Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation.

BACKGROUND: We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS: All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS: Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS: Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients.

BACKGROUND: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. METHODS: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. RESULTS: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. CONCLUSIONS: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment.

EGFR and K-Ras mutations in women with lung adenocarcinoma: implications for treatment strategy definition.

BACKGROUND: We aimed at investigating the outcomes of female patients with stage IIIB-IV adenocarcinoma of the lung according to EGFR and K-Ras mutational status. METHODS: One hundred and three consecutive female patients genotyped at a single Italian Institution were analyzed. Patients were planned to receive first-line platinum-based chemotherapy (CT) and a salvage treatment with anti-EGFR tyrosine-kinase inhibitors (TKIs) was proposed irrespective of tumor mutational status. EGFR (exons 18-21) and K-Ras (exon 2, codons 12-13) mutations were evaluated by real-time PCR and pyrosequencing. The association of mutational status with clinical variables and treatment benefit was investigated by chi-square test and log-rank test. RESULTS: EGFR and K-Ras mutations were found in 31 (30%) and 13 (15%) cases, respectively. Sixty-six patients received platinum CT: no correlation was observed between EGFR or K-Ras mutational status and response rate (RR) (p > 0.05). However, patients treated with first-line CT harboring EGFR activating mutations experienced a significantly reduced progression-free survival (PFS) in comparison with wild-type ones (4.4 vs. 6.4 months, respectively; HR 0.597, 95% CI 0.287-0.975; p = 0.048). Thirty-nine patients received salvage treatment with erlotinib: EGFR activating mutations were significantly correlated with RR (60% vs. 12.5%; p = 0.004) and PFS (11.4 vs. 4.5 months; HR 0.491, 95% CI 0.216-0.936; p = 0.044). Responses to erlotinib were not reported among women with K-Ras mutant tumors, while 50% of those with wild-type K-Ras achieved an objective remission (p = 0.296). Median PFS (3.5 vs. 8.8 months; HR 0.284, 95% CI 0.015-0.510; p = 0.010) and OS (3.9 vs. 19.8 months; HR 0.158, 95% CI 0.001-0.075; p < 0.001) were significantly shorter among K-Ras mutant patients treated with TKI. CONCLUSIONS: In our population of Caucasian women with advanced lung adenocarcinoma we observed that the presence of EGFR activating mutations correlates with a significant reduction in the benefit from first-line platinum-based CT, emphasizing the importance of an upfront use of anti-EGFR TKIs in this patient subset. K-Ras mutations seem to correlate with a detrimental effect from anti-EGFR TKI, but this finding deserves further investigation.

Clinical benefit of bone-targeted radiometabolic therapy with 153Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Bone metastases are responsible for most of the morbidity associated with hormone-refractory prostate cancer (HRPC). 153Sm-ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) has been approved for palliation of painful skeletal metastases. We retrospectively investigated the possible synergistic effect on survival of 153Sm-EDTMP (given to HRPC patients for bone pain palliation) and chemotherapy. METHODS: Forty-five HRPC patients were evaluated, with a median age of 71 years. The number of metastatic bone sites was 10 in 20 patients. Median serum PSA was 224 ng/ml. Bone pain was mild in 6 patients, moderate in 16, severe in 22 and intolerable in 1. Fifteen patients were only treated with 153Sm-EDTMP (group A), while 30 patients also received chemotherapy (estramustine phosphate or mitoxantrone plus prednisone) at variable times: between 3 and 5 months after 153Sm-EDTMP (14 patients, group B) or within 1 month after 153Sm-EDTMP (16 patients, group C). RESULTS: Haematological toxicities observed after either regimen were in general mild, consistent with common observations after either 153Sm-EDTMP or chemotherapy, and without any additive adverse effects in the patients receiving both 153Sm-EDTMP and chemotherapy. Bone pain palliation to some degree was induced by 153Sm-EDTMP in 32/45 patients (71.1%), the proportion of patients with a favourable clinical response being significantly higher in group C than in group A (87.5% vs 53.3%, p = 0.0388). Also in terms of biochemical response (serum PSA levels), patients of group C performed significantly better than patients of group A (p = 0.0235). Overall median survival from the time of administration of 153Sm-EDTMP was 15 months in the total cohort of 45 patients, and was significantly longer in group C than in either group B (30 months vs 11 months, p = 0.023) or group A (30 months vs 10 months, p = 0.008). CONCLUSION: The results of this study confirm that 153Sm-EDTMP is effective in terms of pain relief and PSA response, with minimal toxicity. When it was administered in combination with chemotherapy, prolonged survival indicated actual clinical benefit, while there were no additive toxicities. These results provide the rationale for future prospective evaluation of combined therapeutic strategies.

Gemcitabine plus epirubicin in patients with advanced urothelial carcinoma who are not eligible for platinum-based regimens.

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of gemcitabine plus epirubicin in previously untreated patients with advanced urothelial carcinoma who were not eligible for cisplatin-based regimens. METHODS: Patients with advanced urothelial carcinoma and at least one of the following characteristics were eligible: impaired renal function (creatinine clearance < 60 mL per minute), an Eastern Cooperative Oncology Group performance status (PS) >or= 2, and age >or= 75 years. The treatment included epirubicin 70 mg/m(2) as an intravenous bolus on Day 1 and gemcitabine 1000 mg/m(2) over 30 minutes on Days 1 and 8 of a 21-day cycle. RESULTS: Thirty-eight patients entered the study, and a total of 152 cycles were administered, with a median of 4 cycles per patient (range, 1-6 cycles per patient). The following Grade 3-4 hematologic toxicities were reported (percent of cycles): neutropenia, 22.4%; anemia, 11.2%; and thrombocytopenia, 6.5%. No cardiac, renal, or hepatic toxicities were observed. Dose intensities of epirubicin and gemcitabine were 19.6 mg/m(2) per week (84%) and 532.2 mg/m(2) per week (80%), respectively. There were 2 complete responses (5.3%), 13 partial responses (34.2%), 11 patients with stable disease (28.9%), and 12 patients with progressive disease (31.6%), for an overall response rate of 39.5% (95% confidence interval, 25.1-55.1). The median progression free survival (PFS) and overall survival (OS) rates were 4.8 months and 8.0 months, respectively. The 1-year survival rate was 38%, and the median PFS and OS were 6.4 months and 16.4 months, respectively, in patients with PS 0-1. Thirty patients were symptomatic: Seventeen patients (56.7%) achieved a complete response, and 5 patients (16.7%) achieved a partial symptomatic response. CONCLUSIONS: At the doses given in this study, gemcitabine and epirubicin had a good tolerability profile with interesting activity in patients with advanced urothelial carcinoma who were not fit for cisplatin-based regimens.