David Pfister

Vandetanib for the Treatment of Patients With Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer

PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.

Identification and validation of potential new biomarkers for prostate cancer diagnosis and prognosis using 2D-DIGE and MS.

This study was designed to identify and validate potential new biomarkers for prostate cancer and to distinguish patients with and without biochemical relapse. Prostate tissue samples analyzed by 2D-DIGE (two-dimensional difference in gel electrophoresis) and mass spectrometry (MS) revealed downregulation of secernin-1 (P < 0.044) in prostate cancer, while vinculin showed significant upregulation (P < 0.001). Secernin-1 overexpression in prostate tissue was validated using Western blot and immunohistochemistry while vinculin expression was validated using immunohistochemistry. These findings indicate that secernin-1 and vinculin are potential new tissue biomarkers for prostate cancer diagnosis and prognosis, respectively. For validation, protein levels in urine were also examined by Western blot analysis. Urinary vinculin levels in prostate cancer patients were significantly higher than in urine from nontumor patients (P = 0.006). Using multiple reaction monitoring-MS (MRM-MS) analysis, prostatic acid phosphatase (PAP) showed significant higher levels in the urine of prostate cancer patients compared to controls (P = 0.012), while galectin-3 showed significant lower levels in the urine of prostate cancer patients with biochemical relapse, compared to those without relapse (P = 0.017). Three proteins were successfully differentiated between patients with and without prostate cancer and patients with and without relapse by using MRM. Thus, this technique shows promise for implementation as a noninvasive clinical diagnostic technique.

Retroperitoneal lymphadenectomy and resection for testicular cancer: an update on best practice.

Clinical stage I testicular nonseminomatous germ cell tumours (NSGCTs) are highly curable. Following orchidectomy a risk-adapted approach using active surveillance (AS), nerve-sparing retroperitoneal lymph node dissection (nsRPLND) and primary chemotherapy is recommended by the current guidelines. Clinical stage I is defined as negative or declining tumour markers to their half-life following orchidectomy and negative imaging studies of the chest, abdomen and retroperitoneum. Active surveillance can be performed in low-risk and in high-risk NSGCTs with an anticipated relapse rate of about 15% and 50%. The majority of patients will relapse with good and intermediate prognosis tumours which have to be treated with three to four cycles chemotherapy. About 25–30% of these patients will have to undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for residual masses. Primary chemotherapy with one or two cycles of cisplatin (Platinol), etoposide and bleomycin (PEB) is a therapeutic option for high-risk clinical stage I NSGCT associated with a recurrence rate of only 2–3% and a minimal acute and long-term toxicity rate. nsRPLND, if performed properly, will cure about 85% of all high-risk patients with clinical stage I NSGCT without the need for chemotherapy. PC-RPLND forms an integral part of the multimodality treatment in patients with advanced testicular germ cell tumours (TGCTs). According to current guidelines and recommendations, PC-RPLND in advanced seminomas with residual tumours is only indicated if a positron emission tomography (PET) scan performed 6–8 weeks after chemotherapy is positive. In nonseminomatous TGCT, PC-RPLND is indicated for all residual radiographic lesions with negative or plateauing markers. Loss of antegrade ejaculation represents the most common long-term complication which can be prevented by a nerve-sparing or modified template resection. The relapse rate after PC-RPLND is around 12%, however it increases significantly to about 45% in cases with redo RPLND and late relapses. Patients with increasing markers should undergo salvage chemotherapy. Only select patients with elevated markers who are thought to be chemorefractory might undergo desperation PC-RPLND if all radiographically visible lesions are completely resectable. PC-RPLND requires a complex surgical approach and should be performed in experienced, tertiary referral centres only.

