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After POUT: Implications of Perioperative Chemotherapy for Upper Tract Urothelial Carcinoma

Before the POUT Trial

Before the POUT trial, the largest randomized Phase III trial assessing perioperative chemotherapy for locally advanced UTUC, decisions in management relied primarily on retrospective studies and expert opinion. Furthermore, the data from these studies are conflicting regarding the efficacy of perioperative chemotherapy. In 2009, Hellenthal and colleagues⁵ used an international collaborative database to assess the utilization and outcomes of adjuvant chemotherapy after radical nephroureterectomy in patients with UTUC. They identified 1,390 patients who underwent nephroureterectomy for nonmetastatic UTUC between 1992 and 2006. Of these cases, 39% were classified as high-risk (pT3N0, pT4N0 and/or lymph node-positive). For the analysis, these patients were divided into two groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Among the 542 high-risk patients, 22% received adjuvant chemotherapy, which was more commonly administered in the context of increased tumor grade and stage (p <0.001). The median survival for the entire cohort was 24 months (range 0 to 231 months), and there was no significant difference in all-cause death (chemotherapy vs none: hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.80-1.40) or cancer-specific death (chemotherapy vs none: HR 1.26, 95% CI 0.93-1.71) between patients who did and did not receive adjuvant chemotherapy.

A subsequent study from the European Association of Urology – Young Academic Urologists and the Upper Tract Urothelial Collaboration also assessed adjuvant chemotherapy after radical nephroureterectomy.⁶ This study collated data from 15 centers (1,544 patients) between 2000 and 2015; patients were required to have pT2-4N0/Nx or N+ disease and had undergone a radical nephroureterectomy. The primary analysis used 1:1 propensity score matching, with inverse probability of treatment weighting with a primary endpoint of overall survival (OS). Among the 1,544 patients included, 312 received adjuvant chemotherapy and 1,232 underwent observation. In the matched analysis, there was no difference observed in OS between adjuvant chemotherapy and observation (HR 1.14, 95% CI 0.91-1.43; P = 0.268). Furthermore, a six‐month landmark analysis demonstrated little impact of early events on the treatment effect on OS, with an HR of 1.28 (95% CI 1.00–1.64; p = 0.051).

In contrast to these two studies that failed to demonstrate a benefit to adjuvant chemotherapy, a systematic review and meta-analysis published in 2014 assessed the role of adjuvant and neoadjuvant chemotherapy for patients with UTUC.⁷ Not surprisingly, this systematic review found no randomized trials investigated the role of adjuvant chemotherapy for UTUC. There was one prospective study comprising 36 patients that investigated adjuvant carboplatin-paclitaxel. Furthermore, there were nine retrospective studies (totaling 482 patients) among patients receiving cisplatin-based or non-cisplatin-based adjuvant chemotherapy after nephroureterectomy compared to 1,300 patients receiving nephroureterectomy alone. Across the three cisplatin-based studies, the pooled hazard ratio for OS was 0.43 (95% CI, 0.21-0.89; p=0.023) favoring adjuvant cisplatin compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24-0.99; p=0.048) favoring adjuvant cisplatin. Among the non-cisplatin-based chemotherapy studies, there was no benefit for neoadjuvant chemotherapy. For the neoadjuvant chemotherapy section of the systematic review, the authors identified two Phase II trials that demonstrated favorable pathologic downstaging rates (60%-75% downstaging to ≤pT1N0). Across two retrospective studies investigating neoadjuvant chemotherapy, there was a disease-specific survival (DSS) benefit for neoadjuvant chemotherapy, with a pooled HR of 0.41 (95% CI, 0.22-0.76; p=0.005).

The POUT Trial

The POUT trial was a Phase III, parallel group, open-label, randomized controlled trial done at 71 National Health Service (NHS) hospitals in the United Kingdom.⁸ Eligible patients were ≥16 years, had received a radical nephroureterectomy for UTUC, were postoperatively staged with either muscle-invasive (pT2–pT4, pN_any) or lymph node-positive (pT_any, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients also had to have a glomerular filtration rate (GFR) of ≥30 mL/min. Prespecified stratification factors included platinum chemotherapy agent (cisplatin vs carboplatin), preoperative radiologically or pathologically assessed nodal involvement (N0 vs N1 vs N2 vs N3), the status of surgical margins (positive vs negative), and treatment center. Patients were randomized 1:1 to receive either surveillance or adjuvant chemotherapy: four 21-day cycles of platinum-based chemotherapy (cisplatin 70 mg/m²) within 14 days of randomization; gemcitabine (1000 mg/m²) given on days one and eight of each cycle. Patients with impaired renal function (GFR ≥30 mL/min and <50 mL/min) received carboplatin rather than cisplatin.

Patients were followed at 3, 6, 9, and 12 months, then every 6 months to 36 months from randomization, and annually thereafter. The radiographic assessment included a CT of the thorax, abdomen, and pelvis at 3, 6, 9, 12, 18, 24, 30, and 36 months, then annually to 60 months. Cystoscopy was done every 6 months to 24 months, then annually up to 60 months after surgery. Toxicity was assessed by CTCAE v4. Furthermore, this was the first trial in UTUC to collect patient-reported outcomes: patients filled out the EORTC quality-of-life of cancer patients questionnaire (QLQ-C30) and the EuroQol five dimensions five levels questionnaire (EQ-5D-5L) at baseline and before cycle three and at 3, 6, 12, and 24 months after randomization. The primary endpoint of this trial was DFS defined as time from randomization to either first recurrence in the tumor bed, first metastasis, or death from any cause. Secondary endpoints included metastasis-free survival (MFS), OS, treatment compliance, acute toxicity, late toxicity, and patient-reported quality of life. The trial was powered to detect a hazard ratio of 0.65 (i.e. improvement in three-year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p<0.001) early stopping rules for efficacy and inefficacy.

There were 261 patients included in the trial between June 19, 2012 and November 8, 2017 at 57 of the 71 participating centers in the UK, including 129 patients randomized to surveillance and 132 to chemotherapy; 260 patients were included in the intention to treat analysis. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date met the early stopping rule for efficacy. Included patients were a median 68.5 years of age (IQR 62.0-74.1 years). With respect to tumor characteristics, 94% of patients had pT2-T3 disease and 91% were N0. The median follow-up was 30.3 months (IQR 18.0-47.5 months). There were 7 of 131 patients allocated to chemotherapy that did not start treatment and 75% of those that started chemotherapy received four cycles. There were 60 (47%) DFS events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95% CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001). The three-year DFS rate was 46% for surveillance (95% CI 36-56) and 71% for chemotherapy (95% CI 61-78). MFS also favored chemotherapy, with an HR of 0.48 (95% CI 0.31-0.74, log-rank p = 0.0007), and the three-year event-free rates were 53% (95% CI 42-63) for those on surveillance and 71% (95% CI 60-79) for those receiving chemotherapy. Currently, there have been 62 deaths recorded (38 for surveillance, 24 for chemotherapy) and the OS analysis is planned for when 88 deaths occur, or all patients have ≥2 years of follow-up.

Grade ≥3 toxicities were reported in 44% of chemotherapy patients and 4% surveillance patients (p < 0.0001). During the treatment period, the most common grade ≥3 toxicities in chemotherapy patients were neutropenia (36%) and thrombocytopenia (10%). Analysis of late toxicity is planned after a two-year follow-up of all patients. Quality of life questionnaires were returned by 95% of patients at baseline (95% of those allocated to surveillance and 95% of those allocated to chemotherapy), 82% at three months (81% of those allocated to surveillance and 82% of those allocated to chemotherapy), and 70% at 12 months (70% of those allocated to surveillance and 70% of those allocated to chemotherapy). The mean overall global health status score at baseline was 77% (standard deviation 19) for the chemotherapy group and 76% (standard deviation 19) for the surveillance group. Subsequently, the overall global health status was lower during chemotherapy (before cycle 3) and immediately afterward (at three months) in participants allocated chemotherapy versus surveillance, however the difference resolved by six months of follow-up.

Implications and Future Considerations Following the POUT Trial

Given the rarity of UTUC and the clinical equipoise for conducting a perioperative chemotherapy trial in this disease state, the trialist and the patients involved in this study are to be congratulated for completing this important Phase III trial. As has been discussed amongst thought leaders in the field and summarized in a discussion between Dr. Ashish Kamat and trial lead Dr. Alison Birtle, this is practice-changing data: all patients with locally advanced UTUC after radical nephrectomy should be considered for receipt of adjuvant cisplatin-based chemotherapy.

There are several important considerations as we move into the post-POUT trial era of treating locally advanced UTUC. First, patients with adequate renal function should receive the combination of cisplatin-gemcitabine adjuvant chemotherapy. Typically, a GFR of <60 mL/min is deemed “cisplatin-ineligible”, however, the POUT trial included patients with GFRs as low as 50 mL/min, which is standard practice in the UK. However, even for those with a GFR < 50 mL/min that received the combination of carboplatin-gemcitabine (n=96), there was still a non-significant DFS benefit (HR 0.66, 95% CI 0.35-1.26).⁸ As such, essentially all pT2–pT4, N_any or pT_any, N1–3M0 patients should be considered for an adjuvant chemotherapy regimen that fits their performance status and post-radical nephroureterectomy renal function profile.

Second, the argument for adjuvant chemotherapy as standard of care should only grow stronger as the data matures. Indeed, the benefit of adjuvant chemotherapy was based on DFS and MFS benefit, however with such strong hazard ratios favoring chemotherapy vs surveillance (DFS HR 0.45; MFS HR 0.48) there likely will be a survival benefit with longer follow-up. Furthermore, early survival data reported in the POUT publication favor chemotherapy vs surveillance (38 deaths in surveillance arm; 24 deaths in chemotherapy arm). As such, there is a signal for a more than likely survival benefit based on DFS/MFS benefit and early survival data.

Third, as POUT has demonstrated a survival benefit to perioperative chemotherapy in the adjuvant setting it has re-raised questions regarding the role of neoadjuvant therapy. As nephroureterectomy removes a significant nephron mass, neoadjuvant administration would allow more patients to receive cisplatin, which is known to be more efficacious than carboplatin. However, this must be balanced against issues of poor pre-operative staging in UTUC. Unlike bladder cancer in which TURBT fairly reliably can distinguish superficial from muscle-invasive disease, this distinction is much more difficult in UTUC. Certainly, in patients with obvious invasive disease based on axial imaging and marginal renal function, extrapolation from POUT would suggest that neoadjuvant chemotherapy may be a rational approach.

Finally, the question remains as to how immunotherapy fits into the picture given the POUT data. There are currently no Phase III trials underway to address the role of immunotherapy in the adjuvant treatment of UTUC alone, however, ongoing trials assessing pembrolizumab (Neoadjuvant Pembrolizumab in Combination with Gemcitabine Therapy in Cis-eligible/Ineligible Urothelial Carcinoma Patients) in the perioperative setting for bladder urothelial carcinoma have preplanned subgroup analyses for patients with UTUC. Atezolizumab has shown real-world efficacy in metastatic UTUC, as evaluated in the SAUL study (22% included had UTUC)⁹, however, what role immunotherapy plays in the perioperative setting for UTUC remains to fully elucidated.

Published Date: April 2020

Related Content:
Watch: Moving the Field Forward, Upper Tract Urothelial Carcinoma, The POUT Study - Alison Birtle

The Opioid Crisis in Urology

The United States (U.S.) is currently in an opioid epidemic. Although the U.S. makes up only 4% of the global population, Americans consume 80% of worldwide opioids. Data from the U.S. National Institute on Drug Abuse indicates that 21-29% of patients prescribed opioids for chronic pain misuse them, and 8-12% of patients subsequently develop an opioid use disorder.¹ Furthermore, an estimated 4-6% of patients who misuse an opioid prescription transition to heroin; 80% of people who use heroin first previously misused prescription opioids.¹ Data from the CDC notes that 55% of patients that abuse opioids obtain them free from a friend or relative, while 17.3% of abusers obtained a prescription from a medical doctor. However, overprescribing of opioids is not a straightforward issue, as clinicians are faced with addressing acute postoperative pain, acute painful disease processes (ie. kidney stones), and chronic pain. This article will review the literature highlighting the opioid crisis in urology, assess non-opioid measures for pain control, and highlight prospective studies in an effort to stem the opioid crisis in urology.

The Opioid Crisis in Urology

A study in 2011 from the University of Utah provided surveys to consecutive patients undergoing surgery during a 3-month time frame to assess perception of pain control, type and quantity of medication prescribed, quantity of leftover medication, refills needed, disposal instructions, and surplus medication disposition.² Surveys were performed 2 to 4 weeks postoperatively, and with the exception of the investigators, prescribing physicians had no prior knowledge of the study. Among the 586 patients undergoing surgery, 47% participated in the study. Hydrocodone was prescribed most commonly (63%), followed by oxycodone (35%); 86% of the patients were satisfied with pain control. Of the dispensed narcotics, only 58% were consumed, while 12% of patients requested refills. A total of 67% of patients had surplus medication from the initial prescription and an alarming 92% received no disposal instructions for surplus medication. Among patients with leftover medication, 91% kept the medication at home while 6% threw it in the trash, 2% flushed it down the toilet, and less than 1% returned it to a pharmacy. Indeed, the retained surplus of medication provides a readily available source of opioid excess.

In a prospective observational study of 155 opioid naïve patients who underwent a major prostate or kidney operation, investigators conducted a telephone survey 3-4 weeks postoperatively to assess the number of 5 mg oxycodone-equivalents prescribed, opioid use, and disposal.³ Most patients were male (86%), most were married (74%), the median was age 64 (IQR 59-70) years of age, and the majority were Caucasian (84%). Most patients reported social alcohol use (56%), but most denied current tobacco use (77%) or current and/or previous drug use (76%). Opioid prescribing exceeded use from 1.9- to 6.8-fold for all procedural categories. Overall, a total of 4,065 oxycodone-equivalents were prescribed during the study and 60% of pills prescribed went unused, resulting in 2,622 excess pills in the community.

Unfortunately, opioid overprescribing is not limited to the adult population, as it has also been demonstrated in pediatric urology patients. At the University of North Carolina, 117 pediatric urology patients’ parents were contacted with 39% completing a two-week post-operative telephone survey. The three most common pediatric urology procedures were inguinal hernia repair (n = 39), circumcision (n = 27), and cystoscopy (n = 16). Across all procedures, there was an average excess of 9.8 doses prescribed, corresponding to an over-prescription rate of 64%. Among the patients prescribed opioids, 41 (62%) had leftover opioid medication two weeks postoperatively. Thirty-two of 41 (78%) patients did not dispose of their leftover medication. Furthermore, only 13 patients received perioperative counseling on appropriate storage and disposal of opiates. A recent randomized control trial among 202 pediatric patients undergoing otolaryngologic or urologic procedures found that compared with providing only standard postoperative discharge instructions on opioid use, storage, and disposal, also providing a drug disposal bag significantly increased the rate of proper disposal of excess opioids by approximately 20%.⁴ These results suggest that a greater availability of disposal products may complement ongoing prescribing reduction efforts aimed at decreasing opioid misuse.

There are several reasons for the opioid crisis in urology, namely a culture of overprescribing.⁵ This may be due to:

A historic failure to address acute pain in hospitalized patients, leading to the American Pain Society suggesting that pain should be akin to the fifth vital sign.⁶ Subsequently, physicians became more aware of their patients’ pain and were expected to treat their pain leading to an environment where liberal use of narcotics was tolerated.
Over the past two decades, reimbursement, specifically through the Center for Medicare and Medicaid Services (CMS), has been linked to Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. In the questionnaire, there were three questions dedicated to how well the patient’s pain was managed. These additional measures emphasizing the importance of pain management likely influenced the number of narcotics prescribed at discharge in order to maintain positive survey scores.
Because narcotics must be prescribed via a hand-written prescription and obtaining additional pain medication is inconvenient for both patient and physician, providers may be more likely to overprescribe narcotics at discharge “just in case”.

The rates of opioid dependence and overdose after urological surgery are as follows:

table 1 opiods in urology2x

The American Urological Association’s (AUA) Quality Improvement Summit on Opioid Stewardship in Urology

The AUA Quality Improvement Summit took place at AUA headquarters in December 2018 and was divided into four sessions:

Session 1: Physician-led Multicomponent Interventions in Opioid Stewardship. Dr. Richard Barth discussed procedure-specific opioid prescribing guidelines, Dr. Jonah Stulberg discussed opioid reclamation efforts, and Dr. Jim Dupree presented the Michigan MUSIC initiative on opioid stewardship.
Session 2: Understanding Post-operative Pain. Dr. Brooke Chidgey discussed the pathophysiology of post-operative pain, Dr. Meghan Sperandeo-Fruge highlighted complementary alternative medicine pain management strategies, and Dr. Margaret Rukstalis discussed cognitive behavioral therapy and other non-pharmacologic approaches to pain management. In a sub-session discussing challenging cases in opioid management, Dr. Vernon Pais discussed the impact on prescription opioid use in patients with kidney stones, Dr. Matthew Nielsen highlighted the University of North Carolina Health Care System’s opioid stewardship program, and Dr. Benjamin Davies discussed his initiative of no opioids after a robotic prostatectomy.
Session 3: High-Risk Patients and Expectations. Dr. Behfar Ehdaie presented on the expectation setting for opioid prescribing, Dr. Margaret Rukstalis discussed a surgeon’s role in the management of opioid misuse disorders, and Dr. Brooke Chidgey discussed the role of pain specialists for managing high-risk patients.
Session 4: Policy and Outreach. Dr. Jennifer Waljee discussed opioid education and outreach, Dr. Scott Winiecki presented on opioid prescribing and the FDA safe use initiative, and Dr. Gregory Murphy completed the program discussing policy change and legislature to address the opioid crisis.

