Fiaschi, Ai

Francini, E

Laera, L

Petrioli, R

Roviello, G

English

Florence Research

Effects of Abiraterone Acetate on Chronic Kidney Disease in2 Patients With Metastatic Castration-resistantProstate CancernaEdoardo Francini, MD, Roberto Petrioli, MD, Ano REurope for chemotherapy-naive mCRPC. This approval fol-lowed positive results from a phase III COU-AA-302 trial inwhich 1088 chemotherapy-naive men with metastatic CRPC2.6mg/dL, and creat4 CKD). Due to ageelectrolytes, and the lEditor: Chun-Xia Cao.Received: August 24, 2014; revised and accepted: September 9, 2014.From the Medical Oncology Unit, Policlinico Umberto I Hospital,University of Rome, Roma (EF); Pharmacology Unit (AIF); and MedicalOncology Unit, University of Siena, Siena, Italy (RP, LL, GR).Correspondence: Dr Giandomenico Roviello, Oncology Unit, Siena 53100,Italy (e-mail: giandomenicoroviello@hotmail.it).Ethical approval was obtained from the ethics committee of the University ofSiena. Written informed consent was obtained from the patients forpublication of these case reports.The authors have no conflicts of interest to disclose.Copyright # 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.This is an open access article distributed under the Creative CommonsAttribution License 4.0, which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.ISSN: 0025-7974DOI: 10.1097/MD.0000000000000163Medicine  Volume 93, Number 27, December 2014maD, Letizia LGiandomenicAbstract: Prostate cancer is the second leading cause of cancer-relateddeath in men in most Western countries. In this report, we present 2cases of metastatic castration-resistant prostate cancer and chronickidney disease. Both patients underwent and developed clinical resist-ance to androgen-deprivation therapy. Subsequently, the patients weretreated with the conventional chemotherapeutic approach, whichresulted in the worsening of renal function and performance status.Therefore, we opted for treatment with abiraterone acetate, and thepatients exhibited improvements in renal function with good response ofthe disease.(Medicine 93(27):e163)Abbreviations: AA = abiraterone acetate, CKD = chronic kidneydisease, FDA = Food and Drug Administration, mCRPC =metastatic castration-resistant prostate cancer, PSA = prostate-specific antigen, WBC = white blood cell count.INTRODUCTIONA biraterone acetate (AA) is a novel irreversible inhibitor ofCYP17 that was approved by the Food and Drug Admin-istration (FDA) on April 28, 2011 in combination with pre-dnisone for the treatment of metastatic castration-resistantprostate cancer (mCRPC), which was previously treated withdocetaxel. The approval of this agent was based on a multi-national randomized, double-blind, placebo-controlled, phaseIII trial that involved 1195 patients with docetaxel-refractoryCRPC.1 This study demonstrated a median overall survival inthe AA arm of 14.8 months compared with 10.9 months in theplacebo arm (hazard ratio: 0.646, 95% confidence interval:0.54–0.77; P¼ 0.0001). Furthermore, in 2013, AA wasapproved by regulatory agencies in the United States andIda Fiaschi, Phar aera, MD, andoviello, MDwho were treated with AA/prednisone exhibited prolongedoverall survival compared with those treated with a regimenof placebo/prednisone.2 More recently, the prespecified interimanalysis of the efficacy and safety outcomes in the COU-AA-302 study revealed median overall survivals of 35.3 months onAA versus 30.1 months on placebo.3Within the histories of patients with prostate cancer, thedevelopment of a chronic kidney disease (CKD) is not uncom-mon. In this report, we describe 2 patients with mCRPC andCKDwho were treated with AA and experienced improvementsin renal function, dramatic declines in prostate-specific antigen(PSA) levels, improvements in performance status, andreductions in bone pain.CASE REPORT 1In 2002, a 76-year-old man presented with a PSA level of15 ng/mL. His physical examination was normal, and a digitalrectal examination revealed a slightly enlarged prostate. Biop-sies revealed a prostate cancer with no evidence of distantmetastases and a Gleason score of 7 (4þ 3). Given the patient’sadvanced age, surgery was excluded. Moreover, the patientrefused to undergo radiotherapy; therefore, he was treated withleuprolide and oral bicalutamide.Follow-up visits were scheduled every 3 months thatincluded serial physical examination, routine blood evaluationsthat included serum PSA determinations at regular intervals(every 2–3 months) and radiological assessments