Curr Urol Rep (2014) 15:419 DOI 10.1007/s11934-014-0419-0
PROSTATE CANCER (D PAREKH, SECTION EDITOR)
Management of Advanced Prostate Cancer – Role of the Urologist Neal Shore
Published online: 10 May 2014 # Springer Science+Business Media New York 2014
Abstract There now exists an enhanced opportunity for urologists to continue to successfully identify, treat, and manage advanced prostate cancer patients in partnership with our medical oncology and radiation oncology colleagues. For urologists and their supporting staff who are dedicated to caring for patients with advanced prostate cancer, there are novel therapies that delay disease progression, maintain – and oftentimes improve – quality-of-life metrics, and prolong overall survival. These therapies are not unusually difficult to manage, nor are they too intimidating with regard to understanding their mechanisms of action and respective safety profiles. They provide the opportunity to improve and enhance patient care, as well as to further augment the urological role in both the academic and community multidisciplinary prostate cancer clinic. Keywords Prostate cancer . Immunotherapy . Androgen receptor . Oral hormonal therapy . Radiopharmaceutical . Antiresorptive
The Evolution of Advanced Prostate Cancer Management Prostate cancer (PCa) is the most common cancer diagnosed in men in the United States [1], resulting in over 28,000 cancer-specific deaths in 2012 [2]. After primary interventional therapy for localized disease, surgical extirpation, or radiation therapy, approximately 20 % to 30 % will not have a curative result, reflective of biochemical (PSA) relapse or radiographic metastatic disease. Assuming continued
This article is part of the Topical Collection on Prostate Cancer N. Shore (*) Carolina Urologic Research Center, Myrtle Beach, SC, USA e-mail: [email protected]
survival, and no resultant mortality from other comorbidities, the patient disease continuum will evolve from an androgen-sensitive phenotype to castration-resistant prostate cancer (CRPC) status. It is estimated that there are 35,000 men in the United States who have radiographically demonstrable mCRPC [3]. Since 2010, the U.S. Food and Drug Administration (FDA) has approved five new PCa therapies for mCRPC, more than the total approved over the last three decades. Importantly, each drug approval has a unique mechanism of action (MOA), suggesting opportunities to better elucidate sequencing and combinatorial strategies. Additionally, these unique MOAs result in unique and specific monitoring requirements. The therapeutic options for mCRPC were largely palliative until 2004, when docetaxel, a microtubule stabilizing agent, demonstrated clinically significant survival benefit in mCRPC patients in contradistinction to the use of secondary hormonal manipulations, and was thus received as a first-line cytotoxic chemotherapy for mCRPC patients [4, 5]. In the years since docetaxel was approved, additional agents that have received FDA approval for treatment of mCRPC patients include: hormonal agents abiraterone acetate [6] and enzalutamide [7], the immunotherapy agent sipuleucel-T [8], the chemotherapy agent cabazitaxel [9], and a bone microenvironmenttargeting agent, denosumab [10]. Some of these agents, including cabazitaxel [9], enzalutamide [7], and the newly approved radioactive therapeutic agent radium Ra 223 dichloride (radium-223) [11], are specific to treatment in patients with regard to the timing of administration of docetaxel-based therapy. These novel agents provide urologists with the opportunity to manage their patients’ care as well as their disease transitions from androgen-sensitive to castration-resistant status. As the therapeutic algorithm of options for men with CRPC has undergone significant progress, the roles of oncologists, radiation oncologists, and urologists are also evolving [12].
419, Page 2 of 8
Historically, many urologists reflexively referred their CRPC patients to a medical oncologist. There are potential implications of this transference of patient care. Certainly, the patient should have access to the best clinician to offer and monitor therapeutic selections and patient response. Issues regarding patient satisfaction with the transition of care, avoidance of duplication of services, and the overall economics of care and its impact on both providers and the healthcare model continue to be addressed. With the approval of sipuleucel-T in April 2010 and the approval of abiraterone acetate for the treatment of docetaxel-naïve patients with mCRPC in December 2012, urologists are presented with the choice of administering mCRPC therapies other than a cytotoxic chemotherapy. Electing to offer these therapies presumes an interest and dedication to understanding appropriate indications and the required clinical monitoring for these patients. Assuredly, these are not insurmountable issues, but they do require a commitment and an understanding of their administration. The availability of antiresorptive agents such as zoledronic acid and denosumab, which reduce the occurrence of skeletalrelated events (SREs, e.g., fractures, radiation or surgery to bone, and spinal cord compression) also provide additional therapeutic options for urologists to successfully manage their CRPC patients. In light of the rapidly evolving therapeutic options for CRPC patients, the following provides a brief overview of therapies most recently approved as well as the required monitoring for the safe and effective management of these patients .
