Reviews in Urology Volume 22, No. 3 2020Current and Future Management of Locally Advanced and Metastatic Prostate Cancer

Current and Future Management of Locally Advanced and Metastatic Prostate CancerNeal D. Shore, MD, FACSMedical Director, Carolina Urologic Research Center, Myrtle Beach, SCWith increasing treatment options available, the management of locally advanced and metastatic prostate cancer (PCa) is growing more complex, nuanced, and individualized. Strategies for combining surgery, radiation, chemotherapy, and androgen deprivation therapy (ADT) continue to evolve, as do ADT and immunotherapy options. Additionally, multiple adjunctive agents for metastatic PCa have been recently approved or are pending approval. As the number of locally advanced and metastatic prostate cancers being diagnosed rises, so does the need to consider patients’ clinical situations and personal preferences. This review discusses current and potential future approaches to managing locally advanced and metastatic PCa.[Rev Urol. 2020;22(3):110–123]© 2020 MedReviews®, LLCKeywordsAs diagnostic techniques and treatments for locally advanced and metastatic prostate cancer (PCa) continue to evolve, men with these more advanced prostate cancers are living longer.^1,2 Yet PCa remains the second-leading cause of cancer death among American men.³The National Cancer Institute predicts that in 2020, 191,930 American men will be diagnosed with PCa, and 33,330 men will die of PCa.⁴ Since 1999, the rate of PCa incidence per 100,000 American men has fallen from approximately 170 to 109.5,⁵ as organizations began advising against routine prostate-specific antigen (PSA) testing in 2008.⁶ Although incidence of low-risk prostate cancers fell 37% between 2004 and 2013, incidence of metastatic PCa during those years rose 72%.⁷ To help clinicians better understand and navigate the treatment landscape for locally advanced and metastatic PCa, this review assesses present and potential future therapies.In brief, when selecting nonsurgical options for androgen deprivation therapy (ADT), physicians must consider multiple factors, including these drugs’ pharmacological profiles, efficacy, and cost. For initial treatment of intermediate- and high-risk localized PCa, guidelines recommend radical prostatectomy (RP) or radiotherapy (RT), with or without ADT. Management of biochemical recurrence (BCR) remains controversial. First-line treatment for newly diagnosed M1 PCa (metastatic hormone-sensitive prostate cancer [mHSPC]) involves ADT alongside guideline considerations for adding approved androgen receptor axis inhibitors as well as docetaxel. For castration-resistant prostate cancer (CRPC), guidelines recommend maintaining castrate testosterone (T) levels through continued ADT.To discuss current treatments and future concerns in locally advanced and metastatic PCa, the author searched PubMed, meeting abstracts, and clinicaltrials.gov from 1941 through early 2020 using search terms such as locally advanced prostate cancer (LAPC) guidelines, gonadotropin-releasing hormone (GnRH) agonist/antagonist, ADT, and intermediate, high-risk, and metastatic PCa. The author ultimately selected 102 of the most relevant publications for inclusion in this article.ResultsThe vast majority of US cancers—77%, according to National Cancer Institute/Surveillance, Epidemiology, and End Results (NCI/SEER) data (2009-2015)—remain localized at diagnosis, whereas 13% and 6% of PCas have spread to regional lymph nodes and distant sites, respectively.⁴ The aggressiveness of initial PCa treatment generally depends on the risk level with which disease presents (Table 1, Table 2).Tab1Tab2Therapeutic Goals of ADTSince Huggins and Hodges first elucidated the androgen-dependent nature of PCa growth, reducing serum testosterone levels through ADT has become the first-line strategy for treating advanced and metastatic disease.^11,12 The American Urological Association (AUA), the National Comprehensive Cancer Network (NCCN), and the European Association of Urology (EAU) all recommend ADT as primary systemic therapy for advanced and metastatic PCa, and in combination with neoadjuvant or adjuvant radiation therapy in localized or locally advanced PCa.^8,13,14 Over the years, the target T level of ADT has arguably evolved from ≤50 ng/dL to below 20 ng/dL based on some association guidelines and consensus papers, suggesting that the latter lower level represents a more effective medical castration.¹¹
