Articles

Nephrectomy in the Era of Targeted Therapy: Takeaways from the CARMENA Trial

A 62-year-old man presents with a one-week history of hematuria. Ultrasound and computed tomography identify a 7-cm exophytic anterior left renal tumor, adenopathy, and two
small lung nodules. No bone or central nervous system lesions are detected. His Eastern Cooperative Oncology Group (ECOG) performance-status (PS) and Memorial Sloan-Kettering Cancer Center (MSKCC) scores are 1. The patient asks whether to undergo cytoreductive nephrectomy. What do you tell him?

Spacers and Prostate Radiation Therapy: What Urologists Should Know

Radiation has been used to treat prostate cancer since the early 1900s.¹ In recent decades, advances in radiation delivery systems and the advent of computed tomography and magnetic resonance imaging have spurred the development of targeted, high-dose radiotherapy techniques such as intensity-modulated radiotherapy (IMRT), image-guided radiation therapy (IGRT), stereotactic radiation therapies, proton beam radiation therapy, and high-dose rate (HDR) brachytherapy.^2,3,4,5 These modalities have significantly improved biochemical disease-free survival in patients with localized prostate cancer and have added to the armamentarium of interventional localized prostate cancer options.⁶

Nonetheless, improved and extended long-term survival following prostate radiotherapy raises the concern of late-onset radiation-induced toxicity.⁷ Sequelae such as chronic diarrhea, rectal stricture, tenesmus, rectal bleeding, urinary obstruction, urgency, incontinence, and sexual dysfunction may seriously undermine a patient’s quality of life and also contribute substantially to healthcare costs.^8,9,10,11

These toxicities are still encountered despite our ability to render more precise radiotherapies such as IMRT and IGRT.⁵ In a meta-analysis of five randomized trials, every 8 to 10-Gy increase in radiation dose to the prostate approximately doubled the odds of severe late-onset gastrointestinal or genitourinary toxicities and led to a 63% increase in the likelihood of more moderate toxicities.⁷ In other recent trials of prostate radiotherapy, rates of late-onset grade 2 or worse toxicities were 14% to 25% for rectal sequelae and 12% to 46% for genitourinary sequelae.^4,12,13,14

PROTECTING THE ORGAN AT RISK

The rectum is the radiation dose-limiting anatomical structure within the pelvis because of its fixed position immediately adjacent to the prostate.^5,6,15 Indeed, some studies suggest that as many as 75% of patients who undergo prostate radiotherapy develop acute proctitis, and some 20% develop chronic symptoms.¹⁵ These risks further increase in the presence of conditions that predispose patients to vascular injury and ischemia, such as smoking, hypertension, diabetes, and atherosclerosis.¹⁵ Studies using three-dimensional imaging show a strong correlation between rates of late rectal bleeding after prostate radiotherapy and the volume of rectal tissue receiving more than 70 Gy radiation.^6,16,17 More moderate radiation doses (40 to 50 Gy) also can lead to substantial late-onset gastrointestinal toxicities if a larger surface area of the rectum is exposed.⁶

Given these findings, investigators have tested various strategies for shielding the organ at risk (OAR), the rectum, during prostate radiotherapy. For example, endorectal balloons have been used to immobilize the prostate, and in some studies, they also appeared to reduce rectal irradiation during three-dimensional conformal radiotherapy (3DCRT).⁶ However, endorectal balloons showed no significant dose-sparing effect during IMRT, which in many settings has replaced 3DCRT for prostate radiotherapy.^6,18 In addition, an improperly placed endorectal balloon can potentially decrease the efficacy of radiotherapy.^6,19 In one real-world study, researchers reported an average placement error of 0.5 cm, enough to partially shift the prostate outside the planned radiation effective treatment area.¹⁹

More recent work has focused on administering transperineal injections of various materials into Denonvilliers’ space in order to shift the anterior rectal wall away from the prostate during radiotherapy.^20,21 Hyaluronic acid, blood patches, and collagen all have been tested; all were found to be well-tolerated, relatively easy to position under transrectal ultrasound guidance, and protective regarding rectal irradiation.^22,23,24,25 However, the deployment of these materials was not uniform. Untoward effects included the creation of too limited a perirectal space (buffer), material shift after placement, or too rapid biodegradation after deployment.^21,26

In contrast, studies of off-label injections of DuraSeal^® polyethylene glycol (PEG), a spinal sealant, showed excellent tolerability, ease of use, and significant rectal sparing during IMRT and low- and high-dose brachytherapy.^27,28

DEVELOPMENT OF SPACEOAR®

SpaceOAR® (Augmenix, Bedford, MA, USA) was developed as an absorbable perirectal spacer made of biodegradable PEG-based hydrogel that is injected transperineally between the prostate capsule and the rectum under transrectal ultrasound guidance.²⁹

In a multicenter single-arm phase II trial of 52 men with localized prostate cancer, CT simulation scans performed before and after placement of this spacer revealed decreases in rectal radiation that were consistent across investigative institutions.30 Significant rectal sparing was observed across a radiation treatment range of 10 to 75 Gy.30 The mean decrease in rV70 was 8.0% (standard deviation 4.2 %), and the median decrease was 7.8% (95% confidence interval, 0.3% to 19.5%).

In this phase II trial, initial and 12 month follow-up results demonstrated no grade 3-4 gastrointestinal toxicities and no grade 4 genitourinary toxicities, while only 2.1% of patients developed grade 3 genitourinary toxicities.³¹ At 12 months, gastrointestinal toxicities were uncommon (4.3%) and were always grade 1, with no cases of gastrointestinal ulcer, stricture, or necrosis.³¹ The incidence of late genitourinary toxicities was 17% for grade 1 events, 2.1% for grade 2 events, and 0% for grade 3 or worse events.³¹

PHASE III TRIAL

Based on the phase II results, researchers evaluated SpaceOAR in a 3-year, multicenter, randomized, controlled trial of 222 men with stage T1 or T2 prostate cancer (NCT01538628).³² After undergoing CT and MRI-based radiation treatment planning and fiducial marker placement, participants were randomly assigned on a 2:1 basis to the spacer or control (no spacer) arm. Men in the spacer arm had the hydrogel spacer placed under intravenous anesthesia. Patients in both arms then received another set of planning scans followed by dose-escalated (79.2 Gy) IMRT of the prostate (with or without the seminal vesicles) in 44 fractions.³²

The results of the phase III trial supported those from the phase II study. Spacer placement increased the perirectal space by a mean of 11.0 mm.³² In the spacer arm, 97.3% of men had at least a 25% decrease in average projected volume of rectal tissue receiving at least 70 Gy (rV70).32 Mean rectal v70 values were 3.3% after spacer placement versus 12.4% at baseline (P < .0001).³² Rates of acute rectal toxicities generally were similar between groups, but men who received the spacer reported significantly less acute rectal pain compared with controls (P = .02).³²

From 3 months onward, no patients in the spacer arm and 5.7% of controls developed grade 2 or worse rectal toxicities such as fecal incontinence, proctitis, or bleeding (P = .012).33 Rates of late-onset grade 1 or worse rectal toxicities also favored the spacer arm (2% vs. 9.2% in the control group; P = .028). Men who received the spacer also had a significantly lower rate of grade 1 or worse urinary incontinence (4% versus 15%; P = .046), although rates of grade 2 or worse urinary toxicity were identical (7%) between arms.³³

Secondary analyses of the phase III trial correlated SpaceOAR placement with significantly improved long-term patient-reported quality of life.³³ From 6 months onward, men who had received the spacer reported significantly better post-radiotherapy bowel quality of life compared with controls (P = .002), and the difference remained statistically significant at 3 years.³³ Additionally, 41% of controls reported long-term declines in bowel quality of life that met a predefined threshold for minimally important difference (MID), compared with only 14% of spacer recipients (P = .002). Men who received the spacer also reported significantly improved 3-year urinary quality of life versus controls (P < .05). Furthermore, 30% of controls reported declining urinary quality of life that met the MID threshold, versus only 17% of spacer recipients (P = .04).

Preliminary data also have correlated SpaceOAR placement with preserved sexual function after prostate radiotherapy.^5,34 In the phase III trial, the spacer reduced the average and maximum radiation doses to the penile bulb, as well as the volume of the penile bulb receiving 10 to 30 Gy (all P < .05).34 Most (59%) men in this trial had low baseline sexual function, scoring below 60 on the Expanded Prostate Cancer Index Composite (EPIC).³⁴ However, among men with adequate baseline sexual quality of life, those who received the spacer reported better sexual function at 3-year follow-up versus controls (mean EPIC scores, 57.7 vs. 44.6, respectively; P = .1). Furthermore, among baseline-potent men, 66.7% of spacer recipients retained erections sufficient for intercourse at 3 years compared with only 37.5% of controls (P = .046).

SpaceOAR placement in the phase III trial also demonstrated similar safety and tolerability as that seen in the phase II trial. The rate of successful spacer deployment in the pivotal trial was 99%, and nearly all investigators reported that placing the spacer was easy or very easy.³² There were no rectal perforations, serious bleeding events, or rectal infections in either study arm.

