2-weekly versus 3-weekly docetaxel for metastatic castration-resistant prostate cancer: complete quality of life results from the randomised, phase-III PROSTY trial.

INTRODUCTION: Treatment with 2-weekly docetaxel 50 mg/m2 was shown to improve overall survival and was better tolerated than the standard 75 mg/m2 3-weekly regimen in men with metastatic castration-resistant prostate cancer (mCRPC) in the original randomised PROSTY trial. The aim of this study was to investigate, whether quality of life (QoL) effects would differ between the 2-weekly docetaxel 50 mg/m2 regimen from the standard 3-weekly 75 mg/m2 treatment. MATERIALS AND METHODS: QoL data were collected with the Functional Assessment of Cancer Therapy - Prostate (FACT-P) and Functional Assessment of Cancer Therapy Advanced Prostate Symptom Index - 8 Item version (FAPSI-8). Pain was measured using the Visual Analogue Scale (VAS). A total of 743 forms from 163 patients were analysed in Arm A (2-weekly docetaxel), and 704 forms from 173 patients were analysed in Arm B (3-weekly docetaxel). The data were analysed using both the Wilcoxon signed rank test (with Holm-Bonferroni adjustment) and Mann-Whitney U models. RESULTS: No major differences were found in total QoL. Total QoL was higher at month 8 in Arm B (p = .020), but this was reversed in the following month (p = .043), and no statistically significant differences were found during other months. Compared to Arm A, participants in Arm B had longer-lasting deterioration in FAPSI-8 scores and emotional well-being subdomain at the beginning of treatment (p < .05). Various one-month differences were found in FACT-P subdomains (except for functional well-being), and these favoured participants in Arm A, except for the prostate-cancer subdomain. There were no differences in pain. CONCLUSION: Based on our results, 2-weekly docetaxel was not inferior to 3-weekly docetaxel in terms of total health-related QoL and seemed to be superior at least in terms of the FAPSI-8 and emotional well-being subdomain in the first three to four months of treatment. More research on the topic is suggested to confirm the results.

2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial.

BACKGROUND: Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. METHODS: Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. FINDINGS: 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). INTERPRETATION: Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. FUNDING: Sanofi.

Safer and More Convenient Modern Curative Radiotherapy for Patients With Early Prostate Cancer.

BACKGROUND/AIM: New fractionation schedules with modern tools are a very rapidly developing area in curative radiotherapy (RT) for early prostate cancer (PC). To apply these techniques in everyday clinical practice, we planned this phase II trial with different fractionation schedules and followed up patients using careful health-related quality of life (QoL) questionnaires for three years. PATIENTS AND METHODS: Seventy-three PC patients with one or two intermediate PC risk factors according to the National Comprehensive Cancer Network criteria were recruited. Forty-two patients were treated with 78/2 Gy (conventional fractionation, CF) or 60/3 Gy (moderately hypofractionation RT, MHF), and 31 patients were treated with 36.25/7.25 Gy (stereotactic body RT, SBRT). Their PSA levels were measured, and QoL data were assessed for genitourinary (GU), gastrointestinal (GI), and sexual well-being between the baseline and three years after treatment. A Rectafix™ (RF) fixation device was used in 30 patients in the CF/MHF group. RESULTS: Three years after radiotherapy (RT), there were no differences between the groups regarding GU, GI, sexual well-being, PSA response, or clinical outcomes. On QoL questionnaires, men in the SBRT group were more satisfied with their QoL at the end of RT. Urinary symptoms (p=0.004) and urinary incontinence were more common in the CF/MHF group (p=0.016) three months after RT. The use of RF reduced GI toxicity, especially urgency (p=0.002), at three years after RT. CONCLUSION: Modern, short, five-fraction stereotactic radiotherapy as a local curative treatment for PC is well tolerated and safe. Our novel results showing a decrease in GI toxicity using Rectafix™ fixation should be confirmed in future randomized trials.

Health-related Quality of Life of Patients Treated With Different Fractionation Schedules for Early Prostate Cancer Compared to the Age-standardized General Male Population.