every 6 to 12months or as clinically indicated.In January 2010, an episode of hematuria, urinary reten-tion, and bilateral hydronephrosis with acute renal failure(creatinine 6.39mg/dL) occurred, and a percutaneous ureter-ostomy was performed. However, although the episode of acutekidney failure was resolved, the patient presented with CKD insubsequent tests (creatinine 2.0mg/dL, creatinine clearance35mL/min). Stage 3B CKD was diagnosed and required obser-vation and control of blood pressure and other risk factors.In May 2010, the patient reported low-grade, constant backpain. A radionuclide scintigraphy revealed several areas sug-gestive of metastatic bone disease (ie, the right parietal bone,lumbar spine, sternum, ribs, pelvis, and right femur), and aserum PSA determination revealed a level of 210 ng/mL.Therefore, the patient began chemotherapy with estramus-tine phosphate 560mg per os daily and zoledronic acid intra-venously every 28 days. Laboratory data revealed the followingvalues: haemoglobin level 11.8 g/mL, hematocrit 38.5%,white blood cell count (WBC) 4200 cells/mm3, platelets179,000 cells/mL, blood urea nitrogen 69mg/dL, creatinineinine clearance 26.92mL/min (stageof the patient, the normality of theow urea value, renal replacement waswww.md-journal.com | 1his PSA level is 0.1 ng/mL (24 months without an increase inPSA), his creatinine is 1.6mg/dL, and his creatinine clearance is38.16mL/min (stage 3B CKD).not considered. Abdomen CT revealed the presence of abilateral percutaneous ureterostomy with reduction of bothkidneys, particularly the left, and the CT also revealed thepresence of multiple osteosclerotic lesions in the lumbar spineand pelvis.Follow-up visits that included determination of theserum PSA were scheduled every 2 months. These evaluationsrevealed a progressive increase in PSA to 421 ng/mL (Figure 1);therefore, in July 2011, the patient received a second line ofchemotherapy with docetaxel 40mg/m2 intravenous infusion ondays 1, 8, 15, 22, and 29 in a 6-week cycle.Over the first 3 months, the PSA exhibited a small decreaseto 339.7 ng/mL; after 6 months of treatment, the PSA wentdown to 243.7 ng/mL, but the laboratory data revealed a wor-sening of renal function with a blood urea nitrogen level of60mg/dL, a creatinine level of 3.5mg/dL, and a creatinineclearance of 19.64mL/min (stage 4 CKD). Furthermore, thepatient reported a partial resolution of the back pain. In contrast,the patient experienced considerable toxicity with side effectsincluding neutropenia, anemia, thrombocytopenia, fatigue, nailchanges, dry eyes, which were grades I or II in most of theexaminations, and a worsening of performance status. Treat-ment with docetaxel was discontinued, and, due to the toxicity, ahormonal approach with oral AA was undertaken (1000mg die,administered as four 250-mg tablets and prednisone 10mg diein 2 daily dosings).Six months after beginning the new treatment, the PSAexhibited a substantial reduction (48.57 ng/mL; Figure 1), animprovement in renal function was observed (blood urea nitro-gen 45mg/dL, creatinine 2.1mg/dL, and creatinine clearance32.14mL/min [stage 3B CKD]), electrolytes were normal, andthe patient reported a reduction in bone pain with a decrease inanalgesic consumption and an improvement in performancestatus. The treatment was well-tolerated without considerableside effects.Currently, the patient is continuing treatment, hisPSA level is 24.5 ng/mL (28 months without an increase inPSA), his creatinine is 2mg/dL, and his creatinine clearance is33.13mL/min (stage 3B CKD).CASE REPORT 2In November 2004, a 59-year-old man presented with aPSA of 13.7 ng/mL and a Gleason 7 (3þ 4) prostate adeno-Francini et alcarcinoma. He underwent radical prostatectomy, and extensiveperineural invasion and an extracapsular extension of the tumorwere found. Subsequently, he was treated with radiation therapy2 40801201602002402803203604004407121722273237CreatinineCL ml/min10 2 3 4 5 6 7 8 9 10 11 12AA MonthsDCASE 1PSAng/mlFIGURE 1. Trend of creatinine clearance and PSA during doce-taxel and abiraterone acetate therapy.2 | www.md-journal.comand androgen-deprivation therapy consisting of leuprolide andoral bicalutamide.Follow-up visits were scheduled every 3 months withserial physical examinations, routine blood evaluations, whichincluded serum PSA determinations at regular intervals(every 2 to 3 months), and radiological assessments every 6to 12 months or as clinically indicated.In October 2009, his PSA increased to 53.45 