REAL-WORLD EXPERIENCE

In order to further characterize real-world experiences with SpaceOAR, a single-arm trial was prospectively conducted of 99 men with prostate cancer who received the spacer at 16 urology group practices.³⁵ A total of 95% of cases were performed within the office-clinic setting, while 5% were performed at ambulatory surgery centers. The average postprocedural perirectal space created was 10.7 mm, and 80% of urologists described the procedure as easy or very easy, while the rest described it as moderately easy. Fully 94% of patients said the would recommend the SpaceOAR procedure to other patients. Furthermore, 97% of patients said that they were less anxious about their pending radiation therapy knowing that they had SpaceOAR in place during treatment.

Everyday Urology issue3 vol 3 SpaceOAR MRI images

Everyday Urology issue3 vol 3 SpaceOAR MRI images

Figure 1. SpaceOAR Clinical Trial Patient, MRI Images: Normal Anatomy, During Prostate RT and 6 months Following

Placing SpaceOAR is technically straightforward for urologists who are familiar with ultrasound-guided transperineal injections. The spacer can be deployed at the same time that fiducial markers are placed.

Patients are placed in a lithotomy position and may receive either conscious sedation, local anesthesia with oral anesthesia or general anesthesia.³⁶ Under stepper-mounted side-fire transrectal ultrasound guidance, 18-gauge needle is advanced through the perineal midline into the perirectal fat posterior to Denonvilliers’ fascia and anterior to the rectal wall. ³⁶

Proper placement of the transperineal needle within the midline of Denonvilliers’ space is key. It must be advanced at the prostate midline to prevent lateral injection of the hydrogel precursor and accelerator solutions.36 If the needle enters the rectal lumen at any time during injection, the procedure should be abandoned to prevent infection.³⁶

After confirming that the needle has been placed correctly, mid-gland hydrodissection with a sterile saline solution is performed to expand the space between Denonvilliers’ fascia and the anterior rectal wall. The needle is aspirated to confirm it is not intravascular. Then, without moving the needle, 10 ml of PEG hydrogel precursor and accelerator solutions are injected into the expanded perirectal space.³¹ These solutions polymerize within 10 seconds to form a soft hydrogel spacer approximately 1 cm in diameter.³⁶ The spacer persists for 3 months and is completely absorbed and cleared by renal filtration within 6 months.^30,36

In the phase III trial, SpaceOAR was placed under intravenous sedation.³² In my practice, I now use local anesthesia. I pre-medicate patients with an oral anxiolytic and wait 30 to 45 minutes before injecting any perineal local anesthetic. Next, I perform a perineal subcutaneous block, fan out the anesthetic along the skin, and then perform a diffuse block around the prostatic apex. I avoid injecting anesthetic along the right or left lateral aspects of the prostate to avoid creating any ultrasound artifact. The learning curve for SpaceOAR is fairly rapid. Urologists who have experience with transperineal procedures and transrectal ultrasound should be very comfortable performing SpaceOAR insertions after just a few cases. Those who are comfortable with transrectal ultrasound, but not with transperineal needle placement, may consider using more anesthesia for their first few SpaceOAR cases in order to become comfortable with the technique. SpaceOAR procedures require a side-fire transrectal ultrasound probe and a stepper. A floor-mounted stepper is more mobile and may be preferable to a table-mounted or bedmounted stepper, but individual preferences will vary. Although a template grid often is useful for placing fiducial markers, it is not necessary and can impede proper angling of the needle when placing SpaceOAR.

REIMBURSEMENT AND TREATMENT PLANNING

Spacer placement can be performed in an outpatient setting or in a hospital surgery center. For patients with Medicare coverage, reimbursement is approved under CPT code 55874 (transperineal placement of biodegradable material, peri-prostatic single or multiple injections, including image guidance, when performed).³⁷ Reimbursement in clinic settings is favorable. As of 2018, the national Medicare reimbursement averages were $3,797.24 for physician office-based spacer placement and $3,706.03 for hospital outpatient procedures.³⁸

Based on this reimbursement rate, urologists whose practices purchased a side-fire transrectal ultrasound probe and stepper may achieve revenue neutrality after approximately 40 SpaceOAR cases.³⁵ Further efforts are underway to approve Medicare reimbursement of SpaceOAR placement in ambulatory surgery facilities.

Repeat imaging should occur about 5-10 days after placing the spacer to allow post-injection swelling to resolve.^39,40 This prevents overestimation of the prostate volume, which will presumably be coordinated by our radiation oncology colleague.

Some radiation oncologists elect to obtain a T2-weighted MRI and fuse to the repeat planning CT in order to better distinguish the hydrogel from the rectal wall.^39,40 The addition of MRI also helps confirm that the spacer was properly injected. It is not necessary to further monitor the spacer volume during radiotherapy in the pivotal multicenter trial, the spacer consistently retained a stable volume for 3 months after placement.³⁹

TOXICITIES AND CAUTIONS

SpaceOAR has been well tolerated in studies to date. There have been no reports of local irritation or allergic reactions. However, several contraindications should be considered. First, use of SpaceOAR is not recommended for locally advanced prostate cancer because it may not be possible to create an effective perirectal space, and also because a transperineal needle could potentially disseminate tumor cells within the pelvis.³⁹ Men who have previously undergone high-intensity focused ultrasound, cryotherapy, or radiotherapy of the prostate may have adhesions that could impede the injection of SpaceOAR.³⁹ SpaceOAR also is contraindicated for patients with clinically significant coagulopathies or active bleeding disorders. For other patients on anticoagulants, it may be possible to discontinue anticoagulants temporarily for the purpose of SpaceOAR placement.³⁹ Finally, SpaceOAR may not be appropriate for patients with prostatitis or anorectal inflammatory diseases for which there is increased risk of ulceration, fistula, or bleeding, such as ulcerative colitis or Crohn’s disease.³⁹

Although transient perineal discomfort has been reported, there have been no reports of rectal perforation, rectal infection, or serious rectal bleeding after placing SpaceOAR.³⁹ However, there has been a single report of a necrotic 1-cm rectal ulcer occurring 2 months after a patient underwent SpaceOAR placement prior to I-125 prostate brachytherapy.⁴¹ This was the first case of rectal ulceration that the reporting physicians had observed in 55 SpaceOAR procedures.⁴¹ The patient and physicians closely monitored the ulcer, and sigmoidoscopy showed complete resolution 3 months after the SpaceOAR procedure.⁴¹

After reviewing the case, the physicians reported that SpaceOAR had been placed under sterile conditions with routine antibiotic prophylaxis consisting of perioperative intravenous cephazolin plus 5 days of postprocedural norfloxacin (400 mg twice daily).⁴¹ The only unusual aspect of this case was that the hydrogel had solidified prematurely within the SpaceOAR delivery system, requiring the system to be replaced mid-procedure.⁴¹ The physicians concluded that mechanical injury might have been the cause of this ulcer. Since then, these physicians have begun tilting patient beds “head up” before inserting SpaceOAR to reduce downward angling of the needle and premature leaking of the precursor and accelerator solutions.⁴¹ This is an appropriate precaution to consider. These physicians also remove the brachytherapy template to improve maneuverability of the SpaceOAR needle, advance the needle with the bevel away from the rectum to avoid perforation, take care to reduce pressure of the transrectal ultrasound probe against the anterior rectal wall, hydrodissect with normal saline to expand the perirectal space, inject no more than 10 mL of the precursor and accelerator solutions, and stop if they encounter resistance.⁴¹

FUTURE DIRECTIONS

Research continues to evaluate the safety and efficacy of SpaceOAR across a range of prostate radiotherapies. One such modality is stereotactic ablative radiotherapy, an emerging external beam technique that delivers fewer but larger radiation fractions to the tumor target over an abbreviated treatment schedule.⁴²

Earlier this year, oncologists in Ireland reported their experience with the first six participants in a clinical trial of SpaceOAR placement prior to stereotactic ablative radiotherapy.⁴³ All spacers were placed successfully, the only acute toxicity was grade 1 proctitis, spacer placement did not significantly alter clinical target volume dose coverage, and rectal irradiation dropped substantially: for example, by at least 42% for the volume of rectum receiving 36 Gy radiation.⁴³ Furthermore, the probability of grade 2 or worse rectal bleeding fell from 4.9% to 0.8% (P = .03).⁴³

Unfortunately, late-onset rectal ulceration is common after patients undergo stereotactic ablative radiotherapy. To understand whether placing a hydrogel spacer can meaningfully reduce this risk, a phase II trial (NCT02353832) at the University of Texas Southwestern Medical Center has enrolled 44 patients with low-risk prostate cancer. Planned follow-up time is 5 years, and secondary outcome measures include acute toxicities, at least a 50% reduction in the circumference of rectum receiving 24 and 39 Gy radiation, and the stability of the spacer during treatment.