The full resources and slides for the AUA Quality Improvement Summit are available at: https://www.auanet.org/education/educational-calendar/quality-improvement-summit

Non-Opioid Measures for Pain Control

Data from Sweden suggests that opioid dependence may be specific to the U.S. Among 25,703 men in the National Prostate Cancer Register of Sweden who underwent radical prostatectomy, 16,368 men (64%) filled an opioid prescription during the 13 months before or after surgery.⁸ The use of strong opioids increased with time and the use of weak opioids decreased. There were 1.9% of men that had opioid prescriptions during the baseline period, followed by a spike to 59% around the time surgery, which sharply decreased by two months postoperatively. However, thereafter the proportion of men with opioid prescriptions remained slightly higher at 2.2% compared to the baseline before radical prostatectomy. Of chronic late users, 57% were previous users and 43% were new chronic users. Higher cancer risk category, greater comorbidity, unmarried status and low educational level were associated with the risk of new chronic opioid use. Although more than half of male Swedish patients filled an opioid prescription after radical prostatectomy, less than 1% of men became chronic opioid users.

Professor Benjamin Davies from the University of Pittsburgh has been a thought leader and advocate for minimizing opioid prescriptions among patients undergoing urologic procedures, namely advocating for the “No Opioid Robotic Radical Prostatectomy”.^9,10 This protocol is as follows:

Pre-operative: Oral neurontin, acetaminophen, +/- celebrex
Quadratus lumborum block (ropivicaine, decadron, precedex)
Intraoperative: separate infusions of propofol, ketamine, and precede
Post-operative: Toradol 15 mg IV PRN while in the hospital
Tylenol and Motrin for 48 hours

Amid the opioid crisis, there has been an increased focus on increasing the use of regional anesthesia as part of opioid-sparing multimodal analgesia. Tranversus abdominis plane (TAP) block has been shown to improve early and late pain, and reduce opioid consumption after minimally surgery.¹¹ These benefits have indirectly reduced the incidence of postoperative delirium, pneumonia, urinary retention, and falls. Furthermore, compared to epidural analgesia, a TAP block provides similar pain control, has a lower incidence of hypotension, and is associated with a shorter length of stay. A TAP block provides a safe intervention and should be integrated into enhanced recovery protocols for patients undergoing urologic procedures.

Prospective Initiatives

In an effort to evaluate the effect of opioid reduction after radical prostatectomy on post-discharge opioid prescribing, use, and disposal, the ORIOLES trial was designed as a prospective, non-randomized, pre-post interventional trial.1² An evidence-based intervention included a discharge sheet, nursing education, and standardized prescribing guideline; the primary outcome was total oral morphine equivalents used after surgery. Secondary outcomes included opioid prescribing, opioid disposal, need for additional opioid medication, and presence of incisional/post-surgical abdominal pain beyond 30-days. There were 214 men in the pre-intervention arm and 229 men in the post-intervention arm with 100% follow-up. The intervention reduced post-discharge opioid prescribing from 224.3 mg to 120.3 mg (p=0.01), reduced opioid use from 52.1mg to 38.3mg (p<0.01), and increased opioid disposal by 13.5% (p<0.01). Greater post-discharge opioid use was associated with greater prescribing of opioids at discharge, higher body mass index, and use of opioid medication prior to surgery.

From this prospective initiative, the authors demonstrate that a simple, three-component opioid reduction intervention was able to reduce opioid prescribing, reduce opioid use, and increase opioid disposal at 30-days after radical prostatectomy. Importantly, this prescribing guideline met the needs of 84% of patients, while only 2.2% of patients required additional opioid medication for pain. Furthermore, an impressive one-third of patients used no opioid pain medication after discharge.

Investigators from the Mount Sinai School of Medicine have also recently assessed the effect of implementing a nonopioid protocol for patients undergoing robotic-assisted radical cystectomy with extracorporeal urinary diversion.¹³ Among 52 patients undergoing surgery, patients received a multimodal pain management protocol, including a combination of nonopioid pain medications and regional anesthesia. These patients were compared to 41 patients undergoing robotic cystectomy prior to the implementation of the nonopioid protocol. In this study, the authors found that patients on the nonopioid protocol received a much lower dose of postoperative morphine milligram equivalents (2.5 vs. 44, p < 0.001), with no difference in pain scores. In the non-opioid protocol patients, the median time to regular diet was significantly shorter (4 days vs. 5 days, p = 0.002), and the length of stay was two days shorter compared to the control group (5 days vs. 7days, p < 0.001).

Conclusions

The urologic community has by no means been spared by the current opioid epidemic across the U.S. Several studies in both the adult and pediatric settings have demonstrated overprescribing measures with little to no counseling or options for appropriate disposal of opioids. Several measures are now in place to solve this problem⁵, including (i) greater utilization and implementation of Prescription Drug Monitoring Programs (PDMPs) to provide alerts to providers to patients who may be filling opiate prescriptions with multiple providers; (ii) CMS has removed the three questions from the HCAHPS survey related to pain control, effective January 2018; (iii) increased utilization of Enhanced Recovery After Surgery (ERAS) pathways as a measure for decreasing intra- and post-operative use of opioids; (iv) each of the 50 states have passed legislation to make readily available naloxone, which rapidly reverses the effects of opioids in the overdose setting; (v) the creation of procedure-specific guidelines for discharge opioid recommendations. For example, a Johns Hopkins expert panel assessing 20 common surgical procedures suggest that the ideal range of oxycodone 5-mg tablets prescribed to opioid naïve patients at discharge is 0-1014; (vi) the DEA sponsored “National Rx Takeback” initiative, providing collection sites (primarily pharmacies) for returning opioids. Certainly, the current opioid epidemic is multifactorial. However, judicious prescribing of opioids amongst the urology community is one actionable item that will make a difference for the betterment of our patients.

Published Date: December 2019

Bundle (ABCDE) Checklist for Prevention of CAUTIs

Adherence to infection control principles, standard supplies, procedures and processes

Hand hygiene - the most important factor in preventing nosocomial infections
Aseptic catheter insertion procedure
Proper Foley catheter maintenance, education, and care by nursing staff
Foley catheter use surveillance and feedback

The Genetics of Prostate Cancer

Germline mutations in prostate cancer carcinogenesis

Some of the first data to delineate the value of assessment of inherited genetic changes in prostate cancer came from Pritchard and colleagues who assessed the prevalence of mutations in 20 DNA-repair genes among 692 patients with metastatic prostate cancer⁸. They identified such mutations in 82 men (11.8%).

Beyond Bladder Cancer: Bacillus Calmette-Guérin (BCG) Vaccination Revisited as a Strategy to Reduce COVID-19 Related Adverse Events in High Risk Health Care Workers and the Elderly

First Published April 2, 2020

The ongoing pandemic involving severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its resulting coronavirus disease 2019 (COVID-19) has caused widespread infection worldwide, with over 660,000 confirmed cases as of March 28, 2020 and nearly 31,000 deaths.¹ Data from the Italian National Institute of Health (Istituto Superiore di Sanità [ISS]) where fatalities are thus far the highest suggest a fatality rate of 7.2%, significantly higher than that which has been observed in other countries.² Elderly patients are at greatest risk of mortality from COVID-19, and approximately 23% of the Italian populace is aged 65 years or older, making the country particularly vulnerable.²

Oligometastatic Prostate Cancer – Treatment of the Primary Tumor and Metastasis Directed Therapy

In 2018 1.3 million prostate cancer (PCa) cases were diagnosed worldwide, with approximately 20% having metastatic disease.¹ Oligometastatic PCa is defined as a state of low-volume metastatic disease that appears to be prognostically different and likely amenable to different treatment options, which could potentially change the disease trajectory when compared with high-volume metastatic disease.²

Safe and Efficacious Therapies Urgently Needed for the Difficult to Treat Non-muscle Invasive Bladder Cancer Patient Population

A newly published systematic review and meta-analysis: Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non–muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis

Prostate Cancer Survivorship

Physical Side Effects

Urinary Dysfunction

Urinary dysfunction is a side effect of both surgical and radiotherapy (RT) for local treatment of prostate cancer (PCa). Surgical side effects typically include a period of urinary incontinence for several months postoperatively followed by a degree of stress urinary incontinence that may persist for months or even years. RT-induced urinary dysfunction typically manifests as bladder irritability/overactivity either during treatment or shortly thereafter. Longer-term urinary dysfunction issues after RT may include urethral strictures necessitating periodic interventions and/or catheterization.

The ProtecT trial randomized 1,643 men from 1999 to 2009 to undergoing either active monitoring (n=545), surgery (n=553), or RT (n=545), finding that at a median 10 years of follow-up, PCa-specific mortality was low irrespective of treatment.² As part of this trial, patient-reported outcomes were collected and have now become one of the benchmarks for counseling patients with regards to long-term side effects of treatment for localized PCa treatment.³ Questionnaires were completed at the time of diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety, and depression, and general health. The rate of questionnaire completion during follow-up was outstanding at >85% for most measures. Regarding urinary dysfunction, radical prostatectomy (RP) had the greatest negative effect on urinary continence, and although there was some recovery over time, these patients remained worse throughout follow-up compared to patients undergoing active monitoring or RT. Interestingly, RT had little effect on urinary incontinence, and there was a gradual decrease in urinary function over time for the men undergoing active monitoring. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Urinary incontinence has been cited as being the most important factor for decision regret among receiving local therapy for PCa and may be incompletely explained/discussed with ~80% of patients prior to undergoing treatment.⁴

Sexual Dysfunction

Similar to urinary dysfunction, sexual dysfunction is a common side effect of localized therapy for PCa. Patients undergoing RP will suffer a degree of sexual dysfunction in the immediate postoperative period with a degree of recovering over 12-24 months after surgery. Many studies have been published assessing predictors of postoperative recovery of sexual function, commonly highlighting younger age and adequate function pre-operatively as predictors of post-operative recovery. Men undergoing RT, similar to urinary dysfunction, will not notice an immediate effect on sexual function during the treatment phase, but generally, suffer sexual dysfunction in the years post-radiation.

In the ProtecT trial, RP incurred the greatest degree of sexual dysfunction among all three treatment arms, with some recovery of function over time.³ The negative effect of RT on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter. Sexual dysfunction also declined in the active monitoring group over time.

Primarily secondary to the sexual side effects of localized treatment for PCa, many cancer centers now have fellowship-trained experts that see these patients concomitantly with the oncologist. There are a variety of treatment options offered, including oral PDE-5 inhibitors (sildenafil, tadalafil, etc.), intracavernosal injection therapy, and penile prosthetics.

Bowel Dysfunction

Bowel dysfunction is typically low for patients undergoing RP or active surveillance (AS) but may be a detrimental side effect among men undergoing RT. In the ProtecT trial, bowel function was worse in the RT group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the active monitoring and RP groups.³

Bowel dysfunction and rectal toxicity has improved with the recent FDA approval of hydrogel rectal spacers. Prior to RT, patients may have a hydrogel rectal spacer (SpaceOAR®) placed in a transperineal fashion in the fat between the rectum and Denonvilliers' fascia. In the pivotal clinical trial assessing hydrogel spacers, 114 patients were enrolled between 2010 and 2011 with 54 patients selected for a hydrogel injection before the beginning of RT.⁵ Patients were surveyed at various time-points with the EPIC PCa questionnaire – among patients treated with a hydrogel spacer, mean bowel function and bother score changes of >5 points in comparison with baseline levels were found only at the end of RT (10-15 points; p < 0.01). Mean bowel bother score changes of 21 points at the end of RT, 8 points at 2 months, 7 points at 17 months, and 6 points at 63 months after RT were found for patients treated without a spacer. These bowel quality of life results have given hydrogel spacers an option among patients considering RT.

Other health-related effects

There is evidence that both RT and androgen deprivation therapy (ADT) may contribute to the development of coronary heart disease, sudden cardiac death, myocardial infarction, and skeletal-related events such as fracture.⁶

Psychological Side Effects

Depression and Anxiety

Depression is the most common psychiatric comorbidity among cancer patients, including patients with PCa. Ravi et al.⁷ previously utilized the SEER-Medicare database to assess the burden of mental health issues (anxiety, major depressive disorder, suicide) in patients with localized PCa. Among 50,586 men >65 years of age without a diagnosis of mental illness, 20.4% of men developed a mental illness with a median 55-month follow-up. Interestingly, patients undergoing WW (29.7%) and RT (29.0%) had a significantly increased incidence of mental illness compared to patients undergoing RP (22.6%; p<0.001). A systematic review of depression and anxiety in patients with PCa identified 27 articles comprising 4,494 patients.⁸ The meta-analysis of prevalence rates identified pretreatment prevalence of depression of 17.27% (95% confidence interval (CI) 15.06%-19.72%), on-treatment prevalence of 14.70% (95% CI 15.06%-19.72%) and post-treatment prevalence of 18.44% (95% CI 15.18%-22.22%). For anxiety, pretreatment prevalence was 27.04% (95% CI 24.26%-30.01%), on-treatment was 15.09% (95% CI 12.15%-18.60%) and post-treatment was 18.49% (95% CI 13.81%-24.31%). For patients undergoing AS, nearly one-third of patients (29%) report cancer-specific anxiety in the year following diagnosis.⁹ Interestingly, over time, this anxiety decreased significantly.

There is also increasing evidence that ADT for locally advanced and metastatic PCa is associated with depression. A study from 2016 using SEER-Medicare data found that men that received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2), inpatient psychiatric treatment (2.8% v 1.9%), and outpatient psychiatric treatment (3.4% v 2.5%).¹⁰ Furthermore, the risk of depression increased with the duration of ADT, from 12% with ≤ 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with ≥ 12 months of treatment. A recent meta-analysis of 18 studies among 168,756 men found that ADT use conferred a 41% increased risk of depression (RR 1.41, 95%CI 1.18-1.70).¹¹ These results were consistent when limiting the analysis to studies in localized disease (relative risk (RR) 1.85, 95%CI 1.20-2.85). Interestingly, this analysis did not find an association for continuous ADT with depression risk compared to intermittent ADT (RR 1.00, 95%CI 0.50-1.99).

Suicidal Risk

Patients with PCa have been shown to be at increased risk of suicide across several population-level studies. In a SEER analysis assessing suicide risk among patients with genitourinary malignancies from 1988-2010, Klaassen et al.¹² found an age-adjusted standardized mortality ratio (SMR) of 1.37 for patients with PCa (95%CI, 0.99-1.86) Increasing age, metastatic disease and Caucasian race were risk factors for suicide among these patients. Interestingly, even patients >15 years after diagnosis were at increased risk of suicide compared to the general population (SMR 1.84, 95%CI 1.39-2.41). In an assessment of PCa suicidal risk compared to individuals with other malignancies, Dalela et al.¹³ found that risk of suicidal death was no different in men with PCa (1,165 [0.2%]) compared to men with other cancers (2,232 [0.2%]), However, within the first year of diagnosis, men with PCa had an increased risk of suicide (absolute risk reduction (ARR) 3.98, 95% CI 3.02-5.23 0-3 months after diagnosis). Furthermore, men with non-metastatic PCa who were Caucasian, uninsured, or recommended but did not receive treatment (hazard ratio (HR) vs treated 1.44, 95%CI 1.20-1.72) were at increased risk of suicidal death.

A meta-analysis of observational studies assessing incidence and risk factors of suicide after PCa diagnosis was recently published.¹⁴ This study included 8 observational studies involving 1,281,393 men diagnosed with PCa and 842,294 matched PCa-free men. Guo et al. found an overall increased relative risk of suicide of 2.01 (95% CI 1.52-2.64) among men diagnosed with PCa compared with those without PCa during the first year after diagnosis, particularly during the first 6 months after diagnosis (RR 2.24, 95%CI 1.77-2.85). Additionally, PCa patients were at an increased risk of suicide among men aged 75 years or older (RR 1.51, 95% CI 1.04-2.18) and for those treated with ADT (RR 1.80, 95% CI 1.54-2.12).

Until recently, all population-level studies assessing risk of suicide among PCa patients have not accounted for psychiatric comorbidities at the time of diagnosis. This is important, considering that being unable to adjust for psychiatric comorbidities makes it impossible to assess the true risk associated with a PCa diagnosis on suicidal risk. At the AUA 2019 annual meeting, Klaassen et al.¹⁵ presented data assessing all residents of Ontario, Canada diagnosed with either prostate, bladder or kidney cancer (1997-2014). Each patient was assigned a psychiatric utilization gradient (PUG) score in the five years prior to cancer diagnosis: 0 (none), 1 (outpatient), 2 (emergency department), 3 (hospital admission). Non-cancer controls were matched 4:1 to cancer patients based on sociodemographic variables and a marginal cause-specific hazard model was used to assess the effect of cancer on the risk of suicidal death. Among 191,068 patients included (137,699 PCa, 29,884 bladder cancer, 23,485 kidney cancer), 109,154 (57.1%) were PUG score 0, 79,553 (41.6%) PUG score 1, 1,596 (0.84%) PUG score 2, and 765 (0.40%) PUG score 3. Patients with genitourinary cancer had a higher risk of dying of suicide compared to controls (HR 1.16, 95%CI 1.00-1.36). Specifically, among individuals with PUG score 0, those with cancer were significantly more likely to die of suicide compared to patients without cancer (HR 1.39, 95%CI 1.12-1.74).

