Metastatic Prostate Cancer: An Update on Treatments and a Review of Patient Symptom Management.

BACKGROUND: Available treatment options have improved overall survival and contributed to delayed progression, but metastatic prostate cancer remains incurable. Treatment strategies are based on disease progression assessed by a combination of biochemical, radiographic, and symptomatic changes. OBJECTIVES: The aim of this article is to review metastatic prostate cancer, symptoms representing disease progression, disease treatments, and symptom management. METHODS: A PubMed® search restricted to English-language articles published since 1990 was conducted in August 2018 with combinations of the keywords "metastatic prostate cancer," "symptom assessment," and "treatment." Review articles were excluded, but their reference lists were reviewed to identify additional articles. Information from relevant articles published after August 2018 was added as appropriate based on author consensus. FINDINGS: Nursing professionals play vital roles in symptom recognition and reporting, identification of disease progression, patient education, and implementation of individualized treatment strategies.

Analysis and Temporal Evolution of Extubation Parameters for Patients Undergoing Single-Stage Circumferential Cervical Spine Surgery.

OBJECTIVE: Airway obstruction after postoperative extubation is a dreaded but uncommon complication in patients undergoing circumferential cervical spine surgery (CCSS). The cuff leak test (CLT) has been utilized to assess air leak around the endotracheal tube which may reflect airway swelling. In this prospective observational study, we analyze the temporal evolution of CLT and perioperative factors that may influence it. METHODS: Twenty patients undergoing single-stage CCSS were managed according to our extubation protocol. Patients were maintained intubated overnight following surgery. They were extubated if a CLT > 200 mL and both intensive care unit (ICU) and Neurosurgery teams agreed that it was safe. Patients extubated in the first postoperative day (8 of 20) comprised the early group, and the remaining patients (12 of 20) the delayed group. Patient and operative data were analyzed as a single group and comparing both groups. RESULTS: The main indication for surgery was cervical deformity. Median number of levels fused was 5 anteriorly (range, 1-6) and 6 (range, 1-13) posteriorly. Patients were kept intubated for an average of 73.6 hours (range, 26-222 hours) and stayed in the ICU for 119.1 hours (range, 36-360 hours). There were 4 failed extubations and 3 patients (15%) required a tracheostomy. Patient profiles between both groups were very similar across most patient variables but differed significantly regarding infraglottic luminal area (p < 0.05). Patients with larger preoperative cuff leak values tended to have a shorter intubation period (p = 0.053). CONCLUSION: This study objectively demonstrates the difficulties in airway management following CCSS and provides useful insight for preoperative planning and counseling. Local anatomic factors influence airway outcome more than operative factors. The study format does not allow for testing of interventions but we suggest that patients with favorable anatomy (larger infraglottic luminal area) may benefit from a less strict airway management protocol.

Recognizing Symptom Burden in Advanced Prostate Cancer: A Global Patient and Caregiver Survey.

BACKGROUND: Bone metastases in men with prostate cancer are often initially asymptomatic, resulting in delayed identification, diagnosis, and appropriate treatment. To assess how patients with advanced prostate cancer (aPC) communicate symptoms to health care providers, an international patient survey was conducted. METHODS: An online and phone survey was conducted by Harris Poll in 11 countries (Brazil, France, Germany, Japan, Italy, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States) from February 12 to October 27, 2015, in men with aPC (ie, those who reported as having PC beyond the prostate [metastatic]) and their caregivers. Cell weighting was used to ensure equal weight of data across countries. Percentages are based on weighted n values. RESULTS: A total of 927 men with aPC (weighted n = 664) and 400 caregivers completed the survey. Most commonly reported symptoms were fatigue (73%), urinary symptoms (63%), sexual function symptoms (62%), and bone pain (52%). Of 568 patients with bone metastases (weighted n = 421), most (73%) noticed pain before receiving a diagnosis of metastatic PC. Most patients with aPC (56%) were uncertain if their pain was cancer related, 55% felt they had to live with daily pain, 45% sometimes ignored pain, and 39% had difficulty talking about pain. Patients who had a caregiver were more likely than those without to discuss pain at every visit (45% vs. 32%, P < .05). CONCLUSIONS: Disease symptoms in aPC are often underrecognized. Tools encouraging effective communication among patients, caregivers, and health care providers on early symptom reporting may lead to enhanced symptom and disease management.

Nursing management of patients with castration-resistant prostate cancer undergoing radium-223 dichloride treatment.