Additionally, a post-marketing surveillance trial (NCT01999660) in Germany is recruiting an estimated 250 patients with T1 to T2, N0, M0 prostate cancer. The primary endpoint is late rectal complications for up to 5 years after IMRT, 3DCRT, or brachytherapy. The secondary outcome is quality of life based on the EPIC questionnaire in combination with the Short Form Health Survey (SF-12). The investigators also are evaluating the immediate feasibility and safety of hydrogel injection. Primary results are expected in January 2019. The results of this study will help clarify the effects of SpaceOAR placement on late toxicities and quality of life across a range of radiotherapy modalities for prostate cancer.

SUMMARY

Injecting a transperineal spacer prior to radiotherapy can help prevent rectal adverse events by protecting the organ at risk (OAR) from radiation toxicity. Currently, the only FDA-approved prostate cancer spacing device available for use in the United States is SpaceOAR, a polyethylene glycol (PEG) hydrogel spacer. In clinical trials, SpaceOAR placement significantly reduced irradiation of the rectum and penis during prostate radiotherapy. Long-term follow-up of the pivotal phase III trial also showed significant reductions in late gastrointestinal and genitourinary toxicities, with corresponding improvements in bowel, urinary, and sexual quality of life.^{5, 32, 33,34} The spacer is well tolerated, inserting it is straightforward, and the risk of postprocedural adverse events is low. It is becoming an important component of prostate radiotherapy. Additional studies of hydrogel spacers are ongoing. Urologists and radiation oncologists can work in tandem in order to further benefit prostate cancer patients who elect to proceed with radiation therapy.

Written By: Neal Shore, MD, FACS

References:
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4. Wortel RC, Incrocci L, Pos FJ, et al. Late side effects after image guided intensity modulated radiation therapy compared to 3D-conformal radiation therapy for prostate cancer: results from 2 prospective cohorts. Int J Radiat Oncol Biol Phys 2016 Jun;95(2):680-689
5. Karsh LI, Gross ET, Pieczonka CM, et al. Absorbable hydrogel spacer use in prostate radiotherapy: a comprehensive review of phase 3 clinical trial published data. Urology 2018 May;115:39-44.
6. Serrano NA, Kalman NS, Anscher MS. Reducing rectal injury in men receiving prostate cancer radiation therapy: current perspectives. Cancer Manag Res 2017 Jul;9:339-350.
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9. Thor M, Olsson CE, Oh JH, et al. Radiation dose to the penile structures and patient-reported sexual dysfunction in long-term prostate cancer survivors. J Sex Med 2015 Dec;12(12):2388-2397.
10. Redmond EJ, Dolbec KS, Fawaz AS, et al. Hospital burden of long-term genitourinary and gastrointestinal toxicity after radical radiotherapy for prostate cancer. Surgeon 2018 Jun;16(3):171-175.
11. Budäus L, Bolla M, Bossi A, et al. Functional outcomes and complications following radiation therapy for prostate cancer: a critical analysis of the literature. Eur Urol 2012 Jan;61(1):112-127.
12. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol 2017 Jun;35(17):1884-1890.
13. Dearnaley D, Syndikus I, Mossop H, et al; CHHiP Investigators. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2016 Aug;17(8):1047-1060.
14. Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol 2016 Apr;17(4):464-474.
15. Grodsky MB, Sidani SM. Radiation proctopathy. Clin Colon Rectal Surg 2015 Jun;28(2):103-111. 16. Vargas C, Martinez A, Kestin LL, et al. Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys 2005 Aug;62(5):1297-1308.
17. Huang EH, Pollack A, Levy L, et al. Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2002 Dec;54(5):1314-1321.
18. Van Lin EN, Hoffmann AL, van Kollenburg P, et al. Rectal wall sparing effect of three different endorectal balloons in 3D conformal and IMRT prostate radiotherapy. Int J Radiat Oncol Biol Phys 2005 Oct 1;63(2):565-576.
19. Jones BL, Gan G, Kavanagh B, et al. Effect of endorectal balloon positioning errors on target deformation and dosimetric quality during prostate SBRT. Phys Med Biol 2013 Nov;58(22):7995-8006.
20. Nicolae A, Davidson M, Easton H, et al. Clinical evaluation of an endorectal immobilization system for use in prostate hypofractionated Stereotactic Ablative Body Radiotherapy (SABR). Radiat Oncol 2015 May;10:122.
21. Hatiboglu G, Pinkawa M, Vallée JP, et al. Application technique: placement of a prostate-rectum spacer in men undergoing prostate radiation therapy. BJU Int 2012 Dec;110(11 Pt B):E647-52.
22. Prada PJ, Fernández J, Martinez AA, et al. Transperineal injection of hyaluronic acid in anterior perirectal fat to decrease rectal toxicity from radiation delivered with intensity modulated brachytherapy or EBRT for prostate cancer patients. Int J Radiat Oncol Biol Phys 2007 Sep;69(1):95-102.
23. Noyes WR, Hosford CC, Schultz SE. Human collagen injections to reduce rectal dose during radiotherapy. Int J Radiat Oncol Biol Phys 2012 Apr;82(5):1918-1922.
24. Morancy TJ, Winkfield KM, Karasiewicz CA, et al. Use of a blood-patch technique to reduce rectal dose during cesium-131 prostate brachytherapy. Int J Radiat Oncol Biol Phys 2008 Sep;72(1):S331-S332.
25. Melchert C, Gez E, Bohlen G, et al. Interstitial biodegradable balloon for reduced rectal dose during prostate radiotherapy: results of a virtual planning investigation based on the pre- and post-implant imaging data of an international multicenter study. Radiother Oncol. 2013 Feb;106(2):210-214.
26. Tang Q, Zhao F, Yu X, et al. The role of radioprotective spacers in clinical practice: a review. Quant Imaging Med Surg. 2018 Jun;8(5):514-524.
27. Heikkilä VP, Kärnä A, Vaarala MH. DuraSeal as a spacer to reduce rectal doses in low-dose rate brachytherapy for prostate cancer. Radiother Oncol 2014 Aug;112(2):233-236.
28. Strom TJ, Wilder RB, Fernandez DC, et al. A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate rachytherapy±intensity modulated radiation therapy. Radiother Oncol. 2014 Apr;111(1):126-131.
29. FDA. De Novo Classification Request for SpaceOAR System: Decision Summary. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN140030.pdf Accessed August 15, 2018.
30. Song DY, Herfarth KK, Uhl M, et al. A multi-institutional clinical trial of rectal dose reduction via injected polyethylene-glycol hydrogel during intensity modulated radiation therapy for prostate cancer: analysis of dosimetric outcomes. Int J Radiat Oncol Biol Phys. 2013 Sep;87(1):81-87.
31. Uhl M, Herfarth K, Eble MJ, et al. Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial. Radiat Oncol 2014 Apr;9:96.
32. Mariados N, Sylvester J, Shah D, et al. Hydrogel spacer prospective multicenter randomized controlled pivotal trial: dosimetric and clinical effects of perirectal spacer application in men undergoing prostate image guided intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 2015 Aug;92(5):971-977.
33. Hamstra DA, Mariados N, Sylvester J, et al. Continued benefit to rectal separation for prostate radiation therapy: final results of a phase III trial. Int J Radiat Oncol Biol Phys 2017 Apr;97(5):976-985.
34. Hamstra DA, Mariados N, Sylvester J, et al. Sexual quality of life following prostate intensity modulated radiation therapy (IMRT) with a rectal/prostate spacer: Secondary analysis of a phase 3 trial. Pract Radiat Oncol. 2018 Jan - Feb;8(1):e7-e15. doi: 10.1016/j.prro.2017.07.008. Epub 2017 Jul 19.
35. Urology Times. What every urologist needs to know about SpaceOAR hydrogel: how Augmenix is improving QOL for prostate cancer patients.
legacy/mm/digital/media/ut0718_ezine.pdf Accessed August 18, 2018.
36. SpaceOAR® System: Instructions for Use. http://www.spaceoar.com/assets/lcn-80-2101-001-rev-a_spaceoar-system-10ml-ifu-us.pdf Accessed August 16, 2018.
37. American Medical Association, Current Procedural Terminology, CPT®, Professional Edition, 2018.
38. Augmentix. 2018 SpaceOAR coding and payment quick reference guide. https://www.spaceoar.com/assets/AUG-148-Payment-and-Coding-Sheet_final.pdf Accessed August 17, 2018.
39. Müller AC, Mischinger J, Klotz T, et al. Interdisciplinary consensus statement on indication and application of a hydrogel spacer for prostate radiotherapy based on experience in more than 250 patients. Radiol Oncol 2016 Sep; 50(3): 329-336.
40. Fischer-Valuck BW, Chundury A, Gay H, et al. Hydrogel spacer distribution within the perirectal space in patients undergoing radiotherapy for prostate cancer: Impact of spacer symmetry on rectal dose reduction and the clinical consequences of hydrogel infiltration into the rectal wall. Pract Radiat Oncol. 217 May-Jun;7(3):195-202.
41. Teh AY, Ko HT, Barr G, et al. Rectal ulcer associated with SpaceOAR hydrogel insertion during prostate brachytherapy. BMJ Case Rep 2014 Dec;2014. pii: bcr2014206931.
42. Mantz C. A phase II trial of stereotactic ablative body radiotherapy for low-risk prostate cancer using a non-robotic linear accelerator and real-time target tracking: report of toxicity, quality of life, and disease control outcomes with 5-year minimum follow-up. Front Oncol 2014 Nov;4:279.
43. King RB, Osman SO, Fairmichael C, et al. Efficacy of a rectal spacer with prostate SABR-first UK experience. Br J Radiol. 2018 Feb;91(1083):20170672.