Guideline Recommendations

The Commission on Cancer requires cancer programs to develop and implement processes to monitor formation and dissemination of a survivorship care plan for all cancer patients with stage I-III disease treated with curative intent, and to have this plan in place within 1-year of diagnosis of cancer and no later than 6 months after completing adjuvant therapy.¹⁶ Guideline recommendations for PCa survivorship have primarily been driven by the American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO). The ACS noted in their 2014 guideline that survivorship should promote comprehensive follow-up care and optimal health and quality of life for the post-treatment PCa survivor.¹⁷ The guidelines also address health promotion, surveillance for PCa recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and non-oncology specialists. Subsequently, the ASCO Endorsement Panel reviewed the ACS guidelines, endorsing these guidelines with the following recommendations:¹⁸

• Measure PSA level every 6 to 12 months for the first 5 years and then annually, considering more frequent evaluation in men at high risk for recurrence and in candidates for salvage therapy.

• Refer survivors with elevated or increasing PSA levels back to their primary treating physician for evaluation and management.

• Adhere to ACS guidelines for the early detection of cancer.

• Assess and manage physical and psychosocial effects of PCa and its treatment.

• Annually assess for the presence of long-term or late effects of PCa and its treatment.

Screening Measures

There are several screening tools to assess for quality of life, depression and suicidal risk. A study from 2017 assessed differences in the scores, relative severity and major depressive disorder from three standardized self-report scales for depression in PCa patients [The Hospital Anxiety and Depression Scale Depression subscale (HADS-D), the Self-rating Depression Scale (SDS) and the Patient Health Questionnaire (PHQ-9) for depression].¹⁹ Among 138 PCa patients, despite significant correlations between the total scores from the three scales, severity classification differed across the three scales. Furthermore, there was considerable underestimation of depression by the HADS-D compared to the PHQ-9 and a similar tendency for the SDS. This study highlights that scale construction and depression items included can produce different results across scales, making inter-study comparisons difficult. Despite these findings, we recommend that at minimum oncologists should be using at least one depression index to assess patient well-being at each clinic visit.

In addition to the aforementioned HADS-D, SDS, and PHQ-9 metrics, the National Comprehensive Cancer Network (NCCN) provides a guideline for identifying and explaining risk factors in patients with cancer, in addition to providing a “distress thermometer”. The NCCN defines distress, in the setting of cancer, as a multifactorial emotional experience of a psychological, social, and/or spiritual nature that may interfere with the ability to cope effectively with the diagnosis.²⁰ Distress can range from sadness and fear to more disabling symptoms such as anxiety and depression. Furthermore, the time periods at which patients are at increased vulnerability begin with the realization of a suspicious symptom, all the way through to failure/disease recurrence and near the end of life. The NCCN recommends screening all patients for distress to recognize, monitor, and treat patients effectively.²⁰

Previous work has also suggested that screening for depression and erectile dysfunction may be a way to decrease suicidal risk among PCa patients.²¹ A proposed algorithm allows for an initial evaluation with the EPIC-CP and PHQ-9 tools to assess for health-related quality of life and depression, respectively. If the EPIC-CP or PHQ-9 are negative for depression or erectile dysfunction, these tools should still be used at each visit to regularly evaluate patients. If EPIC-CP or PHQ-9 suggest problems with depression or erectile dysfunction, then an 8-question suicidal ideation questionnaire (adapted from Recklitis et al.²²) should be completed. If the suicidal ideation questionnaire demonstrates any level of suicidal ideation, clinicians should make an urgent referral for psychiatric evaluation. This is particularly true when the patient has the concomitant high-risk suicidal risk profile of being elderly, white, single, or with high-risk or disease progression. Given that, at maximum, the patient must answer a 27-point composite questionnaire, this should be feasible in the busy clinical setting and can be provided to the patient at appointment check-in and completed in the waiting room before the physician-patient encounter. Regardless of the results from these screening tools, if any member of the healthcare team has an index of suspicion for suicidal ideation, the physician should immediately make a referral for psychiatric evaluation.

Conclusions

With nearly 3 million men in the United States living with PCa, survivorship programs are now mandated by the Commission on Cancer and play an integral role in health and well-being of men with PCa. In addition to the physical side effects of treatment that should be addressed at each clinic visit, there are crucial psychiatric side effects, including depression, anxiety, and suicidal ideation that should be screened for and recognized by all members of the healthcare team.

Published Date: December 2019

The History of Imaging for Prostate Cancer

Diagnosis and assessment of primary tumor – TRUS and mpMRI

Historically, prostate cancer diagnosis was made on the basis of transrectal or transperineal needle biopsy guided by digital palpation per rectum (so-called, finger guided biopsies).¹ These biopsies were typically directed at palpable abnormalities. A number of significant changes occurred to this approach beginning in the early 1990s. First, a systematic approach to prostate biopsy advocated by Hodge et al., as opposed to directed cores, was widely adopted.²

Second, the use of transrectal ultrasound (TRUS) for prostate visualization and biopsy guidance became widespread. The use of TRUS allowed for direct visualization of the prostate, any of its anomalies, as well as the biopsy needle. Thus, TRUS-guided prostate biopsy became the gold standard approach to prostate cancer diagnosis.³ However, there are well-known limitations to TRUS-guided prostate biopsy including inherent random and systematic errors. Unless clear visible hypoechoic suspicious areas are seen in TRUS, sampling occurs by chance, and specific zones are under-sampled, including the anterior region and apex.⁴ Further, TRUS-guided systematic prostate biopsy can miss up to 20% of clinically significant prostate cancer, resulting in underdiagnosis and undertreatment.⁵ However, at the same time, TRUS-guided systematic prostate biopsy detects a relatively high percentage of clinically insignificant prostate cancer (Gleason grade group [GGG] 1), which may result in overtreatment.⁶

Thus, thirdly, multiparametric magnetic resonance has recently been evaluated for the identification of prostate lesions likely to be cancerous, as well as the guidance of prostate biopsy.

Initially, MRI was used as a staging test in patients with prostate cancer for assessment of direct extra-prostatic extension utilizing T2-weighted imaging. This approach was marked by significant variability in diagnostic performance, limited ability to detect microscopic disease and inability to localize the tumor within the gland itself.⁷ These factors limited the widespread adoption of MRI for local tumor staging. Indeed, to this data, TNM staging for prostate cancer relies on digital rectal examination rather than radiographic findings for local tumor staging.

However, multiparametric MRI, particularly with the addition of diffusion-weighted imaging has allowed for increasingly informative studies, including the visualization of tumors within the prostate. This has allowed for the use of mpMRI to guide prostate biopsy, either directly with in-bore biopsy or more commonly using a fusion device platform.⁸ When performed in the evaluation of patients with elevated prostate-specific antigen (PSA) levels with previous negative prostate biopsy, multi-parametric magnetic resonance imaging has been shown to identify clinically significant prostate cancers which would have been otherwise missed by routine systematic biopsy.⁹ A recent systematic review and meta-analysis from Kasivisvanathan and colleagues suggested that multi-parametric magnetic resonance imaging targeted biopsy detects more clinically significant prostate cancer than standard TRUS-guided systematic biopsy alone and requires fewer prostate cores to do so; that the question of whether to include systematic biopsy along with multi-parametric magnetic resonance imaging targeted biopsy remains controversial; and that the omission of the systematic biopsy risks missing the diagnosis of clinically significant disease in approximately 13% of men while the inclusion of systematic biopsy increases the likelihood of diagnosing clinically insignificant prostate cancer.¹⁰

The most recent European Association of Urology Prostate cancer guidelines conclude that, when at least one functional imaging technique is employed, mpMRI has good sensitivity for the detection and localization of clinically significant (Gleason Grade Group 2 or greater) prostate cancers⁶ with lower sensitivity for the detection of Gleason Grade Group 1 cancers, likely a beneficial characteristic. Potential limitations of the widespread use of a multi-parametric magnetic resonance imaging driven diagnostic pathway include only a moderate inter-reader reproducibility of multi-parametric magnetic resonance imaging, the lack of standardization of targeted biopsy, and cost-effectiveness concerns in certain jurisdictions.

Even more recently, high-resolution micro-ultrasound has emerged as a novel imaging modality for prostate cancer. High-resolution micro-ultrasound has a very fine resolution (approximately 70 µm) which allows for visualization of alterations in ductal anatomy and cellular density consistent with prostate tumors.¹¹ In early experiences, high-resolution micro-ultrasound has demonstrated an ability to detect clinically significant cancers that were not apparent on either traditional TRUS or mpMRI.¹² In contrast to mpMRI, high-resolution micro-ultrasound has the advantage of providing real-time imaging results, a finding that authors from the Cleveland Clinic demonstrated was associated with a relative increase in prostate cancer detection of 26.7%.¹² Aggregate data from early clinical experience at multiple centers suggests that high-resolution micro-ultrasound has comparable or increased sensitivity for clinically significant prostate cancer compared with mpMRI and comparable or slightly reduced specificity.¹¹

Distant staging – from radiographs to molecularly targeted imaging

While mpMRI has revolutionized imaging of the prostate and substantially changed the diagnostic algorithm for prostate cancer, perhaps even greater changes have occurred in the imaging for distant disease.

Initially, a radiographic diagnosis of bony prostate cancer metastasis was made on the basis of plain radiographs. However, bony metastases may be difficult to identify based on plain films as an extensive bone mineral loss (exceeding 30-50%) may be required before such changes are radiographically apparent.¹³ However, plain films remain useful for the immediate investigation of patients who present with bony pain and for the assessment of bony stability in those deemed at risk of pathologic fracture.

Following plain projectional radiography, skeletal scintigraphy was the next imaging modality widely adopted for the assessment of bony metastases in patients with prostate cancer. To date, it remains widely utilized and is currently recommended, along with abdominal and pelvic computed tomography, for the staging of patients according to many guideline bodies. Skeletal scintigraphy, when performed in patients with known cancer in the absence of bony pain, has a sensitivity of 86% and specificity of 81% for the detection of metastatic lesions.¹³ As with any imaging modality, these characteristics differ somewhat on the basis of the patient population being tested (i.e. the pre-test probability or population-based disease prevalence). Among patients with prostate cancer, PSA levels are predictive of the likelihood of a positive bone scan. Across a number of different cancers, Yang et al. found that bone scintigraphy had a specificity of 81.4% and sensitivity of 86.0%, on a per-patient basis, for the detection of bony metastases.¹⁴

Computed tomography has been utilized for the assessment of nodal metastatic disease, visceral disease, and bony metastasis. CT is highly sensitive for both osteoblastic tumors (such as prostate cancer) and osteolytic lesions in the cortical bone but is less sensitive in tumors that are restricted to the marrow space.¹³ As a result, CT is of relatively limited utility as a screening test for bony metastasis due to relatively low sensitivity (73%) despite excellent specificity (95%) – numbers based on a large scale meta-analysis from Yang and colleagues.¹⁴For this reason, conventional staging recommendations for patients with prostate cancer include bony scintigraphy for the detection of bony lesions along with computed tomography for identification of nodal/visceral lesions and correlation of any bony lesions.¹⁵

In addition to its role in the local staging of the prostate and guidance of prostate biopsy, mpMRI may also assist with evaluation for distant metastatic disease. Routine pelvic/prostate MRI typically allows for assessment of local/regional nodal involvement including obturator and external iliac nodal chains. However, the high soft-tissue contrast and high spatial resolution afforded by MRI call also allow for the identification of bony metastasis in marrow spaces much early than would be apparent based on CT scan.¹⁴ Further, use of T1-weighted sequences and STIR sequences can allow for adequate assessment for bony metastasis without the need for intravenous contrast agents; use of MRI for staging does not require the use of ionizing radiation. Thus, abdominal/pelvic or whole-body MRI may be considered for the identification of distant metastatic disease. Additionally, MRI with contrast has become the imaging modality of choice for the evaluation of liver metastases.¹⁶ Thus, this approach may be particularly valuable in patients at a high risk of visceral metastatic disease.

Traditional positron emission tomography (PET) imaging utilizing fluorodeoxyglucose (FDG) is not typically effective in the initial diagnosis of prostate cancer metastasis owing to the relatively low metabolic activity associated with the disease. However, at least four other PET imaging approaches have been assessed and employed in patients with prostate cancer including ¹⁸F-NaF PET/CT, choline-based PET/CT, fluciclovine (Axumin®) PET/CT, and PSMA-targeted PET/CT.¹⁷ These modalities have been used in the staging of both primary and recurrent prostate cancer. While clearly improved compared to bony scintigraphy, the limitations are similar – namely, that sensitivity is highly dependent on PSA levels. However, choline-based PET/CT has demonstrated significantly higher sensitivity for the diagnosis of metastatic lesions at the time of biochemical recurrence compared to conventional imaging with a bone scan and computed tomography.¹⁷ However, compared to MRI, the benefits of choline-based PET/CT are less clear.¹⁸ MRI clearly outperformed choline-based PET/CT for the detection of local recurrence (36.1% vs 1.6%), while choline-PET/CT was superior for identification of lymph node metastasis and both were effective at identifying bony metastatic disease.¹⁹

Choline-based PET/CT is not widely available in the United States. However, fluciclovine PET/CT (also known as Axumin® PET/CT) which utilizes the proliferation of tumor cells for localization, is much more available. Fluciclovine (¹⁸F-FACBC; 1-amino-3-fluorine 18F-flurocyclobutane-1-carboxylic acid) is a synthetic amino acid analog with the advantage of negligible renal uptake and no activity in the urinary tract.¹⁸ Nevertheless, non-specific prostate uptake limits its utility in the identification of primary prostate tumors due to an inability to distinguish from benign prostatic inflammation. Instead, fluciclovine-PET/CT has proven efficacy in the detection of recurrent prostate cancer with biochemical recurrence following local therapy, with a sensitivity of 90% and specificity of 40% (higher in distant, 97%, and nodal disease, 55%, than locally).²⁰ Compared to choline-PET/CT, fluciclovine-PET/CT demonstrated lower false-negatives and false-positive rates in patients with biochemical recurrence.^{21, 22}

Finally, receptor-targeted PET imaging has recently been examined, most notably, PSMA-based PET/CT. PSMA is a transmembrane glycoprotein found on prostatic epithelium. The ratio of PSMA to its truncated isoform (PSM’) is proportional to tumor aggressivity. The most well examined PSMA based approach is ⁶⁸Ga-PSMA-PET/CT. In patients with biochemical recurrence following radical prostatectomy, ⁶⁸Ga-PSMA-PET/CT demonstrated superior detection rates of metastatic disease (56%) compared with fluciclovine-PET/CT (13%).²³ This benefit was consistent in detecting pelvic nodal disease and extrapelvic disease. PSMA-based PET/CT demonstrated a particular benefit in the evaluation of patients with low absolute PSA levels. Further, ⁶⁸Ga-PSMA-PET/CT appears to be superior to MRI in primary staging of patients prior to local therapy.²⁴ Other radiotracers including ¹⁸F-DCFPyL and ¹⁷⁷Lu-PSMA-617 have recently been examined in place of ⁶⁸Ga-PSMA.²⁵

Recent work has also assessed the role of PET/MRI, rather than PET/CT. This approach leverages the advantages of the sensitivity of receptor-targeted imaging and the spatial resolution of MRI.²⁴

Conclusion

The evolution of imaging in prostate cancer has allowed a more nuanced understanding of the disease. Assessing the local tumor, both mpMRI and high-resolution micro-ultrasound allow for a more informed prostate biopsy which may assist in more accurate initial disease characterization²⁶ as well as local staging. Ongoing advances in receptor-targeted PET imaging continue to refine the identification of metastatic disease. This has important implications for what we understand to be M0 and M1 prostate cancer. Whether early detection of metastatic disease utilizing these modalities translates into improvements in patient outcomes, or simply lead-time bias, remains to be assessed.

Published Date: March 2020

Updates in Systemic Therapy for Upper Tract Urothelial Carcinoma: Perioperative Considerations

In this article, we will discuss data for the use of systemic therapy in upper tract urothelial carcinoma with a focus on perioperative systemic therapy.
Until recently, there have been very limited randomized data to guide the provision of perioperative systemic therapy in upper tract urothelial carcinoma. Thus, data has been extrapolated from patients with urothelial carcinoma of the bladder.