ng/mL, and anabdominal magnetic resonance imaging identified metastases tothe pelvic lymph nodes. From 2010 through 2011, the patientreceived docetaxel and epirubicin (11 cycles) followed byweekly navelbine per os for 6 months. In November 2011,there was a substantial increase in the PSA value (72.68 ng/mL;Figure 2), and the patient underwent docetaxel rechallenge withweekly docetaxel alone for 4 months.During the first cycle of docetaxel rechallenge, an episodeof urinary retention and bilateral hydronephrosis with acuterenal failure (creatinine 7.34mg/dL) occurred, and a percuta-neous ureterostomy was performed. When the episode of acutekidney failure was resolved, laboratory tests revealed CDKwitha creatinine level of 2.6md/dL and a creatinine clearance of24.62mL/min. A stage 4 CDK was diagnosed and requiredobservation and control of blood pressure and other risk factors.Other options were not considerate due to the age of the patientand the normality of the electrolytes and urea.In March 2012, the PSA value decreased to 29.78 ng/mL;however, laboratory data revealed a partial improvement inrenal function with a blood urea nitrogen level of 83mg/dL, acreatinine level of 3.1mg/dL, and a creatinine clearance of20.32mL/min (stage 4 CDK). Moreover, the patient began tosuffer from the side effects of chemotherapy; therefore, somecycles were delayed due to toxicity.Subsequently, he began AA (1000mg die, administered asfour 250-mg tablets and prednisone 10mg die in 2 daily dosing).His PSA exhibited a substantial reduction (4.91 ng/mL;Figure 2), improvements in renal function were observed (bloodurea nitrogen 57mg/dL, creatinine 1.7mg/dL, creatinine clear-ance 37.06mL/min, stage 3B CKD), his electrolyte levels werenormal, and the treatment was well tolerated without consider-able side effects. Currently, the patient is continuing treatment,Medicine  Volume 93, Number 27, December 201490807060504030201001 2 3 4 5 6 7 8 9 10 11 12 13CreatinineCL ml/minPSA ng/mlD AA MonthsCASE 2FIGURE 2. Trend of creatinine clearance and PSA during doce-taxel and abiraterone acetate therapy.# 2014 Lippincott Williams & WilkinsneDISCUSSIONUntil recently, patients who had progressed followingdocetaxel treatment had very limited options that includedmitoxantrone, which was the first cytotoxic agent to beapproved for the palliative treatment of men with CRPC.4 Otheragents have been tested, but most studies have reported noobjective responses or responses of <15%,5 and unfortunately,all of these agents have provided short-term clinical responsesthat are associated with a considerable toxicities. Moreover, theantifungal agent ketoconazole, which is used as an inhibitor ofthe activities of several enzymes involved in androgen synthesissuch as CYP17 and CYP11, has been investigated.6 However,ketoconazole lacks specificity for the CYP17 family ofenzymes, which unfortunately leads to significant toxicities(eg, hepatotoxicity, gastrointestinal toxicity, and adrenal insuf-ficiency).6In the past 3 years, several new agents with differentmechanisms of action have been developed for the treatmentof prostate cancer1,2,7,9–12 with the goal of prolonging theoverall survival of CRPC patients. Sipuleucel-T has been foundto improve the overall survival of asymptomatic or mildlysymptomatic men, most of whom had not received chemother-apy.7 However, sipuleucel-T has primarily been used in theUnited States and has been used less in Europe.8 Cabazitaxelwas approved by the FDA for the treatment of patients withmCRPC who have previously been treated with docetaxelchemotherapy.9Unfortunately, treatment with cabazitaxel is not withouttoxicity; indeed, severe neutropenia is common (89%), and 18%of patients discontinue the drug due to adverse events.9 Radium-223 has been reported to have a favorable safety profile withminimal myelotoxicity10; nevertheless, reports on the efficacyof radium-223 are recent, and at the time of this report, radium-223 was not commercially available. Rather, based on asystemic hormonal approach, AA and enzalutamide wereapproved for the treatment of patients with mCRPC followingdocetaxel treatment.1,2–11 Although enzalutamide exhibits afavorable toxicity profile,11,12 it could not be used for ourpatients because it is not yet commercially available; therefore,we opted for treatment with AA and excluded further lines ofchemotherapy with cabazitaxel.Since the first phase II studies of AA,13 it has been clearthat the blockade of cytochrome CYP17 is associated withincreased mineralocorticoid levels that result in some adverseevents, the most common of which are hypokalemia, fluidretention, and hypertension; however, these toxicities are lar-gely abrogated by the co-administration of low-dose glucocor-ticoids.As illustrated by the 2 cases reported herein before, thepatients continued to respond to treatment with docetaxel, buttheir laboratory data revealed worsening of their renal functionthat prevented the continuation of treatment with this che-motherapeutic agent. Conversely, after initiating AA, their renalfunctions exhibited improvements (Figures 1 and 2) withoutsignificant toxicity. Notably, in our patients, AA exhibited itsefficacy via substantial PSA responses that were sustained overtime. Indeed, after 28 and 24 months, the patient’s PSAs did notMedicine  Volume 93, Number 27, December 2014 Abirateroresistant Prostate Cancerprogression and the overall median survival of patients whowere treated with AA in the trial by de Bono (10.2 and 14.8# 2014 Lippincott Williams & Wilkinsmonths, respectively). Interestingly, our patients also exhibitedlonger times to PSA progression than the median time of thepatients in the COU-AA-302 trial (11.1 months). Therefore, theprognoses were better for our cases. However, it is difficult toexplain the reasons for the prolonged survivals observed in ourcases and whether the CDK played a role. To date, both patientsare still receiving AA treatment.CONCLUSIONSRecent studies showed that systemic hormone therapy is awell-tolerated option by the patients with CRPC. AA is one ofthe emerging novel therapies for advanced prostate cancer thatemploys a systemic hormonal approach.REFERENCES1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone andincreased survival in metastatic prostate cancer. N Engl J Med.2011;364:1995–2005.2. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastaticprostate cancer without previous chemotherapy. N Engl J Med.2013;368:138–148.3. Rathkopf DE, Smith MR, de Bono JS, et al. Updated interimefficacy analysis and long-term safety of abiraterone acetate inmetastatic castration-resistant prostate cancer patients without priorchemotherapy (COU-AA-302). Eur Urol. 2014Mar 6. pii: S0302-2838(14)00185-7. doi: 10.1016/j.eururo.2014.02.056.4. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy withmitoxantrone plus prednisone or prednisone alone for symptomatichormone-resistant prostate cancer: a Canadian randomized trial withpalliative end points. J Clin Oncol. 1996;14:1756–1764.5. Garmey EG, Sartor O, Halabi S, et al. Second-line chemotherapy foradvanced hormone-refractory prostate cancer. Clin Adv HematolOncol. 2008;6:118–122127-32.6. Vasaitis T, Bruno R, Njar V. CYP17 inhibitors for prostate cancertherapy. J Steroid Biochem Mol Biol. 2011;125:23–31.7. Kantoff PW, Higano CS, Shore ND, et al., IMPACT StudyInvestigators. Sipuleucel-T immunotherapy for castration-resistantprostate cancer. N Engl J Med. 2010;363:411–422doi: 10.1056/NEJMoa1001294.8. Di Lorenzo G, Buonerba C, Kantoff PW. Immunotherapy for thetreatment of prostate cancer. Nat Rev Clin Oncol. 2011;8:551–561.9. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisoneplus cabazitaxel or mitoxantrone for metastatic castration-resistantprostate cancer progressing after docetaxel treatment: a randomisedopen-label trial. Lancet. 2010;376:1147–1154.10. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223and survival in metastatic prostate cancer. N Engl J Med.2013;369:213–223.11. Scher HI, Fizazi K, Saad F, et al., AFFIRM Investigators. Increasedsurvival with enzalutamide in prostate cancer after chemotherapy.N Engl J Med. 2012;367:1187–1197.12. Beer TM, Armstrong AJ, Rathkopf DE, et al., the PREVAILInvestigators. Enzalutamide in Metastatic Prostate Cancer beforeChemotherapy. N Engl J Med. 2014;371:24–33.Acetate on Chronic Kidney Disease in 2 Patients With Castration-13. Attard G, Reid AH, A’Hern R, et al. Selective inhibition ofincrease. These durations are longer than the time to PSA CYP17 with abiraterone acetate is highly active in the treatment ofcastration-resistant prostate cancer. J Clin Oncol. 2009;27:3742–3748.www.md-journal.com | 3

Effects of abiraterone acetate on chronic kidney disease in 2 patients with metastatic castration-resistant prostate cancer

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Effects of abiraterone acetate on chronic kidney disease in 2 patients with metastatic castration-resistant prostate cancer

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