Gemcitabine: Progress in the treatment of pancreatic cancer

Unresectable pancreatic cancer has a dismal prognosis with a median survival of 3-5 months in untreated disease. Since the introduction of gemcitabine, pancreatic cancer may no longer be regarded a chemotherapy-resistant tumor. Treatment with single-agent gemcitabine achieved clinical benefit and symptoms improvement in 20-30% of patients. While 1-year survival was observed in 2% of 5-fluorouracil (5-FU)-treated patients, it was raised to 18% by single-agent gemcitabine. Good treatment tolerability and low incidence of side effects are clear advantages of single-agent gemcitabine. Improvement of efficacy is, however, expected from combination treatment. Gemcitabine and cisplatin given as first-line treatment in three studies achieved a median survival of 7.4-8.3 months. One-year survival was raised to 28% as reported in one study. Comparable activity was obtained by a combination of gemcitabine with 5-FU. Nine studies using gemcitabine in combination with standard-dose or high-dose 5-FU reported a median survival ranging from 5.5 to 13 months. Notwithstanding these promising results, recommendations regarding palliative chemotherapy of pancreatic cancer remain tentative and still need confirmation by presently ongoing phase III trials. Inclusion of pancreatic cancer patients into clinical trials should be a major goal. Outside clinical trials, patients should present with an adequate PS (Karnofsky-performance index greater than or equal to 70) to qualify for chemotherapy. Copyright (C) 2001 S. Karger AG, Basel

Role of gemcitabine in the treatment of advanced and metastatic breast cancer

Gemcitabine is an antimetabolite drug with proven antitumor activity and tolerability in metastatic breast cancer. In a total of nine studies, gemcitabine monotherapy has reached response rates of up to 37% in the first-line setting, 26% in the second-line setting, and 18% or better in the third-line setting. Gemcitabine is an excellent choice for combination therapy by its unique mechanism of action and favorable toxicity profile, thus limiting the risk of pretreatment-related drug resistance and overlapping toxicity, and by its potential for synergistic interaction with some combination partners as indicated in preclinical studies. Numerous phase II clinical studies have combined gemcitabine with other active agents such as the taxanes, vinorelbine, vindesine, cisplatin, 5-fluoro-uracil, as well as anthracyclines across various regimens and conditions of pretreatment. Most of these two-drug combinations have consistently demonstrated higher efficacy than either single agent, particularly in pretreated patients. Even higher efficacy has been obtained with triple-drug regimens including gemcitabine, anthracyclines (epirubicin or doxorubicin), and paclitaxel; these regimens have yielded overall response rates of 58-92% as first-line treatment. In view of these results, gemcitabine may be regarded as a valuable alternative to the palliative treatment of metastatic breast cancer, and an excellent option for the development of effective combination treatment not only in first-line therapy, but also for intensively pretreated patients previously exposed to anthracyclines and/or the taxanes. Copyright (C) 2003 S. Karger AG, Basel

Bevacizumab plus Irinotecan-Based Regimens in the Treatment of Metastatic Colorectal Cancer

Objectives: Bevacizumab is a monoclonal antibody that directly inhibits vascular endothelial growth factor, a key regulator of angiogenesis. Bevacizumab significantly improves progression-free and/or overall survival in metastatic colorectal cancer in combination with standard chemotherapy. This review describes the evolution of irinotecan-based regimens for metastatic colorectal cancer and evaluates the addition of bevacizumab to these regimens. Methods: Literature searches from large publication databases (PubMed, ASCO, ASCO GI, ESMO) were performed to capture key data relevant to bevacizumab, irinotecan, and the treatment of colorectal cancer. Results: Data from numerous large, multinational studies support the addition of bevacizumab to irinotecan-containing chemotherapy regimens for further improvement in patient outcomes. In a randomized, placebo-controlled trial, addition of bevacizumab to irinotecan significantly improved progression-free survival, overall survival and response rate in patients with metastatic colorectal cancer, and these results are supported by a number of other clinical trials and observational studies. Furthermore, the addition of bevacizumab to irinotecan improves outcomes regardless of K-ras mutational status. Bevacizumab has a well-established safety profile and the toxicities associated with its use are usually mild in severity and easily manageable. Conclusions: Addition of bevacizumab to irinotecan-containing regimens is an effective therapy option for the treatment of metastatic colorectal cancer. Copyright (C) 2010 S. Karger AG, Base

Capecitabine as second-line treatment for metastatic cholangiocarcinoma: A report of two cases

Background: The management of recurrent, metastatic cholangiocarcinoma still remains a problem since this tumor entity is classified as chemotherapy-resistant. When advanced or metastatic disease is diagnosed, the therapeutic efforts are essentially directed toward palliation. Patients and Methods: We report on 2 patients suffering from metastatic cholangiocarcinoma. Both had received previous chemotherapy for metastatic disease, including hepatic artery infusion {[}5-fluorouracil (5-FU)/folinic acid (FA) and oxaliplatin] and a combination therapy consisting of 5-FU/FA and gemcitabine. Since a progression of the disease was diagnosed, both patients were started on oral capecitabine at a daily dose of 2,500 mg/m(2) in 2 divided doses for 2 weeks, followed by 1 week rest. Results: Capecitabine was tolerated well and severe side effects were not observed. A stop of progression, documented by imaging procedures and tumor marker kinetics, was achieved in both patients. Conclusion: Capecitabine could potentially be used for second-line treatment in patients with progressive metastatic cholangiocarcinoma

Stand und Perspektiven der Chemotherapie beim anthrazyklinvorbehandelten Mammakarzinom – Ergebnisse randomisierter Studien

