80 (78.4%) completed the study. Most aspects of QOL did not change considerably over time. At EOT, patients reported only significant increases in fatigue and significant decreases in sleep disturbance. Although no significant changes emerged in the rates of anxiety or depression throughout chemotherapy, nearly one-third of the patients experienced severe emotional distress at both points in time. In addition, the authors observed neither significant alteration in the cognitive performance over time nor reliable associations between scores on the MMSE and subjective cognitive function, emotional distress, or QOL. Finally, depression proved to be the leading predictor of global QOL at baseline and at EOT. CONCLUSIONS: The results indicated that a significant proportion of Greek patients with cancer experienced intense anxiety and depression throughout chemotherapy and confirmed the importance of depression as a strong predictor of global QOL. Routine screening of emotional distress across all phases of cancer is mandatory because it will contribute to the identification of patients who are in need of pharmaceutical and/or psychologic intervention.
Abstract: AIMS AND BACKGROUND: The objective of the study was to assess the efficacy of surgical resection of solitary brain metastasis in patients with non-small-cell lung cancer. METHODS AND STUDY DESIGN: We report a retrospective analysis of 32 patients with single brain metastasis surgically excised at our hospital. All but one patient underwent postoperative whole brain radiation therapy. RESULTS: The median survival of patients was 12.5 months postoperatively (mean, 17 months), and the overall 1-year survival was 53%. Thirteen patients had recurrence of brain metastasis: 6 of 13 underwent reoperation for the recurrent lesion, and 1 of the 6 patients had a third craniotomy. Baseline characteristics, which significantly influenced survival, included age less than 60 years, tumor histology (ie, adenocarcinoma), and treatment of the primary lung cancer. The analysis did not yield any significant differences between treatment modalities. CONCLUSIONS: Our findings correspond well with those reported in the literature and suggest that surgical resection of single brain metastasis in patients with non-small cell lung cancer can improve survival over conservative management. Furthermore, surgical treatment of the primary tumor and the single brain metastasis, combined or not with radiotherapy and chemotherapy, represents an approach that merits further investigation with more patients and a prospective longitudinal design.
Abstract: The purpose of this study was to assess whether the administration of recombinant human erythropoietin (rHuEPO) would correct anemia and improve the quality of life (QOL) in cancer patients receiving chemotherapy. One hundred twenty-two patients with hemoglobin </=11.0 g/dl were randomized to receive rHuEPO 10,000 U three times weekly (n = 61) or no additional treatment (n = 61). Response was assessed by measuring changes in hemoglobin level and QOL. QOL was evaluated before each cycle of chemotherapy at baseline, Week 4, and Week 12 using two separate self-report questionnaires. The analyses indicated that the rHuEPO-treated patients experienced significantly less fatigue (P < 0.05) than their control group counterparts, and reported significantly higher scores on energy level (P < 0.05), ability to perform daily activities (P < 0.01), and overall QOL (P< 0.05). The overall change in hemoglobin level was significantly greater in the rHuEPO group than in the control group (1.7 g/dl versus 0.3 g/dl, P < 0.001). rHuEPO effectively corrects anemia and significantly improves QOL in patients with solid tumors receiving chemotherapy.
Abstract: AIMS: To look for correlations between expression of cell cycle regulatory proteins p34(cdc2), p21(WAF1), and p53 in node negative invasive ductal breast carcinoma, or between these proteins and clinicopathological parameters, and to assess their prognostic value. METHODS: Immunohistochemistry using formalin fixed, paraffin wax embedded sections from 94 breast carcinomas. Adjacent benign epithelial breast tissue was available in 74 cases. Median follow up was 72 months. RESULTS: Nuclear and cytoplasmic p34(cdc2) expression was seen in 80 and 62 tumours, respectively; nuclear expression was seen in adjacent benign epithelium in 12 cases. p21(WAF1) and p53 were positive in 48 and 21 tumours, respectively. High expression of p34(cdc2) in neoplastic nuclei was associated with higher histological grade and p53 expression, but not with tumour size, steroid receptor status, patient age, menopausal status, recurrence, metastasis, disease free survival (DFS), or overall survival (OS). p34(cdc2) in tumour cytoplasm was associated with p34(cdc2) nuclear positivity, high tumour grade, and DFS in univariate but not multivariate analysis. In contrast, p34(cdc2) expression in benign tissue independently predicted DFS and OS in univariate and multivariate analysis. Expression of p53 was associated with high tumour grade and negative steroid receptors, but not with recurrence, metastasis, DFS, or OS. p21(WAF1) expression was not associated with the examined parameters. CONCLUSIONS: p34(cdc2), p21(WAF1), and p53 expression does not predict outcome in node negative breast carcinoma, although p34(cdc2) expression in benign tissue is related to prognosis. The association between p34(cdc2) and p53 implicates p53 in G2-M cell cycle checkpoint control, possibly via mediators unrelated to p21(WAF1).
Abstract: 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.
