Long-term quality of life of testicular cancer survivors differs according to applied adjuvant treatment and tumour type.

PURPOSE: To evaluate the quality of life (QoL) in long-term testicular cancer (TC) survivors. METHODS: QoL was assessed in TC survivors treated between March 1976 and December 2004 (n = 625) using the EORTC-QLQ-C30 questionnaire, including a TC module. The assessment was performed at two time points (2006: response rate: n = 201/625 (32.2%), median follow-up (FU): 12.9 years (range 1.1-30.9); 2017: response rate: n = 95/201 (47.3%), median FU: 26.2 years (range: 13.0-41.2)). TC survivors were grouped according to treatment strategy, tumour entity, clinical stage and prognosis group. Linear and multiple linear regression analyses were performed, with age and time of follow-up as possible confounders. RESULTS: Radiation therapy (RT) compared to retroperitoneal lymph node dissection (RPLND) was associated with a higher impairment of physical function (2017: ß = - 9.038; t(84) = - 2.03; p = 0.045), role function (2017: ß = - 12.764; t(84) = - 2.00; p = 0.048), emotional function (2006: ß = - 9.501; t(183) = - 2.09; p = 0.038) and nausea (2006: ß = 6.679; t(185) = 2.70; p = 0.008). However, RT was associated with a lower impairment of sexual enjoyment (2017: symptoms: ß = 26.831; t(64) = 2.66; p = 0.010; functional: ß = 22.983; t(65) = 2.36; p = 0.021). Chemotherapy (CT), compared to RPLND was associated with a higher impairment of role (2017: ß = - 16.944; t(84) = - 2.62; p = 0.011) and social function (2017: ß = - 19.160; t(79) = - 2.56; p = 0.012), more insomnia (2017: ß = 19.595; t(84) = 2.25; p = 0.027) and greater concerns about infertility (2017: ß = 19.830; t(80) = 2.30; p = 0.024). In terms of tumour type, nonseminomatous germ cell tumour (NSGCT) compared to seminoma survivors had significantly lower impairment of nausea (2006: ß = - 4.659; t(187) = - 2.17; p = 0.031), appetite loss (2006: ß = - 7.554; t(188) = - 2.77; p = 0.006) and future perspective (2006: ß = - 12.146; t(175) = - 2.08; p = 0.039). On the other hand, surviving NSGCT was associated with higher impairment in terms of sexual problems (2006: ß = 16.759; t(145) = 3.51; p < 0.001; 2017: ß = 21.207; t(63) = 2.73; p = 0.008) and sexual enjoyment (2017: ß = - 24.224; t(66) = - 2.76; p = 0.008). CONCLUSIONS: The applied adjuvant treatment and the tumour entity had a significant impact on the long-term QoL of TC survivors, even more than 25 years after the completion of therapy. Both RT and CT had a negative impact compared to survivors treated with RPLND, except for sexual concerns. NSGCT survivors had a lower impairment of QoL compared to seminoma survivors, except in terms of sexual concerns. IMPLICATIONS FOR CANCER SURVIVORS: Implications for cancer survivors are to raise awareness of aspects of long-term and late effects on QoL in TC survivors; offer supportive care, such as psycho-oncological support or lifestyle modification, if a deterioration in QoL is noticed; and avoid toxic treatment without compromising a cure whenever possible.

Robotic Salvage Lymph Node Dissection in Recurrent Prostate Cancer: Lessons Learned from 68 Cases and Implications for Future Clinical Management.

