Acute coronary syndrome associated with continuous 5-fluorouracil infusion in a patient with metastatic colorectal cancer-a case report with a discussion on this clinical dilemma

Introduction: 5-Fluorouracil (5-FU) is considered to be the backbone of colorectal cancer (CRC) systemic therapy since the great majority of recommended regimens include its administration. A clinical picture consisting of chest pain, sometimes cardiac enzyme elevation, electrocardiogram abnormalities consistent with myocardial ischemia, and normal coronary angiogram associated with 5-FU administration have been infrequently reported. The clinical dilemma is: Which chemotherapy regimen should we use in CRC patients with a previous acute coronary syndrome (ACS) associated with 5-FU? Case Report: We describe the case of a 55-year-old otherwise healthy woman with metastatic colon adenocarcinoma who presented an ACS probably secondary to arterial vasospasm while receiving continuous intravenous 5-FU infusion (mFOLFOX6 regimen). After the ACS, the patient was treated with raltitrexate plus oxaliplatin (TOMOX) and subsequently with irinotecan plus cetuximab with no other cardiac event. Conclusion: The risk of cardiotoxicity associated with 5-FU is low but real. The probable mechanism is arterial vasospasm, as suggested by our case report. Both the use of the TOMOX regimen and irinotecan plus cetuximab seems to be safe regimens to be considered in this clinical scenario. © 2009 Humana Press Inc.

Autophagy in cancer and chemotherapy

Cancer cells often exhibit mutations in critical molecules of the apoptotic machinery, resulting in resistance to common anticancer therapies. In the absence of apoptosis, autophagic cell death can be an alternative form of cell death by excessive self-digestion. Therefore, autophagic cell death can be considered as a backup cell death mechanism when apoptotic cell death mechanisms fail. However, many tumors also exhibit deficiencies in autophagy that may result in both genomic instability and further anticancer drug resistance. This chapter summarizes our current understanding regarding the regulation of autophagy in tumors and discusses potential new anticancer drug treatment strategies.

The Role of Autophagy in Cancer and Chemotherapy

Resistance to current chemo- and radiation therapy is the principal problem in anticancer treatment. Although intensively investigated, the therapeutic outcome is still far from satisfactory. Among the multiple factors which contribute to the drug resistance in cancer cells, the involvement of autophagy is becoming more and more evident. Autophagy describes a cellular self-digestion process, in which cytoplasmic elements can be selectively engulfed and finally degraded in autophagolysosomes to supply nutrients and building blocks for the cells. Autophagy controls cellular homeostasis and can be induced in response to stresses, like hypoxia and growth factor withdrawal. Since the essential physiological function of autophagy is to maintain cellular metabolic balance, dysregulated autophagy has been found associated with multiple diseases, including cancer. Interestingly, the role of autophagy in cancer is two-sided; it can be pro- or antitumor. Autophagy can suppress tumor formation, for example, by controlling cell proliferation and the production of reactive oxygen species. On the other hand, autophagy can provide nutrients to the tumor cells to support tumor growth under nutrition-limiting conditions, thereby promoting tumor development. This ambivalent behavior is also evident in anticancer therapy: By inducing autophagic cell death, autophagy has been shown to potentiate the cytotoxicity of chemotherapeutic drugs, but autophagy has also been linked to drug resistance, since inhibiting autophagy has been found to sensitize tumor cells toward anticancer drug-induced cell death. In this chapter, we will focus on the dual role of autophagy in tumorigenesis and chemotherapy, will classify autophagy inducers and inhibitors used in anticancer treatment, and will discuss topics related to future drug development which have arisen.

A systematic review of the cost-effectiveness of targeted therapies for metastatic non-small cell lung cancer (NSCLC)

