The use of bevacizumab in colorectal,lung, breast,renal and ovarian cancer: Where does it fit?

Bevacizumab is approved for the treatment of colorectal cancer, breast cancer, non-small cell lung cancer and renal cell cancer. Before embracing this expensive agent for many other indications, it remains critical to be aware of the evidence upon which oncologists base their day-to-day clinical practice. In this review, we address the results of clinical studies upon which bevacizumab's current use is based and discuss some future perspectives.     

Serial evaluation of coronary flow reserve by transesophageal doppler echocardiography after angioplasty of proximal left anterior descending coronary artery: a 6-month follow-up study

BACKGROUND: Coronary flow reserve can be estimated by transesophageal Doppler echocardiography (TDE). OBJECTIVE: To evaluate the coronary flow reserve by TDE, serially over 6 months' follow-up, after successful percutaneous transluminal coronary angioplasty (PTCA) of proximal left anterior descending coronary artery (LADA). METHODS AND RESULTS: We performed TDE examination of 30 patients (mean age 55 +/- 9 years) 72 h, 3 months, and 6 months after PTCA of LADA. Selective angiography of LADA was repeated 72 h and 6 months after PTCA of LADA. Velocity of flow in LADA was measured before and 2 min after cessation of intravenous infusion of dipyridamole (0.56 mg/kg in 4 min). The dipyridamole: rest mean diastolic velocity ratio was considered as an index of coronary flow reserve (CFR). For 20 of 21 patients with CFR > 2 there was no restenosis, whereas coronary angiography revealed restenosis in eight of nine patients with CFR < 2. The sensitivity was 88.9% and the specificity was 95.2%. For the 21 patients without restenosis mean CFR was 2.1 +/- 0.1 72 h after PTCA, had increased to 3.1 +/- 0.3 (P < 0.0001) 3 months after PTCA, and remained stable thereafter (3.0 +/- 0.9). CONCLUSION: CFR after PTCA of proximal LADA can be evaluated serially by transesophageal Doppler echocardiography. CFR of LADA in patients without restenosis is increased 3 months after PTCA and remains stable thereafter.     

The distribution of drug-efflux pumps, P-gp, BCRP, MRP1 and MRP2, in the normal blood-testis barrier and in primary testicular tumours

The drug-efflux pumps P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are present in the blood-testis barrier (BTB) and may hamper the delivery of cytotoxic drugs to the testis. The precise localisation of P-gp and MRP1 in testicular tissue and the presence of the efflux pumps MRP2 and breast cancer resistance protein (BCRP) in the BTB are unknown. We therefore studied the localisation of these pumps in the BTB in normal testis (n = 12), in non-seminoma (n = 10) seminoma (n = 10), and testicular lymphoma (n = 9). Slides were scored semi-quantitatively for P-gp, MRP1, MRP2 and BCRP and blood vessels with factor VIII antibody. In normal testis, P-gp and BCRP were strongly expressed by myoid cells and luminal capillary endothelial wall and P-gp also by Leydig cells. MRP1 was observed at the basal side of Sertoli cells and on Leydig cells. MRP2 was only weakly expressed by myoid cells. Seminomas and non-seminomas expressed P-gp and/or BCRP and/or MRP1, lymphomas strongly expressed P-gp, weakly expressed BCRP and did not or showed weak expression of MRP1. There was very little staining for MRP2 in the tumours. Newly formed vessels in all tumours only expressed P-gp and BCRP. P-gp, BCRP and MRP1 are present in different cell layers of the normal testis, suggesting the optimal protection of spermatogenesis. In germ cell tumours, this expression pattern may explain the chemoresistance observed to P-gp, BCRP and MRP1 substrates. In germ cell tumours and testicular lymphomas, P-gp and BCRP expression by tumour cells and by newly formed vessels may also contribute to chemoresistance. These findings underscore the importance of removing the affected testis in cases of primary germ cell tumours and testicular lymphomas, irrespective of whether the patient has already undergone chemotherapy.     

Thoracotomy as a Staging Procedure after Chemotherapy in the Treatment of Stage III Nonseminomatous Carcinoma of the Testis

Of 108 patients with a nonseminomatous testicular carcinoma, 28 with lung metastases were studied. After combination chemotherapy with cisplatin, vinblastine, and bleomycin (PVB), 11 patients underwent exploratory thoracotomy. Viable carcinomatous tissue, along with fibrosis, necrosis, and mature teratoma, was found in 4 patients. Three of these patients were successfully retreated with VP 16-213, cisplatin, and actinomycin D. In patients with residual pulmonary or mediastinal masses after chemotherapy, resection of the lesions is mandatory to demonstrate viable carcinoma so that treatment can be readministered. Thus, in our view, thoracotomy is a diagnostic procedure.     

Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer.

PURPOSE: After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. PATIENTS AND METHODS: In 65 testicular cancer patients (median age, 27 years; range, 18 to 48 years), we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy: platelet numbers, plasma levels of hemostatic and fibrinolytic factors, 24-hour ambulatory blood pressure, baroreflex sensitivity, intima-media thickness of the common carotid artery, and flow-mediated vasodilation of the brachial artery. RESULTS: Compared with prechemotherapy values, the intima-media thickness of the carotid artery and plasma von Willebrand factor levels increased significantly after treatment. Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly. Blood pressure decreased significantly, but flow-mediated vasodilation and baroreflex sensitivity did not change. CONCLUSION: In testicular cancer patients treated with cisplatin-based chemotherapy, we found an increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term.     

Early sCD8 plasma levels during subcutaneous rIl-2 therapy in patients with renal cell carcinoma correlate with response.

Plasma sIl-2R and sCD8 levels of 12 patients with renal cell carcinoma were determined before and during subcutaneous rIl-2 therapy. Patients with a complete/partial remission showed a significantly stronger initial increase of sCD8 compared to patients with stable disease or tumour progression.     

Left ventricular and cardiac autonomic function in survivors of testicular cancer

BACKGROUND: Following cisplatin-based chemotherapy, survivors of testicular cancer have a high prevalence of cardiovascular risk factors and an increased risk of cardiovascular disease. Cardiac function has not been extensively studied and no comparisons have been made with men from the general population. DESIGN: Left ventricular and cardiac autonomic function were evaluated in chemotherapy-treated testicular cancer patients, in stage I patients after orchidectomy only, and in healthy men using Doppler echocardiography [wall motion score index, peak early (E) and atrial filling (A) velocities across the mitral valve, E/A-ratio, isovolumetric relaxation time, and deceleration time of the early peak flow] and measurements of N-terminal pro-brain natriuretic peptide and baroreflex sensitivity. Furthermore, 24-h ambulatory blood pressure was measured. RESULTS: Ninety chemotherapy-treated patients (median age 37 years, range 20-65; median follow up of 7 years, range 3-13) were compared with 44 stage I patients (median age 36 years, range 24-63) and 47 healthy controls (median age 37 years, range 22-55). Wall motion score index was less than 1.5 in all participants. Chemotherapy-treated patients had a higher peak A-wave and a lower E/A-ratio than stage I patients and controls. Isovolumetric relaxation and deceleration times did not differ between groups. Age, 24-h diastolic blood pressure and treatment with chemotherapy were significantly associated with E/A-ratio. Natriuretic peptide levels were normal. Baroreflex sensitivity was similar in the three groups. CONCLUSIONS: Chemotherapy-treated testicular cancer survivors have a lower E/A-ratio than healthy subjects from the general population, which may indicate impaired relaxation of the left ventricle and reflect the high prevalence of cardiovascular risk factors previously reported in these men.     

Validation of Serum Amyloid α as an Independent Biomarker for Progression-Free and Overall Survival in Metastatic Renal Cell Cancer Patients

Background

We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model.

Objective

Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs).

Design, setting, and participants

For training we used 114 interferon-treated mRCC patients (inclusion 2001–2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003–2009).

Measurements

Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect.

Results and limitations

Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6–8 wk of TKI treatment had no value in predicting treatment outcome.

Conclusions

SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management.     

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 × 10⁹ CAR T cells. CTC grade 2–4 liver enzyme disturbances occurred at the lowest CAR T cell doses, necessitating cessation of treatment in four out of eight patients in cohorts 1 and 2. Examination of liver biopsies revealed CAIX expression on bile duct epithelium with infiltration of T cells, including CAR T cells. Subsequently four patients were pre-treated with CAIX monoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed no liver toxicities and indications for enhanced peripheral T cell persistence. No clinical responses were recorded. This report shows that CAIX-targeting CAR T cells exerted antigen-specific effects in vivo and induced liver toxicity at the lowest dose of 0.2 × 10⁹ T cells applied, illustrating the potency of receptor-modified T cells. We provide in-patient proof that the observed “on-target” toxicity is antigen-directed and can be prevented by blocking antigenic sites in off-tumor organs and allowing higher T cell doses.