PURPOSE: Salvage lymph node dissection is a rescue treatment for patients with nodal recurrence after radical prostatectomy. Very limited data are available on robotic salvage lymph node dissection. Our purpose was to investigate perioperative and oncological outcomes of robotic salvage lymph node dissection in a large monocentric series. MATERIALS AND METHODS: Perioperative data, complications within 30 days after surgery and oncological outcomes as assessed by histology, prostate specific antigen changes, prostate specific antigen nadir after salvage lymph node dissection, and time to further therapy were analyzed. To identify predictive factors for oncological outcome, Kaplan-Meier and Cox-regression analyses were performed. For cases with a mismatch between preoperative positron emission tomography/computed tomography and the number of histologically positive lymph nodes, prostate specific membrane antigen immunohistochemistry was performed on removed lymph nodes. RESULTS: A total of 68 patients underwent robotic salvage lymph node dissection with a median operation time of 126 minutes, a blood loss of 50 ml, and a length of stay of 4 days. No major complications (>Clavien 3) occurred. Median followup was 12.1 months. Median time to further therapy was 12.4 months, 37% of patients experienced complete biochemical response (prostate specific antigen <0.2 ng/ml) and 11% reached an undetectable prostate specific antigen, which was maintained for >1 year in 3 cases. Lower preoperative prostate specific antigen, longer time between radical prostatectomy and salvage lymph node dissection, preoperative prostate specific membrane antigen positron emission tomography/computed tomography and complete biochemical response after salvage lymph node dissection were significant predictors of longer therapy-free survival (all p <0.005). Prostate specific membrane antigen immunohistochemistry revealed that prostate specific membrane antigen positron emission tomography/computed tomography tends to miss small lymph node metastases <5 mm. CONCLUSIONS: Robotic salvage lymph node dissection is a feasible approach with low perioperative morbidity and delays further systemic therapy in most patients. Prostate specific membrane antigen positron emission tomography/computed tomography detection is mostly limited to tumor foci >5 mm.

Guideline adherence in bone-targeted treatment of cancer patients with bone metastases in Germany.

PURPOSE: To assess adherence to the current European Society for Medical Oncology (ESMO) clinical practice guideline on bone health in cancer patients and the German guidelines for lung, breast, and prostate cancer among German oncologists in hospitals and office-based physicians and to identify predictors of guideline compliance to assess the needs for dedicated training. METHODS: This was a retrospective sample analysis representing hospitals and office-based physicians in Germany in 2016. Records from lung, breast, and prostate cancer patients who had received a diagnosis of bone metastasis between April 1, 2015, and March 31, 2016, were included. Oncologists at participating centers answered a self-assessment survey on aspects related to their professional life, including guideline adherence and years of clinical experience in medical oncology. Guideline adherence rates were assessed from patient records. Treatment variables and survey data were used to identify predictors of guideline compliance in a Classification and Regression Tree (CART) analysis. RESULTS: Disregarding recommendations for supplementation of calcium and vitamin D, guideline adherence among physicians treating lung, breast, or prostate cancer patients was 62%, 92%, and 83%, respectively. Compliance was 15%, 42%, and 40% if recommendations for dietary supplements were taken into account. Identified predictors of guideline compliance included treatment setting, medical specialty, years of professional experience, and frequency of quality circle attendance. CONCLUSIONS: Compliance with the ESMO and the German guidelines in cancer patients varies between medical specialties. In particular, patients with lung cancer and bone metastases often do not receive the recommended osteoprotective treatment and required supplementation. Discrepancies between guideline recommendations and common practice should be addressed with dedicated training.

Radical prostatectomy in T4 prostate cancer after inductive androgen deprivation: results of a single-institution series with long-term follow-up.

OBJECTIVES: To determine the outcomes of complete surgical resection of T4 prostate cancer after inductive androgen-deprivation therapy (ADT), as inductive ADT and subsequent radical prostatectomy (RP) is not recommended by any guideline yet. PATIENTS AND METHODS: A monocentric RP database was queried for patients initially diagnosed with T4 prostate cancer, considered primarily as inoperable because of a fixed mass defined by rectal examination in combination with high PSA level and/or large foci of biopsy confirmed undifferentiated prostate cancer. Treatment consisted of primary ADT until PSA nadir with consecutive RP. Patients underwent retropubic RP (RRP) or robot-assisted laparoscopic RP (RALP) after inductive ADT until achievement of the PSA nadir, which is in general reached after 6-7 months. The intraoperative course and complications were analysed. Finally, Kaplan-Meier estimates were calculated for overall survival (OS) and prostate cancer-specific survival (PCSS). RESULTS: We retrospectively identified 116 patients treated between 2000 and 2014. At diagnosis, the median (range) PSA level was 37.6 (2.44-284) ng/mL. The preoperative median (range) PSA after inductive ADT was 0.73 (0.01-34) ng/mL. Thereafter, patients underwent RRP or, since 2006, RALP. The median (95% confidence interval) OS was 156 (118.9-193.1) months. The PCSS at 150 months was 82%. CONCLUSIONS: Surgical therapy of primarily inoperable prostate cancer is feasible and safe after inductive ADT. The OS of this cohort seems comparable with results described for patients with primary operable high-risk prostate cancer.

Organ-Preserving Surgical Treatment of a Horseshoe Kidney Occupied by a Large Renal Cell Carcinoma with Extensive Venous Invasion: A Case Report.