Neoadjuvant therapy

Data for the use of neoadjuvant chemotherapy prior to radical cystectomy in urothelial carcinoma of the bladder are robust: the Advanced Bladder Cancer meta-analysis collaboration, in a meta-analysis of 11 trials with 3,005 patients, demonstrated a significant survival benefit to the use of neoadjuvant platinum-based combination chemotherapy as compared to upfront surgery (hazard ratio 0.86, 95% confidence interval 0.77 to 0.95). In absolute terms, this corresponds to a 5% absolute survival at 5 years.⁵

In contrast, there is extremely limited data regarding the use of neoadjuvant chemotherapy in patients with upper tract urothelial carcinoma. No institution has published data on more than 50 patients who received neoadjuvant chemotherapy prior to nephroureterectomy. In two publications, the MD Anderson Cancer Center group has reported on their experience. Matin et al. reported on 43 patients with biopsy-proven high-grade upper tract urothelial carcinoma who underwent neoadjuvant chemotherapy prior to nephroureterectomy.⁶ They demonstrated a 14% pathologic complete response rate in this cohort. Additionally, when compared to historical controls, there was an increased likelihood of downstage (p=0.004): pT2 disease was found in 49% compared with 65% in controls and pT3 disease was found in 28% compared with 48%. In a more recent analysis, Porten et al. provided a retrospective review of 31 patients who underwent neoadjuvant chemotherapy prior to nephroureterectomy compared to 81 historical controls who received initial surgery for high-risk upper tract urothelial carcinoma.⁷ They demonstrated that patients receiving neoadjuvant chemotherapy had improved five year overall survival (80% versus 58%, p=0.02) and five year disease-specific survival (90% versus 58%, p=0.002). After adjusting for relevant patient, treatment and tumor characteristics, the risk of overall mortality (hazard ratio 0.42, p=0.035) and disease-specific mortality (hazard ratio 0.19, p=0.006) were significantly lower among patients who received neoadjuvant therapy.

More recently, Kubota and colleagues reported a multi-institutional analysis of 101 patients with high-risk upper tract urothelial carcinoma (stage cT3-4 or cN+) who received neoadjuvant chemotherapy prior to nephroureterectomy at 5 medical centers in Japan and compared these to 133 patients who received surgery alone.⁸ Most patients who received neoadjuvant chemotherapy in this cohort were given gemcitabine and carboplatin (75%) while a minority received gemcitabine and cisplatin (21%). The authors found that while neoadjuvant chemotherapy increased pathological downstaging and was independently predictive of improved recurrence-free survival and cancer-specific survival, they were unable to demonstrate improvements in overall survival.

Finally, in 2018, Liao et al reported their experience from Johns Hopkins.⁹ They compared 32 patients who received neoadjuvant chemotherapy prior to nephroureterectomy for biopsy-proven high-grade upper tract urothelial carcinoma to 208 patients who underwent surgery alone. These authors found a 9.4% pathologic complete response rate in addition to significant pathologic downstaging.

In comparison to the use of neoadjuvant chemotherapy for urothelial carcinoma of the bladder, there is potentially even greater rationale for its use in upper tract urothelial carcinoma. First, patients are much more likely to be able to tolerate a highly efficacious regime (gemcitabine and cisplatin) with two functioning kidneys prior to nephroureterectomy than they will post-operatively. Additionally, important prognostic information can be derived if patients experience pathological downstaging.¹ However, one of the primary barriers to the use of neoadjuvant chemotherapy is the lack of reliable pre-operative pathologic specimens to identify invasive disease, as mentioned previously. Second, there are concerns regarding the delay to definitive surgical treatment, particularly in patients who may have chemoresistant disease. Third, there are concerns regarding a potential increase in perioperative morbidity.

Finally, there is a concern of overtreatment through the use of toxic medications in patients who may or may not have invasive disease. There have been attempts to assess the role of neoadjuvant chemotherapy in this patient population. A trial from the University of Michigan was terminated due to poor accrual (NCT01663285). Memorial Sloan Kettering is a sponsor for a trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with upper tract urothelial carcinoma, which according to the last update remains active but is no longer recruiting. This trial sought to enroll 57 participants in a Phase II design to assess the primary outcome of pathological response rate. Additionally, a Phase II ECOG-ACRIN trial seeking to assess pathologic complete response rates following neoadjuvant chemotherapy (MVAC or gemcitabine and cisplatin) among 36 patients with high-grade upper tract urothelial carcinoma. Results have not yet been published though they were presented at AUA 2018. While the gemcitabine and cisplatin arm did not meet accrual, 30 patients were accrued to the ddMVAC arm. Pathologic complete response was seen in 6 of 29 evaluable patients. None of these trials have provided a randomized comparison to surgery alone. In contrast, NCT02876861 is a trial from Xiangya Hospital of Central South University which is actively recruiting patients and randomizing to neoadjuvant chemotherapy with gemcitabine and cisplatin prior to nephroureterectomy or surgery alone. They are targeting accrual of 50 patients to assess the primary outcome of disease-free survival.

Adjuvant chemotherapy

Again, there is strong evidence for adjuvant chemotherapy in urothelial carcinoma of the bladder. In contrast to neoadjuvant chemotherapy, the data for adjuvant chemotherapy in upper tract urothelial carcinoma are more robust.

First, there is a meta-analysis of nine retrospective cohort studies comparing 482 patients who received adjuvant chemotherapy to 1,300 patients who were treated with surgery alone. Those who received adjuvant therapy had significantly improved disease-free survival (hazard ratio 0.49, 95% confidence interval 0.24 to 0.99) and overall survival (hazard ratio 0.43, 95% confidence interval 0.21 to 0.89)¹⁰. This analysis is limited by significant selection biases.

In contrast, a Phase III randomized trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) is a Phase III, multicenter trial from the Institute of Cancer Research in the United Kingdom which randomized patients who are chemotherapy eligible with pT2-4, pN0-3 or pT1, pN+ following nephroureterectomy to adjuvant platinum-based chemotherapy or surveillance. The results of this trial remain to be published, although they have been presented at ASCO GU and EAU in 2018. To summarize, 123 patients were randomized to surveillance and 125 to adjuvant chemotherapy at 57 different centers. Patients in the intervention arm received either gemcitabine and cisplatin or gemcitabine and carboplatin as their renal function allowed. The majority of enrolled patients had pT3 disease (65%) and were node-negative (pN0, 91%). The authors demonstrated that adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0.49, 95% confidence interval 0.31 to 0.76) as well as metastasis-free survival (hazard ratio 0.49, 95% confidence interval 0.30 to 0.79). However, overall survival data were not yet mature at the time of presentation, so despite the separation of the curves, a meaningful benefit cannot be shown yet. Grade 3 or greater toxicity was experienced by 60% of patients receiving adjuvant chemotherapy and 24% of patients undergoing surveillance.

Previous analyses have demonstrated that patients are much less likely to derive benefit from non-cisplatin based regimes¹⁰. Thus, a significant decline in renal function attributable to nephroureterectomy may result in many patients being unable to receive optimal systemic therapy.

Immunotherapy

The data discussed this far center on the use of cytotoxic chemotherapy, whether gemcitabine and cisplatin, MVAC, or gemcitabine and carboplatin, as these have been the traditional agents used for patients with urothelial carcinoma. Following data supporting the role of immunotherapy using checkpoint inhibitors in patients with advanced metastatic urothelial carcinoma, the recently published Phase II PURE-01 trial examined neoadjuvant pembrolizumab for muscle-invasive urothelial bladder carcinoma¹¹. This analysis demonstrated higher rates of pathologic complete response (42%) and downstaging to non-muscle invasive disease (54%) than would be expected from historical use of cytotoxic chemotherapy, though a randomized control was not employed in this analysis. Analyses of durvalumab plus tremelimumab and of gemcitabine plus cisplatin plus pembrolizumab demonstrated similarly promising results. This approach has not, to our knowledge, been tested in upper tract urothelial carcinoma but such an approach may be particularly valuable in these patients.

Conclusions

At the 2018 Society of Urologic Oncology meeting, Dr. Jean Hoffman-Censits presented on the role of neoadjuvant chemotherapy in these patients. She discussed differences between urothelial carcinomas of the bladder and of the upper urinary tract. Notably, she highlighted that pathologic response rates appear to be lower in patients with upper tract urothelial carcinoma (9-15%) as compared to bladder cancer (>20%). The ongoing URANUS trial will better delineate the role of neoadjuvant therapy in upper tract urothelial carcinoma.

Published Date: December 2019

Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

While androgen deprivation therapy (ADT) is nearly ubiquitously successful in suppressing testosterone to castrate levels with resultant declines in prostate-specific antigen (PSA) levels, the development of resistance is nearly as inevitable. While the natural history is variable, evidence suggests that most patients with advanced or metastatic prostate cancer will have disease progression within two to three years after initiation of androgen deprivation therapy, resulting in so-called “castration-resistant prostate cancer.”

Bone-Targeted Therapy in Prostate Cancer

Zoledronic acid

To maintain bone integrity during bone remodeling, homeostasis of osteoblasts increasing bone mass and osteoclasts resorbing bone is required. Bisphosphonates are rapidly absorbed on the bone surface and inhibit osteoclast activity by affecting cytoskeletal dynamics. The Phase III Zoledronic acid 039 trial showed that among men with metastatic castration-resistant prostate cancer (mCRPC), a greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%, p =0.021) or those who received zoledronic acid at 8 mg (38.5%, p = 0.222

First Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma

As previous UroToday Center of Excellence articles have highlighted, clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC). Likely due to its much higher prevalence, the vast majority of systemic therapies for RCC have been investigated among patients with ccRCC.

Second perhaps only to advanced prostate cancer, the metastatic clear cell renal cell carcinoma disease space has undergone rapid and transformational change over the past fifteen years. This rapidly shifting treatment landscape was highlighted recently at the American Society of Clinical Oncology 2019 Annual Meeting:

Early years: cytokine therapy

It has been recognized for many decades that renal cell carcinoma is an immunologically active tumor. As a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC. Prior to 2005, treatment for metastatic RCC (mRCC) was limited to cytokine therapies (interferon-alfa and interleukin-2).

Interferon-α was one of the first cytokines assessed for the treatment of metastatic ccRCC. Based on early data suggesting a response rate between 10 to 15%⁵ and comparative data demonstrating a survival benefit compared to other available systemic therapies available at the time,⁶ interferon-alfa retained utilization despite significant toxicity. Further, it was among patients with metastatic RCC receiving interferon-alfa that the Motzer prognostic criteria were derived.⁶ In their seminal paper in the Journal of Clinical Oncology, Motzer and colleagues demonstrated that low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and short time from initial RCC diagnosis to start of interferon-alfa therapy (<1 year) could be used to risk-stratify patients with renal cell carcinoma. However, even among patients treated at a center of excellence, median overall survival was only 30 months in favorable-risk patients, 14 months in intermediate-risk patients and five months in poor-risk patients.⁶

Other immunologic therapies were explored including interleukin-2. While response rates were similar to interferon-based therapies (~15 to 20%),⁷ interleukin-2 was distinct in that durable complete responses were observed in approximately 7 to 9% of patients.⁸ This observation led to the U.S. Food and Drug Administration (FDA) approval of high-dose IL-2 in 1992. However, IL-2 is associated with significant toxicity which has limited its widespread use.

Combinations of interferon and interleukin therapies were explored subsequently those these data demonstrated no improvement in overall survival,⁹ with significantly increased toxicity compared to monotherapy with either agent.

A new standard: molecularly targeted agents

Based on work into the molecular biology underlying ccRCC, researchers were led to “rational targeted therapeutics” including targeting of the vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR). Mammalian target of rapamycin (mTOR) plays a key role in regulating HIF-α, thus modulating the pathway between abnormalities in VHF and proliferation.

Bevacizumab, a humanized monoclonal antibody against VEGF-A, was the first inhibitor of the VEGF pathway used in clinical trials. As is standard in an oncology pathway, it was first tested in patients who had progressed on the current standard of care (cytokine therapy) and subsequently tested in untreated patients. In head-to-head trials against interferon-alfa, the addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival.^10,11 Today, bevacizumab is uncommonly used as monotherapy in untreated patients but is considered as second-line therapy in patients who have failed prior therapy with tyrosine kinase inhibitors.

Tyrosine-kinase inhibitors also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-β, raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). In 2006, sorafenib was shown to have biologic activity in ccRCC. Subsequent studies demonstrated improvements in progression-free survival compared with placebo in patients who have previously failed cytokine therapy and improvements in tumor regression compared to interferon in previously untreated patients. As highlighted in the Figure above, sorafenib was one the first molecularly targeted agents clinically available. However, despite FDA approval, sorafenib was quickly supplanted by sunitinib as a first-line VEGF inhibitor.

In keeping with the aforementioned oncology pipeline, sunitinib was first evaluated among patients who had previously received cytokine treatment. Subsequently, it was compared to interferon-α in a pivotal Phase III randomized trial.¹² Among 750 patients with previously untreated, metastatic RCC randomized, median progression-free survival was significantly longer among those who received sunitinib (11 months) than those who received interferon-alfa (5 months; hazard ratio 0.42, 95% confidence interval 0.32 to 0.54). Similar benefits were seen in the overall response rate with subsequent follow-up demonstrating a strong trend towards improved overall survival. In the pivotal trial, patients who received sunitinib had a significantly better quality of life than those who received interferon-alfa¹², despite class-based toxicity profile including gastrointestinal events, dermatologic complications including hand-foot desquamation, hypertension, and general malaise. On account of these data, sunitinib is widely used as a first-line treatment of RCC.

Since the approval of sunitinib and sorafenib, there has been the development and subsequent approval of a number of other tyrosine kinase inhibitors. For the most part, the goal of these agents has been to reduce the toxicity of VEGF inhibitors while retaining oncologic efficacy. Comparative data of pazopanib and sunitinib have demonstrated non-inferior oncologic outcomes with decreased toxicity among patients receiving pazopanib.¹³ Axitinib was evaluated first as second-line therapy¹⁴ and then in the first-line setting compared to sorafenib.¹⁵ Among 192 patients with previously untreated ccRCC randomized to axitinib and 96 patients randomized to sorafenib, median progression-free survival was not significantly different (10.1 months and 6.5 months, respectively; hazard ratio 0.77, 95% confidence interval 0.56 to 1.05)15. Finally, tivozanib has been compared to sorafenib among patients who had not previously received VEGF or mTOR-targeting therapies. While this study demonstrated tivozanib’s activity, it was not FDA approved and is therefore not used.

Most recently, a multikinase inhibitor, cabozantinib has been approved for the first-line treatment of mRCC. In the Phase II CABOSUN trial, cabozantinib was compared to sunitinib in the first-line treatment of patients with intermediate or poor-risk mRCC.¹⁶ Assessing the primary outcome of progression-free survival, the 79 patients randomized to cabozantinib had significantly longer progression-free survival (8.2 months) compared to the 78 randomized to sunitinib (5.6 months; hazard ratio 0.66, 95% confidence interval 0.46 to 0.95). A recent update on this trial utilizing independent progression-free survival (PFS) review demonstrated comparable results (hazard ratio 0.48, 95% confidence interval 0.31 to 0.74)17. Even with an increased follow-up (median 34.5 months), no significant difference in overall survival was demonstrated (26.6 months in patients receiving cabozantinib and 21.2 months in those receiving sunitinib; hazard ratio 0.80, 95% confidence interval 0.53 to 1.21). While this appears to demonstrate a significant benefit to cabozantinib, median survival in the sunitinib arm was lower than may be expected¹⁸ which would serve to exaggerate the apparent benefit of cabozantinib.

In parallel to the development, clinical appraisal and utilization of VEGF inhibitors have come the development of mTOR inhibitors. Temsirolimus was the first mTOR inhibitor to reach clinical utility in patients with metastatic RCC. In the Global ARCC Trial, temsirolimus, interferon, and the combination were compared among 626 patients with pre-defined poor-risk metastatic RCC who had not previously received systemic therapy.¹⁹ Notable compared to many trials in this disease space that have utilized progression-free survival as the primary outcome, overall survival was the primary outcome, with the study powered based on comparisons of the temsirolimus group and the combination group to the interferon-alfa group. Patients who received temsirolimus had significantly improved overall survival compared to those receiving interferon-alfa (hazard ratio 0.73, 95% confidence interval 0.58 to 0.92). Notably, the combination arm did not offer a benefit compared to interferon alone. Unlike temsirolimus which must be administered intravenously, everolimus is an oral agent.

What’s old is new: immunotherapy for RCC

The immunologic basis for the treatment of advanced RCC has been well established, including the aforementioned cytokine therapies. Thus, it should not be surprising that the use of checkpoint inhibitors has demonstrated benefit in patients with metastatic RCC.

First presented at ESMO in the fall of 2017 and subsequently published in the spring of 2018, CheckMate 214 demonstrated an overall survival (OS) benefit for first-line nivolumab plus ipilimumab vs sunitinib.²⁰ This trial randomized 1096 patients to the combination immunotherapy approach of nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients). The majority of patients had intermediate or poor-risk disease (n=847). Overall survival was significantly improved in the overall patient population; however, stratified analyses provide more nuanced results. Among the subgroup of patients with intermediate or poor-risk RCC, treatment with nivolumab plus ipilimumab resulted in significantly improved overall response rate, comparable progression-free survival, and significantly improved overall survival. In contrast, among patients with favorable-risk disease, progression-free survival and overall response rate were higher among patients who received sunitinib. Recently, Escudier and colleagues have assessed the efficacy of nivolumab and ipilimumab according to the number of IMDC risk factors.²¹ In keeping with the previously reported differences in the comparative benefit of nivo/ipi versus sunitinib on the basis of risk category (intermediate/poor versus favorable), the authors demonstrated stable overall response rate (ORR) across increasing numbers of IMDC risk factors (from zero to six) for those who received nivolumab and ipilimumab, while the ORR in patients treated with sunitinib decreased with an increasing number of IMDC risk factors.

