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Feature: Intravesicular Chemo for Non-Muscle Invasive Bladder Cancer -to Instill or Not to Instill, That is the Question

Brendan Mangan, PharmD
Clinical Pharmacy Specialist
Hospital of the University of Pennsylvania
Philadelphia, PA

Background on Non-Muscle Invasive Bladder Cancer

Bladder cancer is the fourth most common malignancy in men in the United States and accounted for 62,100 new cases and 7% of all male malignancies in 2020.1 In patients with Non-Muscle Invasive Bladder Cancer (NMIBC), a transurethral re­section of the bladder tumor (TURBT) should be performed upon diagnosis. At this time, the patient should be clinically staged and risk stratified as “low-,” “intermediate-” or “high-risk.” Stratification is based on grade (high vs. low), tumor invasion, recurrence, histology, and previous treatment.2 Post TURBT, intravesicular chemotherapy has been used immediately or, based on patient risk, as an adjuvant treatment to prevent re­currence. Intravesicular chemotherapy is the process of instilling chemotherapy directly into the bladder through a catheter and al­lowing it to dwell until removal.

Immediate Post-Operative Intravesicular Chemotherapy

In the setting of low-risk NMIBC, a single intravesicular dose of chemotherapy may be given immediately after the TURBT (within 24 hours).2 The rational for immediate instillation is based on antitumor effects—destroying tumor cells suspended in the irrigation fluid post-TURBT, and the killing of re­sidual tumor cells at the site—and possibly, overlooked tumors.3,4,5 A systematic review and meta-analysis of immediate intravesicular chemotherapy post-TURBT found a 35% decreased risk of recur­rence and a decreased five-year recurrence (from 58.8% to 44.8%) when compared to TURBT alone in patients with a recurrence rate of <1 recurrence per year.3

Two Phase III trials have investigated the use of single-dose intravesicular chemotherapy immediately post-TURBT. The use of gemcitabine was investigated in a randomized, double-blind, placebo-controlled Phase III trial of 406 patients with suspected low-grade NMIBC. Immediate instillation of gemcitabine led to a 35% four-year recurrence rate compared to 47% in the placebo group (HR, 0.66; 95% CI, 0.48-0.90; P < 0.001). Adverse events, including voiding dysfunction, voiding pain, and hematuria, were similar in both groups.6

Mitomycin C was studied in a Phase III, prospective, multi­center, randomized study investigating recurrence rates in imme­diate (within 24 hours) versus delayed (two weeks) instillation post-TURBT. Patients were stratified into groups based on risk with the primary endpoints of recurrence as follows: five-year recurrence risk in low-risk group and three-year recurrence risk in the interme­diate- and high-risk groups. When stratified by group, recurrence rates in patients who received immediate instillation were signifi­cantly lower in the intermediate- and high-risk groups (20% vs. 32%, P=0.037 and 28% vs. 35%, P=0.007, respectively).

As an entire cohort, the recurrence risk was 27% for immediate instillation compared to 36% for delayed instillation (P < 0.001). Adverse events, including exanthema and urinary symptoms, were similar in both groups.7 When the agents were compared in a systematic review, the rates of adverse events were significantly less with gemcit­abine (38.8% vs. 72.2%, P=0.02).8 It should be noted that immediate post-TURBT intra­vesicular chemotherapy or immunotherapy should not be administered in patients with a suspected bladder perforation.

Adjuvant and Maintenance Intravesicular Chemotherapy

In patients with intermediate- to high-risk NMIBC, the use of intravesicular chemo­therapy or immunotherapy should be given as a six-week induction regimen.2 Similar to low-risk patient settings, gemcitabine and mitomycin C are the most common chemo­therapy agents for patients in this setting, with gemcitabine also preferred.8