Non-surgical ADT OptionsThe variety of treatment options for LAPC and metastatic PCa allows individualization of choices for selecting ADT. Through shared decision-making (SDM), physicians and patients must consider not only clinical factors, but also patients’ lifestyles, injection preferences, and compliance factors, along with accessibility and costs.Widely used non-surgical ADT options include GnRH agonists and GnRH antagonists (Table 3). Popular extended-release formulations allow dosing at intervals ranging from 1 to 12 months.¹¹Tab3Mechanistically, GnRH agonists bind to GnRH receptors, initially provoking profound stimulation, which leads to substantial increases in GnRH/luteinizing hormone (LH), follicle-stimulating hormone (FSH), and T.^15,16 Sustained overstimulation of the pituitary desensitizes GnRH receptors, thus leading to decreased hormone levels.¹⁷ To block clinical flare symptoms such as urinary obstruction and bone pain stemming from the initial hormonal surge provoked by GnRH agonists, physicians should prescribe a first-generation anti-androgen (bicalutamide, flutamide, or nilutamide) before or along with GnRH agonist therapy (combined androgen blockade [CAB]) and continuing in combination for at least 7 days.⁸GnRH antagonists block androgen receptors, immediately halting GnRH/LH production. Results include rapid T suppression without an initial hormonal surge, and prolonged suppression without escapes or microsurges as can occur upon re-administration of GnRH agonist doses.¹⁵ Additionally, GnRH antagonists quickly suppress FSH, which contributes to flares associated with GnRH agonist therapy.¹⁶ In the CS21 phase 3 trial, degarelix achieved faster T decline in the first month, superior PSA decline in the first 2 months, and slightly better efficacy in metastatic disease than did leuprolide.¹⁸ However, this trial did not provide evidence to support a short- or long-term advantage of degarelix over leuprolide in patients with BCR. Disadvantages of GnRH antagonists in clinical practice may include their cost, convenience level (only monthly dosing is available), and administration tolerability.¹⁹Additional SDM considerations include serum T nadir level. Increasing evidence indicates that very low T levels may be associated with improved outcomes, including survival.^21-23 Such studies underscore the importance of both monitoring T levels and choosing an ADT that achieves T nadir efficacy.¹⁴Adverse events (AEs) associated with ADT also require discussion. In 2010, the US Food and Drug Administration (FDA) and other organizations warned users of GnRH agonists regarding the statistically significant increased risks of diabetes and cardiovascular (CV) events with these drugs, and recommended that physicians evaluate patients for these risk factors.^24,25An analysis of six phase 3 trials by Albertsen and colleagues showed that patients treated with degarelix in comparison to an LHRH agonist had a 40% reduction in risk of CV event or death during their first year of ADT.²⁶ Among patients with preexisting cardiovascular disease (CVD), degarelix-treated patients had an HR of 0.44 for CV (95% confidence interval (CI), 0.26-0.74; P = 0.002) event or death. In the first prospective trial to analyze CV outcomes among patients treated with either GnRH agonists or antagonists, Margel and colleagues showed that men in the agonist group experienced more major adverse cardiovascular and cerebrovascular events (MACCE) compared with the GnRH antagonist group (20% vs 3%, respectively; P = 0.013).²⁷In the ongoing phase 3 PRONOUNCE trial (NCT02663908), investigators will randomize a total of 900 patients to receive either leuprolide 3-month depot or degarelix monthly for 1 year. The primary endpoint is time from randomization to first confirmed occurrence of the composite MACE endpoint (nonfatal myocardial infarction, nonfatal stroke, or death due to any cause).The decision to initiate ADT should encompass further detailed discussion with the patient and family regarding the myriad of ADT AEs as well as preventative strategies to diminish or avoid ADT complications.^1,28-31Although T monitoring should be standard practice for men on ADT, the optimal timing of T measurement is still debated. A 3- to 6-month interval has been suggested,¹⁴ but the author’s clinical experience favors obtaining a baseline T before ADT initiation, then confirming castrate T levels 1 to 3 months following medical or surgical castration. If T >50 (or 20) ng/dL, consider checking GnRH level to differentiate incorrect administration from ineffective castration. If the latter, consider switching to another GnRH agonist/antagonist or bilateral orchiectomy. If T remains elevated, some authors have suggested adding an estrogen or an anti-androgen for further hormonal manipulation, although the clinical benefit remains uncertain.⁸