The horseshoe kidney is one of the most common congenital disorders affecting the urogenital system. Following a fusion of the lower kidney poles, which in turn lead to the formation of an isthmus, this anatomical variation is accompanied by other characteristic properties like an incomplete ascension, ventral rotation of the pelvices as well as atypical vascular supply. Even though renal carcinoids and Wilms tumors are more common in horseshoe kidneys, the incidence of renal cell carcinomas seems to be unaffected. Here we report the case of a locally advanced renal cell carcinoma with extensive venous invasion occurring in a horseshoe kidney and its complex surgical management. The whole primary tumor as well as a majority of venous tumor thrombi could be removed by a combination of 2/3 nephrectomy and cavotomy with thrombectomy. During 1 year of follow-up, the patient neither suffered from a tumor relapse, nor did he require renal replacement therapy. Thus, we conclude that even in cases of RCC where advanced disease is associated with complex anatomical situations, organ-preserving surgical treatment should be pursued to achieve excellent functional and oncological results.

CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3ß,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone.

CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF-mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone. We further evaluated the effects of Abi on steroid metabolism of testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) by enzyme immunoassays (EIAs). Androgen-responsive cell lines metabolized pregnenolone primarily to mitogenic steroid 5α-pregnan-3ß,6α-diol-20-one under serum starvation. Co-administration of Abi lead to detectable concentrations of the Abi metabolite Δ4-Abi (D4A), known to inhibit enzymes other than CYP17A1 in steroid metabolism. In addition, co-administration of Abi abrogated pregnenolone metabolism and resulted in a CYP17A1-independent significant increase of DHEA (13- to >100-fold) and DHT (2.5-fold) in androgen-responsive cells. Our results demonstrate the CYP17A1-independent formation of 5α-pregnan-3ß,6α-diol-20-one by androgen-responsive prostate cancer cells under serum starvation and its inhibition by Abi. Its metabolism from pregnenolone suggests a major steroidogenesis shift in these cells, hinting at a neuroendocrine transdifferentiation phenomenon. The marked increase of DHEA levels by Abi resembles the steroidogenic pathways in nervous tissue, in a manner that precludes CYP17A1 activity. To which extent these processes are responsible or involved in the development of resistance to Abi, needs to be further elucidated.

[PREFERE - Study on the rise]. / PREFERE-Studie im Aufwind.

The PREFERE study, which compares the treatment options for prostate cancer with low and early intermediate risk, has recorded a noticeable upswing in recruitment since mid-2015. Responsible for this are the revised inclusion criteria and the wide support for this study in Germany. The inclusion criteria opened the study to the use of imaging techniques (MRI, C­Trus / Anna) and the inclusion of all Gleason 3 + 3 = 6 cancers, regardless of tumor extent. In addition, patients can now be included who, for example due to the size of the prostate or existing obstructive micturition disorders, had a contraindication to percutaneous radiotherapy or brachytherapy - these can now be randomized between active surveillance and radical prostatectomy. With the increased recruitment numbers, it seems realistic that the required milestones in recruiting will be achieved.

Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients.

Piwi-like 2 (Piwil 2) belongs to the family of Argonaute genes/proteins. The expression of Piwil 2 is associated with stem cells. A role in tumorigenesis and/or tumor progression is proposed for different cancers but not yet for bladder cancer (BCa). We investigated the Piwil 2 expression by immunohistochemistry in a cohort of 202 BCa patients treated by cystectomy and adjuvant chemotherapy. The association between Piwil 2 expression and disease-specific (DSS) or progression-free survival (PFS) was calculated using Kaplan Meier analyses and univariate/multivariate Cox's regression hazard models.In a multivariate Cox's regression, Piwil 2 expression, either in the cytoplasm or the nucleus, was significantly associated with DSS and PFS. A weak cytoplasmic staining pattern was associated with poor DSS and tumor progression (RR=2.7; P=0.004 and RR=2.4; P=0.027). Likewise,, absent nuclear Piwil 2 immunoreactivity was associated with poor DSS and tumor progression (RR=2.3; P=0.023 and RR=2.2; P=0.022). BCa patients whose tumors exhibited a combination of weak cytoplasmic and absent nuclear immunoreactivity had a 6-fold increased risk of tumor-related death (P=0.005) compared to patients with strong expression. Considering only patients with high grade G3 tumors, a 7.8-fold risk of tumor-associated death and a 3.6-fold risk of tumor progression were detected independently of the histologic tumor subtype or the chemotherapy regimen. In summary, a combination of weak cytoplasmic and absent nuclear expression of Piwil 2 is significantly associated with an increased risk of DSS and tumor progression. This implicates that Piwil 2 could be a valuable prognostic marker for high-risk BCa patients.

Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone.

BACKGROUND: Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication. OBJECTIVE: This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone. DESIGN, SETTING, AND PARTICIPANTS: Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone. RESULTS AND LIMITATIONS: The median duration of abiraterone treatment was 9.0 mo (range: 2.0-19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4-7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0-6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation. CONCLUSIONS: Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.

Novel options for the treatment of castration-resistant prostate cancer.

Docetaxel had been the only treatment of castration-resistant prostate cancer (CRPC) that demonstrated a survival benefit for the patients. After its approval, no considerable progress has been made for several years until cabazitaxel and abiraterone acetate demonstrated a significant survival benefit in phase III clinical trials. Apart from that several other new drugs appeared including inhibitors of the androgen receptor (MDV3100), endothelin receptor antagonists (atrasentan, zibotentan), bone-targeted drugs (denosumab, Alpharadin) and immunotherapies (sipuleucel-T) capable of improving the prognosis of patients with CRPC. Here, we review the most recent advances in the treatment of CRPC and highlight the most promising new agents currently being investigated in clinical trials.

Anatomical extent of pelvic lymphadenectomy in patients undergoing radical prostatectomy.

OBJECTIVES: The rationale for locoregional staging lymphadenectomy in prostate cancer (pCA) lies in the accurate diagnosis of occult micrometastases to stratify patients who might benefit from adjuvant therapeutic measures. In pCA, the issues of the necessity and the therapeutic advantage of pelvic lymphadenectomy (PLND]) in patients with low-, intermediate-, and high-risk disease are still discussed controversially. The aim of this review manuscript is to critically evaluate the current status on PLND in pCA. METHODS: A review of the literature was performed concerning radical prostatectomy and PLND with respect to anatomical extent, oncological outcome, and associated complications. RESULTS: The anatomical lymphatic drainage of the prostate includes the obturator fossa, and the external and internal iliac arteries; therefore, at least these areas should be included in PLND. According to the current clinical studies, extended PLND (ePLND) significantly increases the yield of both total lymph nodes and lymph node metastases independent of the risk classification of pCA. Lymph node metastases will be detected in about 5-6%, 20-25%, and 30-40% of low-, intermediate-, and high-risk pCA, respectively. Exclusively 25% of all positive lymph nodes are located in the area around the internal iliac artery. With regard to progression-free and cancer-specific survival, retrospective analysis of the SEER data and additional case-control studies indicate a direct positive relationship between the number of removed lymph nodes and long-term oncological outcome in patients with limited lymph node involvement or negative lymph nodes. In these patients, cancer-specific survival is improved by about 15-20%. On the basis of results of large case-control studies, complication rates of ePLND are not significantly increased. CONCLUSIONS: On the basis of current data, the following conclusions can be drawn: (1) If performed, PLND has to be done in the extended, anatomically adequate variant. (2) The frequency of lymph node metastases in low-risk pCA is low, and the issue of PLND has to be discussed with the patient. (3) If radical prostatectomy is performed in intermediate- and high-risk pCA, an ePLND should be option of choice. For the future, ongoing prospective trials have to demonstrate a benefit in terms of biochemical-free and cancer-specific survival.

Application of thalidomide/interleukin-2 in immunochemotherapy-refractory metastatic renal cell carcinoma.

Thalidomide has been reported to yield anti-tumor activity in advanced renal cell carcinoma (RCC). We evaluated safety and efficacy of a combination therapy comprising interleukin (IL)-2 and thalidomide in patients with metastatic RCC refractory to both immuno- and chemotherapy. Twelve patients with progressive metastatic RCC who had failed prior treatment with immunochemotherapy and desired further active therapy were enrolled in this study. Oral thalidomide was started at 200 mg/day and escalated after 2 days to 400 mg/day at week 0. IL-2 at 7 MIU/m was given by s.c. injection, starting at week 1, days 1-5, weeks 1-4, with rest from IL-2 at weeks 5 and 6. Response was assessed every two therapy cycles. Ten patients were evaluable for response. There was no objective response; four patients showed stable disease for 14+, 11+, 10+ and 9 months, respectively. Toxicities were predominantly grade I-II, and included somnolence and constipation, as well as flu-like symptoms associated with IL-2. However, one patient developed serious constipation which led to a paralytic ileus and discontinuation of treatment. Another patient left the study after 7 weeks due to increasing disorientation/confusion. Eight patients required IL-2 dose reduction. Time on therapy ranged from 3 to 44 weeks (median 20 weeks). Median overall survival was 12+ months. At present, all patients have discontinued treatment. We conclude that outpatient administration of thalidomide/IL-2 is feasible in patients with heavily pretreated and progressive RCC who desire further active treatment. However, toxicity and costs are considerable, and clinical benefit is uncertain. Therefore, thalidomide/IL-2 might not represent a promising therapeutic approach for this subgroup of patients.

