Michael Hejna

Cardiac Toxicity of Sunitinib and Sorafenib in Patients With Metastatic Renal Cell Carcinoma

PURPOSE Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) that have considerable efficacy in metastatic renal cell carcinoma. TKI-associated cardiotoxicity was reported in approximately 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. PATIENTS AND METHODS In this observational, single-center study, all patients intended for TKI treatment were analyzed for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, ECGs, and biochemical markers (ie, creatine kinase-MB, troponin T). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. A cardiac event was defined as the occurrence of increased enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new left ventricular dysfunction, or acute coronary syndrome. RESULTS A total of 86 patients were treated with either sunitinib or sorafenib. Among 74 eligible patients, 33.8% experienced a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or intensive care admission. All patients recovered after cardiovascular management (ie, medication, coronary angiography, pacemaker implantation, heart surgery) and were considered eligible for TKI continuation. Statistically, there was no significant survival difference between patients who experienced a cardiac event and those who did not experience a cardiac event. CONCLUSION Our observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.

Oral Mucositis Complicating Chemotherapy and/or Radiotherapy: Options for Prevention and Treatment†

Chemotherapy‐ and radiotherapy‐induced oral mucositis represents a therapeutic challenge frequently encountered in cancer patients. This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses.

Endoscopic Ultrasound Guided Therapy of Benign and Malignant Biliary Obstruction: A Case Series

OBJECTIVES:Endoscopic retrograde cholangiography is an established method for treatment of common bile duct stones as well as for palliation of patients with malignant pancreaticobiliary strictures. It may be unsuccessful in the presence of a complex peripapillary diverticulum, prior surgery, obstructing tumor, papillary stenosis, or impacted stones. Percutaneous transhepatic biliary drainage and surgery are alternative methods with a higher morbidity and mortality in these cases. Recently, endoscopic ultrasound (EUS) guided biliary stent placement has been described in patients with malignant biliary obstruction. We describe our experience with this method that was also used for the treatment of cholangiolithiasis for the first time.METHODS:The EUS guided transduodenal puncture of the common bile duct with stent placement was performed in 5 patients. In 2 of these patients, the stents were removed after several weeks and common bile duct stones were extracted. In another patient with gastrectomy, the left intrahepatic bile duct was punctured transjejunally and a metal stent was introduced transhepatically to bridge a distal common bile duct stenosis.RESULTS:Biliary decompression was successful in all 6 patients. No immediate complications occurred. One patient developed a subacute phlegmonous cholecystitis.CONCLUSIONS:Interventional EUS guided biliary drainage is a new technique that allows drainage of the biliary system in benign and malignant diseases when the bile duct is inaccessible by conventional ERCP.

Monitoring of serum Her-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer

Purpose: The present pilot study was performed to elucidate whether early changes in serum Her-2/neu extracellular domain (ECD) levels during trastuzumab-based treatment would predict the clinical course of disease in patients with metastatic breast cancer. Experimental Design: Sera from 55 patients with Her-2/neu-overexpressing metastatic breast cancer obtained immediately before each weekly administration of trastuzumab were analyzed by a serum Her-2/neu ELISA. Results: Whereas response rates were significantly higher in patients with elevated (≥15 ng/ml) ECD levels before initiation of treatment (35% versus 7%, P = 0.045), progression-free and overall survival did not differ significantly between patients with normal and elevated ECD levels. In patients responding to treatment, ECD levels decreased significantly as early as from day 8 of treatment onwards (all P for weekly measurements versus baseline <0.001). In contrast, no significant change in ECD levels was observed in patients with progressive disease. Multiple logistic regression analyses identified kinetics of ECD levels as the only factor that allowed for the accurate prediction of response likelihood as early as from day 8 of trastuzumab-based treatment onwards (P = 0.020). In addition, determination of serial ECD levels allowed for the prediction of the risk for disease progression within the observed period as early as day 15 of treatment (P = 0.010). Conclusions: Serial monitoring of the ECD may represent a valuable tool for early prediction of the probability of response and progression-free survival to trastuzumab-based treatment and is thus likely to contribute to an optimization of treatment and resource allocation.

