Peter Wilson

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.

International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate : a meta-analysis of 1446 patients

To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen‐independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment.

Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer

Purpose: To test the hypothesis that sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant. Experimental Design: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. 18F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUVmax) at 4 and 16 weeks with overall survival (OS). Results: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUVmax = 6.8, range: <2.5–18.4). In multivariate analysis, a high SUVmax and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36–8.45) and 3.67 (95% CI: 1.43–9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40–1.99) or OS (HR for responders = 0.80; 95% CI: 0.34–1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43–19.02) and HR = 12.13 (95% CI: 3.72–46.45), respectively]. Conclusions: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant. Clin Cancer Res; 17(18); 6021–8. ©2011 AACR.

Long-Term Outcomes in Patients with Prostate Cancer Managed with Intermittent Androgen Suppression

Objectives: To assess the long-term outcomes of patients with prostate cancer managed with intermittent androgen suppression (IAS) following their enrolment in an open, non-randomised feasibility study initiated 10 years ago. Patients and Methods: Patients with prostate cancer who developed marked side effects following androgen deprivation were considered for entry into the study. All patients were required to have been managed with androgen deprivation for a minimum of 9 months and to have achieved PSA remissions to levels <4 ng/ml or falls to greater than 90% of pre-treatment levels. Patients remained off treatment until PSA values rose to >20 ng/ml or individuals became symptomatic – at which stage a 9-month cycle of androgen suppression was repeated. Such on-off cycling continued until hormone-resistant disease developed and patients proceeded (off trial) to second-line therapies. Results: 75 patients were recruited to the study following an initial referral with treatment-related side effects specifically associated with androgen deprivation. 86% of these remain alive at a median of 134 months (11 years) since initial histological diagnosis. Survival times and times to hormone resistance (from first cycle hormone deprivation) have also been calculated. Overall there is a median survival time of 95 months (8 years) from initial (first-cycle) androgen deprivation in those presenting with localised or locally advanced disease and a median survival time of 87 months (7 years) for those presenting with metastatic disease. There exists a median of 83 months to hormone resistance in the localised and locally advanced group and a median of 50 months in those presenting with metastatic disease. We have calculated a 100% 5-year actuarial survival rate for those presenting with localised or locally advanced disease (from time of first cycle hormone ablation) and a 70% 5-year actuarial survival rate for those presenting with metastatic. Conclusions: Long-term outcome figures and actuarial survival rates presented here provide further support for a pulsed or intermittent approach to androgen ablation in patients with prostate cancer. In addition, they serve as valuable extended outcome data for patients managed in this way. Likewise, data presented here suggests that apparent survival advantages appear related, at least in part, to a delay in the onset of androgen resistance and that such a management approach is both safe and effective in those presenting with both metastatic disease as well as those with more localised pathology.

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol.

Background:The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS).Methods:From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1u2009:u20091 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Coxs proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance.Results:At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79u2009ngu2009ml−1, and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ⩾11u2009gu2009dl−1 decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001).Conclusion:Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer

When chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7–10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P=0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIPC.

A distinct DNA methylation profile associated with microsatellite and chromosomal stable sporadic colorectal cancers.

Aberrant DNA methylation, microsatellite instability (MSI) and chromosomal instability (CIN) are well‐characterised molecular features of sporadic colorectal cancers (CRCs). In addition to CpG island methylator phenotype (CIMP) associated with MSI, an intermediate methylation subgroup is also a feature of non‐MSI cancers. A large proportion of CRCs have no evidence of either MSI or CIN, here called Microsatellite and Chromosomal Stable (MACS), and require their methylation profile to be established. The clinical and molecular features of 170 sporadic CRC patients were investigated and stratified into MSI, CIN and MACS groups. MACS were most often found in the left colon and had a significantly lower BRAF mutation frequency (p < 0.001) compared with MSI. MACS had better survival [hazard ratio (HR) = 0.244, p = 0.017] compared with CIN, but were similar to MSI. The methylation status of 1,505 CpG loci from cancer‐related genes was analysed in a subset of CRCs (n = 44 normal–tumour pairs) and compared with CIN, MSI and MACS status. Using two‐way hierarchical clustering, three subgroups were identified, which associated with CIN, MSI and MACS status. Using significance analysis of microarray, 16 CpG loci demonstrating methylation changes associated with MACS were identified. A combination of six loci identified MACS with 81% sensitivity and 93% specificity. This result now requires independent validation. Hypomethylation of a CpG locus within the sonic hedgehog (SHH) promoter correlated with increased gene expression and was associated significantly with MACS cancers. In conclusion, we propose that MACS have distinct clinicopathological features and can be distinguished from other CRCs by a specific set of methylation loci.

Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding

The management of androgen independent prostate cancer is increasingly disputed. Diethylstilbestrol and steroids have useful second-line activity in its management. The value of chemotherapy still remains contentious. This paper reports a phase 2 study of two orally active chemotherapy drugs in patients who are absolutely hormone refractory having failed primary androgen blockade and combined oestrogens and corticosteroids. In total, 37 patients who were biochemically castrate with absolute hormone refractory prostate cancer and performance status of 0–3 were enrolled. Therapy consisted of chlorambucil 1u2009mgu2009kg−1 given as 6u2009mg a day until the total dose was reached and lomustine 2u2009mgu2009kg−1 given every 56 days (CL56). During this time all hormone therapy was stopped. One patient normalised his PSA with a further two having a greater than 50% decline leading to an objective response rate of 10%. The median time to progression was 3.6 months with an overall survival of 7.1 months. The median survival of this group of patients from first becoming androgen independent was 23.5 months. Eight of 17 (47%) patients who were subsequently re-challenged with hormonal therapy following failure of chemotherapy had a further PSA reduction, three (17%) of which were >50%. The median progression-free interval for the eight patients was 4 months. In conclusion, CL56 has a low objective response rate in the management of absolute hormone refractory prostate cancer. Toxicity was mild. Re-induction of hormone sensitivity following failure of chemotherapy was an unexpected finding that requires further study.

GAMEC – a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours

There is no consensus as to the management of untreated poor prognosis or relapsed/refractory germ cell tumours. We have studied an intensive cisplatin-based regimen that incorporates high-dose methotrexate (HD MTX) and actinomycin-D and etoposide every 14 days (GAMEC). Sixty-two patients were enrolled in a phase 2 study including 27 who were untreated (IGCCCG, poor prognosis) and 35 with progression despite conventional platinum based chemotherapy. The pharmacokinetics of the drugs were correlated with standard outcome measures. Twenty of the untreated patients were progression free following GAMEC and appropriate surgery, as were 18 individuals in the pretreated group. None of the established prognostic factors for therapy for pretreated patients could identify a poor-prognosis group. Five out of nine late relapses to prior chemotherapy were progression free following GAMEC and appropriate surgery. All patients had at least one episode of febrile neutropenia and there were five (8%) treatment-related deaths. PK values were not predictive of efficacy or toxicity, although the dose intensity in the pretreated group of patients, especially of HD MTX, was significantly correlated with progression-free survival (PFS). GAMEC is a novel intensive regimen for this group of patients producing encouraging responses, although with significant toxicity. For those in whom it fails, further therapy is still possible with durable responses being seen.

IPM chemotherapy in cytokine refractory renal cell cancer.

Renal cell carcinoma (RCC) is notoriously chemoresistant. Current management of metastatic disease usually includes immunological agents of which the most clearly evaluated is alpha interferon. Following the failure of such agents no clear second-line therapy exists. The use of a novel combination of cisplatin, irinotecan and mitomycin may offer some palliative benefit in this situation. Thirty-three patients with cytokine refractory RCC and documented progression and documented active progressive disease with performance status 0–3 were enrolled. Therapy consisted of cisplatin 40u2009mgu2009m−2 on day 1 and day 15, irinotecan 100u2009mgu2009m−2 on day 1 and day 15, and mitomycin 6u2009mgu2009m−2 on day 1 of a 28-day cycle. The results showed that one patient (3%) had a partial response, eight (24%) had minor responses and nine (27%) had stable disease, overall 61% had symptomatic responses. Quality-of-life (QOL) assessment did not change significantly during therapy. Seventy-one percent of those who had primary refractory disease to cytokine therapy subsequently responded to IPM. The median progression-free interval was 4.8 months in this cohort on chemotherapy, compared to 3.9 months with their previous cytokine treatment. In conclusion, IPM produced symptomatic relief for a majority of patients with cytokine refractory RCC without any deterioration in QOL. Disease stabilisation on radiological assessment and symptomatic improvement were associated with prolonged survival. A degree of non-crossresistance to cytokine therapy was seen. IPM may be considered in patients with renal cancer following failure of cytokines.