ADT ± Bone-targeted TherapyMen who initiate ADT may already be at risk for osteoporosis due to advanced age, hypogonadism, and/or other risk factors.³² To combat ADT-associated bone loss, the NCCN advises screening and treatment for osteoporosis according to general-population guidelines from the National Osteoporosis Foundation.³³ When fracture risk warrants drug therapy, the NCCN recommends denosumab (60 mg SC every 6 months), zoledronic acid (ZA; 5 mg IV annually), or alendronate (70 mg PO weekly) to boost bone mineral density (BMD).Clinical Scenarios and Treatment StrategiesIntermediate- and High-risk Localized PCaRegarding initial treatment, AUA, EAU, and NCCN guidelines recommend RP or RT, with certain caveats, and possible ADT for intermediateor high-risk PCa (Table 4, Figure 1). NCCN recommendations divide intermediate-risk PCa into favorable (1 intermediate risk factor [IRF], Grade Group 1 or 2, and <50% biopsy cores positive) and unfavorable (2 or 3 IRFs and/or Grade Group 3 and/or ≥50% cores positive) strata.Tab4Fig1Radiation With Adjuvant ADTADT is recommended in patients with unfavorable intermediate- and high-risk PCa considering RT.^36,37 Neoadjuvant therapy with a GnRH agonist often reduces overall prostate volume by 25% to 33% within 3 months,^38,39 a finding that supports the common practice of beginning ADT 2 to 3 months before starting radiation. Many studies have shown benefits for the combination of radiation with short-term ADT.^40-45Additional studies support use of radiation and long-term ADT in combined populations of intermediate- and high-risk local PCa.^46-52 Although Level I evidence supports ADT for all intermediate-risk disease, compelling retrospective and post hoc evidence suggests that favorable intermediate-risk disease may be treated adequately with RT alone.⁵³RT in High-risk PCaApproaches to high-risk localized PCa using adjuvant systemic therapies have remained relatively unchanged for the past few decades.⁵⁴ For patients with nodal metastases, standard-of-care approaches include adjuvant ADT, based largely on the trial by Messing and colleagues.⁵⁵ Neoadjuvant or adjuvant ADT is also considered standard in high- and intermediaterisk PCa being treated with RT, although optimal ADT duration has not been established.⁵³Current recommendations for using radiation with long-term ADT in high-risk PCa are based partly on trials showing cancer-specific and overall survival (OS) benefits for 28 to 36 months of ADT in patients with locally advanced disease.^49,56 These findings led to 2010 NCCN guideline changes and clinicalpractice changes to include 2 to 3 years of ADT for high-risk PCa.⁵⁷Considering the AEs associated with ADT, shortening long-term ADT may be desirable. Although the PCS IV phase 3 trial showed an overall survival hazard ratio (OSHR) of 1.02 for 18 versus 36 months ADT,⁵⁸ it remains unclear whether these results support a conclusion that 18 months ADT is noninferior to 36 months because the trial did not use a noninferiority design. However, Yang and colleagues reported that an HR near 1.0, with a relatively narrow CI, raises the likelihood that the OS difference between 18 and 36 months for this population is small. These authors therefore suggested that these emerging data raise the possibility that 18 months may be sufficient for select high-risk patients.⁵³
RP Plus ADTAUA/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) and EAU guidelines recommend against using neoadjuvant ADT for localized PCa in patients who have chosen RP outside of clinical trials.^14,36Moderate evidence suggests that 6 to 8 months of neoadjuvant ADT before RP provides clinical benefit (usually lower positive margin rates after RP and decreased PSA recurrence risk after 2-5 years), but no studies have demonstrated an OS benefit.⁵⁹ Conversely, evidence including a meta-analysis of 11,149 patients⁶⁰ shows that long-term ADT immediately after RP can benefit men with high-risk localized PCa, particularly those with positive lymph nodes.⁵⁹