New Therapies for CRPC Patients Survival-prolonging systemic therapies currently approved for mCRPC include docetaxel [4], cabazitaxel [9], sipuleucel-T [8], abiraterone acetate [6], enzalutamide [7], and radium-223 [11]. Docetaxel [4], cabazitaxel [9], abiraterone acetate [6], and radium-223 [11] may elicit pain palliation due to their direct antitumor effects [13]. Notably, both radium-223 and abiraterone acetate are recommended across mCRPC index patient categories [14••]. Ra-223 demonstrated significant pain palliation in patients with CRPC with painful bone metastases [15]. In patients with mCRPC previously treated with docetaxel, abiraterone acetate plus prednisone was beneficial compared with prednisone alone for pain relief, delayed pain progression, and prevention of SREs [16]. The osteoclast inhibitors zoledronic acid [17] and denosumab [10] are approved for the delay of SREs. In addition, the androgen-signaling inhibitor enzalutamide demonstrated improvements in overall survival and palliative endpoints in the post-chemotherapy setting [13].There are ongoing trials evaluating the use of enzalutamide for mCRPC patients prior to the use of docetaxel.
Curr Urol Rep (2014) 15:419
The American Urological Association (AUA) CRPC Guidelines Panel has published and codified six index patient cases to represent the most common scenarios encountered for mCRPC patients in clinical practice, and has provided a flow diagram of the course of patient therapy (Fig. 1) [14••]. The guidelines were based on the absence or presence of metastasis, pain-related and other clinical symptoms, performance status, and the prior use of docetaxel-based chemotherapy. These evidence-based recommendations serve as a structural framework to assist urologists in assessing and discussing the most appropriate treatments for their patients (Table 1).
Monitoring Patients Appropriate monitoring is essential in providing the most effective and safest therapy for mCRPC patients. A reference guide summarizing common adverse events (AEs) associated with CRPC therapies may be useful to urologists and the clinical care teams. While the list of correlated AEs may at first seem daunting, urologists are already familiar with these AEs, as well as the corresponding laboratory abnormalities and symptoms (Tables 2 and 3). The newer CRPC therapies may have unique monitoring requirements, but many of these requirements and concerns will overlap (Table 2). As an example, prolonged ADT results in bone demineralization and may be associated with an increased fracture risk [18, 19]. Bone loss that occurs with ADT may be more rapid than that associated with normal age-related bone loss [20]. For mCRPC patients with bony metastases, the AUA guidelines suggest that clinicians may choose either denosumab [10] or zoledronic acid [17] when selecting an SRE-preventive treatment [14••]. Additional bone health monitoring is necessary for ADT and antiresorptive therapies (zoledronic acid and denosumab) where hypocalcemia could ensue, as well as with regard to the safety issue of osteonecrosis of the jaw (ONJ) (Table 2). In addition to a comprehensive metabolic panel, levels of calcium, magnesium, and vitamin D should be monitored as necessary in these patients. In response to the warnings and precautions associated with antiresorptives, many urology clinics implement pathways to perform formal dental exams, with consultation from the dentist, prior to commencing any antiresorptive therapy. Patient awareness of the possibility of ONJ and other dental complications is important, and so careful consideration should be undertaken before procedures such as dental extractions are performed. Patient awareness and cursory oral examinations on a regular basis are important when administering antiresorptive therapy. Serum hematologic and chemistry evaluations are important monitoring values for many of the new advanced PCa therapies. For example, monitoring of serum testosterone levels is recommended for all GnRH analogs, as well as