Blue Light Cystoscopy: Insights on Recurrence, Progression, and Clinical Management

More than 81,000 individuals are diagnosed with bladder cancer in the United States every year, of whom 75% have non-muscle invasive disease.^1,2 Unfortunately, half these cases recur despite transurethral resection of bladder tumor (TURBT), and from 5% to 25% of repeated recurrences progress to muscle-invasive disease.^3,4,5

Reliable visualization of bladder tumors is crucial to the success of TURBT, but carcinoma in situ (CIS) and other low-grade flat lesions are difficult to detect under standard white light cystoscopy. ^6,7,8 In a recent meta-analysis of raw data from six prospective studies, white light cystoscopy missed 24.9% of Ta and T1 tumors and 26.7% of CIS tumors.⁹ Other studies have associated white light cystoscopy with miss rates of 10% to 45%, depending on patient subgroups.¹⁰

Evidence consistently indicates that the addition of blue light cystoscopy to white light cystoscopy improves the detection and resection of non-muscle invasive bladder malignancies over white light cystoscopy alone.^11,12 Blue light cystoscopy is used in conjunction with a photoactive porphyrin, either 5-aminolevulinic acid (ALA) or hexaminolevulinate hydrochloride (HAL), which accrues preferentially in neoplastic tissue and fluoresces when exposed to blue light between 375 and 440 nm in wavelength.^13,14 In a large real-world study, HAL-assisted blue light cystoscopy detected bladder carcinoma in situ (CIS) with a sensitivity of 75%, compared with 52.8% for white light cystoscopy (P=.02).¹² In the previously cited meta-analysis of raw data, HAL-assisted blue light cystoscopy detected significantly more Ta tumors and CIS lesions compared with white light alone (P < .001 for each comparison).⁹ Importantly, this result spanned subgroups of intermediate and high-risk patients and patients with both primary and recurrent tumors.⁹

Based on such findings, joint guidelines from the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) now recommend offering blue light cystoscopy to all patients with non-muscle invasive bladder cancer and considering blue light cystoscopy for patients with a history of non-muscle invasive bladder cancer and positive cytology.¹⁵

It is important to emphasize that blue light cystoscopy should be used in conjunction with white light cystoscopy, not as a replacement. In a multicenter study of 311 patients with known or suspected bladder cancer, HAL-assisted blue light cystoscopy missed 9% of tumors visualized by white light cystoscopy, including 5% of T1 tumors.16 In the same study, HAL-assisted blue light cystoscopy detected at least one additional tumor compared with white light cystoscopy in 29% of patients and detected at least one additional T1 tumor in 15% of patients.¹⁶ Thus, both white light and blue light must be used in the same patient to obtain maximum benefit.

Hexaminolevulinate was approved by the U.S. Food and Drug Administration (FDA) in 2010 for the cystoscopic detection of non-muscle invasive bladder cancer in patients with known or suspected lesions based on prior cystoscopy.¹⁷ Because the procedure has required a rigid cystoscope, it generally has been performed under anesthesia.

However, in February 2018, the FDA approved a supplemental new drug application for the use of a HAL in conjunction with a flexible cystoscope, the Karl Storz D-Light C Photodynamic Diagnostic system.^17,18 This approval effectively expanded the use of blue light cystoscopy into outpatient settings. Understanding the advantages and caveats of blue light cystoscopy can help us better care for our hospitalized patients and outpatients with suspected or confirmed bladder cancer.

BLUE LIGHT CYSTOSCOPY REDUCES RISK OF RECURRENCEv
Blue light cystoscopy has been used for approximately 20 years in Europe, and multiple studies there have associated this enhanced technique with significantly prolonged recurrence-free survival that is potentially maintained for years following TURBT.

In one such randomized study, 115 patients with non-muscle invasive bladder cancer underwent TURBT with either conventional white light cystoscopy or ALA-assisted blue light cystoscopy.¹⁹ Cancer recurred after a median of 5 months in the white-light group compared with 12 months in the ALA blue light group.¹⁹ After 36 months, rates of recurrence were 73% in the white-light group versus 59% in the blue-light group.¹⁹ Centers elsewhere in Europe reported similar results. In a single-center randomized trial in Romania, blue light cystoscopy identified 25.8% more non-muscle invasive bladder tumors than did white light cystoscopy, leading to a 27% reduction in the rate of 12-month recurrence.²⁰

Particularly compelling are the results of a phase III, randomized, prospective study of 814 patients in Germany with suspected bladder cancer at increased risk for recurrence.⁶ All patients underwent white light cystoscopy and TURBT with or without intravesical HAL-assisted blue light cystoscopy before and after resection.⁶ Among 286 patients with at least one Ta or T1 bladder tumor detected, blue light cystoscopy was associated with a 16% decrease in recurrence at 9 months.⁶ This effect persisted at a median of 54 months of follow-up, when 38% of patients in the blue light group remained tumor-free versus 31.8% of the white light group (median time to recurrence, 16.4 months vs. 9.6 months, respectively; P = .04).²¹ Furthermore, there was a trend toward a decreased risk of cystectomy in the blue light group.

The meta-analysis of raw data also linked HAL-assisted blue light cystoscopy and resection with a 24% lower risk of recurrence at 12 months compared with white light cystoscopy alone (risk ratio, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P = .006).⁹ In a separate single-center prospective study, researchers in the United Kingdom evaluated the effects of switching from standard white light cystoscopy to white light plus HAL-assisted blue light cystoscopy.²² A total of 345 patients with non-muscle invasive bladder cancer underwent one of these modalities in conjunction with high-quality TURBT, followed by intravesical mitomycin C administered within 24 hours post-surgery.²² One-year rates of recurrence were 38.9% when the hospital used only white light cystoscopy versus 21.5% after the addition of blue light cystoscopy (P < .001). This finding spanned risk-based subgroups and patients matched by age, multifocality, length of follow-up, and tumor grade, stage, and size. Furthermore, the reduction in risk of recurrence remained statistically significant at 3-year follow-up (39.0% vs. 53.3%, respectively; P=.02) (P < .001).²²

Several other studies have compared longer-term rates of recurrence between blue light and white light cystoscopy. In a single-center medical database analysis of 159 cases of recurrent non-muscle invasive bladder cancer treated by a single surgeon performing TURBT, 44 cases involved HAL-assisted blue light cystoscopy and 115 cases were performed with white light cystoscopy alone.²³ In the multivariate analysis, blue light cystoscopy was associated with a significant reduction in 3-year risk of recurrence (adjusted hazard ratio, 0.42; 95% CI, 0.25 to 0.70; P = .001).²³ Three years after TURBT, 53.7% of blue light patients remained recurrence-free versus 27.4% of white light patients.²³

Looking beyond TURBT, blue light cystoscopy also is useful for the surveillance of patients who are considered at high risk for bladder cancer recurrence. In a multicenter phase III study, 304 such patients received intravesical HAL (Hexvix® or Cysview®) and white light flexible cystoscopy, after which they were randomly assigned to undergo either blue light flexible cystoscopy or no additional evaluation.⁸ Among 63 patients with confirmed recurrent malignancies, 20.6% (95% CI, 11.5% to 32.7%) were detected only by blue light cystoscopy.

BLUE LIGHT CYSTOSCOPY AND PROGRESSION
Disease progression is one of the most important clinical sequelae of non-muscle invasive bladder cancer, as it signifies worsening of disease and is an independent predictor of cancer-related mortality. ^24,25,26,27 The effects of blue light cystoscopy on progression are less clear; early studies documented reductions in recurrence that did not appear to translate to an impact progression. ^28,29 For example, in a prospective, randomized, double-blind study, 370 patients with non-muscle invasive bladder cancer received either intravesical 5-ALA or placebo before undergoing cystoscopy under white and blue light.²⁹ Twelve months after tumor resection, rates of progression-free survival were identical (89%) between study arms.

In another 12-month, randomized, multicenter trial, 5-ALAassisted blue light cystoscopy detected more lesions than white light cystoscopy alone but did not confer significant improvements in progression-free survival.³⁰

These results reflect at least two shortcomings in research on cystoscopy and progression. The first is the indolent nature of some early-stage bladder tumors; they may recur and progress over years, rather than months. We need longer-term prospective studies to assess the effects of enhanced tumor detection on the progression of non-muscle invasive bladder cancer.