BCRBCR definitions differ slightly depending on primary treatment and guideline authors. The EAU and AUA define post-RP relapse as PSA >2 ng/mL, and post-RT >2 ng/mL above nadir (or, for the AUA, 3 consecutive PSA increases).^61,62 Because patients with PSA recurrence after primary RP or RT have different risks of subsequent symptomatic metastatic disease, physicians should carefully interpret BCR endpoints when considering treatment initiation, for example, ADTs.¹⁴Once PSA relapse is diagnosed, physicians must determine as accurately as possible whether the recurrence has occurred locally or distantly. Initial clinical and pathologic factors of the recurrence (T category, PSA, and Gleason score) and PSA kinetics (PSA doubling time [PSADT] and interval to PSA failure) help determine the risk of subsequent metastases and PCa-specific mortality (PCSM).¹⁴ For specific recommendations regarding BCR after surgery, radiation, high-intensity focused ultrasound (HIFU), or cryoablation and after primary surgery with adjuvant radiation or after localized salvage failure, please see Figures 2, 3, and 4.Fig2Fig3Fig4The management of BCR following primary curative treatment remains controversial, partly because PSA-only recurrence does not consistently correlate with either PCa-specific or overall survival.⁶³ Recommendations regarding post-RP recurrence illustrate subtle differences between guidelines. For example, the EAU strongly recommends treating patients with a PSA rise from undetectable using salvage radiotherapy (SRT), but not offering hormonal therapy to every pN0 patient treated with SRT. AUA guidelines state that clinicians should offer ADT to patients being treated with SRT after RP failure (PSA ≥0.20 ng/mL).⁶⁴ For low-risk BCR, the EAU strongly recommends offering androgen suppression (AS) and possibly delayed SRT. In 10-year follow-up of the GETUG-AFU 16 trial, progression-free survival for patients treated with RT plus short-term goserelin (10.8 mg on the first day of RT and 3 months later) was 64%, versus 49% for patients treated with radiotherapy alone (HR 0.54; 95% CI, 0.43-0.68; stratified log-rank test, P < 0.0001). These authors concluded with a recommendation for AS plus RT as salvage treatment in patients with rising PSA concentration after RP.⁶⁵For BCR after RT, options include ADT or local procedures such as salvage RP, cryotherapy, interstitial brachytherapy, and HIFU, but weak evidence makes firm recommendations impossible.¹⁴ Ongoing phase 3 trials may help guide future practice in BCR (Table 5).Tab5Newly Diagnosed Metastatic PCaMedian OS for patients who present with mHSPC (Table 6) is approximately 42 months.⁶⁶ Upon conventional radiographic imaging detecting M1 disease, the clinicians’ therapeutic selection choices are now numerous.⁶⁷Tab6EAU guidelines strongly recommend treating both symptomatic and asymptomatic M1 patients (or discussing deferred castration with well-informed patients). The first-line treatment for newly diagnosed M1 PCa is ADT.⁶⁶ No Level I evidence favors a specific type of ADT, except in patients with impending spinal-cord compression, for whom either bilateral orchiectomy or GnRH antagonists are preferred, per the EAU (albeit with a “weak” recommendation).¹⁴ Offer surgical or medical castration alone (with or without an anti-androgen) only to patients unfit for or uninterested in newer combinations including either docetaxel or abiraterone acetate plus prednisone.⁶⁶
ADT in mHSPCADT remains the gold standard in mHSPC, regardless of metastatic volume (low vs high) with Level I evidence for combining treatments (docetaxel, abiraterone, apalutamide), according to NCCN, EAU, and ESMO guidelines.^8,14,68 To avoid castration-dependent pharmacokinetics of docetaxel, physicians commonly start docetaxel 6 to 12 weeks after initiating ADT.Adding the second-generation AR signaling inhibitor (ASI) abiraterone acetate to ADT represents another standard of care.⁶⁹ In the LATITUDE and STAMPEDE trials, this combination produced nearly identical OS improvements of 38% (HR 0.62 and 0.63, respectively).^70,71The phase 3 TITAN trial showed that apalutamide plus ADT significantly improved radiographic progression-free survival (rPFS) and OS versus placebo plus ADT in patients with metastatic castration-sensitive PCa.⁷² In September 2019, the FDA approved apalutamide for use in this population.⁷³ In mid-2019, NCCN guidelines added apalutamide as a category 1 option for M1 castrationnaive PCa.⁸ Additionally, the FDA granted priority review for enzalutamide in mHSPC based on positive results of the ARCHES and ENZAMET phase 3 trials. The ARCHES phase 3 trial showed that at median of 14.4 months, ADT plus enzalutamide significantly improved rPFS over ADT plus placebo.