Improving the accuracy of pre-operative survival prediction in renal cell carcinoma with C-reactive protein.

BACKGROUND: Validated objective biomarkers are needed for patients with renal cell carcinoma (RCC) to guide patient management and define high-risk populations for follow-up or for therapeutic purposes. METHODS: Patients undergoing nephrectomy for RCC (n=286 all stages, 84% with conventional clear cell type) were included with a median duration follow-up of 5 years. The prognostic significance of pre-operative haematological and biochemical variables, including C-reactive protein (CRP) values were examined and whether they added additional information to a recently published pre-operative scoring system was determined. RESULTS: C-reactive protein was the most significant predictor of overall survival (OS; χ(2)=50.9, P<0.001). Five-year OS for patients with CRP ≤ 15 mg l(-1) vs >15 mg l(-1) was 72% (95% CI 65-78%) and 33% (95% CI 23-44%), respectively. Similar results were seen for cancer-specific survival (CSS) and disease-free survival. On multivariate analysis, CRP remained highly significant for CSS (χ(2)=17.3, P<0.0001) and OS (χ(2)=9.8, P<0.002), in addition to other pre-operative variables including log of neutrophil/lymphocyte ratio, red blood cell count and white cell count. C-reactive protein was significant in addition to the pre-operative nomogram score (χ(2)=12.5, P=0.0004 for OS, χ(2)=16.2, P=0.0001 for CSS and χ(2)=8.6, P=0.003 for DFS) and was still significant when other pre-operative variables were included. CONCLUSION: C-reactive protein and other haematological and biochemical variables have independent prognostic significance in RCC and may enhance pre-operative scoring systems.

The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel.

Bisphosphonates are well established in the management of breast-cancer-induced bone disease. Recent studies have suggested that these compounds are effective in preventing the development of bone metastases. However, it is unclear whether this reflects an indirect effect via an inhibition of bone resorption or a direct anti-tumour effect. The breast cancer cell lines, MCF-7 and MDA-MB-231 cells were treated with increasing concentrations of the bisphosphonate, zoledronic acid, for varying time periods, in the presence or absence of paclitaxel. The effects of zoledronic acid were determined by assessing cell number and rate of apoptosis by evaluating changes in nuclear morphology and using a fluorescence nick translation assay. Zoledronic acid caused a dose- and time-dependent decrease in cell number (P< 0.001) and a concomitant increase in tumour cell apoptosis (P< 0.005). Short-term exposure to zoledronic acid was sufficient to cause a significant reduction in cell number and increase in apoptosis (P< 0.05). These effects could be prevented by incubation with geranyl geraniol, suggesting that zoledronic acid-induced apoptosis is mediated by inhibiting the mevalonate pathway. Treatment with zoledronic acid and clinically achievable concentrations of paclitaxel resulted in a 4-5-fold increase in tumour cell apoptosis (P< 0.02). Isobologram analysis revealed synergistic effects on tumour cell number and apoptosis when zoledronic acid and paclitaxel were combined. Short-term treatment with zoledronic acid, which closely resembles the clinical setting, has a clear anti-tumour effect on breast cancer cells. Importantly, the commonly used anti-neoplastic agent, paclitaxel, potentiates the anti-tumour effects of zoledronic acid. These data suggest that, in addition to inhibiting bone resorption, zoledronic acid has a direct anti-tumour activity on breast cancer cells in vitro.

Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease.

BACKGROUND: There is considerable debate as to the optimum schedule of bisphosphonate treatment in advanced malignancy. Short term studies using symptomatic response and biochemical markers of bone resorption may provide useful insight into differences between agents. PATIENTS AND METHODS: Fifty-one patients with metastatic bone disease were randomly allocated to either oral clodronate 1,600 mg daily (group 1), intravenous clodronate followed by the same schedule of oral clodronate (group 2). or intravenous pamidronate 90 mg monthly (group 3). No radiotherapy was delivered or other systemic anticancer treatments were allowed except for long term endocrine therapy. Bone resorption was assessed by measurement of urinary collagen crosslinks. At each visit a pain score was recorded. RESULTS: Symptomatic response was more frequent in the pamidronate group than in patients receiving clodronate. Nine of sixteen patients experienced a sustained improvement in pain score in the pamidronate-treated group, in contrast to only 4 of 16 and 2 of 11 patients in groups 1 and 2, respectively. There was a significant improvement in pain scores in the pamidronate arm compared with the clodronate treated patients after both three months of treatment (P <0.01) and at the last measurement (P <0.05). Biochemical changes correlated with changes in the pain score (P = 0.01). CONCLUSION: Intravenous pamidronate appears to be more effective than oral clodronate in both controlling symptoms and suppressing bone resorption.