The second limitation is that older studies tended to define progression inconsistently, imprecisely, and often too strictly to detect clinically important events. It has been only four years since the International Bladder Cancer Group (IBCG) called for a uniform, more sensitive definition of progression in order to facilitate earlier-stage diagnosis as well as cross-study comparisons.³¹ In this paper, the IBCG suggested defining progression as any one of the following: an increase in T stage leading to invasion of the lamina propria (T1 disease), the development of muscle-invasive disease (stage T2 or greater), progression to lymph node (N+) or distant metastasis (M1), or an increase in grade from low to high.³¹
Based on this new definition, does the addition of blue light cystoscopy to standard white light cystoscopy appear to affect progression? In the phase III study in Germany, which was published prior to the proposed IBCG definition, researchers defined progression as non-muscle-invasive tumors becoming muscle-invasive. Based on this definition, the researchers reported a non-significant trend toward lower risk of progression among patients who underwent HAL-assisted blue light cystoscopy instead of white light cystoscopy only.⁶ After 9 months, progression to muscle-invasive disease had occurred among nine patients in the white light group and seven patients in the blue light group. After a median of 4.5 years, eight and 16 patients, respectively, had progressed to stage T2-T4 disease.²¹

Recently, my colleagues and I re-analyzed the German data based on the IBCG definition.²⁴ We identified more progressors in both groups:³¹ (12.2%) patients in the blue-light group and 46 (17.6%) patients in the white-light group. Progression from Ta to CIS tumors occurred in four (1.6%) blue-light patients and 11 (4.2%) white-light patients.²⁴ The difference in rates of progression trended toward statistical significance, favoring the blue-light group (P = .085).24 Median time to progression also was longer in the blue light group (P = .05), possibly because of better detection and resection of earlier-stage disease.²⁴ Furthermore, blue light cystoscopy was associated with a trend toward improved progression-free survival (P=.05).²⁴

The authors of a recent systematic review and meta-analysis also concluded that the use of HAL-assisted blue light cystoscopy in combination with white light cystoscopy reduced the likelihood of progression following TURBT.³² This meta-analysis, which specifically focused on progression, included four randomized studies and one retrospective study published between 2000 and 2016. Among 1,301 patients who underwent TURBT, approximately half received blue light cystoscopy in addition to white light cystoscopy while the rest were evaluated with white light alone.³² After a median follow-up period of approximately 38 months, 10.7% of white-light patients had progressed, compared with only 6.8% of blue-light patients. As a result, the odds of progression were 64% higher among patients who underwent TURBT without blue light cystoscopy (median odds ratio, 1.64, 95% CI, 1.10 to 2.45; P=.01).³²

In summary, while more research is needed, we have limited data suggesting that blue light cystoscopy can delay progression by facilitating earlier detection and resection of bladder tumors.

IMPACT ON PATIENT MANAGEMENT
vSeveral studies also indicate that improved detection of bladder tumors with blue light cystoscopy leads to important improvements in management, including the use of intravesical therapy, earlier cystectomy, and closer surveillance.

In one prospective, randomized study of 362 patients with suspected non-muscle invasive bladder cancer, the use of HALassisted blue light cystoscopy detected more tumors in 35% of patients compared with white light cystoscopy alone.³³ Respective rates of recurrence were 7.2% versus 15.8% at 3 months, 21.6% versus 32.5% at 1 year, and 31.2% versus 45.6% at 2 years.³³ Although progression rates at 1 and 2 years did not significantly differ (2.4% vs. 4.4%; P=.2, and 4% vs. 7%, respectively; P=.12), the study authors reported that by detecting additional lesions, blue light cystoscopy led to meaningful changes in treatment, such as the use of intravesical BCG or chemotherapy instead of forgoing postoperative therapy.³³

In another randomized study of 146 patients, an independently blinded urologist reviewed two sets of records, one of which only described the results of white light cystoscopy and the other of which also included the results of HAL-assisted blue light cystoscopy.¹¹ The addition of blue light cystoscopy findings improved the management of 21.7% of patients, including more extensive resections in 10 patients and additional postoperative procedures in 15 patients.¹¹ In a third small study of 39 patients, 38% had additional papillary and flat lesions detected by HAL-assisted blue light cystoscopy.34 The use of blue light cystoscopy led to changes in management, including the use of BCG instead of mitomycin C, in 13% of patients.³⁴

Everyday Urology issue3 vol 3 blue light cystoscopy

Everyday Urology issue3 vol 3 blue light cystoscopy

Table 1. Blue light cystoscopy: Randomized controlled trials
BC: bladder cancer
CIS: carcinoma in situ
HAL-BLC: hexaminolevulinate blue light cystoscopy
IBCG: International Bladder Cancer Group
NMIBC: non-muscle invasive bladder cancer
PDD: photodynamic diagnosis
WLC: white light cystoscopy

Blue light cystoscopy also is useful after TURBT to confirm treatment efficacy. By improving the accuracy of post-TURBT assessments, blue light cystoscopy can spare patients the pain, risks, and cost of unnecessary treatment.³⁵ This is because residual tumor that persists after TURBT and instillation therapy can be misinterpreted as treatment failure, leading to more radical treatment.³⁵

SAFETY AND QUALITY OF LIFE
Blue light cystoscopy generally is well tolerated.^17,36 The main cause of adverse events is catheterization. In randomized trials of fluorescence cystoscopy and TURBT with up to 2 years of follow-up, the most common adverse events were hematuria, dysuria, and bladder spasm, which were equally likely with blue and white light cystoscopy and were concluded to be related to resection.³⁶ In another study of post-marketing data from more than 200,000 patients, there were no serious adverse events definitively attributed to HAL-assisted blue light cystoscopy and its repeated use did not appear to increase the risk of toxicities.³⁷

Earlier and more accurate detection of non-muscle invasive disease can reduce and delay the need for more invasive procedures, such as repeat TURBT and cystectomy. As a result, several studies have found that the use of blue light cystoscopy led to significant reductions in health care costs and improvements in patient quality of life.^38,39,40 Perhaps the most robust of these studies was a prospective, multicenter, phase III trial published in July 2018.⁴¹ For the study, researchers used HAL-assisted blue light flexible cystoscopy for the office-based surveillance of non-muscle invasive bladder cancer in patients at high risk of recurrence.⁴¹

Among 304 enrolled patients, 103 individuals were referred for surgical examination, and 63 had histologically confirmed malignancies.⁴¹ After patients underwent blue light cystoscopy, their scores on the anxiety instrument of the Patient-Reported Outcomes Measurement Information System (PROMIS) decreased by 2.6 points, an effect that was independent of patient gender, test performance, or cystoscopy result.⁴¹ Furthermore, 94% of patients reported that blue light cystoscopy was worthwhile and that they would undergo it again, while 91% stated that they would recommend blue light cystoscopy to other patients.⁴¹ Finally, three-quarters of patients said that they would be willing to pay for blue light cystoscopy out-of-pocket.⁴¹ These findings suggest that blue light cystoscopy is acceptable to and valued by high-risk patients in outpatient settings.

ALTERNATIVES TO BLUE LIGHT CYSTOSCOPY
Fluorescence is not our only available option for enhanced cystoscopy. An alternative is narrow band imaging (NBI), a technology that excludes the red spectrum of light in order to increase the contrast between mucosal vasculature and superficial tissue structures of the bladder.⁴² Narrowband imaging does not require instillation of agents into the bladder, and the technology is already present on many cystoscopes used in clinics and hospitals.

Several studies have found that narrow band imaging detected CIS and other non-muscle invasive bladder tumors with greater sensitivity than white light cystoscopy alone.^42,43 In a randomized prospective trial, rates of 1-year post-TURBT recurrence rates were approximately 33% with narrow band imaging versus 51% with white light cystoscopy alone (P = .01).⁴⁴

In another recent meta-analysis of 25 studies, narrow band imaging detected lesions in 10% more patients (95% CI, 5% to 14%) than white light cystoscopy and detected 19% more lesions per patient (95% CI, 15% to 25%).⁴³ Narrow band imaging also was associated with a significantly reduced rate of recurrence compared with white light cystoscopy. Pooled risk ratios were 0.43 (95% CI, 0.23 to 0.79) at 3 months and 0.81 (95% CI, 0.69 to 0.95) at 12 months.⁴³

In another network meta-analysis of 15 randomized controlled trials, narrow band imaging and blue light cystoscopy were associated with a statistically similar risk of recurrence after TURBT (OR = 1.11, 95% CI, 0.55 to 2.1), and both modalities significantly outperformed white light cystoscopy alone.⁴² To date, however, we have no randomized head-to-head studies of blue light cystoscopy versus narrow band imaging in the setting of either resection or surveillance.

SUMMARY
Enhanced cystoscopy techniques are an essential addition to our armamentarium for the detection and treatment of bladder cancer. Two recently developed technologies are currently in clinical use – narrow band imaging (NBI) and blue light cystoscopy. Among the two, blue light cystoscopy has been studied more extensively and has been shown to significantly improve the detection of initial and recurrent non-muscle invasive bladder tumors, particularly CIS and other low-grade flat lesions that are difficult to detect with white light cystoscopy alone. Results from multiple studies indicate that blue light cystoscopy significantly improves recurrence-free survival and also is useful to confirm the efficacy of TURBT and guide post-operative decision-making. Emerging data also suggest that improved tumor detection – and resection - with blue light cystoscopy reduces the risk of progression. However, it must be emphasized that blue light cystoscopy is not a stand-alone technique and must be performed in conjunction with white light cystoscopy.