⁷⁴ In ENZAMET, HR for death in the enzalutamide group was 0.67 (95% CI, 0.52-0.86; P = 0.002) versus ADT alone at a median follow-up of 34 months.⁷⁵Four-year follow-up of STAMPEDE, moreover, showed that ADT plus upfront docetaxel or abiraterone produced no significant differences between these two regimens in median OS, metastasis-free survival (MFS), or PCa-specific survival.⁷⁶ Because castrated patients clear docetaxel roughly twice as quickly as un-castrated patients,⁷⁷ do not delay docetaxel until patients become castration resistant.⁷⁸ Clinicians continue to debate which treatment to add to ADT, and then how to best sequence the next line of therapy.In selecting which combination for high-volume mHSPC patients, guidelines do not recommend either abiraterone or docetaxel over the other. In high-volume mHSPC, there is unequivocal OS benefit to ADT with docetaxel versus ADT alone,⁷⁰ according to NCCN and ASCO guidelines.^8,79 In lowvolume mHSPC, a recent analysis of STAMPEDE results revealed that docetaxel confers additive benefits regardless of metastatic burden—5-year OS in the lowburden group specifically was 72%, versus 57% for ADT alone (P = 0.107).⁸⁰ ADT plus abiraterone also represents a reasonable standard of care irrespective of metastatic burden.⁶⁸In low-volume mHSPC, NCCN and ESMO 2019 guidelines recommend RT to the prostate for patients without contraindications to radiotherapy. ADT is also required, unless medically contraindicated. In a section of the STAMPEDE trial, however, adding radiotherapy to standard care in patients with low metastatic burden improved failure-free survival but not OS.⁸¹ EAU guidelines recommend (although weakly) offering castration plus RT to patients whose first presentation is M1 disease, with low volume as defined by CHAARTED criteria.For patients with metastasis at first presentation (versus relapse/metastases after definitive local therapy), EAU guidelines cite that docetaxel or abiraterone should be consider as standard therapy in conjunction with ADT.¹⁴ However, ASCO recommends ADT plus abiraterone strongly in high-risk de novo mHSPC and moderately in lower-risk cases.⁷⁹
CRPCRegardless of ADT modality, nearly all patients with advanced PCa maintained on ADT eventually develop castration resistance, requiring changes in therapeutic strategy. In all patients with rising PSA and/or clinical progression, physicians must evaluate serum T to confirm castrate resistance before considering treatments.¹³ In CRPC, continuing ADT to maintain castrate T levels (≤20 ng/dL) is strongly recommended and considered the standard of care in both metastatic and nonmetastatic CRPC.^8,14,82In deciding which patients to evaluate for metastatic disease, the EAU suggests using baseline PSA, PSA velocity, and PSADT, which have been associated with time to first bone metastasis, bone MFS, and OS.^83,84 The PROSPER and SPARTAN phase 3 trials in highrisk M0 CRPC showed significant MFS benefits for enzalutamide (HR for metastasis or death vs placebo, 0.29) and apalutamide (HR 0.28), respectively.^85,86 In the ARAMIS trial, median MFS for patients on darolutamide was 40.4 months, versus 18.4 months for placebo (HR for metastasis or death with darolutamide, 0.41; P < 0.001).⁸⁷ NCCN, EAU, and AUA guidelines also offer recommendations regarding treatments such as abiraterone, docetaxel, sipuleucel-T, and bone-targeting therapies in mCRPC decision-making.^8,14,82
Intermittent Androgen Deprivation Therapy (IADT)Another clinical option involves stopping ADT in well-informed and requesting patients who have had a strong PSA response (usually defined as PSA <1 ng/dL in metastatic and relapsing disease) yet have significant tolerability concerns.¹⁴ Patients should undergo examinations every 3 to 6 months and those without evidence of progression should resume ADT if PSA rises above an empirically chosen threshold (subjectively designated in various trials, 10-20 ng/dL).^11,14 Allowing T levels to recover between treatment cycles may reduce ADT-associated AEs (Figure 5).¹¹Fig5Studies in locally advanced, relapsing, and metastatic PCa suggest that IADT is noninferior to continuous ADT (CADT) while offering potentially fewer side effects and better quality of life.^88-91 However, not all IADT studies show clear advantages over continuous CADT. Most IADT trials show only modest reductions in AEs during off-treatment phases.⁹² The ICELAND trial showed no significant differences between IADT and CADT in health-related quality of life or AEs.⁹³EAU and NCCN guidelines note that although IADT appears to reduce sexual and other side effects of CADT, the largest trial addressing IADT in M1b patients (SWOG 9346) failed to demonstrate noninferiority to CADT.⁹⁴ Additionally, a recent analysis of a large metastatic PCa trial revealed an increased risk of CV events for patients on IADT.⁹⁵Ideal IADT candidates have yet to be defined. NCCN guidelines say IADT may be allowed to reduce toxicity in M0 castration-naive patients with PSA persistence or recurrence after RP or EBRT, or those with castration-naive M1 PCa.⁸ The EAU recommends offering IADT only to well-informed patients with significant ADT AEs who had strong PSA responses to ADT induction (PSA <4 ng/mL in metastatic disease).¹⁴