The next frontier: combinations of targeted therapy and immunotherapy

Shortly after the data from CheckMate214 emerged, the results of IMmotion151 were presented at GU ASCO in the spring of 2018 and subsequently published. This Phase III trial compared first-line atezolizumab + bevacizumab versus sunitinib among 915 patients with previously untreated metastatic RCC.²² This regime was active with a significant benefit in progression-free survival (11.2 months versus 7.7 months; hazard ratio 0.74, 95% confidence interval 0.57 to 0.96) among the whole cohort of patients and had lower rates of significant (grade 3-4) adverse events (40% vs 54%).

Since the publication of CheckMate214 and IMmotion151, two trials have reported on combinations of checkpoint inhibitors and tyrosine kinase inhibitors: KEYNOTE-426 and JAVELIN Renal 101.

In KEYNOTE-426, 861 patients with metastatic clear cell RCC who had not previously received systemic therapy were randomized to pembrolizumab plus axitinib or sunitinib and followed for the co-primary endpoints of overall survival and progression-free survival.²³ Similar to CheckMate214, the majority of patients had intermediate or poor-risk disease. While median survival was not reached, patients who received pembrolizumab and axitinib had improved overall survival (hazard ratio 0.53, 95% confidence interval 0.38 to 0.74) and progression-free survival (hazard ratio 0.69, 95% confidence interval 0.57 to 0.84), as well as overall response rate. These results were consistent across subgroups of demographic characteristics, IMDC risk categories, and programmed death-ligand 1 (PD-L1) expression level. Grade 3 to 5 adverse events were somewhat more common among patients getting pembrolizumab and axitinib, though rates of discontinuation were lower.

Similarly, JAVELIN Renal 101 randomized 886 patients to avelumab and axitinib or sunitinib.²⁴ Again, the preponderance of patients had IMDC intermediate or poor-risk disease. This analysis of the primary endpoints was progression-free survival and overall survival in patients with PD-L1 positive tumors. Notably, 560 of the 886 patients had PD-L1 positive tumors. Among the PD-L1 positive subgroup, progression-free survival (hazard ratio 0.61, 95% confidence interval 0.47 to 0.79) was improved in patients receiving avelumab and axitinib compared to sunitinib while overall survival did not significantly differ (hazard ratio 0.82, 95% confidence interval 0.53 to 1.28). In the overall study population, progression-free survival was similarly improved, as compared to the PD-L1 positive population (hazard ratio 0.69, 95% confidence interval 0.56 to 0.84).

Dead-ends

Numerous chemotherapeutic agents have been explored in ccRCC. These include 5-FU, gemcitabine, vinblastine, bleomycin, and platinum. Meta-analyses of these data demonstrate poor response²⁵ and thus cytotoxic chemotherapy is not indicated in the treatment of advanced RCC. Similarly, hormonal therapies including medroxyprogesterone have been explored but have no role in the modern management of advanced RCC.

Integration of treatment options for patients with metastatic ccRCC

Due to the rapid proliferation of treatment options in first-line treatment of metastatic clear cell renal cell carcinoma, there is a paucity of direct comparative data. The majority of new agents have been compared to sunitinib which was the standard of care at the time that trials were designed. Due to the lack of comparative data, it may be difficult to ascertain which treatment to offer patients who present in clinic. There are a number of ways to approach this issue. First, one may take a quantitative approach, utilizing the available comparative data in a network meta-analysis; second, one may rely upon eminence, as in expert-informed guidelines; finally, one may rely on individual clinical experience.

Assessing this quantitatively, we have recently performed a network meta-analysis of first-line agents in metastatic RCC.²⁶ Assessing agents which are commonly utilized in 2019, we examined 12 relevant trials. Depending on the outcome of interest (progression-free survival, overall survival, or adverse events), the preferred treatment varied. However, pembrolizumab and axitinib appeared to have a high likelihood of being preferred for oncologic outcomes.
Second, considering a panel of expert opinion, the European Association of Urology recently updated its guidelines on the treatment of renal cell carcinoma. Their recommendations are highlighted in the following figure, taken from the EAU guideline:

Notably, the most recent version of these guidelines alludes to the recently published data but have not yet integrated the role of atezolizumab plus bevacizumab, pembrolizumab plus axitinib, or avelumab plus axitinib in guideline recommendations.

Finally, we may rely on the guidance of individual clinical experience.

What about surgery?

The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma has dramatically changed with the publication of the CARMENA and SURTIME studies. The available evidence suggests that systemic therapy should be prioritized ahead of cytoreductive nephrectomy. However, there remains a role of cytoreductive nephrectomy in select patients.

Published Date: March 17th, 2020

Adjuvant Systemic Therapy for High Risk Kidney Cancer

Adjuvant targeted therapy

Tyrosine kinase inhibitors (TKIs) quickly became standard of care for patients with metastatic renal cell carcinoma following their introduction in the early 2000s. They have subsequently been investigated as adjuvant therapy in 4 published randomized trials to our knowledge. In addition, the SORCE trial was presented at ESMO 2019 at the end of September 2019.

Prevention of Skeletal-Related Events in Advanced Prostate Cancer

Patients with advanced prostate cancer are at significant risk of skeletal-related events (SREs) due to a complex interplay between bone health and prostate cancer due to cancer biology and the predilection of prostate cancer to spread to bone, the toxicity of prostate cancer treatments, and shared epidemiology of the two conditions.

Skeletal-related events are used to denote events related to osseous metastases, including pathologic bone fractures, spinal cord compression, orthopedic surgical intervention, and palliative radiation directed at the bone.¹ This definition has been widely used in the design of randomized controlled trials and for drug approval. In some circumstances, authors include a change in systemic anti-neoplastic therapy as a result of bony pain in the definition of skeletal-related events. The key to this definition is that skeletal-related events may be clinically manifested due to symptoms or only radiographically detected. Thus, skeletal-related events may or may not be symptomatic. In contrast, symptomatic skeletal-related events (SSEs) is a relatively newer outcome representing a subset of skeletal-related events which symptomatically affect the patient experience. This outcome was first used in the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial,² wherein symptomatic skeletal-related events were defined as bone-directed radiotherapy to relieve bony pain, new symptomatic pathologic fractures, spinal cord compression, or tumor-related orthopedic surgery. While there is a significant overlap between these conditions, there are important differences that relate to both study design and patient care: namely, detection of SREs requires routine radiographic evaluation to detect asymptomatic skeletal-related events while detection of SSEs can be driven by patient evaluation.

Skeletal related events contribute significantly to the disease-related morbidity and mortality of prostate cancer, in addition to being very costly. A range of lifestyle, nutritional, and pharmaceutical interventions can be undertaken to decrease the risk of skeletal-related events in patients with advanced prostate cancer.

Lifestyle and nutrition-based interventions

These recommendations are not unique to patients with prostate cancer, but rather apply to all men with osteoporosis or decreased bone mineral density to reduce the risk of fractures.

The Endocrine Society Clinical Practice Guideline on Osteoporosis in Men recommends the following lifestyle interventions:³

Calcium intake: it is recommended that men with or at risk for osteoporosis consume 1000 to 1200 mg of calcium daily. While dietary sources are preferable, calcium supplementation should be used if dietary calcium intake is inadequate.
Vitamin D intake: men with low vitamin D levels (< 30 ng/mL or < 75 nmol/L) should receive vitamin D supplementation to raise serum vitamin D levels to at least these levels.
Exercise: men at risk of osteoporosis are recommended to participate in weight-bearing activities at least three or four times per week, for 30 to 40 minutes per session.
Alcohol intake: it is recommended that men at risk of osteoporosis reduce their alcohol intake to fewer than three units of alcohol. One unit of alcohol is defined as 10 mL of pure alcohol. This amount could be found in 25 mL of spirits (40% alcohol by volume), one third to one half a pint of beer (5-6% alcohol by volume), or half a standard glass of wine (12% alcohol by volume).
Smoking cessation: it is recommended that all men at risk of osteoporosis stop smoking.

The American Urological Association 2018 Amendment of the Castration-Resistant Prostate Cancer similarly endorses preventative therapy in the form of supplemental calcium and vitamin D in men with castration-resistant prostate cancer.⁴ However, such interventions are likely advisable much earlier in the disease trajectory given the relatively minor risks of these supplements in contrast to the potentially debilitating and costly consequences of skeletal-related events. To this end, the NCCN and the National Osteoporosis Foundation recommend these interventions in all men over the age of 50 years who are receiving androgen deprivation therapy.

Pharmacologic interventions

In addition to calcium and vitamin D as highlighted above, the American Urological Association 2018 Amendment of the Castration-Resistant Prostate Cancer endorses pharmacotherapy with denosumab or zoledronic acid in men with castration-resistant prostate cancer.⁴

While further indications exist, the Endocrine Society Clinical Practice Guideline on Osteoporosis in Men recommends pharmacologic therapy in men at high risk for fracture based on, but not limited to, the following factors:³

Men with a history of previous non-traumatic hip or vertebral fracture.
Men with bone mineral density (T-score) that is 2.5 standard deviations or more below the mean of normal young white men, in the absence of spine or hip fractures.
Men with a bone mineral density (T-score) from 1.0 to 2.5 standard deviations who also have an increased risk of fracture. In the United States, the suggested criteria for increased risk of fracture are a 10-year risk of any fracture equal to or exceeding 20% or a 10-year risk of hip fracture equal to or exceeding 3%, as determined using the FRAX tool. In other regions, the Guidelines recommend the utilization of region-specific guidelines.
Men who are receiving long-term glucocorticoid treatment in significant doses defined by the 2010 American Society of Rheumatology as > 7.5 ng per day of prednisone or equivalent.

Pharmaceuticals - bisphosphonates

Bisphosphonates were among the first agents successfully used to prevent skeletal-related events in advanced prostate cancer. They function by reducing bone resorption through a variety of mechanisms including decreased osteoclast differentiation and survival and increased osteoblast survival. To do so, they compete with pyrophosphate for hydroxyapatite crystal binding sites, thus reducing osteoclast adherence to the bone. While there are a number of bisphosphonates used for a variety of clinical indications, zoledronic acid is most commonly used in patients with metastatic prostate cancer due to the Zometa 039 trial which demonstrated a reduction in SREs for patients who received zoledronic acid as compared to placebo.⁵ Based on these data, zoledronic acid is the only bisphosphonate approved for the prevention of skeletal-related events in men with metastatic prostate cancer.

Pharmaceuticals - denosumab

Denosumab is another agent which targets osteoclast activity. Bone exists in homeostasis between formation (driven by osteoblasts) and resorption (driven by osteoclasts). This homeostasis is regulated by the RANK (receptor activator of nuclear factor κB)/RANK-ligand system. Denosumab is a fully human monoclonal antibody that targets the RANK-ligand by mimicking OPG. Denosumab was first examined in postmenopausal women to prevent the development of osteoporosis and reduce the risk of fracture. Subsequently, denosumab was examined in women with breast cancer. Most relevantly, the Denosumab Protocol 20050103 compared denosumab and zoledronic acid in 1901 men with castrate-resistant prostate cancer.⁶ After a median follow-up of approximately one year, patients receiving denosumab had a significantly prolonged time to first-SRE (3.6 months incremental benefit, hazard ratio 0.82, 95% confidence interval 0.71 to 0.95). As a result of these data, denosumab was approved for the prevention of SREs in patients with metastatic solid tumors.

Pharmaceuticals – radio-isotopes

In addition to these osteoclast targeting agents, radio-isotopes may be used in the prevention of skeletal-related events. While beta-emitting particles (strontium-89 and samarium-153) may be used in the palliation of disease-related bony pain, they don’t have proven benefit in the prevention of SREs. In contrast, the alpha-emitting particle radium-223 has proven both palliative benefit as well as improvements in time to first SRE and overall survival. In the pivotal ALSYMPCA trial, 922 men with castrate-resistant prostate cancer and at least two symptomatic bony metastases who had either previously received or were unfit to receive docetaxel were randomized to radium-223 or placebo. Patients receiving radium-223 had significant improvements in time to first SRE (incremental benefit 5.2 months) as well as overall survival (incremental benefit in median survival of 2.8 months).²

Approach to preventing skeletal-related events

Philosophically, there are a number of times in the natural history of prostate cancer where a clinician may intervene to reduce the risk of prostate cancer related skeletal-related events. These relate to the complex interplay between prostate cancer and bone disease.

First, treatment may be directed at reducing or preventing fragility fractures due to prostate cancer-related therapy. In this disease space, lifestyle and nutrition-based interventions are paramount and are recommended by AUA guidelines as well as the National Comprehensive Cancer Network (NCCN). Pharmacologic interventions, including the use of osteoclast targeting therapies (bisphosphonates and RANK-ligand inhibitors), should be considered in this setting for patients at increased risk of fragility related fracture. Denosumab is FDA approved for this indication on the basis of the HALT 138 trial which found an increase in bone mineral density and a decrease in vertebral fractures among men receiving ADT for non-metastatic hormone-sensitive prostate cancer who receiving denosumab versus placebo.

Second, treatment may be directed at preventing bone metastases. In this disease space, bone-targeting agents including bisphosphonates and denosumab have been examined. The MRC PR04 trial demonstrated no benefit to clodronate in metastasis-free survival. Unfortunately, the Zometa 704 trial assessing the role of zoledronic acid in men with non-metastatic castration-resistant prostate cancer failed to accrue. However, the ZEUS trial accrued 1393 men with high-risk localized prostate cancer. Treatment with zoledronic acid failed to demonstrate an improvement in bone metastasis compared to placebo.⁷ The Denosumab Protocol 20050147 randomized men with high-risk nonmetastatic castrate-resistant prostate cancer to denosumab or placebo. Men receiving denosumab had prolonged metastasis-free survival (incremental benefit of 4.2 months).⁸

However, other approaches utilizing the suppression of the androgen axis in patients with non-metastatic castration-resistant prostate cancer (enzalutamide, apalutamide, and darolutamide) have demonstrated improvements in metastasis-free survival. While not a primary endpoint of these studies, it would be anticipated that delaying metastasis may improve skeletal-related events in these patients.

Third, we may seek to prevent skeletal-related events in men with known metastatic prostate cancer. This applies whether these men are in the castrate-sensitive or castrate-resistant disease space and it is here that the bulk of the evidence for prevention of SREs lies. In men with castrate-sensitive disease, CALGB 90202 demonstrated no improvement in skeletal-related events with the administration of zoledronic acid while castrate-sensitive rather than delayed initiation at the time of castration resistance.⁹ In contrast, there is significant evidence for the role of bone targeting agents in men with castrate-resistant disease. As previously mentioned, Zometa 039 demonstrated improvements in SREs for men receiving zoledronic acid compared with a placebo. Interestingly, CGP 032 and INT 05 failed to demonstrate a benefit to pamidronate. Thus, zoledronic acid is the only bisphosphonate approved in this space. The Denosumab Protocol 20050103 demonstrated an improvement in time to first SRE, as previously mentioned. Further, radio-isotope therapy using radium-223 was demonstrated in ALSYMPCA to improve time to first SRE in men with castrate-resistant prostate cancer and at least two symptomatic bony metastases.

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md

Published Date: February 2020

Radiopharmaceuticals in Prostate Cancer: Systemic “Bone-Seeking” Agents

Radiopharmaceuticals are pharmaceutical agents containing radioisotopes and emitting radiation that may be used for diagnostic or treatment purposes.

A number of small molecules have been used in conjunction with positron emission tomography (PET) scanning for prostate cancer staging. A recent presentation reported on the role of radiopharmaceutical driven imaging, predominately using Ga-PSMA, from the 2018 American Society of Clinical Oncology Annual Meeting.

From a therapeutic perspective, as they are typically given via intravenous infusion, radiopharmaceuticals are systemic radiotherapies, emitting alpha or beta radiation. Radiopharmaceuticals are indicated in patients with castrate-resistant prostate cancer with symptomatic bone metastases. Historically, beta-particle emitting agents including strontium-89 (Metastron®), samarium-153 (Quadramet®), phosphorus-32, and rhenium-186 were used as palliative therapies for patients with symptomatic bone disease.¹ In this context, they are quite effective in relieving bony pain,² however, these agents did not significantly improve survival.³ In contrast, the ALSYMPCA trial, which will be discussed in more detail below, demonstrated an improvement in both overall survival and skeletal-related events for patients receiving the alpha-emitter radium-223.⁴

In December 2018, the European Association of Nuclear Medicine Focus 1 Meeting reported a consensus regarding the use of molecular imaging and theranostics in prostate cancer.⁵ A number of relevant conclusions were derived following a systematic review and modified Delphi process. First, traditional diphosphate bone scan and contrast-enhanced computed tomography scan are mentioned but rarely recommended in the majority of patients in clinical guidelines. Second, magnetic resonance imaging and prostate cancer-targeted positron emission tomography are frequently suggested but the specific clinical scenarios in which they are most useful are poorly defined and how they may affect practice are poorly delineated. Third, sodium fluoride-18 positron emission tomography-CT bone scanning is not widely recommended; however, gallium-68 or fluorine-18 PSMA have gained acceptance. Finally, the palliative use of bone-targeting radiopharmaceuticals strontium-89, samarium-153, and rhenium-186 has been supplanted by radium-223, as well as other systemic therapies including docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel.

