Dominik R. Berthold

Docetaxel Plus Prednisone or Mitoxantrone Plus Prednisone for Advanced Prostate Cancer : Updated Survival in the TAX 327 Study

PURPOSE The TAX 327 study compared docetaxel administered every 3 weeks (D3), weekly docetaxel (D1), and mitoxantrone (M), each with prednisone (P), in 1,006 men with metastatic hormone-resistant prostate cancer (HRPC). The original analysis, undertaken in August 2003 when 557 deaths had occurred, showed significantly better survival and response rates for pain, prostate-specific antigen (PSA), and quality of life for D3P when compared with MP. Here, we report an updated analysis of survival. METHODS Investigators were asked to provide the date of death or last follow-up for all participants who were alive in August 2003. RESULTS By March 2007, data on 310 additional deaths were obtained (total = 867 deaths). The survival benefit of D3P compared with MP has persisted with extended follow-up (P = .004). Median survival time was 19.2 months (95% CI, 17.5 to 21.3 months) in the D3P arm, 17.8 months (95% CI, 16.2 to 19.2 months) in the D1P arm, and 16.3 months (95% CI, 14.3 to 17.9 months) in the MP arm. More patients survived >/= 3 years in the D3P and D1P arms (18.6% and 16.6%, respectively) compared with the MP arm (13.5%). Similar trends in survival between treatment arms were seen for men greater than and less than 65 years of age, for those with and without pain at baseline, and for those with baseline PSA greater than and less than the median value of 115 ng/mL. CONCLUSION The present analysis confirms that survival of men with metastatic HRPC is significantly longer after treatment with D3P than with MP. Consistent results are observed across subgroups of patients.

Abiraterone for prostate cancer not previously treated with hormone therapy

Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long‐term androgen‐deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node‐negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate‐specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure‐free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). Results A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node‐positive or node‐indeterminate nonmetastatic disease, and 28% had node‐negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow‐up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT‐alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment‐failure events in the combination group as compared with 535 in the ADT‐alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT‐alone group (with three grade 5 events). Conclusions Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure‐free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.)

Management of Advanced Prostate Cancer After First-Line Chemotherapy

Hormone refractory prostate cancer (HRPC) causes substantial morbidity and mortality. There are increasing options for both first- and second-line therapy in the palliative treatment of patients with HRPC. Medications to control symptoms should first be optimized in patients with late-stage disease, and radiotherapy applied to dominant painful bone lesions. Docetaxel, mitoxantrone, satraplatin, and ixabepilone are active chemotherapeutic agents in the first- and/or second-line setting for patients with HRPC, and this may be true also of older drugs such as oral cyclophosphamide and vinorelbine. Radioisotopes such as strontium and samarium are useful for treatment of more generalized bone pain. Third-line hormonal maneuvers including glucocorticoids, ketoconazole, and estrogens can lead to further palliation in some patients, and there are provocative data that chemotherapy might restore hormonal sensitivity in a subset of patients.

Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle‐invasive bladder cancer

Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle‐invasive bladder cancer despite the lack of Level I evidence in this setting.

Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

BACKGROUND The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients. OBJECTIVE To develop a new model based on real-world patients. DESIGN, SETTING, AND PARTICIPANTS Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011. INTERVENTION First-line, platinum-based, combination chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms. RESULTS AND LIMITATIONS A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670). CONCLUSIONS We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC. PATIENT SUMMARY We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.

The Transition From Phase II To Phase III Studies

6514 Background: Phase II trials are performed to detect potential anti-tumor effects of a new treatment and should be used to decide whether to proceed to a phase 3 trial or not. However, many pha...

Enzalutamide in Patients With Castration-Resistant Prostate Cancer Progressing After Docetaxel: Retrospective Analysis of the Swiss Enzalutamide Named Patient Program

Micro‐Abstract Therapeutic options for metastatic castration‐resistant prostate cancer have considerably changed in the past decade. In this retrospective analysis of patients included in the Swiss Enzalutamide Named Patent Program, we analyzed the outcome of patients based on different sequencing strategies reflecting current daily practice. We demonstrate a median overall survival of more than 3 years and different effects in regard to treatment sequences. Background: Enzalutamide is a second‐generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration‐resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy‐naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial. Patients and Methods: The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide. Results: The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3‐49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh‐line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1‐21 months). Median progression‐free survival was 3.0 months (95% CI, 2.4‐3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6‐8.1 months). Sixteen patients (36.4%) had a prostate‐specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate‐specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment. Conclusions: Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone.