Randomized trials performed in anthracycline-pretreated breast cancer patients have demonstrated good activity of taxane-based regimens. In a face to face comparison, single-agent docetaxel proved to be significantly more effective than paclitaxel. Treatment with docetaxel was also associated with an increased incidence of grade grade-3/4 toxicities in this trial. Antitumor activity of taxane-based combination regimens was clearly superior to single-agent therapy in two trials. As anticipated, treatment-associated toxicity was greater with combination regimens, but this did not affect quality of life

Role of gemcitabine in the treatment of advanced and metastatic breast cancer

Gemcitabine is an antimetabolite drug with proven antitumor activity and tolerability in metastatic breast cancer. In a total of nine studies, gemcitabine monotherapy has reached response rates of up to 37% in the first-line setting, 26% in the second-line setting, and 18% or better in the third-line setting. Gemcitabine is an excellent choice for combination therapy by its unique mechanism of action and favorable toxicity profile, thus limiting the risk of pretreatment-related drug resistance and overlapping toxicity, and by its potential for synergistic interaction with some combination partners as indicated in preclinical studies. Numerous phase II clinical studies have combined gemcitabine with other active agents such as the taxanes, vinorelbine, vindesine, cisplatin, 5-fluoro-uracil, as well as anthracyclines across various regimens and conditions of pretreatment. Most of these two-drug combinations have consistently demonstrated higher efficacy than either single agent, particularly in pretreated patients. Even higher efficacy has been obtained with triple-drug regimens including gemcitabine, anthracyclines (epirubicin or doxorubicin), and paclitaxel; these regimens have yielded overall response rates of 58-92% as first-line treatment. In view of these results, gemcitabine may be regarded as a valuable alternative to the palliative treatment of metastatic breast cancer, and an excellent option for the development of effective combination treatment not only in first-line therapy, but also for intensively pretreated patients previously exposed to anthracyclines and/or the taxanes. Copyright (C) 2003 S. Karger AG, Basel

Re-evaluation of HER2 status in metastatic breast cancer and tumor-marker guided therapy with vinorelbine and trastuzumab

Background: HER2 is overexpressed in 20 - 30% of breast cancers. Compared to chemotherapy alone, chemotherapy with trastuzumab improves clinical outcome in patients with HER2- positive metastatic breast cancer ( MBC). In general, HER2 status in a primary lesion predicts the status of metastases, so that biopsy of metastatic lesions appears unnecessary. Case Report: A 39- year old woman was diagnosed with primary breast cancer in November 2000. Using the method and scoring system of the DAKO Hercep Test, the tumor has shown low HER2 expression ( DAKO score 1+). After failure of several chemotherapy regimens for metastatic disease ( liver, skeletal), the patient underwent CT- guided needle biopsy of the liver which showed HER2 positive adenocarcinoma ( DAKO score 3+). In consequence, the patient was treated with vinorelbine ( 30 mg/ m(2) d1,8,15 q4w) and trastuzumab ( 4 mg/ kg loading dose, 2 mg/ kg weekly). During a treatment period of 4 months imaging results as well as tumor marker kinetics indicated an excellent response with sustained decrease of tumor markers. A retrospective analysis of the HER2 shed antigen in metastatic stage revealed excessively increased serum levels and supports HER2 overexpression observed in liver metastasis. The kinetics of the HER2 shed antigen during therapy for metastatic disease were found to be in phase with the kinetics of CEA and CA15- 3. Conclusion: This case report demonstrates that re- evaluation of the HER2 status may be helpful in single patients not sufficiently responding to treatment of metastatic disease. Determination of HER2 overexpression may be facilitated by a determination of the HER2 shed antigen level in peripheral blood

Sinnvoller Einsatz von Tumormarkern

Tumor markers refer to all detectable and measurable analytes which are able to indicate a solid tumor or contribute to its characterization or judgment concerning tumor spread and therapy efficacy. Among the markers, humoral circulating tumor substances, such as precursors of normal antigens, ectopically produced hormones or enzymes, ontogenetic old reactivated antigens, hybridoma-defined mucins and cytokeratins are of special interest. Up to now, no tumor specific biomarker has been detected, all markers known so far are physiological components of blood; thus, their diagnostic capacity is more related to quantity than to quality. The tumor marker concentration depends on the tumor blood supply and reflects tumor mass and tumor spread as a sum of marker expression, synthesis, release, the catabolism of the organism, as well as the marker excretion. Changes in biomarker levels without correlation to tumor load can be due to impairment of the liver and kidney function or due to invasive diagnostic methods (endoscopy, biopsy, ureteral catheter) or due to acute reactions on treatment (surgery, radio-chemotherapy). Due to problems with standardization between assays from different producers measuring the same antigen, interpretation of biomarkers of single measurements, such as PSA (prostate specific antigen), must be performed using assay specific reference ranges and interpretation of serial measurements must be performed using the identical assay. The test result has to be indicated together with the assay used (kit and producer). Among the potential indications for tumor marker determinations, the early detection or screening of a tumor is unrealistic - except PSA in prostate cancer detection. In rare cases, biomarkers can be helpful in tumor localization (HTG (human thyreoglobuline), PSA) and support of primary diagnosis, the knowledge about their prognostic relevance is increasing, the most widely used indication is therapy control and follow-up care in context with medical imaging. Provided that markers are critically selected following the localization of the tumor, that serial determinations are performed using the identical assay and that the clinical question is relevant, tumor markers contribute to a significant degree to diagnosis, prognosis, therapy control and early detection of metastatic or recurrent disease. Especially in the field of diagnostic oncology, the quality of the investigator is significantly linked to the quality of the test result