Written By: Ashish M. Kamat, MD, MBBS

References:
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3. Canter DJ, Revenig LM, Smith ZL, et al. Re-examination of the natural history of high-grade T1 bladder cancer using a large contemporary cohort. Int Braz J Urol 2014 Mar-Apr;40(2):172-178.
4. Cookson MS, Chang SS, Oefelein MG, Gallagher JR, Schwartz B, Heap K. National practice patterns for immediate postoperative instillation of chemotherapy in nonmuscle invasive bladder cancer. J Urol 2012 May;187(5):1571-1576.
5. Rieken M, Xylinas E, Kluth L, et al. Long-term cancer-specific outcomes of TaG1 urothelial carcinoma of the bladder. Eur Urol 2014 Jan;65(1):201-209.
6. Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol 2010 Nov;184(5):1907-1913.
7. Pagliarulo V, Alba S, Gallone MF, et al. Diagnostic accuracy of hexaminolevulinate in a cohort of patients undergoing radical cystectomy. J Endourol 2017 Apr;31(4):405-411.
8. Daneshmand S, Patel S, Lotan Y, et al. Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase III, comparative, multicenter study. J Urol. 2018 May;199(5):1158-1165.
9. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 2013 Nov;64(5):846-854.
10. Elferink PO, Witjes JA. Blue-light cystoscopy in the evaluation of non-muscle-invasive bladder cancer. Ther Adv Urol 2014 Feb;6(1):25-33.
11. Jocham D, Witjes F, Wagner S, et al. Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol. 2005 Sep;174(3):862- 866; discussion 866.
12. Palou J, Hernández C, Solsona E, et al. Effectiveness of hexaminolevulinate fluorescence cystoscopy for the diagnosis of non-muscle-invasive bladder cancer in daily clinical practice: a Spanish multicentre observational study. BJU Int. 2015 Jul;116(1):37-43.
13. Krieg RC, Messmann H, Rauch J, et al. Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells. J Photochem Photobiol 2002 Nov;76(5):518-525.
14. Kennedy JC, Pottier RH and Pross DC, et al. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990 Jun;6(1-2):143-148.
15. American Urological Association. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Joint Guideline. http://www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-(2016) Accessed August 22, 2018.
16. Grossman HB, Gomella L, Fradet Y, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol 2007 Jul;178(1):62-67.
17. Highlights of prescribing information. Cysview (hexaminolevulinate hydrochloride), for Intravesical Solution.
18. BusinessWire. KARL STORZ Announces New Non-Muscle Invasive Bladder Cancer DetectionSystem: Photodynamic Diagnosis (PDD) Blue Light Flexible Video Cystoscopy.
19. Daniltchenko DI, Riedl CR, Sachs MD, et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol. 2005 Dec;174(6):2129-2133.
20. Drăgoescu O, Tomescu P, Pănuş A, et al. Photodynamic diagnosis of non-muscle invasive bladder cancer using hexaminolevulinic acid. Rom J Morphol Embryol 2011 Jul;52(1):123-127.
21. Grossman HB, Stenzl A, Fradet Y, et al. Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol 2012 Jul;188(1):58-62.
22. Gallagher KM, Gray K, Anderson CH, et al. ‘Real-life experience’: recurrence rate at 3 years with Hexvix® photodynamic diagnosis-assisted TURBT compared with good quality white light TURBT in new NMIBC-a prospective controlled study. World J Urol 2017 Dec;35(12):1871-1877.
23. Downs TM, Rushmer TJ, Abel EJ, et al. Fluorescent (blue light) cystoscopy improved 3-year recurrence-free survival rates of recurrent bladder tumor patients. J Am Coll Surg 2017 Oct;225(4):S2(e50-e51).
24. Kamat AM, Cookson M, Witjes JA, et al. The impact of blue light cystoscopy with hexaminolevulinate (HAL) on progression of bladder cancer - a new analysis. Bl Cancer 2016 Apr;2(2):273-278.
25. Pellucchi F, Emilia R, Moschini M, et al. Progression of T1 high-risk into muscle-invasive bladder cancer is an independent prognostic factor of mortality after radical cystectomy. World J Urol 2014 May;191(4S)e685-e686.
26. Schrier BP, Hollander MP, van Rhijn BW, Kiemeney LA, et al. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumours and implications for therapy. Eur Urol 2004 Mar;45(3):292-296.
27. Breau RH, Karnes RJ, Farmer SA, et al. Progression to detrusor muscle invasion during urothelial carcinoma surveillance is associated with poor prognosis. BJU Int 2014 Jun;113(6):900-906.
28. Rink M, Babjuk M, Catto JW, et al. Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature. Eur Urol 2013 Oct;64(4):624-638.
29. Stenzl A, Penkoff H, Dajc-sommerer E, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial. Cancer 2011 Mar;117(5):938-947
30. Schumacher MC, Holmäng S, Davidsson T, et al. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. Eur Urol 2010 Feb;57(2):293-299.
31. Lamm D, Persad R, Brausi M, et al. Defining progression in nonmuscle invasive bladder cancer: it is time for a new, standard definition. J Urol 2014 Han;191(1):20-27.
32. Gakis G, Fahmy O. Systematic review and meta-analysis on the impact of hexaminolevulinate- versus white-light guided transurethral bladder tumor resection on progression in non-muscle invasive bladder cancer. Bladder Cancer 2016 Jul;2(3):293-300.
33. Geavlete B, Multescu R, Georgescu D, et al. Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU Int 2012 Feb;109(4):549-556.
34. Abascal Junquera JM, Hevia Suárez M, Abascal García JM, et al. Initial experience in the diagnosis and treatment of superficial bladder tumors with Hexvix. Arch Esp Urol 2008 May;61(4):475-482.
35. Witjes JA. Fluorescence cystoscopy in bladder cancer: the case pro. Eur Urol Supp 2008 Apr;7(5):426-429.
36. Yang LP. Hexaminolevulinate blue light cystoscopy: a review of its use in the diagnosis of bladder cancer. Mol Diagn Ther 2014 Feb;18(1):105-116.
37. Witjes JA, Gomella LG, Stenzl A, et al. Safety of hexaminolevulinate for blue light cystoscopy in bladder cancer. A combined analysis of the trials used for registration and postmarketing data. Urology 2014 Jul;84(1):122-126.
38. Dindyal S, Nitkunan T, Bunce CJ. The economic benefit of photodynamic diagnosis in non-muscle invasive bladder cancer. Photodiagnosis Photodyn Ther 2008 Jun;5(2):153-158.
39. Malmström PU, Hedelin H, Thomas YK, et al. Fluorescence-guided transurethral resection of bladder cancer using hexaminolevulinate: analysis of health economic impact in Sweden. Scand J Urol Nephrol 2009;43(3):192-198.
40. Wolfgang Otto, Maximilian Burger, Hans-Martin Fritsche, et al. Photodynamic diagnosis for superficial bladder cancer: do all risk-groups profit equally from oncological and economic long-term results? Clin Med Oncol 2009 Apr;3:53-58.
41. Smith AB, Daneshmand S, Patel S, et al. Patient-reported outcomes of blue-light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: results from a prospective multicentre study. BJU Int. 2018 Jul 6. [Epub ahead of print].
42. Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer 2015 Aug;15:566.
43. Xiong Y, Li J, Ma S, et al. A meta-analysis of narrow band imaging for the diagnosis and therapeutic outcome of non-muscle invasive bladder cancer. PLoS One 2017 Feb;12(2):e0170819.
44. Naselli A, Introini C, Timossi L, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence. Eur Urol 2012 May;61(5):908-13.

Immuno-oncology for Bladder Cancer

Initial Considerations
From BCG to interferon gene therapy, physicians have treated bladder cancer with immunotherapy for decades. Treatment particulars generally depend on whether bladder cancer is non-muscle invasive, muscle-invasive, or metastatic. About 75% of patients have non-muscle invasive bladder cancer (NMIBC),¹ which is considered high-risk if it consists of non-invasive papillary carcinoma (TaHG), carcinoma in situ (CIS), or T1 (minimally invasive) tumor of the lamina propria.^2,3 For high-risk NMIBC, multiple peer-reviewed trials and meta-analyses support 1-3 years of intravesical immunotherapy with bacillus Calmette-Guérin (BCG) to significantly lower the risk of recurrence,^4,5,6,7,8 progression, and death.^{^9,10,11}

Imaging Controversies for Localized and Advanced Prostate Cancer

Imaging in prostate cancer (PC) remains a controversial topic that can be challenging to navigate. In this article, I focus on some of the best tools in our current armamentarium: multiparametric prostate magnetic resonance imaging (mpMRI) for local prostate cancer (PC) and positron emission tomography-computed tomography (PET/CT) for advanced disease. In research settings, these modalities often overlap, but here I take a more practical approach by focusing on the use of PET/CT for the detection of metastatic disease.

