Emerging alternative therapy for non-muscle-invasive bladder cancer (NMIBC) in the era of BCG shortage and BCG failure

Bladder cancer epidemiology and treatment of NMIBC

Bladder cancer is the 9^th most common cancer worldwide, with more than 600,000 new cases diagnosed each year. It is considered the 4th most common cancer in Arab countries. Seventy percent of cases are identified at an earlier stage (non-muscle-invasive (NMIBC)), where treatment after endoscopic removal, relies on the administration of drugs into the bladder (intravesical therapy). Bacillus Calmette-Guerin (BCG), a vaccine originally developed to prevent tuberculosis, has become the highly effective standard-of-care to both prevent NMIBC recurrence and eradicate the often-invisible, high-grade and deadly surface cancer called carcinoma-in-situ (CIS).  Unfortunately, BCG fails in 40% of cases by 2 years. Furthermore, worldwide shortages of BCG that started in 2012, continue to be commonplace, this congruence of BCG shortage and failure has become a health catastrophe in search of new topical NMIBC treatments.

Impact of BCG shortage and BCG failure among Arab urologists

A survey was constructed and sent through the Arab Association of Urology (AAU President: Mohamad Moussa – Lebanon), to assess BCG shortage and BCG alternatives. More than 60% of Arab urologists reported shortages of BCG. Coping strategies included: dose reduction of BCG, prioritizing BCG for certain tumor stages (T1 or CIS), and using second-line alternatives such as chemotherapy. The most favored management strategy for BCG-unresponsive NMIBC was radical cystectomy, but still about half felt other conservative treatments were warranted utilizing a variety of intravesical chemotherapy agents but with single agent gemcitabine preferred, a drug with poor activity (< 20% by 2 years) against BCG-unresponsive CIS.

Intravesical Gem/Doce, a potential solution to these BCG-related problems

A BCG-alternative and BCG-rescue therapy for direct bladder instillation was developed by Dr. Michael O’Donnell, Professor and Director of Urologic Oncology, at the University of Iowa (UI) in the US in 2015. It consists of the sequential use (one right after the other) of two common and cheap generic chemotherapy drugs, gemcitabine and docetaxel (Gem/Doce). Therapy consists of weekly bladder treatment X 6 then once monthly treatment for up to 2 years. Each drug is held in the bladder for 60-90 minutes before drainage or voiding.

In terms of efficacy, ~75% of BCG naïve cases (never given BCG) and 42% of BCG failure cases (previously treated with BCG and failed on this therapy) remain free of any cancer recurrence 2 years later if they had received Gem/Doce. Additionally, this therapy was found to work at least as well as BCG for both high and intermediate-risk BCG-naïve cases and even for CIS regardless of its location, including in the upper urinary tract.  For BCG-unresponsive CIS cases, Gem/Doce easily outperformed, by more than 2-fold, the effectiveness reported by any single chemotherapy drug (like gemcitabine) and the three FDA-approved agents (Valrubicin (Valstar), pembrolizumab (Keytruda) and nadoferagene firadenovec (Adstiladrin)). However, it should be noted that the evidence supporting Gem/Doce effectiveness is, to date, only derived from retrospective studies (albeit from several multi-institutional series) rather than randomized trials.

Side effects of Gem/Doce therapy

More than 400 patients have received intravesical Gem/Doce at UI Hospitals & Clinics over almost a ten-year period. Over half of the patients treated had no side effects what-so-ever and less than 1% had a grade 3 treatment-related adverse event. Most of the adverse events after Gem/Doce therapy have been grade 1-2 and mostly mild fatigue or irritative urinary symptoms (dysuria, frequency, and hematuria). In fact, the dropout rate for patients getting Gem/Doce was 3-fold lower (3%) than what was observed for the contemporarily BCG-treated patients (~9%).  Furthermore, an independent randomized study from India comparing Gem/Doce to BCG demonstrated not only statistically significantly less grade 2 side effects but also better quality of life scores for patients receiving Gem/Doce.

Why has Gem/Doce not become routine therapy among Arab urologists?

While in our survey 30% of Arab urologists used intravesical chemotherapy as an alternative treatment for patients in whom BCG failed, only 10% of these urologists reported using Gem/Doce. The reason for low Gem/Doce use is likely several fold. Gem/Doce has not been widely promoted by any pharma company so adoption has been slow. While 70% of US urologic bladder cancer specialists reported using Gem/Doce recently, among US community urologists, a similar survey revealed Gem/Doce use was also under 10%.  Treatment logistics have also likely played a role.  Since patients must wait at their urologist’s office for 1-2 hours to receive sequenced Gem/Doce (vs 10-15 minutes for BCG), workflow can be challenging for a busy clinic with limited waiting space. Most Arab (and US community) urologists are also personally unfamiliar with new intravesical drugs like docetaxel, let alone any doublet intravesical chemotherapy. Furthermore, while the NCCN now in 2024 mentions Gem/Doce as treatment option for BCG-unresponsive NMIBC, European and most local guidelines do not.

However, this situation is poised to change. As per professor Moussa, President of the AAU,

“This novel Gem/Doce therapy, may constitute an alternative to the classic treatment of bladder cancer, especially in underdeveloped countries, decrease the cost burden on the healthcare system, and allow us to treat more patients.”

Future perspectives

A randomized Phase III trial is ongoing to assess the use of intravesical BCG versus Intravesical Gem/Doce in treatment for BCG-naive non-muscle invasive bladder cancer (the BRIDGE Trial). This will provide level 1 evidence of this novel therapy. Further prospective trials of Gem/Doce among patients in whom BCG has failed, are also in development, including in Arab nations.

Message to bladder cancer patients

Despite the fact that bladder cancer is a difficult disease to treat, there are multiple novel therapies emerging to help patients in their battle with this cancer. Gem/Doce offers a novel strategy using commonplace generic chemotherapy drugs that are both safe and effective, and potentially available to all parts of the Arab world, regardless of economic status.

Author’s Biography

Dr. Michael O’Donnell, MD, is the Richard D. Williams Chaired Professor and Director of Urologic Oncology at the University of Iowa Carver College of Medicine and a member of the Holden Comprehensive Cancer Center. Dr. O’Donnell has pioneered new treatments in non-muscle invasive bladder cancer (NMIBC) including combination intravesical immunotherapy and sequential intravesical chemotherapy and directed multiple clinical trials in this space. He has authored over 200 peer-reviewed manuscripts, 20 book chapters, and hundreds of scientific abstracts. He has also lectured extensively nationally and internationally and chaired multiple sessions at national meetings. Currently Dr. O’Donnell is working with the International Bladder Cancer Group (IBCG) to develop new guidelines for the treatment of high-risk BCG-unresponsive NMIBC.

Dr. Mohamad Abou Chakra, MD, is a graduated urologist from the Lebanese University and Sorbonne University. He is currently a clinical research fellow in urologic oncology at the University of Iowa. His clinical and research focus is on understanding and treating patients with urothelial carcinoma. He serves on the editorial board of several high-impact journals and has written more than 75 peer-reviewed articles, mostly in urologic oncology.