Curr Urol Rep (2014) 15:419
Page 3 of 8, 419
Fig. 1 Flowchart summarizing recommendations of the 2013 American Urological Association Guidelines for the treatment of castration-resistant prostate cancer [14••]. H&P=history and physical examination, CRPC=
castration-resistant prostate cancer. Please refer to Table 1 for Index Patient descriptions and their corresponding guideline statements
prostate-specific antigen (PSA) monitoring, in order to assess treatment efficacy and detect biochemical progression. Subsequent testosterone monitoring is recommended with any rise in PSA after achieving a nadir. Serum glucose monitoring is also essential while patients are receiving hormonal suppressive therapies, as treatment with these agents may precipitate insulin resistance and disruption of glycemic homeostasis, particularly in patients with pre-existing diabetes. These patients should be monitored for blood glucose and/or glycosylated hemoglobin and managed for the treatment of hyperglycemia or diabetes according to current practice guidelines. Monitoring by complete blood count (CBC) is vital for therapies in which neutropenia is a concern (docetaxel and cabazitaxel). Neutrophil levels should be closely watched to ensure that levels do not fall below 1,500 cells/mm3. Potential serologic hepatotoxic abnormalities should be monitored for the first- and second-generation antiandrogens as well as for abiraterone acetate and docetaxel. The clinical symptoms of hepatotoxicity may include nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, and right-upper-quadrant tenderness. When administering abiraterone acetate, liver function should be tested by monitoring for elevated levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin every two weeks for the first three months, and then monthly thereafter. If the liver enzymes are elevated to five times the normal level and bilirubin to three times the normal level, the drug should be withheld; otherwise, dose reduction can be instituted [6]. Renal toxicity is a concern for zoledronic acid and cabazitaxel. The risk of renal AEs may be greater in patients
with existing renal impairment or patients who have already had multiple cycles of treatment. Dehydration and the use of other nephrotoxic drugs may predispose patients to these renal effects, and cases of renal failure have occurred in association with sepsis, dehydration, and obstructive uropathy. In the case of suspected renal toxicity with cabazitaxel, the drug should be withheld until renal function is deemed adequate. If it is rechallenged, and renal function deteriorates once again, consider discontinuation of this drug altogether. If a decline in renal function is suspected with zoledronic acid use, the patient can be switched to denosumab. Bone marrow suppression has been demonstrated with radium-223 use (in 10 %) Injection site reactions, hot flashes, increased weight, and increases in serum levels of transaminases and γ-glutamyltransferase (≥10 %) Hot flashes, pain (including general, back, pelvic, and abdominal), asthenia, constipation, and infection (>10 %)
CASODEX® [25] bicalutamide ZYTIGA® [6]
Fatigue, joint swelling or discomfort, edema, hot flush, and diarrhea (≥10 %)
abiraterone acetate PROVENGE® [8]
Chills, fatigue, fever, back pain, and nausea (≥15 %)
sipuleucel-T XTANDI® [7]
Asthenia/fatigue, back pain, diarrhea, arthralgia, and hot flush (≥5 %)
enzalutamide XGEVA® [10]
Fatigue, asthenia, hypophosphatemia, and nausea (≥25 %)
denosumab ZOMETA® [17]
Nausea, fatigue, anemia, bone pain, and constipation (>25 %)
** The prescribing information for FIRMAGON® (degarelix for injection) [22] is included in this table as a representative of GnRH antagonists.
