Christoph C. Zielinski

Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study

PURPOSE Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. METHODS Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. RESULTS We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. CONCLUSION Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

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.

Bevacizumab, Capecitabine, and Oxaliplatin As Neoadjuvant Therapy for Patients With Potentially Curable Metastatic Colorectal Cancer

PURPOSE Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, but can benefit from perioperative chemotherapy and disease resection. Bevacizumab improves outcomes in patients with metastatic CRC; however, its impact on surgical complications and hepatic regeneration after liver resection remains to be determined. PATIENTS AND METHODS Fifty-six patients with metastatic CRC with liver metastases potentially curable by resection were eligible for this single-center, nonrandomized phase II trial. Eligibility criteria defined patients at high risk of early recurrence. Patients received biweekly bevacizumab plus capecitabine and oxaliplatin for six cycles. The sixth cycle of therapy did not include bevacizumab, resulting in 5 weeks between the last administration of bevacizumab and surgery. RESULTS Objective response to neoadjuvant chemotherapy was achieved in 41 patients (73%). Fifty-two patients underwent liver resection including 11 with synchronous primary tumor resection. No increased intraoperative bleeding events or wound-healing complications were observed and only three patients (6%) required perioperative blood transfusions. Further surgery was necessary in a single patient. Postoperative liver function and regeneration were normal in all but one patient. No postoperative mortality occurred and morbidity was encountered in 11 patients (20%). The mean length of postoperative hospitalization was 9 days (+/- 4.0). CONCLUSION These data suggest that bevacizumab can be safely administered until 5 weeks before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or severity of bleeding. To our knowledge, they are also the first to show that neoadjuvant bevacizumab does not affect liver regeneration after resection.

Prediction of venous thromboembolism in cancer patients

The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating 2 biomarkers, soluble P-selectin, and D-Dimer. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

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.

High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients - results from the Vienna Cancer and Thrombosis Study (CATS)

Cancer patients are at high risk for venous thromboembolism (VTE). Laboratory parameters with a predictive value for VTE could help stratify patients into high- or low-risk groups. The cell adhesion molecule P-selectin was recently identified as risk factor for VTE. To investigate soluble P-selectin (sP-selectin) in cancer patients as risk predictor for VTE, we performed a prospective cohort study of 687 cancer patients and followed them for a median (IQR) of 415 (221-722) days. Main tumor entities were malignancies of the breast (n = 125), lung (n = 86), gastrointestinal tract (n = 130), pancreas (n = 42), kidney (n = 19), prostate (n = 72), and brain (n = 80); 91 had hematologic malignancies; 42 had other tumors. VTE occurred in 44 (6.4%) patients. In multivariable analysis, elevated sP-selectin (cutoff level, 53.1 ng/mL, 75th percentile of study population) was a statistically significant risk factor for VTE after adjustment for age, sex, surgery, chemotherapy, and radiotherapy (hazard ratio = 2.6, 95% confidence interval, 1.4-4.9, P = .003). The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin above and 3.7% in those below the 75th percentile (P = .002). High sP-selectin plasma levels independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer could help identify patients at increased risk for VTE.

D-Dimer and Prothrombin Fragment 1 + 2 Predict Venous Thromboembolism in Patients With Cancer: Results From the Vienna Cancer and Thrombosis Study

PURPOSE Venous thromboembolism (VTE) is a well-recognized complication of cancer. Laboratory parameters might be useful to assess the VTE risk in patients with cancer. The aim of this study was to investigate D-dimer and prothrombin fragment 1 + 2 (F 1 + 2), which reflect activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE. PATIENTS AND METHODS In a prospective, observational, cohort study of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive chemotherapy, radiotherapy, or surgery were enrolled and followed for a median of 501 days (interquartile range, 255 to 731 days). The malignancies in these patients were as follows: breast (n = 132), lung (n = 119), stomach (n = 35), lower gastrointestinal tract (n = 106), pancreas (n = 46), kidney (n = 22), and prostate (n = 101) cancers; high-grade glioma (n = 102); malignant lymphoma (n = 94); multiple myeloma (n = 17); and other tumor types (n = 47). The study end point was occurrence of objectively confirmed symptomatic or fatal VTE. RESULTS VTE occurred in 62 patients (7.6%). The cutoff level for elevated D-dimer and elevated F 1 + 2 was set at the 75th percentile of the total study population. In multivariable analysis that included elevated D-dimer, elevated F 1 + 2, age, sex, surgery, chemotherapy, and radiotherapy, the hazard ratios (HRs) of VTE in patients with elevated D-dimer (HR, 1.8; 95% CI, 1.0 to 3.2; P = .048) and elevated F 1 + 2 (HR, 2.0; 95% CI, 1.2 to 3.6; P = .015) were statistically significantly increased. The cumulative probability of developing VTE after 6 months was highest in patients with both elevated D-dimer and elevated F 1 + 2 (15.2%) compared with patients with nonelevated D-dimer and nonelevated F 1 + 2 (5.0%; P < .001). CONCLUSION High D-dimer and F 1 + 2 levels independently predict occurrence of VTE in patients with cancer.

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.

Capecitabine and Trastuzumab in Heavily Pretreated Metastatic Breast Cancer

PURPOSE In human epidermal growth factor 2 (HER-2)-positive advanced breast cancer, taxanes or vinorelbine plus trastuzumab are among the most widely applied options in the first-line setting. We evaluated the efficacy and tolerability of capecitabine plus trastuzumab after anthracycline and docetaxel or vinorelbine failure and prior trastuzumab exposure. PATIENTS AND METHODS Forty consecutive patients were included. Capecitabine was administered at a dose of 1,250 mg/m(2) bid for 14 consecutive days in 3-week cycles, with dose modifications if necessary. Trastuzumab was administered every 3 weeks. Time to progression (TTP) was defined as primary end point. Response was evaluated every 3 months using International Union Against Cancer criteria. RESULTS TTP was a median of 8 months, and overall survival was 24 months. No significant difference was found for second-line and beyond second-line treatment. A complete response (CR) was observed in 2.5%, partial response (PR) in 17.5%, stable disease lasting at least 6 months (SD) in 50%, resulting in a clinical benefit rate (CR + PR + SD > or = 6 months) of 70%. Diarrhea (5%) and hand-foot syndrome (15%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity. Three patients (7.5%) developed brain metastases while receiving therapy. CONCLUSION Capecitabine plus trastuzumab appears to be an effective and safe option in a heavily pretreated population. Therefore, a direct comparison of this regimen with capecitabine monotherapy in this setting is warranted.

High D-dimer levels are associated with poor prognosis in cancer patients

Background Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis. Design and Methods In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay Results The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1st, 2nd and 3rd quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4–1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism. Conclusions High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.