Radium-223

Radium-223 dichloride (Xofigo®), commonly referred to as radium-223, is a targeted alpha emitter. It functions as a calcium mimetic and selectively binds newly forming bone stroma in regions of high bone turnover in osteoblastic or sclerotic bone metastasis.⁶ It then emits high-energy alpha particles with a very short range (less than 100 μm).⁷ This high-energy radiation induces a highly localized cytotoxic effect due to double-stranded DNA breakage.

Initial Phase I and Phase II studies in patients with bone metastasis demonstrated radium-223 to be well tolerated, with minimal myelosuppression.^8,9 Phase II trials also demonstrated that radium-223 effectively reduced bone-related pain and improved disease-related biomarkers, including bone alkaline phosphatase and prostate-specific antigen (PSA).⁹

As a result, the Phase III, Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial was undertaken to assess the efficacy of radium-223 versus placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases across 136 study centers in 19 countries.⁴ The trial enrolled patients with two or more bone metastases, detected on skeletal scintigraphy, without visceral metastasis who had previously received docetaxel, were docetaxel ineligible or declined docetaxel. Patients were required to have symptomatic disease, based on the requirement for regular analgesics or prior treatment with external beam radiotherapy for cancer-related bone pain in the preceding 12 weeks. Additionally, patients had to have a baseline PSA of at least 5 ng/mL with at least two progressive PSA rises; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; life expectancy of at least six months; and adequate hematologic, renal and liver function. Patients who had received chemotherapy within the preceding four weeks were excluded.

A total of 921 patients were enrolled and were randomized in a 2:1 ratio to radium-223 (50 kBq per kilogram of body weight intravenously), once every four weeks, plus best standard of care or placebo plus best standard of care.

The primary study endpoint was overall survival and secondary outcomes included time to first symptomatic skeletal event; biochemical endpoints including time to increase in total alkaline phosphatase level, total alkaline phosphatase response, normalization of alkaline phosphatase, time to increase in PSA; safety endpoints; and quality of life.

An initial, pre-specified, interim analysis was undertaken when 314 deaths had occurred. This demonstrated longer median overall survival among patients who received radium-223 (14.0 months) than those receiving placebo (11.2 months) with a resulting 30% decrease in the risk of death (hazard ratio 0.70, 95% 0.55 to 0.88). A subsequent, updated analysis was performed following 528 deaths. This demonstrated consistent results with longer median overall survival among patients who received radium-223 (14.9 months) than those receiving placebo (11.3 months). Similarly, the updated analysis confirmed a 30% reduction in the risk of death (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58 to 0.83) for patients receiving radium-223. This benefit was observed across subgroups including total alkaline phosphatase level at randomization, current bisphosphonate use, previous docetaxel treatment, baseline ECOG score (0/1 vs 2), extent of disease (<6 metastases, 6-20 metastases, >20 metastases, and super scan), and opioid use.

Assessment of the secondary endpoints demonstrated a consistent benefit for radium-223. Notably, radium-223 delayed time to first symptomatic skeletal event (median, 15.6 months vs 9.8 months; HR 0.66, 95% CI 0.52 to 0.83). Unlike many systemic therapies, patients who received radium-223 were less likely to experience adverse events than those who received placebo: all adverse events (93% vs 96%), grade 3 or 4 adverse events (56% vs 62%), serious adverse events (47% vs 60%), and treatment-discontinuation as a result of adverse events (16% vs 21%). Finally, patients who received radium-223 were significantly more likely to have an improvement in the quality of life compared to patients receiving a placebo (p=0.02).

The authors subsequently published a pre-planned analysis with stratification according to receipt of prior docetaxel.¹⁰ Radium-223 prolonged survival both in patients who had previously received docetaxel (HR 0.70, 95% CI 0.56 to 0.88) and those who had not previously received docetaxel (HR 0.69 (95% CI 0.52 to 0.92).

As both radium-223 and abiraterone acetate^11,12 have demonstrated survival benefits in patients with metastatic castrate-resistant prostate cancer, there was interest in combining these two agents. The ERA 223 trial randomized 806 patients with chemotherapy-naïve, metastatic castrate-resistant prostate cancer with bone metastasis to radium-223 or placebo, in addition to abiraterone acetate. Symptomatic skeletal event-free survival was the primary outcome. Somewhat unexpectedly, the trial was unblinded prematurely as more fractures and deaths were identified in the radium-223 arm than among patients receiving placebo. Median skeletal event-free survival was 22.3 months (interquartile range 17.0 to 25.8 months) among patients receiving radium-223 and abiraterone acetate and 26.0 months (interquartile range 21.8 months to 28.3 months) in patients receiving placebo and abiraterone acetate (HR 1.12, 95% CI 0.92 to 1.37). Fractures were more common among patients receiving radium-223 and abiraterone acetate (29%) than those receiving placebo and abiraterone acetate (11%). Thus, the combination of radium-223 and abiraterone acetate is not recommended in combination, however other combinations of agents with radium-223 are currently being tested (ie. enzalutamide).

Role of Radiopharmaceuticals in the AUA Guideline

The American Urological Association Guideline on Castrate-Resistant Prostate Cancer (amended in 2018) defines a number of clinical scenarios in which radiopharmaceuticals may be considered.¹³

First, among patients with good performance status and have not yet received docetaxel but who are symptomatic (based on a definition requiring regular use of narcotic analgesics for pain that is attributable to documented metastasis), radium-223 may be offered to patients who have symptoms attributable to bony metastatic disease in the absence of visceral disease in addition to standard of care options including abiraterone acetate plus prednisone, enzalutamide, and docetaxel. Patients with symptomatic metastases who decline these standard therapies, alternative treatments including radionuclide therapy (such as strontium-89) may be offered.¹³

Second, for symptomatic patients with poor performance status who have not previously received docetaxel, there is a relative paucity of direct evidence to inform treatment choices as most patients with poor performance status are excluded from clinical trials. Based on extrapolation from studies in patients with better performance status, the guideline recommends considering aggressive prostate cancer treatment where the functional impairments resulting in poor performance status are directly attributable to prostate cancer. In cases where the poor performance status is related to bony metastatic disease, radium-223 is a recommended option.¹³

Third, among patients with metastatic castrate-resistant prostate cancer who have previously received docetaxel-based chemotherapy, radium-223 is one of four agents with a proven survival benefit, along with abiraterone acetate plus prednisone, enzalutamide, and cabazitaxel.

Fourth, and finally, in patients with advanced mCRPC who are symptomatic and have poor performance status following previous docetaxel chemotherapy, symptom management is strongly advocated in keeping with the American Society for Clinical Oncology’s guidance regarding the treatment of patients with advanced solid tumors. However, judicious use of radionuclide therapy, along with abiraterone acetate plus prednisone, enzalutamide, ketoconazole plus steroids, are offered within the AUA guidelines¹³ despite the lack of strong data to support the use of these agents in this patient population.

The Canadian Urologic Association Guidelines similarly recommend radium-223 in patients with metastatic castrate-resistant prostate cancer who have bone pain related to their metastases and no visceral disease.¹⁴

New directions

The ALSYMPCA trial was the first to demonstrate that radiopharmaceuticals could improve overall survival, in addition to skeletal-related events,⁴ in patients with metastatic castrate-resistant prostate cancer. On the basis of this observation, there is an ongoing effort to identify molecular targets for linkage to radiopharmaceuticals. Proposed targets have included prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptors (GRPr),¹⁵ These have the advantage of targeting prostate cancer cells, rather than being inherently bone targeting as is the case for current radiopharmaceuticals. Thus far, preliminary data based on prostate-specific membrane antigen targeted beta-emitters such as lutetium-177 suggest a promise to this approach but further work remains prior to the adoption of this approach.¹ Further, ongoing research assessing prostate-specific membrane antigen targeted alpha-emitters is ongoing.

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: December 2019

Expanding Treatment Options in Non-metastatic Castrate-resistant Prostate Cancer

Prostate cancer (PCa) is the second most common form of cancer diagnosed in US men. It represents 19% of newly diagnosed cancers, and the third leading cause of cancer death, accounting for an estimated 39,430 deaths in 2018.¹

The Current Status of Stereotactic Body Radiation Therapy in Kidney Cancer

Renal cancers are common, accounting for an estimated 65,340 new diagnoses and 14,970 attributable death in 2018 in the United States.¹ The “Epidemiology and Etiology of Kidney Cancer” is discussed at length in the linked article in the UroToday Center of Excellence series. Despite a large number of histologic tumor types that may occur in the kidney, renal cell carcinoma (RCC) is the most prevalent histology and this article will focus on patients with RCC.

There are a number of accepted treatment options for patients diagnosed with localized RCC. These include radical nephrectomy (whether open, laparoscopic or robotic), partial nephrectomy (whether open, laparoscopic, or robotic), surgical or non-surgical ablation, and active surveillance. The most appropriate treatment strategy will depend on patient (host) and tumor characteristics. These details are discussed more fully in the “Malignant Renal Tumors” article in the UroToday Center of Excellence series.

Kidney cancer has been historically thought of as a “radio-resistant” tumor. This is based on in vitro studies² as well as the fact that early trial of adjuvant and neoadjuvant radiotherapy in patients with RCC undergoing surgical resection failed to show benefit.^3,4 As a result, traditionally fractionated radiotherapy has been historically limited to palliative intent for patients with RCC. However, hypofractionated, high-dose radiotherapy has proven successful in the local control of RCC metastasis to the brain and other bony and visceral sites (refs 6-15). Coinciding with these clinical data was the emergence of data demonstrating the efficacy of high dose per fraction radiotherapy in the treatment of RCC in a mouse model.⁵ This led to increasing interest in the use of stereotactic body radiotherapy (SBRT) in the treatment of localized RCC. SBRT is routinely used for the treatment of malignancies of other tissue types including lung, liver, spine, and prostate.⁶ Compared to other radiation techniques, SBRT utilizes a smaller number of higher dose fractions. This is believed to assist with overcoming the previously believed radioresistance of RCC. Further, compared to other ablative approaches, one of the advantages of SBRT is the ability to treat larger lesions.⁶

Given uncertainties about both the efficacy and toxicity of such an approach, initial investigation has focused on patients in whom extirpative surgery, the gold standard approach, is not feasible or safe.

There are currently both retrospective and prospective reports characterising outcomes for patients treated with SBRT for localized RCC. These studies include a variety of treatment approaches including single fraction treatment (often 26 Gy in 1 fraction) and multiple fraction regimes (including regimes ranging from 2 to 10 fractions and total doses ranging from 5 to 85 Gy). As may be expected from some different treatment approaches, there are differences in both efficacy and toxicity between studies.

Prospective cohort studies

A recent systematic review identified eight published prospective studies of SBRT in the treatment of patients with localized RCC.⁷ Apart from one study published in 2006, the remainder have been published in the last five years. The strength of conclusions that can be drawn from these data are limited by small sample sizes (4 to 40 patients with localized RCC per study) and limited follow-up (13 to 52 months, with most 2 years or less).⁷ In addition, as previously mentioned, there were significant differences in total dose delivered and radiotherapy prescription between studies.

In each case, the authors report on patients who were either deemed medically inoperable, at very high risk for surgery due to the risk of dialysis or who refused surgery. Some studies had specific, disease-related criteria (e.g. a single lesion, maximal tumor dimension less than 4 or 5 cm) whereas this was not specified in other manuscripts. Outcomes were variably reported with local control most often reported. Additionally, adverse events were variously, and non-systematically reported.

Local control rates varied, in large part in correlation to the duration of observation: from 87% local control rate at a median 37 months follow up to 100% at two years in one trial8. Notably, even in the publication from Siva and colleagues who reported 100% local control, 10% of patients experienced distant progression, an outcome that is more likely to contribute to morbidity and mortality than local recurrence.⁸ Longer-term outcomes remain to be assessed.

Likely due in part to differing radiotherapy prescriptions, toxicity rates varied significantly. Both Siva and colleagues and Svendman and colleagues reported grade 1-2 toxicity in more than 50% of patients, most notably characterized by chest wall pain, nausea, and fatigue.^8,9 In addition to considerations regarding comorbidity, SBRT and other non-surgical approaches to renal masses are often considered in patients with poor renal function for whom nephron preservation is a top priority. Thus, post-procedural renal function is an important outcome and, again, results vary between reports. Kaplan and colleagues reported worsening of renal function in 2 of 12 patients undergoing SBRT for medically inoperable tumors less than 5cm.¹⁰ McBride et al., in a similar population of patients, found that 2 of 15 patients (13%) had late grade 3 renal dysfunction with a mean decrease in glomerular filtration rate of 18 mg/dL among the whole study population.¹¹ Similarly, Ponsky and colleagues demonstrated an 11% rate of grade 3 renal dysfunction among 19 patients deemed poor surgical candidates who received SBRT.¹² Finally, and perhaps more optimistically, Siva and colleagues found in their cohort of 21 patients that the average decrease in glomerular filtration rate was only 8.7 mL/min at one year following treatment.⁸. Taken together, evidence suggests that increased fractionation (as in 20 to 30 Gy in 10 fractions) was strongly correlated with renal atrophy.¹³

Taken together, these data suggest that, for patients who receive three radiation fractions, a minimum per fraction dose of 11 Gy should be administered as this was the minimum dose that, in prospective cohorts, no patient experienced local failure.⁷

Retrospective cohort studies

In addition to the aforementioned prospective cohort studies, there are a number of retrospective cohort studies examining the use of SBRT in primary RCC. These, for the most part, have the same limitations are the prospective studies including limited sample size, short follow-up and heterogeneity of radiotherapy prescription. While most of these reports demonstrated local control rates comparable to the prospective literature (93 – 100%), one study demonstrated significantly lower local control (65%) among patients who had a history of radical nephrectomy for RCC in the contra-lateral kidney14. Those patients received 60 to 85 Gy in 5 to 7 fractions using stereotactic gamma-ray irradiation.

Patient selection

Surgery remains the mainstay of curative-intent treatment for patients with localized RCC. Ablative approaches, including SBRT, may, therefore, be considered among patients for whom surgery is contraindicated or who refuse surgery. Recent guidelines have recommended emphasizing that SBRT remains an experimental option in RCC due to the relatively limited worldwide experience and lack of long-term data.¹⁵

Treatment recommendations

The International Radiosurgery Oncology Consortium for Kidney performed a 65 item survey among eight institutions who performed SBRT for primary RCC.¹⁶ A number of important conclusions came out of this work and the resulting consensus statement. First, all included centers treat patients with solitary kidneys or pre-existing hypertension. Five of the eight institutions have size cut off criteria ranging from 5 to 8 cm in maximal tumor dimension. The total planning target volume expansion varied between institutions, ranging from 3 to 10 mm. While all centers used pretreatment image verification, seven of the eight utilized intrafractional monitoring of some sort. Radiation prescriptions varied from 1 to 12 fractions with a total dose of 25 to 80 Gy. However, the consensus statement recommends a total dose of 36 to 45 Gy for patients receiving 3 fraction regimes and 40 to 50 Gy for patients receiving 5 fraction regimes. Obviously, the size of the primary tumour and its proximity to critical and adjacent structures will influence the total dose and fractionation regime.

Ongoing surveillance follow-up for local tumor response and recurrence varied with some institutions relying on computed tomography (CT) alone while others used magnetic resonance imaging (MRI) or PET-CT. Typically, follow-up was performed every three to six months in the first two years and every three to twelve months in the subsequent three years.

One of the challenges in the post-treatment monitoring of these patients is the interpretation of radiographic studies and identification of imaging studies. Among 41 tumours treated with SBRT, the largest available study of imaging characteristics following treatment found that the linear growth rate regressed by an average of 0.37 cm per year after treatment but that there were no significant changed in enhancement when comparing imaging before and following treatment.¹⁷

Conclusions

Stereotactic body radiotherapy is an emerging treatment approach for patients with primary renal cell carcinoma. Compared to other ablative approaches (such as radiofrequency ablation or cryotherapy), it offers the opportunity to treat larger tumors and potentially those in closer proximity to critical structures. To date, surgical extirpation via partial or radical nephrectomy remains the gold standard and SBRT has primarily been investigated among patients who are either deemed medically inoperable or who refuse surgery. There are a number of ongoing studies assessing the role of SBRT that will increase the prospective global experience with this approach, however, none will provide comparative data with other treatment approaches. One particular area of interest in the potential for synergistic effects between SBRT and systemic therapy, particularly immunotherapy (ClinicalTrials.gov identifiers: NCT01896271, NCT02781506, NCT02306954, and NCT02334709).