BACKGROUND: The effects of radiotherapy (RT) patients' health-related quality of life (HRQoL) are usually compared to those of other treatment modalities instead of HRQoL of the general population in oncological studies. We examined HRQoL of patients with an early prostate cancer (PC) not receiving hormonal treatment up to 3 years after RT using the 15D instrument and the FACT-P questionnaire. METHODS: The 15D results were compared to those in the age-standardized general male population (N = 952) using an independent-sample t test. The study population (N = 73) received RT either with 78/2 Gy, 60/3 Gy or 36.25/7.25 Gy fractionation. RESULTS: No significant differences in the mean total HRQoL scores were found between the RT groups and the general male population at any time point. Patients with PC had more depression (P = .015) and distress (P = .029) than the general male population before the treatment and depression up to 3 months after treatment (P = .019), which did not persist at 3 years. The sexual activity dimension had declined by the end of treatment, and this decline persisted 3 years later (P = .033). Excretion functions were worse compared to those in peers at the end of treatment (P < .001) but no longer at 3 months and later after RT. Regarding the FACT-P, HRQoL remained good at 3 years after RT in all the treatment groups and there were no significant differences between the different RT groups at this time point. CONCLUSION: This study demonstrated that patients treated with RT for early PC had similar HRQoL compared to the age-standardized general male population at 3 years after treatment.

ANO7 rs77559646 Is Associated With First-line Docetaxel Treatment Response in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Identification of genetic prognostic biomarkers, such as germline variants, are urgently needed to choose optimal treatment for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The prognostic value of anoctamin 7 (ANO7) rs77559646 on docetaxel response was tested in a prospective PROSTY randomized trial and a retrospective Auria Biobank set. The variant rs77559646 was genotyped and its association with progression-free survival (PFS) and overall survival (OS) was tested. RESULTS: In comparison with the non-carriers, the variant carriers had longer PFS (p=0.005) and OS (p=0.003) in the PROSTY cohort. In the retrospective cohort, there was a borderline association with PFS (p=0.09), but not in OS (p=0.9). In both cohorts, Cox regression multivariate models revealed that rs77559646 was an independent prognostic factor for favourable PFS. CONCLUSION: The rs77559646 was shown to be a prognostic germline biomarker for better response to docetaxel treatments. To our knowledge, this is the first time that a non-coding germline variant has been associated with chemotherapy of mCRPC.

A phase I study of an all-oral combination of vinorelbine/capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

BACKGROUND: Few overlapping toxicities and oral formulations make capecitabine plus oral vinorelbine an attractive new combination for treating patients with breast cancer. An all-oral regimen minimizes inconvenience for the patient and saves medical resources. PATIENTS AND METHODS: To determine the recommended dose for this all-oral combination, we conducted a phase I study in 21 patients with metastatic breast cancer after failure of previous chemotherapy with anthracylines and/or taxanes for advanced disease. Capecitabine 1000 mg/m2 twice daily was given on days 2-7 and 9-14. Vinorelbine was administered at escalating doses of 40-80 mg/m2 on days 1 and 8 every 3 weeks. Dose escalation of vinorelbine was performed in cohorts of 3 patients, but the dose of vinorelbine could also be increased to the next level in the same patient after 3 cycles if there were no dose-limiting toxicities. In total, 173 cycles were administered (median, 8 cycles; range 1-21+ cycles). RESULTS: Treatment was well tolerated: there were no grade 4 toxicities, and the only grade 3 toxicities in > 1 cycle were hand-foot syndrome and neutropenia (2% of cycles each). The maximum tolerated dose could not be determined using predefined criteria. However, in this heavily pretreated patient population, intrapatient vinorelbine dose escalation > 60 mg/m2 was rarely achieved. Thus, we considered vinorelbine 60 mg/m2 to offer the best dose level-toxicity ratio. At this dose, grade 3 toxicities occurred in only 7% of the 58 cycles administered. Among 19 evaluable patients, 7 exhibited response or stable disease lasting > 6 months, giving a clinical benefit rate of 37%. Duration of response in the 2 responding patients was 5 months and > 16 months. CONCLUSION: The all-oral combination of capecitabine/vinorelbine is well tolerated and active in heavily pretreated patients. Oral vinorelbine 60 mg/m2 is recommended in combination with capecitabine 1000 mg/m2 twice daily for further evaluation.

Bi-weekly paclitaxel and capecitabine as a second- or third-line treatment for advanced breast cancer: a pilot study.