In addition to chemotherapy, bacillus Calmette-Guerin (BCG) immunotherapy has also been studied. BCG is a vaccine against tuberculosis and contains a live-attenuated mycobacterium tuberculosis.9 BCG activates the innate immunity and acquired immunity of the bladder. It directly reacts to tumor cells leading to apoptosis, necrocytosis, and oxidative stress.10 Aside from eliminat­ing cancer cells, BCG can also induce high expression of PD-L1 on tumor cell surfaces.11 BCG is most commonly administered weekly for six weeks, followed by a rest period, ending with a re-evaluation at Week 12.12 BCG induction has been compared to intravesicular epirubicin, gemcitabine, and mitomycin C. Reduced recurrence and improved overall survival were observed in comparison to epiru­bicin in patients receiving BCG with or without isoniazid.13 When compared to intravesicular gemcitabine in a Phase II quality of life trial, there were no significant quality of life differences, but there was an increase in mild- to moderate-adverse events in the BCG group. It should be noted that this trial utilized a 1/3 BCG dose and both arms received maintenance therapy for a year (monthly instil­lations of gemcitabine or three weekly BCG instillations at 3, 6, and 12 months).14 With similar quality-of-life outcomes, the frequency of administration should be considered when weighing options.

Lastly, when compared to mitomycin C, the use of maintenance therapy weighed heavily on the outcomes. In a large meta-analysis, BCG was inferior to mitomycin C in preventing recurrence in patients receiving induction only, but superior in those who went on to receive maintenance therapy.15

Maintenance therapy remains somewhat controversial. Main­tenance intravesicular chemotherapy is generally given monthly, whereas BCG regimens may differ. A Phase III trial compared the long-term efficacy of intravesical epirubicin, BCG, or BCG with isoniazid, in which patients received three weekly instillations at months 3, 6, 12, 18, 24, 30, and 36. Regardless of isoniazid, BCG demonstrated superiority to epirubicin in time to first recurrence, time to distant metastases, disease-specific survival, and overall survival in intermediate- and high-risk patients.16

There is still some debate regarding the length of maintenance therapy, as data has shown benefits for both one and three year BCG maintenance regimens, stratified by risk catergory.17,18 Based on the results of a randomized trial investi­gating outcomes of 1/3 dose BCG compared to full dose BCG, and one year versus three years of maintenance, full dose BCG for one year may be more appropriate for inter­mediate-risk patients, whereas three-year maintenance may be beneficial for high-risk patients.18 These recommendations are contingent on patient tolerance and BCG toxicities. Due to the immunogenicity of BCG, patients may experience flu-like symp­toms for up to 72 hours after dosing.19 Other side effects, such as localized discomfort and dysuria, are also common.19,20 When compar­ing patients on 1/3 dose BCG and full dose BCG, toxicity outcomes were similar, leading to recommendations for full dose BCG in patients that can tolerate it.18

Intravesicular Use After Recurrence

In patients with recurrence after initial intravesicular treatment, further intravesicular treatment may be appropriate. Following an initial 12-week course of intravascular treatment, intermediate- or high-risk patients with persistent or recurrent disease may receive an additional course of BCG therapy followed by a repeat TURBT.2 A Phase II trial evaluating the use of intravesicular gemcitabine in patients with NMIBC who failed two courses of BCG, including 89% with high-risk NMIBC, demonstrated activity and may be reasonable for those not eligible for cystectomy. In this trial, 47% of patients remained disease free at three months and 28% at one year.21 In intermediate- to high-risk patients with persistence or recurrence after two courses of BCG, further intravesicular chemo­therapy is only recommended in the instance of no available clinical trials.2 Patients with carcinoma in situ (CIS) that is refractory to BCG may be offered intravesicular valrubicin.

A single-arm study evaluated the efficacy of valrubicin in patients with CIS refractory to multiple courses of intravesical therapy, including at least one course of BCG. Valrubicin was given as six weekly instillations of 800 mg. Complete response, defined as no evidence of recurrence for at least six months, was achieved in 21% of patients, with a median time to failure of greater than 18 months in patients with complete responses. In the trial, no complete responders or patients who underwent cystectomy following valrubicin died during the 30-month follow-up period.22 Toxicity wise, local bladder symptoms were observed during the trial. Additionally, systemic pembrolizumab was recently approved for BCG-unresponsive patients based on the results of the Phase II, Keynote-057 trial.23 Cystectomy is still the preferred treatment for patients in this setting, if eligible.2

Upper Tract Urothelial Carcinoma (UTUC)

Upper Tract Urothelial Carcinoma (UTUC) is a malignant process that occurs in the urothelial cells lining the urinary tract. These can occur anywhere from renal calyces, renal pelvis, or ureter down to the ureteral orifice.24 A much less common genitourinary malignancy, these account for 5% of urothelial cancers and less than 10% of renal tumors.25 While surgery is the primary treatment of choice, mitomycin for pyeloca­lyceal solution (mitomycin gel) may be used for adult patients with low-grade UTUC.