Background: Non-small cell lung cancer (NSCLC) imposes a substantial burden on patients, health care systems and society due to increasing incidence and poor survival rates. In recent years, advances in the treatment of metastatic NSCLC have resulted from the introduction of targeted therapies. However, the application of these new agents increases treatment costs considerably. The objective of this article is to review the economic evidence of targeted therapies in metastatic NSCLC. Methods: A systematic literature review was conducted to identify cost-effectiveness (CE) as well as cost-utility studies. Medline, Embase, SciSearch, Cochrane, and 9 other databases were searched from 2000 through April 2013 (including update) for full-text publications. The quality of the studies was assessed via the validated Quality of Health Economic Studies (QHES) instrument. Results: Nineteen studies (including update) involving the MoAb bevacizumab and the Tyrosine-kinase inhibitors erlotinib and gefitinib met all inclusion criteria. The majority of studies analyzed the CE of first-line maintenance and second-line treatment with erlotinib. Five studies dealt with bevacizumab in first-line regimes. Gefitinib and pharmacogenomic profiling were each covered by only two studies. Furthermore, the available evidence was of only fair quality. Conclusion: First-line maintenance treatment with erlotinib compared to Best Supportive Care (BSC) can be considered cost-effective. In comparison to docetaxel, erlotinib is likely to be cost-effective in subsequent treatment regimens as well. The insights for bevacizumab are miscellaneous. There are findings that gefitinib is cost-effective in first- and second-line treatment, however, based on only two studies. The role of pharmacogenomic testing needs to be evaluated. Therefore, future research should improve the available evidence and consider pharmacogenomic profiling as specified by the European Medicines Agency. Upcoming agents like crizotinib and afatinib need to be analyzed as well. © Lange et al.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

Tratamento do carcinoma metastático

The renal cell carcinoma (RCC) is the seventh most common malignancy, accounting for more than 3% of cancer incidence in the United States. RCC is more common in males, occurring primarily in the 5 th to 7 th decades of life. At the time of presentation one third of the patients have advanced disease and about 50% of the patients that underwent radical nephrectomy have recurrence. With the mainstream implementation of imaging modalities, such as ultrasound, the incidental detection of RCC has dramatically increased in recent years. Patients with metastatic RCC without treatment have na average survival of 6 to 10 months, and only 10 to 20% can be expected to survive 2 years. Treatment for patients with advanced disease remains unsatisfactory and the metastatic renal cancer continue to present a therapeutic challenge systemic therapies employed in patients with this tumor include chemotherapy, hormonal therapy, and immunotherapy. The authors review the treatment strategies of the metastatic renal cell carcinoma (RCC).

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma - The DD protocol

Context and Objective: Lipasomial daunorubicin has been used to treat hematological malignancies, including multiple myelomo (MM). The goal was to evaluate efficacy, side-effects and toxicity of liposomal daunorubicin and dexamethasone (DD Protocol). Design and Setting: Prospective study of Sírio-Libonês, São Camilo, Brasil and Alemão Oswaldo Cruz hospitals. Methods: Twenty consecutive patients with active MM received four cycles of liposomal daunorubicin intravenously for two hours (25-30 mg/m 2/day) on three consecutive days per month, with oral dexamethasone, (10 mg every six hours) on four consecutive days three times a month. Results: The male/female ratio was 1:1 and median age 60. Nine patients were stage IIA, ten IIIA and one IIIB. The median from diagnosis to starting DD was 13 months. All patients received four cycles, except one. Fifteen had already received chemotherapy before DD. Responses of > 50% reduction in serum monoclonal paraprotein were observed in six patients after first cycle (30%), six after second (30%) and four after third (20%), while four (20%) did not obtain this. Initially, 17 patients (85%) had anemia: 12 (70%) achieved correction. Progressive disease was observed in three patients (15%), while one had minimal response, four (20%) partial and 12 (60%) complete. Hemotologlical toxicity was acceptable: three patients (15%) had neutrophils < 1,000/mm 3; none had thrombocyfopenia. Gastrointestinal toxicity was mild: nausea (10%), anorexio (15%) and no vomiting. Conclusions: This treatment has mild toxicity and good response rate. It may therefore be feasible before autologous bone marraw transplantation.

Post-ganglionic Horner's syndrome: An unusual presentation of non-Hodgkin lymphoma

In this paper, we present the rare case of a patient with cervical lymphadenopathy diagnosed as a T-cell-rich B-cell non-Hodgkin lymphoma that manifested Horner's syndrome due to a post-ganglionic sympathetic neuron lesion caused by the tumor. Copyright © 2012 S. Karger AG, Basel.

Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non-small-cell lung cancer

Purpose: In non-small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45). Patients and Methods: Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33). Results: Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea. Conclusion: Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs. © 2007 by American Society of Clinical Oncology.

Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy

The PI3-kinase pathway is the target of inactivation in achieving better cancer chemotherapy. Here, we report that p53-mediated transcription is inhibited by pharmacological inhibitors and a dominant-negative mutant of PI3-kinase, and this inhibition was relieved by a constitutively active mutant of PI3-kinase. Akt/PKB and mTOR, the downstream effectors of PI3-kinase, were also found to be essential. LY294002 (PI3-kinase inhibitor) pre-treatment altered the post-translational modifications and the sub-cellular localization of p53. Although LY294002 increased the chemosensitivity of cells to low concentrations of adriamycin (adriamycin-low), it protected the cells from cytotoxicity induced by high concentrations of adriamycin (adriamycin-high) in a p53-dependent manner. Further, we found that LY294002 completely abolished the activation of p53 target genes (particularly pro-apoptotic) under adriamycin-high conditions, whereas it only marginally repressed the p53 target genes under adriamycin-low conditions; in fact, it further activated the transcription of NOXA, HRK, APAF1 and CASP5 genes. Thus, the differential effect of PI3-kinase on p53 functions seems to be responsible for the differential regulation of DNA damage-induced cytotoxicity and cell death by PI3-kinase. Our finding becomes relevant in the light of ongoing combination chemotherapy trials with the PI3-kinase pathway inhibitors and underscores the importance of p53 status in the careful formulation of combination chemotherapies. Oncogene (2010) 29, 3605-3618; doi: 10.1038/onc.2010.123; published online 26 April 2010

BRCA1 and implications for response to chemotherapy in ovarian cancer

Objectives: Treatment of epithelial ovarian cancer (EOC) remains a challenge, despite advances in surgery and chemotherapy. Hereditary ovarian cancer is primarily due to germline mutations in the BRCA1 tumour suppressor gene. In addition, sporadic EOC tumours display signi?cant of loss of BRCA1 function due to epigenetic inactivation of the BRCA1 gene. This article reviews the preclinical and clinical evidence to support a role for BRCA1 as a potential predictive biomarker of response to both platinum and taxane based chemotherapy in EOC.

Methods: We conducted a Medline and Pubmed search for reports between 1990 and 2008 using the search terms: BRCA1 and hereditary ovarian cancer, BRCA1 and sporadic ovarian cancer, ovarian cancer and chemotherapy, ovarian cancer and taxanes, ovarian cancer and platinums, ovarian cancer and clinical response, BRCA1 and DNA damage, BRCA1 and DNA repair, BRCA1 and mitotic checkpoint. If reports identi?ed by these criteria referred to other papers not in the initial search, then these were also reviewed if relevant to BRCA1 and ovarian cancer.

Results: The BRCA1 pathway plays a signi?cant role in the development of both hereditary and sporadic EOC. Evidence suggests that BRCA1 is a potential biomarker of response to platinum chemotherapy in EOC with BRCA1 de?ciency predicting for enhanced response. In contrast, initial evidence suggests that loss of BRCA1 function results in reduced response to antimicrotubule-based chemotherapy. The ability of BRCA1 to differentially modulate response to these agents involves loss of BRCA1 mediated DNA repair and mitotic checkpoint control, respectively.

Conclusions: Standard ?rst line treatment of EOC consists of a combination of platinum and taxane chemotherapy, however clinically useful biomarkers for predicting response to these agents have yet to be established. BRCA1 may prove useful as a biomarker in EOC for assigning chemotherapy treatments based on the presence or absence of BRCA1 function.

Adjuvant chemotherapy followed by goserelin compared with either modality alone: the impact on amenorrhea, hot flashes, and quality of life in premenopausal patients--the International Breast Cancer Study Group Trial VIII

The purpose of this article is to compare quality of life (QOL) and menopausal symptoms among premenopausal patients with lymph node-negative breast cancer receiving chemotherapy, goserelin, or their sequential combination, and to investigate differential effects by age.

Cochrane review summary for cancer nursing : influenza vaccination in children having chemotherapy for cancer

Background: Children having chemotherapy for cancer are prone to developing influenza infections. Influenza virus infection may lead to hospitalization/prolonged hospitalization, interruption of treatment, and other severe adverse outcomes such as death. Although clinical guidelines recommend children who are being treated for cancer be vaccinated against influenza, evidence supporting this recommendation is unclear.--------- Objectives: The objectives of this review were to (1) assess the efficacy of influenza vaccination in stimulating immunologic response in children with cancer receiving chemotherapy, compared with other control groups; (2) assess the efficacy of influenza vaccination in preventing influenza infection; and (3) establish any adverse effects associated with influenza vaccines in children with cancer.