Multiparametric Prostate MRI
The American Urological Association (AUA) recommends mpMRI for men whose prostate specific antigen (PSA) level rises following an initial negative standard prostate biopsy.^1,2 In the
future, targeted biopsy, using a combination of mpMRI and ultrasound guided transrectal or transperineal biopsy, will likely be the favored method of initial biopsy for patients whose PSA level is elevated or whose digital rectal examination is suspicious for PC.² It is also likely that mpMRI can benefit men with presumed localized PC before choosing a definitive therapy and to evaluate local recurrence.²Comparing imaging studies in PC is not easy – they areoften single-site studies and include heterogeneous populations. Nonetheless, a recent meta-analysis of seven studies showed that mpMRI detected PC with a specificity of 88% (95% confidence interval [CI], 82% to 92%) and a sensitivity of 74% (95% CI, 66% to 81%).³ The results held up across subgroups.³
This is reasonably encouraging, but how much is prostatic mpMRI used in practice? In a survey of 302 members of the Society of Urologic Oncology, the Endourological Society, and the European Association of Urology, 86% of respondents reported using prostate MRI and 63% said they used MR-targeted biopsy.⁴ Urologists were more likely to report using prostate MRI when they practiced in academic settings and performed more than 25 radical prostatectomies a year.⁴However, we must keep in mind that response bias is an inherent limitation of such surveys – physicians often do not respond, and respondents tend to be more interested and engaged in the topic than non-respondents.5 Illustrating this point is that in another national survey of 7,400 urologists, only 276 responded.⁶ Among respondents, users of mpMRI were more likely than nonusers to have completed oncology fellowships, to work in academic centers, and to perform more than 30 prostatectomies annually.6 Respondents also described problems with access, test accuracy, and cost.⁶ Strikingly, 74% of respondents said that mpMRI “rarely or never” changed their approach to treating intermediate or high-grade PC, while 62% said mpMRI was not helpful for evaluating patients with elevated PSA or an abnormal prostate exam prior to biopsy.⁶ In addition, only 34% of patients said that their practices used MRI-guided prostate biopsy.⁶
Results such as these reveal a discrepancy between perceptionand reality in prostatic mpMRI. It is a valuable tool, but work remains to surmount current barriers such as availability, interreader variability, and accuracy.

Availability and Access
Data suggest that mpMRI can be clinically and financially worthwhile if we deploy it for the right patient at the right time. In a recent modeling study of biopsy-naïve men with suspected PC, mpMRI followed by up to two transrectal ultrasound-guided biopsies was cost-effective and detected about 95% of clinically significant PCs.⁷ The current standard, initial transrectal ultrasound-guided biopsy, had only a 91% sensitivity.⁷ Also keep in mind that the cost of mpMRI will naturally decrease as it becomes more available. High-quality MRI scanners are plentiful in the United States, including 3T MRI. However, the availability of high-quality prostatic MRI remains limited. Thus, when we talk about lack of availability, we are really talking about availability of quality prostate MRI.

Pirads
We are making strides in terms of quality, especially with the development of the Prostate Imaging Reporting and Data System (PIRADS).⁸ Sponsored by the American College of Radiology, AdMeTech, and the European Society of Radiology, PIRADS establishes global guidelines for high-quality mpMRI of the prostate. The end goal is to improve detection, localization, characterization, and risk stratification in treatment-naïve men with suspected PC.⁹
To this end, PIRADS not only defines minimum technical requirements for image acquisition, but also sets standards for communicating the risk and location of aggressive PC. Lexicon is essential and central to radiology – how we communicate is key. Thus, the 64 pages of PIRADS version 2 provides a detailed, standardized algorithm for how radiologists should read prostate MRI based on the location of the abnormality, and a consistent, standardized MR reporting scheme.¹⁰Under the PIRADS system, each prostatic MRI report specifies lesion location, appearance on different sequences, and its PI-RADS score as well as the patient’s most recent PSA level and previous biopsy and MR results. This approach facilitates comparisons between MR reports and biopsy results and also facilitates better longitudinal and multicenter studies. Its complexity makes it clear that prostate MRI should be read by an experienced subspecialized radiologist.

Moreover, quality improvement measures in mammography provided the precedent for PIRADS. In 1994, the United States enacted the Mammography Quality Standards Act and Program (MQSA) to help ensure high-quality breast imaging for women.¹¹ The federally mandated Breast Imaging Reporting and Data System (BIRADS) aimed to reduce inter-operator variability and standardize the lexicon to help make interpretation more decisive and less confusing.^12,13
With PIRADS, we’re trying to follow this example to increasequality. To do so, we need to instill the mindset that radiology is not a commodity, and that urologists in both private practice and academia should foster strong working relationships with the radiologists who will be reading these specialized examinations.

Indeed, the AUA guidelines highlight the importance of collaboration and coordination between radiologists and urologists, including the need for radiologists to receive regular feedback about image quality and histopathology results of target lesions mapped on mpMRI, and the need for urologists to receive feedback about quality of the targeted biopsy procedure, including results related to possible image fusion/registration and targeting errors.¹ These types of “feedback loops” will help make mpMRI a useful, cost-effective modality in PC clinical care.

Any discussion of diagnostic MRI in 2018 should mention that artificial intelligence (AI) is around the corner and may help improve the quality and throughput of imaging in prostate cancer. Advances in the data sciences will allow computers to use logic, if-then rules, decision trees, and machine learning to mimic human intelligence.¹⁷ Machine learning uses complex statistical techniques to improve task performance based on experience, while deep learning facilitates self-training by exposing multilayered neural networks to vast amounts of data.¹⁷ With these tools, AI machines in radiology will be able to take abundant data, process it, generate standardized impressions, and self-train and improve over time. This may feel intimidating, but it’s a reality -- and an opportunity we can embrace.

PET/CT for Advanced Disease
In order to effectively manage patients with advanced PC, we need to be able to accurately and precisely quantify the extent of bone and soft tissue disease.¹⁷ The imaging of various radiopharmaceuticals using PET/CT is arguably the most valuable tool currently available to cliniciains. Let’s review those most relevant to PC.

C-11 choline
Carbon (C) 11 choline was FDA-approved in 2012 for PET imaging of patients with suspected recurrent PC when bone scintigraphy, CT, or MRI was uninformative.¹⁷ C-11 choline PET/CT was later incorporated into the National Comprehensive Cancer Center (NCCN) guidelines as a recommended option for staging patients with biochemical recurrence.¹⁸

C-11 choline PET/CT is sensitive for bone and soft tissue disease and can help identify biochemically relapsed patients for referral for salvage therapies.^19,20 However, C-11’s short (20-minute) half-life restricts its use to PET centers with an onsite cyclotron and radiopharmacy.^17,2118F-Fluciclovine
Unlike C-11, the radioisotope fluorine (F) 18 has a half-life of 110 minutes.22 Consequently, F-18 tracers can be distributed through networks of existing radiopharmacies, making them more accessible similar to 18F-fluorodeoxyglucose (18F-FDG) which has become the most widely used oncologic tracer.²³In 2016, the FDA approved another F-18 tracer, the synthetic amino acid 18-F-fluciclovine, for PET/CT imaging of patients with biochemical recurrence.²⁴ Robust data support its use: PET/CT with 18-F-fluciclovine has been shown to detect recurrent PC at least as effectively as PET/CT with C-11 choline.²⁵ In January 2018, the NCCN added 18-F fluciclovine PET/CT to its PC guidelines. The test is covered by the Centers for Medicare and Medicaid Services (CMS).^18,26
All of this sounds encouraging, but availability of18-F-fluciclovine PET/CT in the community was an early concern as were concerns about the clinical benefits of the exam. The radiopharmaceutical is manufactured by Blue Earth Diagnostics and distributed through PETNET radiopharmacies in 36 U.S. states.^24,27 So if access is no longer an issue, the main question becomes the value of the exam. Will it improve outcomes? This is the key question. To answer it, we need to consider lead time bias, the length of time between earlier disease detection and its usual diagnosis. Early diagnosis by screening does not necessarily prolong life, it only lengthens the time a patient lives with a diagnosis. Thus, earlier detection can artificially inflate survival rates, making screening look effective when there is no benefit.²⁸ These are difficult and perhaps impossible questions to truly answer. The one fact we do know is that these exams are more accurate and detect disease much earlier than any of our prior FDA approved diagnostic tools.

Does PET/CT improve management and outcomes?
Next Generation Imaging (NGI) has allowed us to detect recurrent PC earlier. This has been shown to have an impact on management. Ultimately, we want that change in management to improve key outcomes, such as quality of life, progression-free survival (PFS) and overall survival (OS). Understanding limitation bias forces us to ask: does PET/CT for biochemical recurrence meet this standard in PC?