zoledronic acid TAXOTERE® [4]
Infections, neutropenia, anemia, febrile neutropenia, and hypersensitivity†
docetaxel JEVTANA®[9]
Neutropenia, anemia, leukopenia, thrombocytopenia, and diarrhea (≥10 %)
† Adverse events across all indications for TAXOTERE®
cabazitaxel XOFIGO® [11]
Nausea, diarrhea, vomiting, and peripheral edema (≥10 %)
GnRH = gonadotropin-releasing hormone
radium-223
receiving abiraterone acetate must also be monitored for adrenocortical insufficiency, which manifests as abdominal pain, vomiting, profound muscle weakness, fatigue, depression, hypotension, renal failure, and ultimately shock. The signs and symptoms of adrenocortical insufficiency may be masked by AEs associated with mineralocorticoid excess. This can occur if prednisone is withdrawn or the dose is reduced, or in cases of infection or stress. However, this was found to occur in
PROSTATE CANCER (D PAREKH, SECTION EDITOR)
Management of Advanced Prostate Cancer – Role of the Urologist Neal Shore
Published online: 10 May 2014 # Springer Science+Business Media New York 2014
Abstract There now exists an enhanced opportunity for urologists to continue to successfully identify, treat, and manage advanced prostate cancer patients in partnership with our medical oncology and radiation oncology colleagues. For urologists and their supporting staff who are dedicated to caring for patients with advanced prostate cancer, there are novel therapies that delay disease progression, maintain – and oftentimes improve – quality-of-life metrics, and prolong overall survival. These therapies are not unusually difficult to manage, nor are they too intimidating with regard to understanding their mechanisms of action and respective safety profiles. They provide the opportunity to improve and enhance patient care, as well as to further augment the urological role in both the academic and community multidisciplinary prostate cancer clinic. Keywords Prostate cancer . Immunotherapy . Androgen receptor . Oral hormonal therapy . Radiopharmaceutical . Antiresorptive
The Evolution of Advanced Prostate Cancer Management Prostate cancer (PCa) is the most common cancer diagnosed in men in the United States [1], resulting in over 28,000 cancer-specific deaths in 2012 [2]. After primary interventional therapy for localized disease, surgical extirpation, or radiation therapy, approximately 20 % to 30 % will not have a curative result, reflective of biochemical (PSA) relapse or radiographic metastatic disease. Assuming continued
This article is part of the Topical Collection on Prostate Cancer N. Shore (*) Carolina Urologic Research Center, Myrtle Beach, SC, USA e-mail: [email protected]
survival, and no resultant mortality from other comorbidities, the patient disease continuum will evolve from an androgen-sensitive phenotype to castration-resistant prostate cancer (CRPC) status. It is estimated that there are 35,000 men in the United States who have radiographically demonstrable mCRPC [3]. Since 2010, the U.S. Food and Drug Administration (FDA) has approved five new PCa therapies for mCRPC, more than the total approved over the last three decades. Importantly, each drug approval has a unique mechanism of action (MOA), suggesting opportunities to better elucidate sequencing and combinatorial strategies. Additionally, these unique MOAs result in unique and specific monitoring requirements. The therapeutic options for mCRPC were largely palliative until 2004, when docetaxel, a microtubule stabilizing agent, demonstrated clinically significant survival benefit in mCRPC patients in contradistinction to the use of secondary hormonal manipulations, and was thus received as a first-line cytotoxic chemotherapy for mCRPC patients [4, 5]. In the years since docetaxel was approved, additional agents that have received FDA approval for treatment of mCRPC patients include: hormonal agents abiraterone acetate [6] and enzalutamide [7], the immunotherapy agent sipuleucel-T [8], the chemotherapy agent cabazitaxel [9], and a bone microenvironmenttargeting agent, denosumab [10]. Some of these agents, including cabazitaxel [9], enzalutamide [7], and the newly approved radioactive therapeutic agent radium Ra 223 dichloride (radium-223) [11], are specific to treatment in patients with regard to the timing of administration of docetaxel-based therapy. These novel agents provide urologists with the opportunity to manage their patients’ care as well as their disease transitions from androgen-sensitive to castration-resistant status. As the therapeutic algorithm of options for men with CRPC has undergone significant progress, the roles of oncologists, radiation oncologists, and urologists are also evolving [12].
419, Page 2 of 8
Historically, many urologists reflexively referred their CRPC patients to a medical oncologist. There are potential implications of this transference of patient care. Certainly, the patient should have access to the best clinician to offer and monitor therapeutic selections and patient response. Issues regarding patient satisfaction with the transition of care, avoidance of duplication of services, and the overall economics of care and its impact on both providers and the healthcare model continue to be addressed. With the approval of sipuleucel-T in April 2010 and the approval of abiraterone acetate for the treatment of docetaxel-naïve patients with mCRPC in December 2012, urologists are presented with the choice of administering mCRPC therapies other than a cytotoxic chemotherapy. Electing to offer these therapies presumes an interest and dedication to understanding appropriate indications and the required clinical monitoring for these patients. Assuredly, these are not insurmountable issues, but they do require a commitment and an understanding of their administration. The availability of antiresorptive agents such as zoledronic acid and denosumab, which reduce the occurrence of skeletalrelated events (SREs, e.g., fractures, radiation or surgery to bone, and spinal cord compression) also provide additional therapeutic options for urologists to successfully manage their CRPC patients. In light of the rapidly evolving therapeutic options for CRPC patients, the following provides a brief overview of therapies most recently approved as well as the required monitoring for the safe and effective management of these patients .