Ibandronate: its pharmacology and clinical efficacy in the management of tumor-induced hypercalcemia and metastatic bone disease.

It is well accepted that tumor cells in the bone, especially from breast cancer, prostate cancer and multiple myeloma, can stimulate osteoclast formation and activity. Bisphosphonates are potent inhibitors of osteoclast-mediated normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert similar effects on macrophages and tumor cells. Currently, it is unknown if this effect can be translated into clinical practice with regard to an effective adjuvant therapeutic regimen for high-risk patients with systemic recurrences following primary treatment of a given cancer. There are several new aspects that might extend the clinical use of ibandronate, a bisphosphate, in oncology: prevention of hypogonadal osteoporosis in men, palliative management of painful osseous metastases and adjuvant therapy of high-risk prostate cancer patients. Safety and tolerability are excellent for the oral and intravenous formulations, and ibandronate can even be safely applied in pre-existing renal insufficiency. The purpose of this review is to critically reflect the pharmacology and clinical efficacy of ibandronate in the management of tumor-induced hypercalcemia, osteoporosis and metastatic bone disease.

Prospective randomized Phase II trial of pegylated doxorubicin in the management of symptomatic hormone-refractory prostate carcinoma.

BACKGROUND: Liposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells. On the basis of doxorubicin's demonstrated clinical efficacy against hormone-refractory prostate carcinoma (HRPCA), the authors conducted a prospective, randomized Phase II clinical trial to evaluate the feasibility, toxicity, and therapeutic efficacy associated with the pegylated form of this agent. METHODS: Forty-eight patients with symptomatic HRPCA were randomized to receive pegylated liposomal doxorubicin at either 25 mg/m2 every 2 weeks for 12 cycles (Group A) or 50 mg/m2 every 4 weeks for 6 cycles (Group B). Thirty-eight of these 48 patients (79%) presented with severe pain (corresponding to a pain score of 7.5 on a visual analog scale [VAS] ranging from 0 to 10) due to osseous metastases. Therapeutic efficacy was assessed by serial evaluation of serum prostate-specific antigen (PSA) concentrations and by serial measurement of pain levels (using a VAS ranging from 0 to 10). Toxicity data were obtained using the National Cancer Institute of Canada/Cancer and Leukemia Group B criteria and the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. RESULTS: The median patient age was 68.9 years (range, 58-79 years), and the mean follow-up duration was 42 months. The mean pretreatment PSA level was 660.4 ng/mL (mean, 8-6340 ng/mL); an objective decrease in PSA levels (i.e., a decrease of > 50%) was observed in 8 of 31 patients (25.8%) in Group B, whereas no other patient in either group experienced such a decrease. The mean time to disease progression was 6.5 months, and the mean survival duration was 13.4 months. Patients in Group B had a significantly higher rate of response with respect to pain (52.6% vs. 28.6%; P = 0.04), and the mean 1-year survival rate also was significantly higher in Group B (42% vs. 15%; P = 0.02). Severe side effects were observed, with 24 patients (50%) experiencing World Health Organization Grade 3/4 toxicity. Toxicity types differed significantly between Group A and Group B; palmar-plantar erythrodysesthesia developed in 60% of patients in the former group (P < 0.0005), whereas tachycardia was more common in the latter group (39% of patients; P < 0.0005). No dose-limiting cardiotoxicities or hematotoxicities were documented. CONCLUSIONS: Pegylated liposomal doxorubicin yielded a noteworthy objective palliative response rate and a mean survival of 13 months for patients with symptomatic HRPCA. The dosage tested in the current study should be used in future Phase II and Phase III trials of pegylated liposomal doxorubicin-containing combination regimens for patients with HRPCA.