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Alternatives to BCG Immunotherapy for Bladder Cancer Treatment

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Alternatives to BCG Immunotherapy for Bladder Cancer Treatment 18 Genitourinary Cancers Symposium Daily News Friday, February 27, 2015 gucasym.org/dn Combination Chemotherapy Alternatives to BCG Immunotherapy for Bladder Borrowing from lessons learned in systemic chemotherapy for bladder cancer, combination chemotherapy for Cancer Treatment During Drug Shortages intravesical use has gained traction. Al- though this has mainly been studied radiation oncologists (e.g., RTOG-0926 prudent course of action during a drug in patients for whom BCG failed, it re- for patients for whom BCG failed). shortage is to reduce the dose, but not mains an option when BCG is not avail- the duration, of BCG therapy to less able, especially for patients with highest- BCG Best Practices for Bladder Cancer than 1 year. Meaning, patients would risk disease (e.g., large T1, high-grade Level 1 evidence supports that best be treated with one-third the dose of disease with CIS). Radical cystectomy Ashish M. Kamat, MD, MBBS, FACS practice for BCG therapy in non– BCG for induction and at least 1 year of or selected multimodal therapy options muscle invasive bladder cancer (NMIBC) maintenance, rather than being treated should be the primary recommendation mmunotherapy for cancer treatment includes an induction course of BCG with full-dose induction and no main- to patients with highest risk disease who has exploded in popularity in recent with six weekly instillations followed by tenance. This treatment plan is based are BCG naive and to patients for whom years, and its use has expanded from maintenance BCG using three weekly in- on the study from Oddens et al. that BCG has failed. melanoma to other cancers, includ- stillations at 3, showed that one-third dose of BCG for 3 Iing urothelial bladder cancer. As data 6, 12, 18, 24, 30, years was not statistically inferior to the Gemcitabine and mitomycin or gem- presented during the 2015 Genitouri- and 36 months full dose for 1 year (recurrence-free sur- citabine and docetaxel nary Cancers Symposium will reveal, from initiation vival was 62.6% with one-third dose and Data from Lightfoot et al. have shown agents such as pembrolizumab (Ab- of induction 58.8% with the full dose).3 effi cacy with high response rates (after stract 296) and MPDL3280A (Abstract therapy.2 Im- This would permit treatment of three BCG has failed) using combination of 297) are being studied and are showing portantly, based times the number of patients without gemcitabine plus mitomycin instilled activity in patients with advanced uro- on the fi nd- risk of harm for 1 year, as long as one- sequentially with dwell times of 60-90 thelial carcinoma. Some would say this ings from the third dose is continued thereafter. It minutes followed by a year of monthly is not surprising and is an extension of EORTC-30911 should be noted that this study did show maintenance for those who demonstrate the fact that immunotherapy for blad- trial, even in pa- that one-third BCG for 1 year was less a complete response.4 Drs. Lamm and Dr. Ashish M. Kamat der cancer—using intravesical bacil- tients at inter- optimal than full-dose BCG for 3 years, O’Donnell have also reported the use lus Calmette-Guérin (BCG) in the early mediate risk, 3-week maintenance BCG so this recommendation must only be of combination gemcitabine followed stages of the disease—has been highly signifi cantly reduced metastasis and considered in the context of BCG short- by docetaxel (37.5 mg in 50 ml of ster- successful in reducing recurrence pro- overall and cancer-specifi c mortality to age. For those who may be concerned ile normal saline) for six weekly instilla- gression rates and decreasing rates of an extent that was even better than for about a reduced immune response for tions followed by monthly maintenance metastatic disease and death.1 patients at high risk. patients treated with lower-strength for 12-24 months (personal communica- The importance of appropriate pa- BCG, interferon alpha can be added to tions 2014) . Immunotherapy for tient selection (e.g., excluding variant boost cytokine response. histologies such as micropapillary or Radical Cystectomy cancer treatment has small-cell histology) and patient prepa- Intravesical Chemotherapy Of course, whether in times of BCG exploded in popularity in ration (e.g., repeat transurethral resec- Intravesical chemotherapy alterna- shortage or excess, the primary goal of tion to ensure all papillary disease has tives to BCG include gemcitabine, treating patients with bladder cancer is recent years, and its use has been surgically removed) prior to ini- mitomycin-C, and valrubicin, which to their ensure survival. Thus, for pa- expanded from melanoma tiation of intravesical therapy is espe- has been approved by the U.S. Food and tients with NMIBC who are at the high- cially relevant when considering which Drug Administration (FDA) for patients est risk of disease progression (e.g., deep to other cancers, including patients would not benefi t from