Abstract: PURPOSE: To evaluate the efficacy and tolerability of irinotecan plus vinorelbine every 2 weeks in patients with advanced non-small cell lung cancer (NSCLC), previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Forty-one patients with advanced NSCLC, refractory or resistant to platinum derivatives, were treated on an out-patient basis with irinotecan 150 mg/m2 intravenous (i.v.) and vinorelbine 25 mg/m2 on days 1 and 15. Chemotherapy was repeated every 4 weeks. The response was evaluated every two cycles. RESULTS: On an intent-to-treat analysis, 6 patients (14.6%) [95% confidence interval (CI) 5.57% to 29.17%] achieved partial response (PR), 15 (36.6%) stable disease (SD) and 20 (48.8%) progressive disease (PD). The median time to tumor progression (TTP) was 4.9 months (range 0.17-15.5 months), the median survival time was 7.8 months (range 0.9 to 19.6 months) and the 1-year survival rate was 37%. Symptomatic benefit response including improvement of performance status (PS), dyspnea, anorexia and fatigue, cessation of hemoptysis, fever and reduction of cough and pain was seen in 10 to 42% of patients. No patient experienced grade 3/4 anemia. Grade 3/4 thrombocytopenia occurred in 2 (5%) patients. Five patients (12%) developed grade 3/4 neutropenia and 5 (12%) had neutropenic fever that required hospitalization, but was successfully treated with antibiotics and G-CSF support. One patient (2%) developed grade 4 fatigue and was withdrawn. Other grade 3/4 adverse events included diarrhea (n = 3; 2 required hospitalization), alopecia (n = 5) and neurotoxicity (n = 1). Six patients required a dose reduction. CONCLUSION: The combination of irinotecan plus vinorelbine administered every 2 weeks demonstrated rather low activity in advanced NSCLC patients who had previously failed platinum-based chemotherapy, but it was well-tolerated and was associated with increased 1-year survival rate and improvement in cancer related symptoms.
Abstract: BACKGROUND: Treatment options for patients with recurrent nonsmall cell lung carcinoma (NSCLC) remain limited as a result of poor activity of older agents after platinum-based therapy. In the current Phase II study, the authors evaluated the combination of gemcitabine and docetaxel in patients with recurrent NSCLC. METHODS: Patients with advanced NSCLC (Stage IIIB-IV), a World Health Organization performance status (PS) < or = 2, prior paclitaxel plus platinum-based chemotherapy, and unimpaired hematopoietic and organ function were eligible. Chemotherapy was administered as follows: gemcitabine 1000 mg/m(2) was administered on Days 1 and 8 followed by docetaxel 100 mg/m(2) on Day 8, and this regimen was recycled every 21 days. Prophylactic granulocyte-colony stimulating factor was administered on Days 10-14 or until the patient achieved a white blood cell count > or = 5000/microL. RESULTS: Of 43 patients who were entered on the study, 41 patients were evaluable for response, and all were evaluable for toxicity. The median patient age was 63 years (range, 47-70 years), the median PS was 1 (range, 0-2), there were 38 male patients, and there were 5 female patients. Four patients had Stage IIIA disease, 17 patients had Stage IIIB disease, and 22 patients had Stage IV disease. Histologies included 19 patients with adenocarcinoma, 18 patients with squamous cell carcinoma, and 3 patients with large cell carcinoma. Metastatic sites included lymph nodes in 28 patients, bone in 6 patients, liver in 5 patients, brain in 5 patients, lung nodules in 8 patients, adrenals in 7 patients, and other sites in 3 patients. All patients had received prior paclitaxel plus platinum-based treatment; 28 patients had received prior paclitaxel, ifosfamide, and cisplatin. Objective responses were partial response (PR) in 14 of 43 patients [33%; 95% confidence interval [95%CI], 18.5-46.6%], stable disease (SD) in 16 of 43 patients (37%; 95% CI, 22.8-51.6%), and progressive disease (PD) in 13 of 43 patients (30%; 95% CI, 16.3-43.7%). The median time to disease progression was 6 months (range, 1.0-20.0+ months), and the median survival was 8.5 months (range, 1.5-20.0+ months). The 1-year survival rate was 28%. Grade 3-4 neutropenia was experienced by 53% of patients (30% Grade 4), with 14% of patients experiencing febrile neutropenia. Grade 3 thrombocytopenia was experienced by 7% of patients (no Grade 4), whereas other Grade 3 nonhematologic toxicities were never encountered. CONCLUSIONS: The combination of gemcitabine and docetaxel is active and is well tolerated in patients with advanced NSCLC who have failed prior taxane plus platinum chemotherapy. This regimen represents a tolerable and effective combination to apply in the palliative treatment of patients with recurrent NSCLC.
Abstract: The purpose of this phase II study was to evaluate the clinical efficacy of mitomycin C and vinblastine in patients with anthracycline-resistant metastatic breast cancer. This single-center, non-randomized trial enrolled 39 patients. Eligible patients must have received at least three chemotherapy regimens with epirubicin or CAF and had treatment failure while on chemotherapy or within 6 months of completing therapy. Treatment consisted of mitomycin C at a starting dose of 8 mg/m2 on day 1 and vinblastine (8 mg/m2, days 1 and 28). The regimen was repeated every 6 weeks with a 20% dose escalation of both drugs after the first cycle in the absence of grade III hematologic or other toxicity. On an intent-to-treat basis, 38 patients were eligible for assessment; 9 (23.7%, 95% confidence interval 1.92-2.45%) achieved a partial response and 13 (34.2%) had stable disease. The median time to disease progression was 6.21+/-4.26 months (range, 1-15; 95% confidence interval, 4.81-7.61), and the median survival was 10.76+/-7.6 (range, 1-29; 95% confidence interval 8.0-13.1%). Responsive patients had a significantly better survival than those with stable and progressive disease. Treatment was well tolerated. Anemia and neutropenia (grade I-III) developed in 28.9% and 26.3% of the patients, respectively. One patient with grade III granulocytopenia developed fever and infection that required hospitalization. Moderate neurotoxicity, myalgia, constipation, diarrhea and alopecia were observed. No toxic death occurred. Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer.