Published Date: November 2019

Contemporary Radiotherapy Clinical Trials for Prostate Cancer

Localized Treatment – Optimizing Fractionation

Several trials have recently focused on delineating the optimal radiotherapy fractionation schedule for the primary treatment of prostate cancer. In 2016, efficacy results of the Dutch HYPRO trial were published, assessing hypofractionated radiotherapy compared with conventionally fractionated radiotherapy among patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer.¹ Patients were assigned 1:1 to either hypofractionated radiotherapy of 64.6 Gy (19 fractions of 3.4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78.0 Gy (39 fractions of 2.0 Gy, five fractions per week) with a primary endpoint of relapse-free survival. There were 804 patients assessed in the intention-to-treat analysis, of which 407 were assigned hypofractionated radiotherapy and 397 were allocated to conventionally fractionated radiotherapy. Additionally, 67% of patients received concomitant androgen deprivation therapy (ADT) for a median duration of 32 months (IQR 10-44). Over a median follow-up of 60 months (IQR 51-69), treatment failure was reported in 21% of patients, including 20% in the hypofractionation group and 22% in the conventional fractionation group. The 5-year relapse-free survival was 80.5% (95% CI 75.7-84.4) for patients assigned hypofractionation and 77.1% (71.9-81.5) for those allocated conventional fractionation (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.63-1.16; log-rank p=0.36). Based on these results, the authors noted that this current regimen of hypofractionated radiotherapy was not superior to conventional radiotherapy.

The CHHiP trial was a multi-center, randomized, Phase III trial, designed as a non-inferiority clinical trial, randomizing men with pT1b-T3aN0M0 prostate cancer 1:1:1 to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks) all delivered with intensity-modulated techniques.² Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. The primary endpoint was time to biochemical or clinical failure, and the critical hazard ratio for non-inferiority was 1.208. In this large trial, 3,216 men were enrolled from 71 centers and randomly assigned: 1,065 patients to the 74 Gy group, 1,074 patients to the 60 Gy group, and 1,077 patients to the 57 Gy group. The median follow-up was 62.4 months (IQR 53.9-77.0) over which the proportion of patients who were biochemical or clinical failure-free at five years was 88.3% (95% CI 86.0-90.2) in the 74 Gy group, 90.6% (95% CI 88.5-92.3) in the 60 Gy group, and 85.9% (95% CI 83.4-88.0) in the 57 Gy group. The 60 Gy hypofractionated schedule was non-inferior to the conventional 74 Gy schedule (HR 0.84, 90% CI 0.68-1.03, p noninferiority = 0.0018), but non-inferiority was not possible for 57 Gy hypofractionation compared with 74 Gy (HR 1.20, 90% CI 0.99-1.46, p noninferiority = 0.48).

Based on these initial studies, recent interest has related to even more intense radiotherapy fractionation. The Scandinavian HYPO-RT-PC randomized controlled Phase III trial was initially presented at ESTRO 2018, and subsequently published in Lancet Oncology.³ This trial randomized men with intermediate and high-risk prostate cancer to either conventional fractionating (n = 602; 78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultrahypofractionated (n=598; 42.7 Gy in seven fractions, three days per week for 2.5 weeks). The primary endpoint was time to biochemical or clinical failure. The estimated failure-free survival at five years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1.002 (95% CI 0.758-1.325; log-rank p=0.99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0.057). Based on these results, there has been support for the use of ultra-hypofractionated radiotherapy for prostate cancer.

However, despite encouraging results regarding biochemical/relapse-free survival as described above, studies have not demonstrated an overall survival (OS) benefit. Patients in the NRG Oncology RTOG 0126 trial that had intermediate-risk prostate cancer were randomized to 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions.⁴ Over a median follow-up of 8.4 years in 1,499 patients, there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (HR 1.00, 95% CI, 0.83-1.20), and the 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR 0.65, 95% CI, 0.42-1.01). As the above trials continue to mature, it will be imperative to evaluate survival outcomes. However, adoption of hypofractionation needn’t require improved survival or toxicity outcomes – on the basis of equivalence, improvements in the patient experience/convenience and cost would support the adoption of this approach.

Localized Disease – Optimizing Androgen Deprivation Therapy (ADT)

A second initiative of recent radiotherapy trials has been delineating the appropriate dose of ADT given concurrently with radiotherapy. The DART01/05 GICOR trial was a randomized, controlled Phase III trial assessing high-dose radiotherapy with short-term or long-term ADT for patients with T1c-T3b N0M0 prostate cancer with intermediate-risk and high-risk features.⁵ Patients were randomly assigned 1:1 to receive either four months of ADT combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term ADT group) or the same treatment followed by 24 months of adjuvant ADT (long-term ADT group), stratified by prostate cancer risk group (intermediate risk vs high risk). In this Spanish multi-center trial, 178 patients were randomly assigned to receive short-term ADT and 177 to receive long-term ADT. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term ADT than among those receiving short-term ADT: 90% (95% CI 87-92) vs 81% (95% CI 78-85), HR 1.88, 95% CI 1.12-3.15. Furthermore, the 5-year OS (95% vs 86%; HR 2.48, 95% CI 1.31-4.68) and 5-year MFS (94% vs 83%; HR 2.31, 95% CI 1.23-3.85) rates were also significantly better in the long-term ADT group than in the short-term ADT group. Not surprisingly, the authors noted that the effect of long-term ADT on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease.

In 2016, the results of the EORTC 22991 randomized trial were published.⁶ This trial assessed if biochemical disease-free survival (DFS) is improved by adding six months of androgen suppression to primary radiotherapy for intermediate- or high-risk localized prostate cancer. Among 819 patients, the median patient age was 70 years, 74.8% were intermediate risk and 24.8% were high risk. At 7.2 years median follow-up, radiotherapy plus androgen suppression significantly improved biochemical DFS (HR 0.52, 95% CI 0.41-0.66), as well as clinical progression-free survival (HR 0.63, 95% CI 0.48-0.84).

Long-term follow-up of the D’Amico trial assessing ADT plus radiotherapy versus ADT alone for patients with localized, unfavorable risk prostate cancer was published in 2015⁷. This analysis importantly showed that underlying comorbidity significantly modified the benefit of ADT: in patients with moderate or severe comorbidity, use of radiotherapy alone was associated with decreased cardiac mortality (HR 0.17, 95% CI 0.06-0.46), non-prostate cancer mortality (HR 2.79, 95% CI 1.02-7.60), and overall mortality (HR 0.36, 95% CI 0.19-0.67). Conversely, in men with no or minimal comorbidity, radiotherapy alone was associated with an increased risk of overall mortality and prostate cancer mortality, without coinciding decreases in cardiac mortality or non-prostate cancer mortality.

The prior standard ADT duration was 28-36 months when combined with radiotherapy for high-risk disease. As such, the TROG RADAR trial assessed whether the addition of 12 months of adjuvant ADT, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive six months of ADT and prostate radiotherapy.⁸ In 2019, this trial reported 10-year outcomes. There were 1,071 patients randomized to radiotherapy plus six months of ADT or radiotherapy plus 18 months of ADT. This trial found that 18 months of ADT plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than six months of ADT plus radiotherapy (HR 0.70, 95% CI 0.50-0.98), but the addition of zoledronic acid to this treatment regimen is not beneficial. Finally, the PCS IV Trial randomized 630 patients with a median follow-up of 9.4 years to radiotherapy plus 18 months of ADT or radiotherapy plus 36 months of ADT.⁹ The 5-year OS rates were 91% for long term ADT arm (95% CI 88-95%) and 86% for short term ADT arm (95% CI 83-90%, p=0.07). The quality of life analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 months of ADT.

Localized Disease – Addition of Chemotherapy

The benefit of adding chemotherapy in the treatment of very high-risk disease has also been recently evaluated. Rosenthal et al.¹⁰ published the multicenter randomized NRG Oncology RTOG 0521 clinical trial, which enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned (n=563) to receive standard long-term ADT plus radiotherapy with or without adjuvant chemotherapy. Over a median follow-up of 5.7 years, the 4-year OS rate was 89% (95% CI, 84% to 92%) for ADT and radiotherapy, compared to 93% (95% CI, 90% to 96%) for ADT and radiotherapy plus chemotherapy (HR 0.69, 90% CI 0.49-0.97). Six-year rate of distant metastasis was 14% for ADT and radiotherapy and 9.1% for ADT and radiotherapy plus chemotherapy, (HR 0.60, 95% CI 0.37-0.99).

Treatment after Radical Prostatectomy

For decades, urologists and radiation oncologists have debated the optimal timing, location, and dose of radiotherapy, in addition to the utilization of ADT among those experiencing biochemical recurrence after radical prostatectomy. The much-anticipated NRG Oncology/RTOG 0534 SPPORT trial reported initial results at the 2019 ASTRO meeting.¹¹ This trial randomized 1,736 patients to either (i) salvage radiotherapy to the prostate bed, (ii) salvage radiotherapy to the prostate bed plus ADT, or (iii) salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. The 5-year freedom from progression rate was 71% for salvage radiotherapy to the prostate bed, 81% for salvage radiotherapy to the prostate bed plus ADT, and 87% for salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. Based on only 108 patients with metastasis, there were minimal differences between the three arms with regards to metastasis-free survival. It is likely that with continued follow-up, these results will likely continue to favor salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes.

Previously, Shipley et al. assessed whether antiandrogen therapy with radiation therapy improves cancer control and prolong OS among patients with biochemical recurrence.¹² In this trial, there were 760 patients who had undergone radical prostatectomy with lymphadenectomy and had biochemically recurrent disease who were randomized to radiation therapy and to receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary endpoint was the OS rate; the actuarial rate of OS at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (HR 0.77, 95% CI 0.59 to 0.99). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (p < 0.001). Finally, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (p = 0.005). As such, the addition of antiandrogen improved clinical outcomes and OS in patients with biochemical recurrence after radical prostatectomy.

Several randomized trials assessing adjuvant vs salvage radiotherapy have been presented earlier this year at academic conferences, but have yet to be published.

Radiotherapy in the Setting of Metastatic Disease

Several trials have recently assessed the impact of radiotherapy to the prostate in the setting of metastatic disease, given retrospective evidence that patients may derive a survival benefit for treatment to the primary prostate tumor. The HORRAD trial was a multi-center randomized controlled trial recruiting 432 patients with a prostate-specific antigen (PSA) >20ng/ml and primary bone metastatic prostate cancer on bone scan (between 2004 and 2014).¹³ Patients were randomized to either ADT with external beam radiotherapy or ADT alone. The median PSA level was 142ng/ml and 67% of patients had more than five osseous metastases. Over a median follow up of 47 months, the median OS was 45 months (95% CI, 40.4-49.6) in the radiotherapy group and 43 months (95% CI, 32.6-53.4) in the control group (p = 0.4; HR 0.90, 95% CI 0.70-1.14). The median time to PSA progression in the radiotherapy group was 15 months (95% CI, 11.8-18.2), compared with 12 months (95% CI, 10.6-13.4) in the control group.

Despite the negative results from HORRAD, there was much anticipation for the results of the STAMPEDE arm H clinical trial assessing the efficacy of radiotherapy to the primary in M1 disease.¹⁴ This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) versus standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84) but not OS (HR 0.92, 95% CI 0.80-1.06). In a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95% CI 0.52-0.90).

The SABR-COMET trial was an important trial published in 2019 assessing stereotactic body radiotherapy to oligometastatic disease.¹⁵ The objective of this study was to assess the standard of care of palliative treatments with or without stereotactic body radiotherapy in up to five metastatic lesions. The trialist’s hypothesis was that patients with oligometastatic disease will have improved outcomes with treatment of their metastatic sites. This study included any cancer (primarily breast, prostate, colorectal, and lung) who were then randomized 1:2 to standard of care versus standard of care plus stereotactic body radiotherapy. The standard of care was at the discretion of the physician and the primary endpoint was OS. There were 99 patients at 10 centers and median follow-up was 25.5 months. Median OS was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the stereotactic body radiotherapy group (HR 0.57, 95% CI 0.30-1.10; p =0.090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the stereotactic body radiotherapy group (p=0.026), an absolute increase of 20% (95%CI 5-34). Treatment-related deaths occurred in three (4.5%) of 66 patients after stereotactic body radiotherapy, compared with none in the control group. The authors concluded that stereotactic body radiotherapy was associated with a 13-month increase in OS and doubling of progression-free survival (PFS).

Conclusions

The last five years have seen several important and practice-changing clinical trials for the treatment of prostate cancer with radiotherapy. Early results suggest that ultra-hypofractionation may make primary treatment with radiotherapy an attractive, less arduous option, however long-term OS results for hypofractionation will be important. There is little doubt that the addition of ADT to radiotherapy in high-risk patients for primary treatment and those experiencing biochemical failure after radical prostatectomy improves outcomes. Furthermore, based on results from the STAMPEDE Arm H clinical trial, many clinicians are now treating the prostate primary among men with low-volume metastatic disease. Finally, ongoing studies utilizing stereotactic body radiotherapy to metastatic sites will be important as we focus on improving quality as well as quantity of life for patients with advanced, heavily treated prostate cancer.

Published Date: January 2020

Beyond First-line Treatment of Metastatic Castrate-resistant Prostate Cancer

In the previous review article (“First-line treatment of metastatic castrate-resistant prostate cancer”), metastatic castrate-resistant prostate cancer (mCRPC) and its approved first-line treatment options were elaborated. Unfortunately, all mCRPC patients will eventually progress despite evidence-based first-line treatments that patients receive. Therefore, an appropriate treatment strategy must be formalized. The working group of the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II (RADAR II) study attempted to offer recommendations on identifying disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific (CRPC) treatments.¹ They recommended a layering approach comprised of approved therapies with unique or complementary mechanisms of action.¹ According to this working group 12 Phase III studies evaluating combinations, layering, or sequencing of these agents are required to help improve clinical outcomes in the castrate clinical state. Following first-line treatment options for mCRPC patients, only second-line treatments given after treatment with docetaxel have been extensively assessed and these are detailed below.

Second-line treatment options for metastatic castrate-resistant prostate cancer

Cabazitaxel

Cabazitaxel is a new taxane drug with activity in docetaxel-resistant cancers. In the TROPIC study, a Phase III prospective randomized trial, cabazitaxel plus prednisone was compared to mitoxantrone plus prednisone in 755 mCRPC patients, who progressed after or during treatment with docetaxel² (Figure 1). Patients received a maximum of ten cycles of cabazitaxel or mitoxantrone plus prednisone. Overall survival (OS) was the primary end-point, being significantly longer in cabazitaxel-treated patients (median: 15.1 vs. 12.7 months p < 0.0001). Progression-free survival (PFS) was significantly improved as well (median: 2.8 vs. 1.4 months, p < 0.0001), and prostate-specific antigen (PSA) response rate was also better (39.2% vs. 17.8%, p < 0.0002). Grade 3-4 adverse events developed more significantly in patients taking cabazitaxel, particularly hematological adverse effects (68.2% vs. 47.3%, p < 0.0002).³ Therefore, cabazitaxel should be given with prophylactic granulocyte colony-stimulating factor and needs to be administered by physicians with expertise in handling neutropenia and sepsis.⁴ When compared to docetaxel in the first-line setting, cabazitaxel was not shown to be superior.⁵

Figure 1. TROPIC study design

Abiraterone following docetaxel

The COU-AA-301 was a large Phase III randomized trial with a total of 1,195 mCRPC patients being randomised in a 2:1 ratio to abiraterone acetate plus prednisone or placebo plus prednisone (Figure 2). Abiraterone is an antiandrogen agent which inhibits the 17α-hydroxylase/C17,20-lyase (CYP17) enzyme. Initial positive results of this trial were reported after a median follow-up of 12.8 months⁶ and confirmed by the final analysis.⁷ All patients in this trial failed at least one chemotherapy regimen, which included docetaxel. The primary end-point was OS, and in the final analysis, after a median follow-up of 20.2 months there was a clear advantage to the abiraterone arm (median survival of 15.8 vs.11.2 months, HR: 0.74, p < 0.0001). The benefit for abiraterone remained in all secondary endpoints as well (PSA, radiologic tissue response, time to PSA or objective progression). No significant difference between the treatment arms was seen in the rate of grade 3-4 adverse events, aside from a higher rate of mineralocorticoid-related side-effects (mainly grade 1-2 fluid retention, edema, and hypokalaemia).⁷

figure 2 COU AA 301

Figure 2. COU-AA-301 study design

Enzalutamide after docetaxel

The AFFIRM trial randomized 1,199 mCRPC patients in a 2:1 fashion to enzalutamide, a nonsteroidal antiandrogen, or placebo (Figure 3). All accrued patients had progressed after docetaxel treatment.⁸ The planned interim analysis of the AFFIRM study was published in 2012 and after a median follow-up of 14.4 months, a clear benefit was shown for the enzalutamide-treated patients (median survival of 18.4 vs. 13.6 months, HR: 0.63, p < 0.001).⁸ This led to the recommendation to halt and unblind the study. Importantly, the observed benefit occurred irrespective of age, baseline pain intensity, and type of progression. Enzalutamide was also beneficial in patients with visceral metastases. The final analysis with longer follow-up had confirmed the OS results despite the crossover and extensive post-progression therapies. Enzalutamide also conferred a clear advantage in all the secondary endpoints (PSA, soft tissue response, quality of life, time to PSA or objective progression).⁸ No significant difference in the rate of side-effects was observed in the two groups, with a lower incidence of grade 3-4 adverse events in the enzalutamide arm. Importantly, enzalutamide-treated patients had a 0.6% incidence of seizures compared to none in the placebo arm.⁸