BCG, for whom BCG has failed. T1, variant histology, multifocal tumors, urothelial bladder cancer. and therefore should not be offered or recurrent disease after BCG) and are the therapy. When BCG is in short sup- Gemcitabine surgical candidates, radical cystectomy ply, physicians should prioritize BCG Clinical experience with intravesical with appropriate urinary diversion must These fi ndings have also raised aware- use based on progression risk. For ex- gemcitabine suggests that this agent has be offered. This achieves the best on- ness of the need for precision in the ample, patients with intermediate-risk the least side effects. It can be used as a cological control of disease and, when administration (dose, scheduling, and disease are at lower risk of progression weekly instillation of 1-2 gm in 50 cc of provided in a timely fashion, can result duration of therapy) of immunologic than patients with high-risk disease. sterile water for 90 minutes, for 6 weeks. in prolonged survival in more than 80% agents. Unfortunately, just when the Therefore, oncologists should counsel Some studies have also used monthly of patients. Notably, both the American urologic oncology world renewed en- patients with intermediate-risk disease maintenance therapy, but this is most Urological Association and European As- thusiasm for the in-depth study of BCG and explain that BCG is reserved for often reserved for when BCG fails. sociation of Urology recommend radical therapy, a worldwide shortage of this the patients who are at higher risk of cystectomy as the preferred option for valuable biologic agent occurred from progression. Mitomycin-C instillations patients for whom BCG has failed, with two major fronts. First, Sanofi Pasteur With this background, what options The largest experience with intravesi- limited evidence supporting the next ceased production of BCG in 2012 (slat- does the treating physician have in times cal chemotherapy is with mitomycin-C. best bladder-preserving therapies. ed to go back in production sometime when BCG is in short supply? This is best administered as a concen- this year), and second, Merck reported trated solution of 40 mg in 20 cc nor- BCG from Other Countries substantial shortages in production Transurethral Resection of Tumor Alone mal saline, again for 6 weeks with or Although there is some variation be- of their product during 2014, leaving All patients with NMIBC must be without monthly maintenance therapy. tween strains of BCG with minor varia- many patients with no access to intra- counselled appropriately and provided However, data are emerging that sug- tion in immunologic activity, most exist- vesical immunotherapy. detailed information regarding their gests that this agent might not be as well ing data suggest that BCG from different In response to this shortage, several risk of—and the difference between— tolerated as other agents. Additionally, sources all have activity when used for organizations and experts have put for- recurrence and progression. For pa- mitomycin-C itself has been in short bladder cancer. However, until the FDA ward recommendations on “What Is the tients with high-risk NMIBC (e.g., supply twice in last 5 years. engages BCG suppliers from outside of Urologist to Do in Times of BCG Short- high-grade papillary or carcinoma in the United States (something that the age?” (This was the title of an article I situ [CIS]), management with transure- Valrubicin Bladder Cancer Advocacy Network has coauthored with Donald L. Lamm, MD; thral resection of tumor (TURBT) and Valrubicin has been approved for CIS; been championing), this option remains Michael O’Donnell, MD; Badrinath observation alone is not appropriate. however, the drug has substantial associ- available only to patients willing to trav- Konety, MD MBA; Stephen B. Williams, These patients should always be offered ated costs, and data are not conclusive el to other countries, such as the Nether- MD, MBBS, FACS; John Taylor, III, MD, an alternative treatment. However, for regarding effi cacy. If used, the most com- lands, India, and Japan. that was featured in AUA News, Novem- patients with intermediate-risk disease mon dosage is 800 mg weekly for 6-8 ber 2014). However, as shown by the (e.g., recurrent, multifocal, or low- weeks. About the Author: Dr. Kamat is a pro- multidisciplinary interest in bladder grade Ta lesions), TURBT may represent fessor of urology and director of fellowship cancer immunotherapy, this topic is rel- a reasonable option, especially with en- Other agents in the Department of Urology at The Univer- evant not only to urologists but also to hanced optical technology followed by Other agents that have been used in sity of Texas MD Anderson Cancer Center. medical oncologists (e.g., GU Cancers close surveillance. this situation include docetaxel, nab- Symposium Abstract S293 will discuss paclitaxel, thiotepa, and epirubicin, but (The complete reference list can be found in trials being developed to study combin- Lower-Dose, Longer-Duration BCG experience in the United States with the online version of this article at gucasym.
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