Comparison of three or fewer high-dose chemotherapy cycles as salvage treatment in germ cell tumors in first relapse

Unique characteristics discriminate germ cell tumors (GCTs) from other solid malignancies. Patients are predominantly young men between 15 and 40 years with few comorbidities (if any); tumors are particularly sensitive to platinum-based chemotherapy; and a cure is still possible with salvage approaches in patients with progression after first-line chemotherapy. Curative salvage strategies involve conventional-dose chemotherapy (CDCT) or, alternatively, high-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT), which—in contrast to virtually all other types of solid tumors—can be highly effective.1, 2, 3, 4, 5, 6, 7, 8, 9, 10

Iterative Reconstructions in Reduced-Dose CT: Which Type Ensures Diagnostic Image Quality in Young Oncology Patients?

RATIONALE AND OBJECTIVES To compare adaptive statistical iterative reconstruction (ASIR) and model-based iterative reconstruction (MBIR) algorithms for reduced-dose computed tomography (CT). MATERIALS AND METHODS Forty-four young oncology patients (mean age 30 ± 9 years) were included. After routine thoraco-abdominal CT (dose 100%, average CTDIvol 9.1 ± 2.4 mGy, range 4.4-16.9 mGy), follow-up CT was acquired at 50% (average CTDIvol 4.5 ± 1.2 mGy, range 2.2-8.4 mGy) in 29 patients additionally at 20% dose (average CTDIvol 1.9 ± 0.5 mGy, range 0.9-3.4 mGy). Each reduced-dose CT was reconstructed using both ASIR and MBIR. Four radiologists (two juniors and two seniors) blinded to dose and technique read each set of CT images regarding objective and subjective image qualities (high- or low-contrast structures), subjective noise or pixilated appearance, diagnostic confidence, and lesion detection. RESULTS At all dose levels, objective image noise was significantly lower with MBIR than with ASIR (P < 0.001). The subjective image quality for low-contrast structures was significantly higher with MBIR than with ASIR (P < 0.001). Reduced-dose abdominal CT images of patients with higher body mass index (BMI) were read with significantly higher diagnostic confidence than images of slimmer patients (P < 0.001) and had higher subjective image quality, regardless of technique. Although MBIR images appeared significantly more pixilated than ASIR images, they were read with higher diagnostic confidence, especially by juniors (P < 0.001). CONCLUSIONS Reduced-dose CT during the follow-up of young oncology patients should be reconstructed with MBIR to ensure diagnostic quality. Elevated body mass index does not hamper the quality of reduced-dose CT.

Radiation Therapy after Radical Prostatectomy: Implications for Clinicians.

Depending on the pathological findings, up to 60% of prostate cancer patients who undergo radical prostatectomy (RP) will develop biochemical relapse and require further local treatment. Radiotherapy (RT) immediately after RP may potentially eradicate any residual localized microscopic disease in the prostate bed, and it is associated with improved biochemical, clinical progression-free survival, and overall survival in patients with high-risk pathological features according to published randomized trials. Offering immediate adjuvant RT to all men with high-risk pathological factors we are over-treating around 50% of patients who would anyway be cancer-free, exposing them to unnecessary toxicity and adding costs to the health-care system. The current dilemma is, thus, whether to deliver adjuvant immediate RT solely on the basis of high-risk pathology, but in the absence of measurable prostate-specific antigen, or whether early salvage radiotherapy would yield equivalent outcomes. Randomized trials are ongoing to definitely answer this question. Retrospective analyses suggest that there is a dose–response favoring doses >70 Gy to the prostate bed. The evidence regarding the role of androgen deprivation therapy is emerging, and ongoing randomized trials are underway.