New Therapies for CRPC Patients Survival-prolonging systemic therapies currently approved for mCRPC include docetaxel [4], cabazitaxel [9], sipuleucel-T [8], abiraterone acetate [6], enzalutamide [7], and radium-223 [11]. Docetaxel [4], cabazitaxel [9], abiraterone acetate [6], and radium-223 [11] may elicit pain palliation due to their direct antitumor effects [13]. Notably, both radium-223 and abiraterone acetate are recommended across mCRPC index patient categories [14••]. Ra-223 demonstrated significant pain palliation in patients with CRPC with painful bone metastases [15]. In patients with mCRPC previously treated with docetaxel, abiraterone acetate plus prednisone was beneficial compared with prednisone alone for pain relief, delayed pain progression, and prevention of SREs [16]. The osteoclast inhibitors zoledronic acid [17] and denosumab [10] are approved for the delay of SREs. In addition, the androgen-signaling inhibitor enzalutamide demonstrated improvements in overall survival and palliative endpoints in the post-chemotherapy setting [13].There are ongoing trials evaluating the use of enzalutamide for mCRPC patients prior to the use of docetaxel.
Curr Urol Rep (2014) 15:419
The American Urological Association (AUA) CRPC Guidelines Panel has published and codified six index patient cases to represent the most common scenarios encountered for mCRPC patients in clinical practice, and has provided a flow diagram of the course of patient therapy (Fig. 1) [14••]. The guidelines were based on the absence or presence of metastasis, pain-related and other clinical symptoms, performance status, and the prior use of docetaxel-based chemotherapy. These evidence-based recommendations serve as a structural framework to assist urologists in assessing and discussing the most appropriate treatments for their patients (Table 1).
Monitoring Patients Appropriate monitoring is essential in providing the most effective and safest therapy for mCRPC patients. A reference guide summarizing common adverse events (AEs) associated with CRPC therapies may be useful to urologists and the clinical care teams. While the list of correlated AEs may at first seem daunting, urologists are already familiar with these AEs, as well as the corresponding laboratory abnormalities and symptoms (Tables 2 and 3). The newer CRPC therapies may have unique monitoring requirements, but many of these requirements and concerns will overlap (Table 2). As an example, prolonged ADT results in bone demineralization and may be associated with an increased fracture risk [18, 19]. Bone loss that occurs with ADT may be more rapid than that associated with normal age-related bone loss [20]. For mCRPC patients with bony metastases, the AUA guidelines suggest that clinicians may choose either denosumab [10] or zoledronic acid [17] when selecting an SRE-preventive treatment [14••]. Additional bone health monitoring is necessary for ADT and antiresorptive therapies (zoledronic acid and denosumab) where hypocalcemia could ensue, as well as with regard to the safety issue of osteonecrosis of the jaw (ONJ) (Table 2). In addition to a comprehensive metabolic panel, levels of calcium, magnesium, and vitamin D should be monitored as necessary in these patients. In response to the warnings and precautions associated with antiresorptives, many urology clinics implement pathways to perform formal dental exams, with consultation from the dentist, prior to commencing any antiresorptive therapy. Patient awareness of the possibility of ONJ and other dental complications is important, and so careful consideration should be undertaken before procedures such as dental extractions are performed. Patient awareness and cursory oral examinations on a regular basis are important when administering antiresorptive therapy. Serum hematologic and chemistry evaluations are important monitoring values for many of the new advanced PCa therapies. For example, monitoring of serum testosterone levels is recommended for all GnRH analogs, as well as
Curr Urol Rep (2014) 15:419
Page 3 of 8, 419
Fig. 1 Flowchart summarizing recommendations of the 2013 American Urological Association Guidelines for the treatment of castration-resistant prostate cancer [14••]. H&P=history and physical examination, CRPC=