Surgical Resection of Urological Tumor Metastases Following Medical Treatment

BACKGROUND The rate of systemic metastases is about 20% in testicular germ cell tumors, 25% to 30% in prostate cancer, 30% in urothelial carcinoma with muscle invasion, and 50% in renal-cell carcinoma. This article is a critical review of current data on the resection of metastases of urological tumors after systemic drug treatment. METHODS Review of pertinent publications retrieved by a selective literature search. RESULTS No pertinent prospective, randomized trials, meta-analyses, or Cochrane reviews have been published. The publications available for review include guidelines and retrospective studies with evidence levels ranging from IIB to III. For non-seminomatous germ cell tumors with tumor markers that are negative or have reached a plateau after chemotherapy, resection of retroperitoneal, intra-abdominal, and intrathoracic metastases with curative intent is now the treatment of choice at clinical reference centers. For urothelial carcinoma that has gone into partial remission after systemic chemotherapy, with full resectability, the resection of metastases prolongs survival from about 13 months to 31-41 months. For prostatic carcinoma with solitary, intrapelvic lymph-node metastases and PSA less than 4 ng/mL, the resection of metastases prolongs 5-year progression-free survival in 40% to 50% of cases. There is, however, no indication for the resection of retro-peritoneal, visceral, or bony metastases. In renal-cell carcinoma, the resection of pulmonary or hepatic metastases is associated with a 5-year survival rate of 40% to 50% or 62%, respectively, and should thus be made a component of the treatment plan for this disease. The indication for resecting metastases of urological cancers should always be established by an interdisciplinary tumor board in the light of the existing scientific evidence. CONCLUSION The resection of metastases of some types of urological cancer after chemotherapy can prolong progression-free and overall survival. This form of treatment deserves consideration as a component of individual care and of the interdisciplinary treatment plan for urological cancers.

The role of palliative surgery in castration-resistant prostate cancer.

Purpose of reviewAndrogen deprivation therapy with luteinising hormone releasing hormone (LHRH) analogues or antagonists represents the treatment of choice in men metastatic prostate cancer (PCA). Depending on the serum concentration of the prostate-specific antigen (PSA) nadir, the survival might vary between 11 and 78 months. About one-third of all patients without local treatment of the primary will develop significant complications of the lower and upper urinary tract because of local progression of PCA. It is the purpose of the review to inform the treating physician about palliative surgical options in men with castration-resistant prostate cancer (CRPC). Recent findingsIn men with CRPC and lower urinary tract symptoms, palliative transurethral resection of the prostate (TUR-P) can be performed with a 60–70% success rate. Infiltration of the pelvic floor, the bladder neck and trigone and the external urethral sphincter can make palliative radical surgery necessary. Bladder neck closure with continent vesicostomy, radical cystoprostatectomy with an incontinent urinary diversion, and anterior and posterior exenteration are individual therapeutic options in men with a good performance status and a considerable life expectancy. Symptomatic involvement of the upper urinary tract can be managed by placement of endoluminal stents or a percutaneous nephrostomy in men with a poor performance. In men with a good response to androgen deprivation therapy (ADT) and a good performance status reconstructive ureteral surgery might be considered and the options of ureteral reimplantation, ureter ileal replacement and a subcutaneous pyelovesical bypass have to be discussed. SummaryThere are various palliative surgical treatment options in the management of men with CRPC and symptomatic deterioration of the lower or the upper urinary tract, which should be considered in well selected patients. The indication to perform one of the above-mentioned surgical approaches needs to be discussed in a multidisciplinary tumour board.

The Role of Palliative Surgery in Castration-Resistant Prostate Cancer

Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) analogues or antagonists represents the treatment of choice in men with metastatic prostate cancer (PCA). Depending on the serum concentration of the prostate-specific antigen (PSA) nadir, the survival might vary between 11 and 78 months. In castration-resistant PCA (CRPC), all new medical treatment options can induce complete and partial remissions in metastatic foci, but they have no profound effect on the prostate itself, as has been shown recently. About one-third of all patients without local treatment of the primary will develop significant complications of the lower and upper urinary tract due to local progression of the PCA. In men with CRPC and lower urinary tract symptoms, palliative transurethral resection of the prostate (TURP) can be performed with a 60-70% success rate. Infiltration of the pelvic floor, the bladder neck and trigone, and the external urethral sphincter can make palliative radical surgery necessary. Bladder neck closure with continent vesicostomy, radical cystoprostatectomy with an incontinent urinary diversion, and anterior and posterior exenteration are individual therapeutic options in men with a good performance status and a considerable life expectancy. Symptomatic involvement of the upper urinary tract can be managed by the placement of endoluminal stents or a percutaneous nephrostomy in men with poor performance. In men with a good response to ADT and a good performance status, reconstructive ureteral surgery might be considered and the options of ureteral reimplantation, ureter ileal replacement, and a subcutaneous pyelovesical bypass have to be discussed. The indication to perform one of the above-mentioned surgical approaches needs to be discussed in a multidisciplinary tumor board.