BACKGROUND: Radium-223 dichloride, or radium-223, is a first-in-class alpha emitter that selectively targets bone metastases with high-energy, short-range alpha particles and is approved for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Nurses are essential in educating patients about radium-223. OBJECTIVES: This article provides oncology nurses with information from the randomized phase III Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, as well as important handling, administration, and safety details unique to radium-223. METHODS: Data from the ALSYMPCA trial and related published information on radium-223 were reviewed. FINDINGS: Radium-223 is the only alpha-emitting radiopharmaceutical that has been shown to improve overall survival in patients with CRPC, as demonstrated in the ALSYMPCA trial. In addition, radium-223 delays time to first symptomatic skeletal event, and it is well tolerated with a low incidence of myelosuppression and gastrointestinal adverse events. Delivered on an outpatient basis, radium-223 requires universal precautions for handling and administration. Because of the potential for additive myelosuppression, the concomitant use of radium-223 with chemotherapy, other systemic radioisotopes, or hemibody external radiation therapy is not recommended.

Using circulating tumor cells as a prognostic indicator in metastatic castration-resistant prostate cancer.

A more reliable tumor marker is needed as a prognostic indicator in metastatic castration-resistant prostate cancer. Circulating tumor cells (CTCs) are cells that have broken away from a tumor and flow in the bloodstream. Evidence has indicated that the presence of CTCs in the peripheral blood of men with solid malignancies correlates with clinical outcomes. When the CTC number is reduced to fewer than five cells per 7.5 ml of blood, survival outcomes often improve. The relationship between the number of CTCs and prognosis has the potential to influence treatment decisions. Therefore, oncology nurses and practitioners must evaluate the scientific evidence, understand the clinical implications, and realize the impact CTC counts may have on practice to effectively communicate the CTC results to a patient. In addition, oncology nurses and practitioners must know that although favorable changes in CTC count are associated with a better prognosis, that alone cannot be used to guide treatment decisions for an individual.

A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors.

PURPOSE: To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies. EXPERIMENTAL DESIGN: Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m(2). 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m(2) in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot. RESULTS: Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m(2)-17-AAG 650 mg/m(2) due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed. CONCLUSIONS: The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m(2) and 17-AAG 500 mg/m(2).

Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer.

BACKGROUND: Growth of selected castration-resistant prostate cancer (CRPC) cell lines and animal models can be repressed by reexposure to androgens. Low doses of androgens, however, can stimulate tumor growth. OBJECTIVE: We performed a phase 1 clinical trial to determine the safety of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer (CRMPC). DESIGN, SETTING, AND PARTICIPANTS: Patients with progressive CRMPC who had been castrate for at least 1 yr received three times the standard replacement dose of transdermal testosterone. INTERVENTION: Cohorts of 3-6 patients received testosterone for 1 wk, 1 mo, or until disease progression. MEASUREMENTS: Toxicities, androgen levels, prostate-specific antigen (PSA) assays, computed tomography (CT) scans, bone scintigraphy, positron emission tomography (PET) scans, and metastatic tumor biopsy androgen receptor levels were assessed. RESULTS AND LIMITATIONS: Twelve patients were treated-three in cohorts 1 and 2 and six in cohort 3. No pain flares were noted. One patient came off study because of epidural disease, which was treated with radiation. Average testosterone levels were within normal limits, although dihydrotestosterone (DHT) levels on average were supraphysiologic in cohort 3. One patient achieved a PSA decline of >50% from baseline. No objective responses were seen. For cohort 3, median time on treatment was 84 d (range: 23-247 d). CONCLUSIONS: We have demonstrated that patients with CRMPC can be safely treated in clinical trials using high-dose exogenous testosterone. Patients did not, on average, achieve sustained supraphysiologic serum testosterone levels. Future studies should employ strategies to maximize testosterone serum levels, use contemporary methods of identifying patients with androgen receptor overexpression, and utilize PSA Working Group II Consensus Criteria clinical trial end points. TRIAL REGISTRATION: ClinicalTrials.gov; NCT00006044.

Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.

PURPOSE: Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS: Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS: Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION: Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.

Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer.

PURPOSE: MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704. PATIENTS AND METHODS: Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed. RESULTS: Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2). CONCLUSION: Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.

Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.

PURPOSE: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. EXPERIMENTAL DESIGN: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m(2) daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. RESULTS: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. CONCLUSION: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.

Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. PATIENTS AND METHODS: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. RESULTS: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline. CONCLUSIONS: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer.

PURPOSE: To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. RESULTS: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. CONCLUSION: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

High-dose calcitriol, zoledronate, and dexamethasone for the treatment of progressive prostate carcinoma.

BACKGROUND: Preclinical and clinical data have suggested that high-dose calcitriol (1,25-dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse-dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse-dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression. METHODS: Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3-6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 microg per day. Doses were escalated to 30 microg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded. RESULTS: Thirty-one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 microg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium-related laboratory findings. Patients tolerated therapy well, even in the 30 microg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 microg and 30 microg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed. CONCLUSIONS: Calcitriol was well tolerated at doses up to and including 30 microg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 microg and 30 microg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned.