Lifestyle factors and colorectal cancer risk (2): a systematic review and meta-analysis of associations with leisure-time physical activity

Objective  Increased physical activity may decrease the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we performed a systematic review and meta-analysis of prospective observational studies to quantify gender-specific risk associated with increased leisure-time physical activity (LT-PA).
Method  We searched MEDLINE and EMBASE (to December 2007), and other sources, selecting reports based on strict inclusion criteria. We used random-effects meta-analyses to estimate summary risk ratios (RR) and 95% confidence intervals (95% CI) for uppermost vs lowermost categories of physical activity. To investigate dose–response, we explored risks ratios as a function of cumulative percentiles of physical activity distribution.
Results  Fifteen datasets from 14 articles, including 7873 incident cases, were identified. For colon cancer, there were inverse associations with LT-PA for men (RR: 0.80; 95% CI: 0.67–0.96) and women (0.86; 0.76–0.98). LT-PA did not influence risk of rectal cancer. The dose–response analysis was consistent with linear pattern reductions in risk of colon cancer in both genders. There was evidence of moderate between-study heterogeneity but summary estimates were broadly consistent across potential confounding factors.
Conclusion  Increased LT-PA is associated with a modest reduction in colon but not rectal cancer risk; a risk reduction, which previously may have been overstated. LT-PA only interventions in public health cancer prevention strategies are unlikely to impact substantially on colorectal cancer incidences.     

Efficacy of taxanes rechallenge in first-line treatment of early metastatic relapse of patients with HER2-negative breast cancer previously treated with a (neo)adjuvant taxanes regimen: A multicentre retrospective observational study

BackgroundTaxanes are one of the most effective chemotherapies (CT) in breast cancer (BC), but the efficacy of taxanes rechallenge in early metastatic relapse has been poorly studied in patients previously treated by taxanes in the (neo)adjuvant setting. Our study aimed to analyse the efficacy of taxane rechallenge in case of early metastatic relapse in a multicentre retrospective observational study compared with other chemotherapies.MethodsWe analysed the French national ESME metastatic BC (MBC) database and selected HER2- MBC patients who received CT in first-line treatment for a metastatic relapse occurring 3–24 months after previous (neo)adjuvant taxanes treatment.ResultsOf 23,501 female patients with MBC in ESME, 1057 met the selection criteria. 58.4% received a taxane-based regimen (75.4% concomitant bevacizumab) and 41.6% received other CT.In hormone-receptor positive (HR+)/HER2- MBC, multivariate analysis showed no difference in OS between taxanes without bevacizumab compared to other CT (HZR = 1.3 [0.97; 1.74], but taxanes was significantly associated with worse PFS (HZR = 1.48 [1.14; 1.93]).In TNBC, taxanes without bevacizumab and carboplatin/gemcitabine were not superior to other CT for OS (HZR = 1.07 [0.79; 1.44] and HZR = 0.81 [0.58; 1.13], respectively), while for PFS, taxanes was inferior (HZR = 1.33 [1.06–1.67]) and carboplatin plus gemcitabine was superior to other CT (HZR = 0.63 [0.46; 0.87]).For both subtypes, the worse outcome observed with paclitaxel was no longer observed with the addition of bevacizumab.ConclusionsWith the limitation of retrospective design, taxanes rechallenge in early metastatic relapse of BC may result in a worse PFS in TNBC and HR+/HER2- MBC, which was not observed with the addition of bevacizumab.     

Long-term results with a long-acting formulation of D-TRP-6 LH-RH in patients with prostate cancer: an Italian prostatic cancer project (P.O.N.CA.P.) study

Ninety-five patients with stage C (C1 + C2) or D (D1 + D2) prostatic carcinoma were treated with the depot formulation of D-TRP-6 LH-RH ("Decapeptyl") for up to 33 months. Serum testosterone (T) levels were significantly reduced to castration levels within 4 weeks and maintained persistently low. Similarly, LH levels were decreased, although they remained in the normal range. Stimulation tests with either Gn-RH or HCG in course of treatment showed the achievement of a complete pituitary desensitization and almost a complete down-regulation of testicular LH receptors. Of 88 patients evaluable for response, about one-half showed an objective response. In most cases, subjective improvement with relief of bone pain and/or urinary symptoms was obtained without major side effects. These results indicate that the depot formulation of D-TRP-6 LH-RH offers an effective therapeutic alternative for patients with advanced prostatic cancer.     

Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial

What’s known on the subject? and What does the study add? Treatment of benign prostatic hyperplasia (BPH) centres on two drug classes, 5α‐reductase inhibitors and α‐blockers. The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study investigated whether the combination of dutasteride and tamsulosin was more effective than either monotherapy in reducing the relative risk of AUR, BPH‐related surgery, and BPH clinical progression in men with moderate‐to‐severe LUTS who were at increased risk of disease progression. Data from the 2‐ and 4‐year, pre‐planned primary and secondary endpoint analyses for the CombAT study have been reported previously. This study reports the outcomes of post hoc analyses of the influence of baseline parameters on the incidence of AUR, BPH‐related surgery, and overall clinical progression in patients treated with tamsulosin, dutasteride, or combination therapy with both agents.

OBJECTIVE

? To investigate the influence of baseline variables on the 4‐year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)‐related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both.

PATIENTS AND METHODS

? The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double‐blind, parallel‐group study of clinical outcomes in men aged ≥50 years with symptomatic (International Prostate Symptom Score [IPSS]≥12) BPH, with prostate‐specific antigen (PSA) levels of ≥1.5 ng/mL and ≤10 ng/mL, and a prostate volume (PV) of ≥30 mL. ? Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. ? The primary endpoint was time to first AUR or BPH‐related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health‐related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q_max] and body‐mass index [BMI]) on the incidence of AUR or BPH‐related surgery, clinical progression of BPH, and symptoms were performed.

RESULTS

? There were 4844 men in the intent‐to‐treat population. Overall baseline characteristics were similar across all patient groups. ? Regardless of baseline subgroup, the incidence of AUR or BPH‐related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. ? Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH‐related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P≤ 0.001). ? Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of <20 or IPSS HRQL score of <4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of <40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. ? Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of <40 mL) and compared with dutasteride in most subgroups.

CONCLUSIONS

? Men with a baseline PV of ≥40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH‐related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. ? These analyses support the long‐term use of combined therapy with dutasteride plus tamsulosin in men with moderate‐to‐severe BPH symptoms and a slightly enlarged prostate.     

Biodegradable braided poly(lactic-co-glycolic acid) urethral stent combined with dutasteride in the treatment of acute urinary retention due to benign prostatic enlargement: a pilot study

OBJECTIVE

To evaluate, in a pilot study, the efficacy and safety of combining a braided poly(lactic‐co‐glycolic acid) (PLGA, a copolymer of l ‐lactide and glycolide) urethral stent and dutasteride in the treatment of acute urinary retention (AUR) due to benign prostatic enlargement (BPE).

PATIENTS AND METHODS

Ten men with AUR due to BPE were treated as outpatients. A biodegradable braided PLGA urethral stent was inserted into the prostatic urethra, using a specially designed insertion device under visual control. Dutasteride treatment was started and the patients were followed up for 3 months after insertion of the stents.

RESULTS

In all patients the stents were placed successfully with the new insertion device. All men were able to void after inserting the stent. At 1 month five patients voided freely with a low residual urine volume (<150 mL), two voided but had a high residual urine volume and a suprapubic catheter was placed, and three needed a suprapubic or an indwelling catheter before 1 month, due to AUR or comorbidities. At 3 months five patients were voiding with no problems.

CONCLUSIONS

We have developed a new and effective insertion device for biodegradable braided prostatic stents. The new braided‐pattern stent overcomes the earlier problems of migration and sudden breakage into large particles associated with biodegradable spiral stents. However, the mechanical properties of the new stent need to be improved and tested in a longer follow‐up. We consider that this new biodegradable braided‐pattern urethral stent could provide a new option in the future treatment of AUR.     

ELIGANT: a Phase 4, interventional,safety study of leuprorelin acetate (ELIGARD®) in Asian men with prostate cancer

BackgroundThe incidence and mortality rate of men with prostate cancer have been increasing in Asia. ELIGARD^® is a formulation of leuprorelin acetate whose safety and efficacy have been well-established in Western regions. However, limited safety data are available for Asian populations.MethodsELIGANT (ELIGard AsiaN sTudy) was a Phase 4, multicenter, prospective, single-arm, interventional study. Men with locally advanced or metastatic prostate cancer without concomitant chemotherapy, or another androgen receptor pathway inhibitor, were enrolled across Asia to receive ELIGARD^® (22.5 mg subcutaneous depot injection) every 3 months for 15 months, with a follow-up visit at 18 months. The primary objective was to establish the safety of ELIGARD^® in Asian men with hormone-dependent prostate cancer. The secondary objectives were to assess efficacy, via prostate-specific antigen (PSA) progression and testosterone levels, and health-related quality of life (HRQoL).ResultsIn total, 106 patients were included in the safety analysis set (SAF). The most common treatment-emergent adverse events (TEAEs) included PSA increase, cough, back pain, hot flush, anemia, and upper respiratory tract infection. TEAEs considered related to ELIGARD^® were reported in 13.2% of patients (n=14), two of which were serious. In the full analysis set (FAS) (n=105), 81.2% (n=56) and 68.5% (n=61) of patients achieved a PSA reduction of ≥90% from baseline at 12 and 18 months, respectively. At 18 months, the numbers of patients with testosterone levels <20, 20–50, and >50 ng/dL were 65 (61.9%), 17 (16.2%), and two (1.9%), respectively; 20% had missing testosterone measurements. HRQoL remained stable throughout the study with minimal change from baseline at study completion.ConclusionsIn conclusion, the safety profile of ELIGARD^® (22.5 mg) in Asian men with hormone-dependent prostate cancer is comparable to previous studies in Western regions.Trial RegistrationClinical trial registration number {"type":"clinical-trial","attrs":{"text":"NCT03035032","term_id":"NCT03035032"}}NCT03035032.     