Association between Helicobacter pylori Infection and Pancreatic Cancer

Purpose: In order to determine whether infection with Helicobacter pylori might be associated with pancreatic adenocarcinoma, we performed a study to compare the H. pylori seroprevalence rate between patients with pancreatic carcinoma and matched control subjects. Patients and Methods: Blood samples from 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma admitted to our hospital between January 1994 and July 1995 were analyzed for the presence of IgG antibodies against H. pylori by a commercially available enzyme-linked immunosorbent assay. Thirty patients with gastric cancer, 35 patients with colorectal cancer, and 27 healthy volunteers served as controls. In addition to these serological analyses, tumor specimens from 20 patients with pancreatic adenocarcinoma were microscopically investigated for the presence of H. pylori. Results: 65% of pancreatic cancer patients and 69% of those with gastric cancer were found to be seropositive, while only 45% of the other controls tested positive. Statistical analysis revealed no difference in seropositivity between the cohort of patients suffering from pancreatic and gastric cancer. The rate of seropositivity was more prominent, however, in pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls (p = 0.035), with an odds ratio of 2.1 (1.1–4.1). Microscopic evaluation of human pancreatic cancer specimens showed no evidence for the presence of H. pylori. Conclusion: Our data suggest an association between H. pylori infection and pancreatic cancer. Despite demonstration of a positive relationship and its physiological plausibility, larger prospective studies are needed to confirm our preliminary findings and to assess H. pylori as a potential carcinogenic risk factor.

Combined Irinotecan and Oxaliplatin Plus Granulocyte Colony-Stimulating Factor in Patients With Advanced Fluoropyrimidine/Leucovorin-Pretreated Colorectal Cancer

PURPOSE To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. RESULTS The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.

Esophageal Cancer: A Critical Evaluation of Systemic Second-Line Therapy

The objective of this article was to review clinical trials that used antineoplastic second-line chemotherapy and/or targeted therapies in patients with esophageal cancer after first-line therapy. Computerized (MEDLINE) and manual searches were performed to identify articles published on this topic between 1996 and 2011. Twenty-five published trials and four abstracts presented at scientific meetings were identified. A total of 10 trials included only patients with squamous cell carcinomas (SCCs), four focused exclusively on adenocarcinoma (AC), the remaining 15 studies included both SCC and AC. The majority of trials (17 of 29) used docetaxel in combination with platinum analogs, eight used single-agent cytotoxic chemotherapy, and six evaluated targeted therapies. The numbers of patients were relatively small, ranging from eight to 55 patients. The response rates were generally low (between 0% and 39%), with only two small studies reporting objective responses of 50% and 63%, respectively. Time to progression ranged from 1.4 to 6.2 months, and the overall survival was disappointing at 4.0 to 11.4 months. Approximately 40% of patients who experience progressive disease after first-line chemotherapy are able to undergo second-line treatment. On the basis of data published so far, no standard second-line therapy has emerged. Future research will need to focus on individual therapy strategies such as genetic receptor mutations to increase the therapeutic outcome.

Antibiotic Treatment Is Not Effective in Patients Infected With Helicobacter pylori Suffering From Extragastric MALT Lymphoma

PURPOSE Apart from anecdotal reports implicating Helicobacter pylori (HP) in the development of extragastric mucosa associated lymphoid tissue (MALT) lymphoma, no large scale prospective studies have been performed on this topic. PATIENTS AND METHODS A total of 77 patients with extragastric MALT lymphoma were prospectively studied. The presence or absence of HP was tested by histology, urease breath test, and serology. Patients were also tested for hepatitis A, B, and C and autoimmune conditions along with assessment of MALT lymphoma-specific genetic changes. RESULTS Evidence for infection with HP was present in 35 of 77 patients (45%), and three of 75 patients tested (4%) were positive for hepatitis C and one for hepatitis B. All patients with HP-infection underwent eradication, 16 before initiation of further therapy. Apart from one patient with lymphoma involving parotid and colon, who achieved regression of the colonic lesions, none of these 16 patients showed regression of the lymphoma after a median follow-up of 14 months (range, 8 to 48+ months) before initiation of definitive treatment. No correlation between HP-status, localization, stage, autoimmune diseases, and genetic findings was seen. CONCLUSION In our series, HP-eradication was ineffective for treatment of extragastric MALT lymphomas. This finding, along with an infection rate of 45%-as could also be expected in the general Austrian population-suggests that HP does not play a role in the development of these lymphomas. Antibiotic treatment targeting HP should, therefore, be discouraged in patients with extragastric MALT lymphomas.

Nonsurgical management of malignant thymoma

Thymoma is a rare tumor entity. Surgery remains the mainstay of treatment, but radiation and chemotherapy also have been applied widely in both the adjuvant and the palliative setting. The objective of this study was to review briefly the clinical trials available in the current literature utilizing nonsurgical oncologic treatment (radiotherapy and chemotherapy) either in patients with advanced (i.e., locally inoperable) or metastatic thymoma or as an adjunct to surgery.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality

Objective Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. Methods We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. Results During a median follow-up of 25 (IQR 16–31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. Conclusions Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.