castration-resistant prostate cancer. Please refer to Table 1 for Index Patient descriptions and their corresponding guideline statements
prostate-specific antigen (PSA) monitoring, in order to assess treatment efficacy and detect biochemical progression. Subsequent testosterone monitoring is recommended with any rise in PSA after achieving a nadir. Serum glucose monitoring is also essential while patients are receiving hormonal suppressive therapies, as treatment with these agents may precipitate insulin resistance and disruption of glycemic homeostasis, particularly in patients with pre-existing diabetes. These patients should be monitored for blood glucose and/or glycosylated hemoglobin and managed for the treatment of hyperglycemia or diabetes according to current practice guidelines. Monitoring by complete blood count (CBC) is vital for therapies in which neutropenia is a concern (docetaxel and cabazitaxel). Neutrophil levels should be closely watched to ensure that levels do not fall below 1,500 cells/mm3. Potential serologic hepatotoxic abnormalities should be monitored for the first- and second-generation antiandrogens as well as for abiraterone acetate and docetaxel. The clinical symptoms of hepatotoxicity may include nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, and right-upper-quadrant tenderness. When administering abiraterone acetate, liver function should be tested by monitoring for elevated levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin every two weeks for the first three months, and then monthly thereafter. If the liver enzymes are elevated to five times the normal level and bilirubin to three times the normal level, the drug should be withheld; otherwise, dose reduction can be instituted [6]. Renal toxicity is a concern for zoledronic acid and cabazitaxel. The risk of renal AEs may be greater in patients
with existing renal impairment or patients who have already had multiple cycles of treatment. Dehydration and the use of other nephrotoxic drugs may predispose patients to these renal effects, and cases of renal failure have occurred in association with sepsis, dehydration, and obstructive uropathy. In the case of suspected renal toxicity with cabazitaxel, the drug should be withheld until renal function is deemed adequate. If it is rechallenged, and renal function deteriorates once again, consider discontinuation of this drug altogether. If a decline in renal function is suspected with zoledronic acid use, the patient can be switched to denosumab. Bone marrow suppression has been demonstrated with radium-223 use (in 10 %) Injection site reactions, hot flashes, increased weight, and increases in serum levels of transaminases and γ-glutamyltransferase (≥10 %) Hot flashes, pain (including general, back, pelvic, and abdominal), asthenia, constipation, and infection (>10 %)
CASODEX® [25] bicalutamide ZYTIGA® [6]
Fatigue, joint swelling or discomfort, edema, hot flush, and diarrhea (≥10 %)
abiraterone acetate PROVENGE® [8]
Chills, fatigue, fever, back pain, and nausea (≥15 %)
sipuleucel-T XTANDI® [7]
Asthenia/fatigue, back pain, diarrhea, arthralgia, and hot flush (≥5 %)
enzalutamide XGEVA® [10]
Fatigue, asthenia, hypophosphatemia, and nausea (≥25 %)
denosumab ZOMETA® [17]
Nausea, fatigue, anemia, bone pain, and constipation (>25 %)
** The prescribing information for FIRMAGON® (degarelix for injection) [22] is included in this table as a representative of GnRH antagonists.
zoledronic acid TAXOTERE® [4]
Infections, neutropenia, anemia, febrile neutropenia, and hypersensitivity†
docetaxel JEVTANA®[9]
Neutropenia, anemia, leukopenia, thrombocytopenia, and diarrhea (≥10 %)
† Adverse events across all indications for TAXOTERE®
cabazitaxel XOFIGO® [11]
Nausea, diarrhea, vomiting, and peripheral edema (≥10 %)
GnRH = gonadotropin-releasing hormone
radium-223
receiving abiraterone acetate must also be monitored for adrenocortical insufficiency, which manifests as abdominal pain, vomiting, profound muscle weakness, fatigue, depression, hypotension, renal failure, and ultimately shock. The signs and symptoms of adrenocortical insufficiency may be masked by AEs associated with mineralocorticoid excess. This can occur if prednisone is withdrawn or the dose is reduced, or in cases of infection or stress. However, this was found to occur in