In a Phase III, single-arm trial of patients with treatment-naïve or recurrent low-grade noninvasive UTUC with at least one measur­able papillary tumor above the ureteropelvic junction, six weekly instillations of mitomy­cin gel was administered to the renal pelvis or calyces. Mitomycin gel was dosed based on patients’ volume of renal pelvis and calyces, and capped at 60 mg. Complete response, defined as a negative three-month uretero­scopic evaluation, negative cytology, and negative for-cause biopsy, was achieved in 59% of patients who received at least one instillation of mitomycin gel. The most common adverse effects reported were ureteric steno­sis, urinary tract infection, hematuria, and flank pain.26 As surgery is the primary treatment, this should be reserved for patients who are not interested in or eligible for a nephroureterectomy.

Recap

Intravesicular chemotherapy has become a mainstay of therapy for patients with NMIBC. In low-risk patients, the immediate single instillation of chemotherapy has significantly prolonged time to recurrence. Gemcitabine is preferred in these patients due to the more benign toxicity profile and lower cost. In the intermediate- to high-risk group, the use of intravesicular BCG with maintenance has been shown to be favorable compared to intravesicular chemo­therapy on outcomes including overall survival. Intermediate- and high-risk patients may receive a repeat course of BCG at time of first recurrence or persistent disease if they are not eligible for a cystectomy, with limited data for subsequent intravesicular che­motherapy. The development of localized intravesicular therapy has prolonged disease-free intervals in patients regardless of risk category in NMIBC. Finally, when it comes to patients with low-risk UTUC, the approval of mitomycin gel has given patients who are not interested in or eligible for a nephroureterectomy an effective option for treatment.

Drug Preparation and Clinical Pearls (American Urological Association Recommendations)27

Handling Chemotherapy

  • Follow institutional policies for the preparation of all hazardous medications
  • Chemotherapy should be prepared utilizing aseptic technique with proper chemotherapy safety precautions
  • All equipment and supplies used to handle cytotoxic agents are disposed of as chemotherapy waste

Gemcitabine (Not FDA-approved)27

  1. Preparation
    1. Use gemcitabine powder for injection 1 gm or 2 gm vials
    2. Reconstitute gemcitabine with normal saline to 1000 mg/50 mL or 2000 mg/50-100 mL, or use premixed gemcitabine with closed system administration set
    3. Containers should be clearly marked “For irrigation only” to avoid accidental intravenous administration
  2. Clinical Pearls27
    • Instruct patient not to void for one to two hours post-procedure
    • Gemcitabine should be instilled via gravity flow
    • Male patients should sit when voiding to avoid splashing post-procedure
    • Instruct patient to wash perineum or glans after voiding to decrease irritation

Mitomycin C (Conventional, Not FDA-Approved)27

  1. Preparation
    1. Dosing: Mitomycin 40 mg reconstituted in 20 mL sterile water
  2. Clinical Pearls27
    • Oral sodium bicarbonate 1.3 g may be recommended to take the night before, morning of, and 30 minutes prior to treatment to help improve effectiveness28
    • Instruct patient not to void for one to two hours post-procedure
    • Male patients should sit when voiding to avoid splashing post-procedure
    • Instruct patient to wash perineum or glans after voiding to decrease irritation
    • Mitomycin is a vesicant