Figure 3. AFFIRM trial design

Apalutamide

Radium-223

Radium-223 is a targeted alpha therapy and is the only bone-specific drug that has been associated with a survival benefit in the mCRPC space. The ALSYMPCA trial was a large Phase III trial accruing 921 symptomatic mCRPC patients, who failed or were unfit for docetaxel chemotherapy.¹³ In this trial, patients were randomized to six injections of radium-223 or placebo, plus standard of care in both arms (Figure 4). The primary end-point was OS, and radium-223 significantly improved median OS by 3.6 months (HR: 0.70, p < 0.001).¹³ Radium-223 also conferred prolonged time to first skeletal event, improvement in pain scores and quality of life.¹³ No significant difference was noted in the rate of adverse effects between the treatment arms, aside from slightly more haematologic toxicity and diarrhea with radium-223.¹³ Whether patients were pretreated with docetaxel did not affect the benefit and safety of radium-223.¹⁴ Due to safety concerns, the label of radium-223 was restricted to use after docetaxel and at least one AR targeted agent.¹⁵ Importantly, the ERA-223 study assessed the effectiveness of early use of radium-223 together with abiraterone acetate and prednisolone (Figure 5). Unfortunately, this trial showed significant safety risks, especially with fractures and more deaths. Therefore, this combination is currently not recommended. These safety risks were more significant in patients without the concurrent use of antiresorptive agents.¹⁶

Figure 4. ALSYMPCA trial design

Figure 5. ERA 223 study design

Third line treatment following treatment with docetaxel and one hormonal treatment for metastatic castrate-resistant prostate cancer

Currently, there are no clear guidelines or recommendations regarding which treatment option is appropriate in this setting and this is open for debate. The choice for further treatment after docetaxel and one line of hormonal treatment for mCRPC is unclear.¹⁷ The available options include radium-223 or second-line chemotherapy (cabazitaxel). In unselected patients, subsequent treatments are expected to have a lower benefit than with earlier use¹⁸. There is also evidence that cross-resistance between enzalutamide and abiraterone exists.¹⁹^,²⁰ There is a unique subset of patients worth mentioning with tumors demonstrating homozygous deletions or deleterious mutations in DNA-repair genes. In these patients Poly(ADP-ribose) polymerase (PARP) inhibitors have been reported to confer high rates of response. Therefore, patients who were previously treated with docetaxel and at least one novel hormonal agent; and whose tumors demonstrated homozygous deletions or deleterious mutations in DNA-repair genes showed an 88% response rate to Olaparib, a PAPR inhibitor.²¹ This represents an example of how treatment can be tailored according to the tumor mutation profile.²² In a randomized Phase II study of mCRPC patients, olaparib combined with abiraterone was compared to placebo and abiraterone. This study demonstrated a clinical benefit in olaparib-treated patients, regardless if mutations in DNA-repair genes existed.²³ However, this combination treatment was shown to be toxic with significant side effects reported in 34% of patients vs. only 18% in the placebo arm.²³

For patients with mismatch repair deficiency, the PD-1 inhibitor pembrolizumab was approved by the FDA for all tumors, including PCa. More specifically, pembrolizumab demonstrated antitumor activity and disease control with acceptable safety in RECIST-measurable and bone-predominant mCRPC, which was previously treated with docetaxel and novel AR antagonists.²⁴

In the COMET-1 trial 1028 patients with progressive mCRPC after treatment with docetaxel and abiraterone and/or enzalutamide were randomly assigned at a 2:1 ratio to either cabozantinib 60 mg, a tyrosine kinase inhibitor, or prednisone 5 mg twice per day.²⁵ The primary endpoint was OS, and the secondary endpoint included bone scan response after 12 weeks of treatment. Additional exploratory analyses included radiographic PFS (rPFS) and effects on circulating tumor cells, bone biomarkers, serum PSA, and symptomatic skeletal events.²⁵ This trial demonstrated that cabozantinib did not significantly improve OS compared with prednisone in heavily pre-treated mCRPC patients (median OS was 11.0 months with cabozantinib and 9.8 months with prednisone, HR 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = 0.213).²⁵ Cabozantinib had some activity in improving bone scan response, rPFS, symptomatic skeletal events, and bone biomarkers but not PSA outcomes.²⁵

Changing and sequencing treatment in metastatic castrate-resistant prostate cancer

There are several open questions and dilemmas regarding when to change treatment in mCRPC patients and what is the most appropriate treatment sequence.

The appropriate time to change treatment in mCRPC patients is not entirely clear. No controversy exists regarding the need to change treatment when patients have symptomatic progression of their metastatic disease. Despite the many available treatment options to date, no head to head comparison has been made publicly available, while data assessing the correct sequence of treatment is being assessed. As data are lacking, physicians have been using the ECOG performance score to stratify patients before deciding on the “appropriate” treatment plan. Men with a good performance status are likely to tolerate more treatments as opposed to men with lower performance scores.

The National Comprehensive Cancer Network (NCCN) considers the onset of visceral disease to be a detrimental factor. Patients with liver metastases have especially poor outcomes for as of yet an unknown reason. In a meta-analysis including over 8,000 mCRPC patients who were enrolled in Phase III trials, patients with lymph-node- only disease appeared to have the best OS (median, 31.6 months; 95% CI, 27.9 to 36.6 months), with patients with lung and bone metastases having shorter and similar median OS (19.4 months [95% CI, 17.8 to 20.7 months] vs. 21.3 months [20.8 to 21.9], respectively), and patients with liver metastases demonstrating the worst OS (median, 13.5 months; 95% CI, 12.7 to 14.4 months).²⁶ Therefore, the type of metastases the patient has can be used as a guide to when and how aggressive the treatment strategy should be.

Abiraterone and enzalutamide are highly active agents harboring a substantial effect on PFS, with trials comparing monotherapy with prednisone or placebo.²⁷^,²⁸ However, a subset of patients will not respond to these drugs. A patient who does not respond well will require a change of treatment. It is therefore important to see these patients frequently once starting therapy and assess their response. If no PSA decline is witnessed, the treatment needs to be changed.

When considering the appropriate treatment sequence in mCRPC, there are no clear guidelines or recommendations to date, and our limited knowledge is based mainly on retrospective data. In one non-randomized retrospective study, PFS, OS, and PSA responses from consecutive patients with chemotherapy-naïve mCRPC were compared between those who received abiraterone followed by enzalutamide and those who received enzalutamide followed by abiraterone.²⁹Initially, a slight improvement in patients who started with abiraterone and transitioned to enzalutamide was seen with improved PFS. An expanded retrospective study confirmed the general trend, showing that patients who started with abiraterone and then transitioned to enzalutamide had better PFS (median, 455 days [95% CI, 385 to 495 days]) than patients who started with enzalutamide and transitioned to abiraterone (median, 296 days; 95% CI, 235 to 358 days).³⁰ However, OS was not significantly different between the groups.³⁰ Furthermore, the authors of an ongoing randomized Phase II study comparing abiraterone vs. enzalutamide in patients with treatment-naïve mCRCP reported their interim results.³¹ After a median follow-up of 22.3 months, a PSA decline of more than 50% occurred in 34% of abiraterone treated patients compared to 4% in the enzalutamide treated patients (p<0.001).³¹ Additionally, the median time to PSA progression on 2nd-line therapy was 2.7 vs 1.3 months (HR 0.38, 95% CI 0.26-0.56) in favor of abiraterone.³¹ Lastly, the median OS was not reached vs 24.3 months (HR 0.82, 95% CI 0.53-1.27) in favor of abiraterone.³¹ As data regarding appropriate treatment sequencing is still being collected and analyzed, many physicians currently base their decision on which medication to start according to the adverse effects that we want to avoid. Abiraterone is commonly associated with edema, and therefore should be avoided in men with congestive heart failure,²⁷ while enzalutamide is more likely to cause central nervous system toxicity and should probably be avoided in older patients.³²

Radioligand therapy for metastatic castrate-resistant prostate cancer patients

PSMA-PET/CT imaging has significantly become more common in recent years. This has led to the emergence of a new field of radioligand directed therapy among heavily pretreated mCRPC patients. PCa metastases express PSMA, making it a promising approach to developing new tracers for targeted radionuclide therapies. PSMA is a non-secreted type II transmembrane protein produced almost exclusively by prostatic tissue and on tumor-associated neovasculature.³³ Unlike other biomarkers, such as PSA, which may decrease with increasing neoplastic de-differentiation, PSMA has been shown to be upregulated in high-grade, de-differentiated PCa.³⁴

Since 2015, several institutional studies have reported promising response rates and a favorable safety profile for radioligand therapy with 177Lu-PSMA-617 in mCRPC patients.^35-37 However, these studies had small sample sizes and questionable generalizability. To addresses these limitations, a large multicenter German analysis assessed a cohort of patients treated with 177Lu-PSMA-617.³⁸ This study included 145 mCRPC patients treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles. The study reported an overall biochemical response rate of 45% after all therapy cycles, with 40% of patients responding after a single cycle. Notably, negative predictors of the biochemical response included elevated alkaline phosphatase and the presence of visceral metastases.³⁸

In a large meta-analysis published in 2017, 10 studies were assessed including 369 patients. This meta-analysis assessed the safety and efficacy of 177-Lutetium in mCRPC patients.³⁹ The pooled proportion of patients with any PSA decline was 68% (95% CI: 61–74%); and the pooled proportion of patients with 450% PSA decline was 37% (95% CI: 22–52).³⁹ This meta-analysis suggested promising early results for the treatment of mCRPC patients, especially in patients treated with the more recently developed radioligands, with approximately two-thirds of them showing a biochemical response.³⁹

Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are additional compounds in development and undergoing initial testing. These include 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.⁴⁰

Treatment and prevention of skeletal-related events

Patients with mCRPC commonly endure painful bone metastases with external beam radiotherapy (EBRT) being a highly effective treatment.⁴¹ Possible complications due to bone metastases include vertebral collapse or deformity, pathological fractures, and spinal cord compression. Cementation can be an effective treatment for a painful spinal fracture, clearly improving both pain and quality of life.⁴² However, standard palliative surgery can still be offered for managing osteoblastic metastases.⁴³ Impending spinal cord compression is an emergency event that must be recognized as soon as possible. Patients should be educated to recognize the warning signs. If this is suspected, high-dose corticosteroids must be given and an MRI is required. A neurosurgeon or orthopedic surgeon consultation needs to be planned to discuss a possible decompression, followed by EBRT.⁴⁴

Zoledronic acid, a bisphosphonate, has been evaluated in mCRPC patients in an attempt to reduce skeletal-related events (SRE). 643 mCRPC patients with bone metastases were randomized to receive zoledronic acid, 4 or 8 mg every three weeks for fifteen consecutive months, or placebo.⁴⁵ The 8 mg dose was poorly tolerated without showing a significant benefit. However, at 15 and 24 months of follow-up, the 4 mg dose conferred fewer SREs compared to the placebo group (44 vs. 33%, p = 0.021), and less pathological fractures (13.1 vs. 22.1%, p = 0.015). Additionally, the time to first SRE was longer in the zoledronic acid group. However, no survival benefit was seen in any prospective trial assessing bisphosphonates.

Denosumab is a fully human monoclonal antibody directed against RANKL (receptor activator of nuclear factor kappa-B ligand). It is a key mediator of osteoclast formation, function, and survival. In non-metastatic CRPC, denosumab has been associated with increased bone-metastasis-free survival compared to placebo (median benefit: 4.2 months, HR: 0.85, p = 0.028).⁴⁴ Like zoledronic acid, this benefit did not translate into a survival difference and neither the FDA or the EMA had approved denosumab for this indication.⁴⁶ A Phase III trial compared the efficacy and safety of denosumab (n = 950) with zoledronic acid (n = 951) in mCRPC patients. Denosumab was shown to be superior to zoledronic acid in delaying or preventing SREs, as shown by time to first SRE (pathological fracture, radiation or surgery to bone, or spinal cord compression) of 20.7 vs. 17.1 months, respectively (HR: 0.82, p = 0.008). However, these findings were not associated with any survival benefit, and in a recent post-hoc re-evaluation of end-points, denosumab had actually shown an identical rate of SREs to zoledronic acid.⁴⁷ It is critical to remember that these medications are associated with substantial toxicity, of 5% and 8.2% in non-metastatic CRPC and mCRPC, respectively.⁴⁷^,⁴⁸ All patients are required to be examined by a dentist prior to initiating this therapy, as the risk of jaw necrosis is increased by several risk factors including a history of trauma, dental surgery or dental infection.⁴⁹ and the number of years the medication is used.

Recently, the randomized, double-blind Phase III trial (COMET-2; NCT01522443) was published, comparing cabozantinib, to mitoxantrone + prednisone in mCRPC patients with narcotic-dependent pain from bone metastases.⁵⁰ All patients had progressed after treatment with docetaxel and either abiraterone or enzalutamide.⁵⁰ The primary endpoint was pain response at week 6 and confirmed again at week 12. Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in mCRPC patients in the companion COMET-1 trial,²⁵ described earlier. At study closure of the COMET-2 trial, only 119 patients were randomized. The trial demonstrated no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone.⁵⁰

Future and ongoing trials

There are currently 24 registered ongoing Phase III trials involving mCRPC patients.

Some studies worth mentioning with much-anticipated results include the following:

The combination of abiraterone and Olaparib as first-line therapy in mCRPC patients (NCT03732820)
A study assessing the role of Rucaparib (a PARP inhibitor) vs. physician’s choice therapy in mCRPC patients (TRITON3 trial - NCT02975934)
The combination of pembrolizumab with various other medications including enzalutamide (NCT03834493 - as part of the MK-3475-641/KEYNOTE-641 trial), docetaxel (NCT03834506 - as part of the MK-3475-921/KEYNOTE-921 trial), and olaparib (NCT03834519 – as part of the MK-7339-010/KEYLYNK-010)
The ACIS trial, which will assess the combination of apalutamide, and abiraterone + prednisone in mCRPC patients (NCT02257736)
A study assessing Masitinib (a tyrosine kinase inhibitor) plus docetaxel (NCT03761225)
The combination of Talazoparib (a PARP inhibitor) + plus enzalutamide (NCT03395197),
The combination of Atezolizumab (an anti-PD-L1 monoclonal antibody) + enzalutamide (NCT03016312)
The combination of docetaxel and Radium-223 (NCT03574571)
A study assessing 177Lu-PSMA-617 in mCRPC patients (NCT03511664)
The IPATential150 trial – assessing the combination of Ipatasertib (an orally administered, ATP-competitive, selective AKT inhibitor) plus abiraterone (NCT03072238)

Conclusions

Substantial progress has been made in the mCRPC space in the last several years. Optimal management of mCRPC patients is a growing challenge as more potential treatments are added to the armamentarium. Choosing the right treatment for the right patient, and the correct sequence and combination of the increasing number of available medications will be the main challenge in the years to come. We currently lack level one evidence regarding the proper sequence and/or combination of current available medications, and physicians are faced with making these decisions without supporting data. Patients will most likely benefit from unique medications with complementary mechanisms of action in order to avoid cross-resistance. An important unmet clinical need thus far consists of acquiring evidence about the efficacy, safety, and tolerability of combination regimens, and optimized approaches for identifying patients most suited for specific treatments.

Published Date: November 19th, 2019

Before the POUT Trial

The POUT Trial

Implications and Future Considerations Following the POUT Trial

The Opioid Crisis in Urology

The American Urological Association’s (AUA) Quality Improvement Summit on Opioid Stewardship in Urology

Non-Opioid Measures for Pain Control

Prospective Initiatives

Conclusions

Germline mutations in prostate cancer carcinogenesis

Physical Side Effects

Psychological Side Effects

Guideline Recommendations

Screening Measures

Conclusions

Neoadjuvant therapy

Adjuvant chemotherapy

Immunotherapy

Conclusions

Zoledronic acid

Early years: cytokine therapy

A new standard: molecularly targeted agents

What’s old is new: immunotherapy for RCC

The next frontier: combinations of targeted therapy and immunotherapy

Dead-ends

Integration of treatment options for patients with metastatic ccRCC

What about surgery?

Adjuvant targeted therapy

Lifestyle and nutrition-based interventions

Pharmacologic interventions

Pharmaceuticals - bisphosphonates

Pharmaceuticals - denosumab

Pharmaceuticals – radio-isotopes

Approach to preventing skeletal-related events

Radium-223

Role of Radiopharmaceuticals in the AUA Guideline

New directions

Prospective cohort studies

Retrospective cohort studies

Patient selection

Treatment recommendations

Conclusions

Localized Treatment – Optimizing Fractionation

Localized Disease – Optimizing Androgen Deprivation Therapy (ADT)

Localized Disease – Addition of Chemotherapy

Treatment after Radical Prostatectomy

Radiotherapy in the Setting of Metastatic Disease

Conclusions

Second-line treatment options for metastatic castrate-resistant prostate cancer

Third line treatment following treatment with docetaxel and one hormonal treatment for metastatic castrate-resistant prostate cancer

Changing and sequencing treatment in metastatic castrate-resistant prostate cancer

Radioligand therapy for metastatic castrate-resistant prostate cancer patients

Treatment and prevention of skeletal-related events

Future and ongoing trials

Conclusions

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