Controversies on individualized prostate cancer care: gaps in current practice.

Prostate cancer (PCa) is a heterogeneous disease with a wide spectrum of aggressiveness. Evidence-based guidelines are invaluable but cannot be expected to be extensive enough to provide detailed guidance on the management of all patients. As such, the use of individualized, risk-adapted approaches to the management of PCa is indispensable. However, wide variation in treatment approaches observed for patients in practice suggests that there is an unmet need to improve the individualized approach towards patient care. A holistic approach that encompasses guidelines and evidence-based medicine could be used to guide individualized care for patients with PCa, from first contact through to final outcomes. As a result of an international expert meeting, this paper proposes this approach and highlights some of the factors that can be considered when aiming to identify patients’ profiles; individualize treatment; and improve communication between patients and the healthcare teams.

Comparison of second-line treatments in patients with castration-resistant prostate cancer with PSA relapse after or during docetaxel chemotherapy.

243 Background: Docetaxel was the first agent with a proven survival benefit and improved quality of life in patients with castration resistant prostate cancer. Recently there are two new agents, Cabazitaxel (Caba) and Abiraterone Acetate (AA) approved for the second-line treatment in case of progressive disease after Docetaxel. We compared the PSA response and complication rate of these three different second-line treatment options: Caba, AA and Docetaxel Re-Challenge (R-Doc). METHODS The data of 71 patients with progressive disease after/during Docetaxel chemotherapy were analyzed retrospectively. 25 patients with R-Doc, 27 patients with AA and 19 patients with Caba. All patients except two had a PSA-Response or stable disease to primary docetaxel chemotherapy. Mean patient age was 74 years for R-Doc, 71 for AA and 69 for Caba with a mean PSA before initiating treatment of 45 ng/ml, 162ng/ml and 563ng/ml. RESULTS PSA response rates (>50% regression) were seen in 14 (56%), 8 (38%) and 6 (32%) patients respectively. PSA stabilization was seen in 7 (28%), 2 (9,5%) and 7 (36,8%) patients. Haematologic complications grade >=3 were seen more frequently in R-Doce (32%) and Caba (42%) compared to AA (4%). Cardiovascular complications >= grade 3 were seen in 30% of the patients with AA whereas none of the patients with R-Doc or Caba had cardiovascular grade 3 or 4 side effects. CONCLUSIONS With AA, Caba and the possibility of R-Doc there are compareable treatment options with regard to PSA response rates, even if a stable disease can be seen more frequently in Caba and R-Doc. As the drugs have different side effects the first second line treatment should be considered to the patients characteristics and comorbidity in the palliative setting. PSA progression free survival and overall survival data are awaited.

Sextant-Specific Analysis of Detection and Tumor Volume by HistoScanning™.

Introduction: Published results of HistoScanning™ (HS) for prostate cancer (PCa) diagnostics are inconsistent and their value remains unclear. We prospectively analyzed the detection rate and tumor volume concordance in PCa patients. Material and Methods: Two hundred and eighty-two patients with biopsy-proven PCa scheduled for radical prostatectomy (RP) were included. All patients underwent ultrasonographical examination by HS prior to surgery. HS was evaluated compared to RP specimen as to (1) the prediction of overall tumor volume and (2) accuracy of HS in detection of PCa lesions larger than 0.2/0.5 ml, separated for each sextant. For each sextant, receiver operating characteristic (ROC)-analysis and area under the curve were determined. Sensitivity and specificity were calculated and visualized in ROC-curves. Results: HS tends to underestimate volume of cancerous lesions, particularly larger lesions >8 ml. Using a 0.2 ml detection threshold, specificity and sensitivity of HS were between 29-68% and 46-78%. For a 0.5 ml detection threshold, sextant-specific specificity increased to 59-92% and sensitivity decreased to 16-54%. Stratification according to pre-operational PSA values did not improve performance characteristics of HS. Conclusions: Our results do not support a significant contribution of HS to PCa diagnostics.

Prostate cancer: Estimated life expectancy: integration of age and comorbidities

Most guidelines recommend integration of estimated life expectancy into the routine decision-making process in prostate cancer treatment. This article underlines the use of both age and comorbidities to calculate life expectancy, which is highly dependent on the health status of the individual patient.