Bacillus Calmette-Guerin (BCG)27

  1. Preparation
    1. Dosing: one vial suspended in 50 mL preservative free 0.9% sodium chloride injection
    2. BCG must be used within two hours of reconstitution; unused solution is discarded as biohazardous waste after two hours
    3. To avoid cross contamination, parental drugs are not prepared in areas where BCG has been prepared
    4. All equipment, supplies, and receptacles in contact with BCG are handled and disposed of as biohazards
    5. If preparation cannot be performed in a biocontainment hood, then a mask, face shield, and non-permeable gown should be worn to avoid inhalation and inadvertent exposure to broken skin
    6. Do not use a filter with BCG instillation
    7. Syringe Method19
      1. Draw 1 ml of sterile, preservative-free saline into a small syringe (~3 mL) and add to one vial of TICE® BCG to resuspend
      2. Gently swirl the vial until it forms a homogenous suspen¬sion; avoid forceful agitation which may cause clumping
      3. Dispense suspension into the top of a catheter-tip syringe containing 49 mL of saline. Total volume is 50 mL. Swirl gently to combine
    8. Reconstitution accessories may be provided with a BCG order. In this case, refer to specific instruction for use with the accessories
    9. Avoid exposing BCG to direct sunlight
  2. Clinical Pearls19,27
    • Patients should not drink fluids for four hours before treat¬ment and should void their bladder prior to administration
    • Instruct patient not to void for one to two hours post-procedure
    • The reconstituted BCG should be administered by gravity flow only, with no pressure applied to the plunger to force the flow of BCG
    • BCG is retained in the bladder for two hours then voided. If patient cannot retain BCG for two hours, they may be allowed to void sooner
    • While BCG is intra-bladder, the patient should be repo¬sitioned from left side to right side and also lie on their abdomen and back. Rotate and reposition every 15 minutes to maximize bladder surface exposure
    • Acetaminophen or ibuprofen may be used to help reduce/ treat fever and body aches
    • Antispasmodic medications may be warranted to help with frequency and urgency
    • If sexually active, condoms should be worn during inter¬course throughout treatment

Valrubicin (FDA-Approved)29

  1. Preparation
    1. Dosing: 800 mg diluted in 75 mL of 0.9% sodium chloride
    2. Allow four 5 mL vials (200 mg/5 mL vials) to slowly warm to room temperature
    3. Withdraw 20 mL from the four vials and dilute with 55 mL of 0.9% sodium chloride injection to provide 75 mL of diluted valrubicin
    4. Diluted valbucin in 0.9% sodium chloride is stable for 12 hours at room temperature (25°C, 77°F)
    5. Valrubicin should be handled and disposed of like other cytotoxic drugs. Please use goggles, gloves, and protective gowns during preparation and administration
  2. Clinical Pearls
    • Valrubicin (Valstar®) contains polyoxyl castor oil, which may cause leaching of di(2-ethylhexyl) phthalate (DEHP) from PVC bags. Prep and store in glass, polypropylene, or polyole¬fin containers and tubing
    • Temperatures less than 4°C (39°F) may cause the polyoxyl castor oil to form a waxy precipitate. If this occurs, gently warm vial in the hand until solution is clear. Do not warm by other forms of heat
    • Valrubicin should be instilled by gravity over several minutes
    • Valrubicin is retained in the bladder for two hours before voiding. If patient cannot retain valrubicin for two hours, they may be allowed to void sooner
    • Patients should maintain adequate hydration post-instillation
    • In patients undergoing a Transurethral Resection of the Bladder (TURB), bladder evaluation is warranted. Adminis¬tration should be delayed at least two weeks after transure¬thral resection and/or fulguration
    • Caution should be used in patients with severe bladder symptoms. Bladder spasms and spontaneous discharge of the instillate may occur; it is not advised to clamp the urinary catheter