BACKGROUND: Chemotherapy given every third week is currently the mainstay in the treatment of metastatic breast cancer (MBC). However, bi-weekly dosing might offer a better dose intensity, with better tolerability and response rates. This hypothesis was tested in a phase II study on bi-weekly paclitaxel combined with capecitabine. PATIENTS AND METHODS: Nineteen patients [median age was 60 (range: 43-68) years] with MBC were treated with paclitaxel (Taxol(®)) 120 mg/m(2), with 1-h infusion on days 1 and 15, and capecitabine (Xeloda(®)) 2650 mg/m(2)/day orally given at two doses on days 1-7 and 15-21 on a 28-day cycle. Metastatic sites included the bone (68%), lung (63%) and liver (47%), and 95% of patients had more than one sites of metastasis. RESULTS: In the response evaluation, one complete and 12 partial responses (overall response rate 68%), two stable disease cases and two progressive disease cases were observed. The median duration of response was 13.4 (range: 3.9-43.5) months. Progression-free and overall survival were 13 (95% CI=10.8-15.3) months and 23 (95% CI=17.7-29.1), respectively. A total of 140 (median 8, range 1-28) cycles were delivered. Grade 3-4 toxicity was uncommon: neutropenia was observed in 5% of the cycles; pulmonary problems in 1.4%; pain in 1.4%; and hand-and-foot syndrome, tiredness and arthralgia/myalgia, each in 0.7% of the study treatment cycles. CONCLUSION: Bi-weekly dosing of paclitaxel and capecitabine seems to yield promising responses in advanced breast cancer, with an acceptable adverse-event profile.

Weekly paclitaxel--an effective treatment for advanced breast cancer.

AIM: Weekly paclitaxel is widely used in the treatment of metastatic breast cancer (MBC). Our aim was to test its efficacy and tolerability as a second-line therapy for MBC in daily oncology practice. PATIENTS AND METHODS: Paclitaxel (90 mg/m(2)) was given intravenously three times weekly in a 4-week cycle to 91 patients with disease progression after hormonal (42%) or cytostatic therapy (57%). The median age was 54 years; metastatic sites were the lung (39%), liver (52%) and bone (47%). 64% of patients had more than one site of metastasis. RESULTS: Median time-to-progression was 7.5 months (range=6.5-8.5 months) and median overall survival time was 20.1 months (range=13.7-26.5 months). We observed 10 complete (12%) and 37 partial (43%) responses (an overall response rate of 55%). Severe side-effects were rare (grade 3-4 neutropenia 13% and septic episodes in three cases). CONCLUSION: Weekly paclitaxel was shown to be an effective and well-tolerated treatment for advanced breast cancer.

Biweekly docetaxel is better tolerated than conventional three-weekly dosing for advanced hormone-refractory prostate cancer.

BACKGROUND: Docetaxel administered every three weeks is the standard treatment for advanced hormone-refractory prostate cancer (HRPC). However, biweekly administration might be better tolerated due to the reduced peak drug concentrations. Therefore, we compared biweekly to triweekly docetaxel as first- or second-line chemotherapy for advanced HRPC in this prospective randomized multicenter trial. PATIENTS AND METHODS: In this study, 360 patients were randomly allocated to receive docetaxel 75 mg/m(2) i.v. d1 q3 weeks (tT) or 50 mg/m(2) i.v. d1 and d 14, q4 weeks (bT) from March 2004 to May 2009. Oral prednisolone (10 mg/day) was administered in both groups. The groups were well balanced according to the WHO performance status in terms of mean age (70 vs. 68, range 45-87 years) and median serum PSA level at the time of study entry (109 vs. 98 µg/l, range 11-1490 µg/l). The primary endpoint was time to treatment failure (TTF). ClinicalTrials.gov study identifier: NCT00255606. RESULTS: Ultimately, 158 patients (tT=79; bT=79) were included in this preplanned interim safety analysis; 567 and 487 cycles (equivalent to 1701 and 1948 weeks of treatment) were administered in the tT and bT groups, respectively. The most common grade 3-4 adverse events (expressed as %/cycles) in tT /bT were neutropenia 20%/14%; infection with/without neutropenia 8%/3%; fatigue 3%/3%; febrile neutropenia 2%/1%; and bone pain 2%/1%. Serious adverse events occurred more frequently in the group tT (n=60, 10.6% of cycles) than in the group bT (n=29, 6.0%, p=0.012). One patient died due to coronary infarction, and another was diagnosed with acute lymphocytic leukemia (both in the bT group). Thirty patients (38%) in the bT group and 22 patients (28%) in the tT group were still receiving treatment at 6 months (p=0.176). CONCLUSION: Biweekly docetaxel was tolerated better than conventional triweekly with fewer serious adverse events and more patients were still on the therapy at 6 months. Biweekly docetaxel therapy might be considered as an option for elderly patients exhibiting a compromised general condition.