Wednesday, August 27, 2014

BCG Alternatives for Non-Muscle Invasive Bladder Cancer

Bacillus Calmette-Guerin (BCG) immunotherapy is the standard, most commonly used intravesical treatment for patients with NMIUBC (non-muscle invasive urothelial bladder cancer).  [Please see our prior blog entries on BCG treatment below]  However, upwards of 40% of patients will "fail" intravesical treatment and have a recurrence or progression of their bladder cancer. Due to the aggressive nature of MIUBC (muscle-invasive urothelial bladder cancer), early radical cystectomy is advocated by many urologists who care for patients with progressive disease.  However, radical cystectomy is a morbid and life-changing operation and many patients seek alternative treatments to BCG before submitting to radical surgery.  In addition, some patients cannot tolerate BCG treatment due to side effects.  Finally, in times of shortage (we are currently undergoing a BCG shortage in the US), alternative treatments can be used in lieu of premature radical surgery.

A prior blog entry reviewed Immunotherapy Alternatives to BCG.  Many of these medications are in the experimental phase of investigation and have not been proven to be useful in humans.  In this blog, we review intravesical chemotherapy, device-assisted chemotherapy and thermochemotherapy alternatives to intravesical BCG and the data with each modality.


INTRAVESICAL CHEMOTHERAPY

Mitomycin C (MMC) has long been used for low-grade, non-invasive urothelial cancer of the bladder.  However, MMC has limited efficacy after BCG failure with only 4 of 21 patients responding in a small, Scandinavian study.[1]

Gemcitabine is the standard systemic therapy given to patients with MIUCB.  Two early (Phase I-II) studies demonstrate the potential efficacy of gemcitabine given intravesically.  In one study of 18 patients, 7 demonstrated a complete response (negative biopsy and cytology for cancer) and 4 patients demonstrates a partial response (negative biopsy, positive cytology).[2]  Twenty-two of 39 (56%) patients with intermediate- and high-risk of recurrence after BCG therapy were recurrence free after 6 weeks of treatment.  In addition, none of the non-responders had progression of disease while receiving gemcitabine therapy.[3]

Docetaxel is another systemic chemotherapeutic agent used in advanced cancers. Researchers at Columbia University in New York demonstrated a 59% complete response rate in 32 of 54 patients after 6 weekly cycles (18 patients received maintenance therapy).  This translated into recurrence-free survival rates of 40% and 25% at 1- and 3-years respectively; 25% underwent radical cystectomy; and 5-year cancer-specific survival was 85%.[4]

In preliminary research, the combination of Gemcitabine/Docetaxel demonstrates promising results with lower side effect profiles than other intravesical chemotherapies and with excellent short-term response rates. We are currently using this regimen at Johns Hopkins in patients with BCG failures, refractory disease and in those patients who cannot receive BCG with promising results.
   

DEVICE-ASSISTED CHEMOTHERAPY

Photodynamic therapy (PDT) involves treating the bladder with a photosensitizing medication that selectively binds to tumors and using a strong intravesical light source to destroy tumors.  Five-aminolevulinic acid (5-ALA) was given orally to 24 BCG-failure patients and, after two years, 16 were tumor free.[5]

From Wild P J et al. Mol Cancer Ther 2005;4:516-528
MMC and EMDA (electromotive drug administration) has been demonstrated to enhance the delivery of the medication to the urothelial cells lining the bladder.  Using a pulsed electrode inserted into the bladder via a urinary catheter, 108 BCG-failure patients were randomized to MMC, MMC with EMDA or BCG.  MMC with EMDA demostrated a better response rate (58%) at 6 months than MMC alone (31%), however this was not improved compared to BCG (64%) alone.[6]

THERMOCHEMOTHERAPY

Heating the bladder to 42 degrees Celsius (107 degrees F) while administering MMC has been demonstrated to have some effect in patients with BCG failure.  Using a special microwave and catheter, the recurrence rates have been observed between 14% at 1-year and 24% at 2-years if no prior BCG exposure; and in patients who previously failed BCG treatment, 1- and 2-year recurrence rates were 23% and 41% respectively.[7]  In a study of 15 European centers, the complete response rate was 92% at 1-year but fell precipitously to 50% at 2-years.[8] A recent meta-analysis of 22 studies demostrated a 59% relative reduction in risk of recurrence for all patients with NMIUBC treated with heated MMC compared to MMC alone.[9] 

Thermochemotherapeutic system demonstrated from Lammers etal [9].

SUMMARY

May patients do not continue with intravesical BCG treatments due to "failure" (recurrence or progression of disease), intolerance of the medication or inavailability of the drug.  Reasonable intravesical chemotherapeutic agents include: mitomycin c, gemcitabine, docetaxel and combinations of these medications.  Device-assisted therapeutics and thermochemotherapy remain alternatives.

Availability of BCG alternatives will vary by center and urologist.  Any patient who fails BCG is at high-risk for disease progression and death from urothelial cancer.  A thorough discussion of the alternatives and risk of disease progression should be undertaken prior to embarking on any alternative treatment.



Prior Blog Entries on BCG Therapy:
Success Rates for Intravesical BCG Treatments for Bladder Cancer (2/24/14)
BCG Complications for Bladder Cancer: Who, What, When and How to Treat? (3/12/14)
BCG For Bladder Cancer: Why it Works, How it Works (4/25/14)
BCG Immunotherapy Alternatives (7/16/14)
References
[1] Malmstrom PU, Wijkstrom H, Lundholm C, et al. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol. 1999;161:1124–7.
[2] Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol. 2002;20:3193–8.
[3] Gontero P, Casetta G, Maso G, et al. Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC) Eur Urol. 2004;46:339–43.
[4] Barlow L, McKiernan JM, Benson MC.  Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy.  J Urol. 2013 Mar;189(3):834-9. doi: 10.1016/j.juro.2012.10.068. Epub 2012 Oct 30.
[5] Waidelich H, Stepp R, Baumgartner E, et al. Clinical experience with 5-aminolevulinic acid and photodynamic therapy for refractory superficial bladder cancer. J Urol. 2001;165:1904–7.
[6] Di Stasi SM, Giannantoni A, Stephen RL, et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol. 2003;170:777–82.
[7] Van Der Heijden AG, Kiemeney LA, Gofrit ON, et al. Preliminary European results of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma of the bladder. Eur Urol. 2004;46:65–72.
[8] Alfred Witjes J, Hendricksen K, Gofrit O, Risi O, Nativ O.  Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party.World J Urol. 2009 Jun;27(3):319-24. doi: 10.1007/s00345-009-0384-2. Epub 2009 Feb 22.
[9] Lammers RJ, Witjes JA, Inman BA, Leibovitch I, Laufer M, Nativ O, Colombo R. The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review.  Eur Urol. 2011 Jul;60(1):81-93. doi: 10.1016/j.eururo.2011.04.023. Epub 2011 Apr 20. Review.


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