Mitomycin for Pyelocalyceal Solution (Jelmyto®, FDA-Approved)30

  1. Preparation
    1. Dosing: The volume administered is based on volumetric measurements using pyelography. Maximum dose is 15 mL (60 mg of mitomycin)
    2. BCG must be used within two hours of reconstitution; unused solution is discarded as biohazardous waste after two hours
    3. To avoid cross contamination, parental drugs are not prepared in areas where BCG has been prepared
    4. All equipment, supplies, and receptacles in contact with BCG are handled and disposed of as biohazards
    5. If preparation cannot be performed in a biocontainment hood, then a mask, face shield, and non-permeable gown should be worn to avoid inhalation and inadvertent exposure to broken skin
    6. Do not use a filter with BCG instillation
    7. Syringe Method19
      1. Draw 1 ml of sterile, preservative-free saline into a small syringe (~3 mL) and add to one vial of TICE® BCG to resuspend
      2. Gently swirl the vial until it forms a homogenous suspen¬sion; avoid forceful agitation which may cause clumping
      3. Dispense suspension into the top of a catheter-tip syringe containing 49 mL of saline. Total volume is 50 mL. Swirl gently to combine
    8. Reconstitution accessories may be provided with a BCG order. In this case, refer to specific instruction for use with the accessories
    9. Avoid exposing BCG to direct sunlight
  2. Clinical Pearls19,27
    • Patients should not drink fluids for four hours before treat¬ment and should void their bladder prior to administration
    • Instruct patient not to void for one to two hours post-procedure
    • The reconstituted BCG should be administered by gravity flow only, with no pressure applied to the plunger to force the flow of BCG
    • BCG is retained in the bladder for two hours then voided. If patient cannot retain BCG for two hours, they may be allowed to void sooner
    • While BCG is intra-bladder, the patient should be repo¬sitioned from left side to right side and also lie on their abdomen and back. Rotate and reposition every 15 minutes to maximize bladder surface exposure
    • Acetaminophen or ibuprofen may be used to help reduce/ treat fever and body aches
    • Antispasmodic medications may be warranted to help with frequency and urgency
    • If sexually active, condoms should be worn during inter¬course throughout treatment

REFERENCES

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  10. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8):1499-1505.
  11. Mukherjee N, Svatek R. Cancer Immune Therapy: Prognostic Significance and Implications for Therapy of PD-1 in BCG-Relapsing Bladder Cancer. Ann Surg Oncol. 2018;25(9):2498-2499.
  12. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
  13. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized Phase III study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate-and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-773.
  14. Gontero P, Oderda M, Mehnert A, et al. The impact of intravesical gemcitabine and 1/3 dose Bacillus Calmette-Guérin instillation therapy on the quality of life in patients with non-muscle invasive bladder cancer: results of a prospective, randomized, Phase II trial. J Urol. 2013;190(3):857- 862.
  15. Malmström PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol. 2009;56(2):247-256.
  16. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized Phase III study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate-and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-773.
  17. Ehdaie B, Sylvester R, Herr HW. Maintenance bacillus Calmette-Guérin treatment of non-muscle-invasive bladder cancer: a critical evaluation of the evidence. Eur Urol. 2013;64(4):579-585.
  18. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63(3):462-472.
  19. U.S. Food and Drug Administration. Prescribing Information. TICE® (BCG live), for intravesical use. 2009. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM163039.pdf. Accessed February 27, 2021.
  20. van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV; EORTC Genito-Urinary Tract Cancer Group. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol. 2003;44(4):429- 434.
  21. Skinner EC, Goldman B, Sakr WA, et al. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with non-muscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. J Urol. 2013;190(4):1200-1204.
  22. Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette- Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group [published correction appears in J Urol. 2008 Jan;179(1):386]. J Urol. 2000;163(3):761-767.
  23. Balar AV, Kulkarni GS, Uchio EM, et al. Keynote 057: Phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette- Gue´rin (BCG). J Clin Oncol. 2019; 37:350–1350.
  24. Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol. 2020;9(4):1794-1798.
  25. Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973- 2005. BJU Int. 2011;107(7):1059-1064.
  26. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, Phase III trial. Lancet Oncol. 2020;21(6):776-785.
  27. American Urological Association. Intravesical Administration of Therapeutic Medication for the Treatment of Bladder Cancer. 2020. Available at: https://www.suna.org/resources/ intravesicalMedAdminStatement.pdf. Accessed February 27, 2021.
  28. Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized Phase III trial. J Natl Cancer Inst. 2001;93(8):597-604.
  29. U.S. Food and Drug Administration. Prescribing Information. Valstar® (Valrubicin), for intravesical use. 2011. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020892s019lbl.pdf. Accessed February 27, 2021.
  30. U.S. Food and Drug Administration. Prescribing Information. Jelmyto® (Mitomycin), for intravesical use. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211728s002lbl.pdf. Accessed February 27, 2021.
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