Metastasis-directed Therapy (MDT)Oligometastatic PCa denotes an intermediate state between localized disease and widespread metastases, marked by a limited number of metastases (usually 3-5).⁹⁶ By targeting metastases directly, MDT could potentially delay the need for systemic treatment in patients relapsing after local therapy; however, no data suggest an OS improvement for MDT.¹⁴ Research regarding optimal strategies for oligometastatic PCa are lacking, and MDT remains experimental. However, numerous clinical MDT trials are ongoing.⁹⁷DiscussionPresently, ADT remains the gold standard for advanced PCa. Regarding the combination of ADT with chemotherapy and/or novel AR antagonist therapy in mHSPC, several ongoing trials will help determine ideal treatment sequencing (Table 7).Tab7However, growing awareness of ADT side effects and availability of novel hormonal agents—along with healthcare payers’ concern for value-based care—are impacting the treatment landscape for therapeutic selections.Although the 2010 warnings from the FDA, AUA, and other organizations regarding the need to evaluate baseline cardiovascular risk in patients being considered for ADT have had less impact than expected, ADT usage appears to be shifting. One study showed that compared with 2008 through 2009, patients with low-risk PCa were significantly less likely to receive ADT in 2011 through 2012 (10.0% vs 14.7%; P < 0.001).⁹⁸ In the same study, patients with intermediaterisk disease were slightly less likely to receive ADT post-2010 (33.4% vs 35.1%; P < 0.001), and patients with high-risk PCa were slightly more likely to undergo ADT after 2010 (71.1% vs 66.8%; P < 0.001).Among hormonal agents, 150 mg bicalutamide (now generic) is used for LAPC in the EU and elsewhere, as either adjuvant therapy or a monotherapeutic alternative to surgical or medical castration.⁹⁹ The oral drug relugolix, now under FDA review, may allow for a oncedaily GnRH antagonist. Relugolix phase 3 results have recently been published.¹⁰⁰Meanwhile, the rise in publications examining T replacement for men who have or have had PCa reflects patients’ and providers’ interest in minimizing consequences of T suppression.^101,102 Immunotherapy trials and other drug-targeted pathways in development may someday obviate the need for ADT for select advanced PCa populations. Examples include SNS-301 (Sensei Biotherapeutics Inc., Gaithersburg, MD) and the novel nanoparticle vaccine candidate INO-5150 (Inovio Pharmaceuticals Inc., Plymouth Meeting, PA), both presently in phase 2. The role of small-molecule or antibodydelivered targeted alpha therapy, which can reach prostate-specific membrane antigen–expressing tumors regardless of metastatic location, may hold promise.¹⁰³ Also, there is continued interest in MDT to avoid or delay ADT.^93,104ConclusionsThe understanding and application with which physicians apply ADT will continue to evolve with new combinatorial approaches and better understanding of AE management. Additional research exploring these combinations and sequencing strategies, as well as the evaluation of novel ADT options and potential alternative approaches, is ongoing and will continue to require educational awareness.
Dr. Shore is a researcher and/or consultant for Astellas, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Janssen, Merck, Myovant, Nymox, Pfizer, Sanofi, and Tolmar. However, he receives no salary from nor owns stock or patents for these companies.
Financial support for medical writing of this manuscript was provided by Ferring Pharmaceuticals Inc.; however, the company had no control over the manuscript content. Additionally, medical writer John Jesitus assisted in preparing the manuscript with the assistance of editorial services from Carden Jennings Publishing Co., Ltd.Main PointsReferences

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