In my opinion, we don’t know yet, but preliminary data are compelling. Recently, in a single-center trial (NCT01666808), 87 post-prostatectomy patients with detectable PSA levels
(biochemical recurrence) were randomly assigned to undergo conventional imaging with or without additional 18-F-fluciclovine PET/CT.29 In a preplanned secondary analysis, positive results of 18-F-fluciclovine PET/CT significantly altered the radiotherapy plan in 41% of cases, a statistically significant result (P < .0001).²⁹ In 75% of cases, radiotherapy field was changed from prostate bed to prostate bed and pelvis. In 25% of cases, the field was narrowed from prostate bed and pelvis to prostate bed.²⁹ Another 6% of patients declined radiotherapy because PET/CT revealed extrapelvic recurrence, but the study was not large enough for this result to be significant (P = .15).²⁹ We await results for the primary outcome of this trial, failure-free survival at 3 years.³⁰
Other studies have examined whether PET/CT alters themanagement of biochemically recurrent PC.^31,32 In a recent survey of 126 referring providers, 53% said they made a major change in management after receiving the results of 68-gallium (Ga)- labeled prostate-specific membrane antigen (PSMA)-11 PET.31 Baseline PSA level did not predict whether PET results substantially altered management.³¹ The researchers recommended
studying whether changes in management ultimately led to better patient outcomes.³¹In another single-center study of 68 patients with biochemical recurrence after radical prostatectomy, 60% of patients had recurrence on 18F-DCFBC Prostate-Specific Membrane Antigen-Targeted PET/CT.32 Results varied according to patients’ PSA levels; a PSA level of 0.78 ng/mL predicted a positive PET/CT scan with an area under the curve of .764. Similar to the previous study, positive PET imaging led to changes in treatment strategy for 51% of patients.³²
Change in management is a valuable intermediate endpoint– it was the basis for the initial approval of FDG. However, we must acknowledge that the bar is higher now. In most cases, we don’t yet know whether PET/CT ultimately improves outcomes in PC. In the single-arm, prospective FALCON (Fluciclovine (18F) PET/CT in biochemicAL reCurrence Of Prostate cancer) trial (NCT02578940), 18-F-fluciclovine PET/CT substantially altered the clinical management of men with first biochemical recurrence of PC after primary therapy aimed at cure.³³ Trial recruitment was halted early after the researchers determined that 61% of patients underwent a change in management post-scan.³³ However, data on therapeutic response are still pending.

Summary of imaging options in advanced prostate cancer
What other options do we have besides PET/CT for imaging in advanced PC? Table 1 summarizes these, including their performance for bone and soft tissue imaging and whether they are covered by Medicare.
EU vol 3 issue 2 Koo article table2x

Let’s first consider technetium (Tc)-99m labeled bisphosphonate bone scans. Nearly 90% of patients with metastatic PC have osseous metastases, making this test a mainstay of imaging.³⁴ The Tc-99m scan is highly sensitive for bone metastases and is covered by CMS, but does not reliably detect soft tissue disease.^35,36In contrast to Tc-99-m bone scan, CT performs substantially better for soft tissue, is less sensitive for bone disease, and is also covered by CMS.^16,37 Whole-body MRI is excellent for detecting bone disease³⁸ and is commonly used in Europe but there are currently no reimbursable codes in the US.³⁸Another option is NaF PET/CT, which is excellent for detecting bony disease but less useful for soft tissue disease. Until recently, this test was covered by the National Oncologic PET Registry (NOPR), through which CMS reimbursed PET scans while simultaneously evaluating whether their results influenced patient management.^39,40 Unfortunately, this program closed in December 2017 with no plans for renewal. Currently, CMS is evaluating data and we await its decision regarding future coverage.

FDG PET/CT in prostate cancer has not been proven to be beneficial especially at initial diagnosis and biochemical recurrence given the metabolic characteristics of the disease at these specific disease states. However, 18-F-FDG PET/CT has more utility in advanced PC and is covered by Medicare when used to evaluate for “Subsequent Treatment Strategy.”^36,41 As discussed, C-11 choline PET/CT provides excellent detection of bone and soft tissue disease; Medicare offers limited coverage.^20,36 18-F-fluciclovine PET/CT is highly sensitive for bony and soft tissue disease, and Medicare now reimburses the cost of this test for patients with biochemical PSA recurrence.³⁶In recent studies, PSMA-based PET imaging was generally superior to all other types of scans for detecting PC bone and soft tissue metastases.^42,43,44 In a small head-to-head study of 10 patients with PSA recurrence, five (50%) were negative on 18-F-fluciclovine but were positive on 68-Ga-PSMA.⁴² Although PSMA-based PET imaging is not yet FDA-approved or reimbursed by Medicare, it’s a tool widely used around the world and will likely be more widely available for use in the US soon.

Theranostics
We cannot discuss imaging in advanced PC without touching on theranostics, an exciting new field that combines targeted therapy with companion diagnostics to advance personalized medicine.^45,46 In theranostics, we identify a target on the cell of interest (in PC, it is typically PSMA), attach a binding molecule to the target, and then link this binding molecule to a radioisotope aimed at treatment or diagnosis.⁴⁶Clearly, this paradigm is directly applicable to personalized medicine. By using PET/CT with the appropriate tracers, we can identify the distribution and expression levels of a particular receptor and target it.⁴⁷Consider a recent study in which PSMA-positive PC tumorswere identified by using Ga-68-PSMA-11 PET/CT and then treated with a beta emitter, (177)Lu-PSMA-617-targeted radionuclide therapy.⁴⁸ Among 30 patients with metastatic, castration-resistant PC (CRPC) resistant to other treatments, 23 had a PSA response and 13 had more than a 50% decrease in PSA level.⁴⁸ Among 11 patients who received three treatment cycles, eight had a greater than 50% PSA response for more than 24 weeks, which correlated with radiologic response.⁴⁸In this study, patients with bone marrow involvement were more likely to develop treatment-related myelosuppression, but they could be identified ahead of time.⁴⁸ Based on the findings, the investigators concluded that (177)Lu-PSMA-617 is a “promising new option” for treating mCRPC that needs further study.⁴⁸Targeted alpha therapies also deserve our attention. Alpharadiation is short-range and highly cytotoxic.49 The first FDA approved agent was radium 223 which we use to target bone mets in patients with symptomatic mCRPC. This therapy leads to an improvement in overall survival, an outcome not seen with prior nuclear medicine therapies in prostate cancer.⁵⁰ By attaching an alpha particle to a PSMA targeted agent, we create a much more disease-specific therapy that retains a powerful punch against the disease which is more targeted than traditional beta therapies.

The emergence of targeted alpha therapy creates new possibilities in oncology. In a small cases series of patients with mCRPC, clinicians used Ga-68-PSMA-11 to confirm the presence of PSMA-expressing tumor and then used Ac-225-PSMA-617 as targeted treatment. Two patients thus treated had undetectable PSA levels and complete responses based on restaging with Ga-68-PSMA-11. There were no hematologic toxicities or other treatment-emergent adverse events except xerostomia.⁵¹ These treatments are not yet available in the United States, but it’s clear that this is where we’re heading.

Conclusion
Advanced imaging modalities such as mpMRI and PET-CT perform far better than traditional methods for imaging PC. They can detect disease earlier, enabling urologists to change how they manage patients with the goal of improving outcomes. However, reliable data on outcomes are still pending and questions persist about which patients would most benefit from these tools. That being said, we must embrace the improved performance of these tools to find the “sweet spot” where value is maximized.

Projects such as the Prostate Imaging Reporting and Data System (PIRADS) aim to improve standards for imaging and communication, hopefully enhancing the value and cost-effectiveness of mpMRI. We should set similar goals for PET/CT and (in the future) PSMA-targeted imaging and treatment. These tools have tremendous potential if they can be used in the right patients, at the right time, and with careful and accurate communication of findings.

Finally, radiology is not a commodity. It is a highly specialized clinical service where value is optimized when practiced side by side with our urology colleagues. We encourage urologists to give us ready feedback, and work together to push the bar forward with regards to quality and effectiveness of care.

Written By: Phillip J Koo, MD

References
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An Unmet Need is Met: (The PROSPER Study): Evaluating the Safety and Efficacy Study of Enzalutamide in Patients with Nonmetastatic Castration- Resistant Prostate Cancer

For men with non-metastatic, castration-resistant prostate cancer (nmCRPC), who are invariably at risk of metastasis, the PROSPER trial clearly demonstrated that combining enzalutamide to androgen-deprivation therapy (ADT) resulted in prolonging metastasis-free survival by a median of 22 months compared with ADT plus placebo in a global, double-blind, phase III study (Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer), presented at the plenary session of ASCO GU 2018.^¹

How I Manage First-Line Therapy for Advanced Kidney Cancer

Urologists are primed to acquire the knowledge to use targeted agents and immuno-oncologic (IO) therapies for the treatment of advanced and metastatic renal cell carcinoma (RCC). Toxicities are manageable given appropriate patient/caregiver education, on-call and nursing support, and multi-disciplinary care with consulting specialists.

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