Neo‐adjuvant Capecitabine Chemotherapy in Women with Newly Diagnosed Locally Advanced Breast Cancer in a Resource‐poor Setting (Nigeria): Efficacy and Safety in a Phase II Feasibility Study

The majority of clinical trials of neo‐adjuvant therapy for breast cancer have been conducted in resource‐rich countries. We chose Nigeria, a resource‐poor country, as the major site for a phase II feasibility open‐label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo‐adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m² twice daily (2,000 mg/m² total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11–59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20–70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand–foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo‐adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.     

Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration‐resistant prostate cancer and bone metastases who were pain‐free or mildly symptomatic for pain: a double‐blind,placebo‐controlled,randomized Phase II trial

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVES

To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once‐daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety.

RESULTS

In total, 312 patients were randomized (placebo, n= 107; zibotentan 10 mg, n= 107; zibotentan 15 mg, n= 98). The median duration of study treatment and median follow‐up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61–0.94; P= 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67–1.02; P= 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion.

CONCLUSIONS

The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme.     

Feasibility,Acceptability, and Behavioral Outcomes from a Technology-enhanced Behavioral Change Intervention (Prostate 8): A Pilot Randomized Controlled Trial in Men with Prostate Cancer

BackgroundIncreasing evidence suggests that lifestyle factors may decrease the risk of prostate cancer progression. Lifestyle guidelines and tools may support lifestyle modification after diagnosis.ObjectiveTo determine the feasibility and acceptability of a digital lifestyle intervention among men with prostate cancer.Design, setting, and participantsA 12-wk pilot randomized controlled trial among 76 men with clinical stage T1–T3a prostate cancer. Eligibility included Internet access, no contraindications to aerobic exercise, and engaging in four or fewer of eight targeted behaviors at baseline.InterventionWebsite, Fitbit One, and text messaging to facilitate adoption of eight behaviors: vigorous activity, smoking cessation, and six diet improvements.Outcome measurements and statistical analysisOur primary outcomes were feasibility and acceptability based on recruitment and user data, and surveys, respectively. Secondarily, we evaluated the change in eight lifestyle behaviors, and also objective physical activity. Each factor was assigned one point, for an overall “P8 score” (range 0–8). Analysis of covariance (ANCOVA) was conducted. Exploratory outcomes included quality of life, anthropometrics, and circulating biomarkers after 12 wk, and behaviors after 1 yr.Results and limitationsAt baseline, men in both arms met a median of three targeted behaviors. Sixty-four men (n = 32 per arm) completed the study; 88% completed 12-wk assessments (intervention, 94%; control, 82%). Intervention participants wore their Fitbits a median of 82 d (interquartile range [IQR]: 72–83), replied to a median of 71% of text messages (IQR: 57–89%), and visited the website a median of 3 d (IQR: 2–5) over 12 wk. Median (IQR) absolute changes in the P8 score from baseline to 12 wk were 2 (1, 3) for the intervention and 0 (?1, 1) for the control arm. The estimated mean score of the intervention arm was 1.5 (95% confidence interval: 0.7, 2.3) higher than that of the control arm at 12 wk (ANCOVA p < 0.001). Changes were driven by diet rather than exercise. Limitations include self-reported diet and exercise data.ConclusionsOverall, in this novel pilot trial, the intervention was feasible and acceptable to men with prostate cancer. Next steps include improving the intervention to better meet individuals’ needs and focusing on increasing physical activity in men not meeting nationally recommended physical activity levels.Patient summaryTailored print materials combined with technology integration, including the use of a website, text messaging, and physical activity trackers, helped men with prostate cancer adopt healthy lifestyle habits, in particular recommended dietary changes, in the Prostate 8 pilot trial.