Badar M. Mian, MD

“Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, Albany, NY.

Maintenance intravesical bacillus Calmette-GuÃ©rin (BCG) for high-grade urothelial bladder cancer has been the standard of care for nearly 2 decades. The 36-month maintenance regimen, popularly known as the Lamm protocol, has proven quite effective but many patients are unable to complete the protocol due to adverse effects of BCG. Thus, the dose and duration of intravesical BCG has been a subject of numerous studies over the years to develop a more tolerable and efficacious regimen.

Grimm et al report on the latest of such trials assessing the efficacy of an alternative schedule of maintenance BCG.

 The NIMBUS trial was designed to assess whether reduced number of instillations using the standard-dose (full-vial) BCG was “noninferior” to the standard number of instillations.

BCG-naÃ¯ve patients with high-grade, non-muscle-invasive bladder cancer (NMIBC: Ta or T1), with or without carcinoma in situ (CIS), were recruited between December 2013 and October 2019. The study was conducted at 51 sites in 5 countries. The control group (standard frequency, SF) received induction BCG, once per week for 6 consecutive weeks, followed by maintenance instillations, weekly for 3 weeks at 3, 6, and 12 months (total instillations: 15). The experimental group (reduced frequency, RF) received induction BCG once per week at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3, at 3, 6, and 12 months (total instillations: 9). The strain used in the study was BCG Medac in 90% of cases.

The primary end point of interest was time to first recurrence of urothelial cancer, and secondary end points included risk of disease progression, as well as the number and severity of adverse effects. The initial statistical plan called for 500 patients per study arm, but it was revised to 412 patients due to the BCG shortage and prolonged time needed for recruitment and follow-up. The trial was designed to show that the recurrence rate in the RF arm was not inferior to that of the SF arm. A hazard ratio of < 0.75 would have signified inferiority of the RF schedule.

At this pre-planned interim analysis, 175 patients had been randomized to the SF arm and 170 patients to the RF arm. Majority of these patients had primary tumor (92%), without CIS (75%) and stage T1 (54%). At a median follow-up of about 12 months, cancer recurrence was noted in 27% in the RF arm and 12% in the SF arm. Most of the recurrence in the RF arm occurred in the first 6 months. Only 1 patient (0.5%) experienced disease progression to muscle-invasive stage in the SF arm, while 6 patients (3.5%) in the RF arm progressed to muscle-invasive disease.

On Cox regression analysis, HR of 0.40 for time to first recurrence was noted in favor of the SF arm. These data prompted the independent data monitoring committee to halt further recruitment because the primary end point-non-inferiority of RF arm-could not be proved with continuation of the study. Reduced frequency of maintenance instillations (even with the full dose of BCG) was inferior to the standard frequency of BCG maintenance.

The toxicity profile of each arm was determined by analyzing the frequency and severity of adverse effects (Grade ≥ 3). There were no deaths related to the study drugs. In the RF arm, 113 patients (68.5%) experienced 670 adverse effects. In the SF arm, 136 patients (82.4%) reported 1469 adverse effects. Three patients in the RF arm and 14 patients in the SF arm withdrew their consent. The study cohorts will continue to be monitored for adverse effects.

Importantly, the study design required repeat transurethral resection to ensure complete resection and reduce under-staging which is frequently noted after initial transurethral resection. In the RF arm, nearly 60% of the recurrences occurred early; ie, within the first 6 months. The reduced number of instillations given in the RF arm for induction course (3 instillations instead of 6) could explain the poor efficacy of this approach resulting in increased risk of early recurrence and possibly disease progression.

In the era of BCG shortage, it would have been highly desirable to demonstrate the efficacy and safety of fewer BCG instillations for high-risk bladder cancer. However, reduced frequency of maintenance BCG instillations is associated with increased risk of cancer recurrence, albeit with fewer adverse effects. Previous attempts at reducing the toxicity associated with maintenance BCG while maintaining efficacy have demonstrated that 1 instillation every 3 months resulted in increased risk of recurrence than the standard schedule. Similarly, reduced dose (1/3rd dose) was associated with increased risk of recurrence compared with standard dose instillations.

We no longer have the luxury to use organ-preserving BCG regimens as we did a few years ago for high-risk NMIBC. Reserving the use of BCG to those with BCG-naÃ¯ve, high-risk NMIBC, with a full 6-week induction course, followed by standard maintenance schedule for at least 1 year appears to be most practical and efficacious in the current circumstances. BCG therapy should be avoided in those without high-risk disease. If necessary, intravesical chemotherapy (mitomycin or gemcitabine) may be used in intermediate-risk situations. Depending upon the BCG supply at hand, it may be necessary to use reduced dose of BCG (½ or 1/3rd vial) for each maintenance instillation. Every attempt should be made to optimize the delivery and retention of intravesical agents (dehydration, anticholinergics).

For the foreseeable future, the BCG shortage will necessitate vigilance, modification of recommendations, changes in workflow, and training of clinical staff to maximize the use of available BCG.

 Grimm MO, van der Heijden AG, Colombel M et al. Treatment of high-grade non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: results of the European Association of Urology Research Foundation randomised phase III clinical trial “NIMBUS”. 

. 2020 May 20;S0302-2838(20)30334-1. doi: 10.1016/j.eururo.2020.04.066 Online ahead of print

Articles

"In the era of BCG shortage, it would have been highly desirable to demonstrate the efficacy and safety of fewer BCG instillations for high-risk bladder cancer. However, reduced frequency of maintenance BCG instillations is associated with increased risk of cancer recurrence, albeit with fewer adverse effects," writes Badar M. Mian, MD.

Is a reduced bacillus Calmette-Guérin regimen feasible?

Urothelial cancers are sensitive to platinum-based chemotherapy, but due to the low incidence of upper tract urothelial cancer (UTUC) and difficulty in conducting clinical trials, strong evidence supporting the use of chemotherapy has been lacking. However, recently published results of a multi-institutional, randomized, phase 3 trial from the United Kingdom demonstrate significant benefit of adjuvant chemotherapy after nephroureterectomy 

The investigators carried out the POUT (Peri-Operative Chemotherapy Versus Surveillance in Upper Tract Urothelial Cancer) trial to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUC. The eligible patients included those with UTUC after nephroureterectomy, stages pT2-T4 or N1-3, without distant metastasis. Before randomization, patients underwent imaging studies and those with residual lymphadenopathy were excluded.

Between June 2012 and November 2017, 261 patients were recruited from 57 of the 71 open sites. The number of patients assigned to receive 4 cycles of platinum-based chemotherapy was 132, and 129 patients were assigned to undergo initial surveillance, with the option to undergo chemotherapy in case of disease progression. Cisplatin was the agent of choice to be used with gemcitabine, but patients with low glomerular filtration rate (GFR; 30-50 ml/min) could be treated with carboplatin. The primary end point of the study was disease-free survival, defined as time from randomization to either first recurrence in the tumor bed or first metastasis or death from any cause.

The trial was designed to detect a hazard ratio of 0.65 in favor of chemotherapy, equivalent to a 15% absolute improvement in 3-year disease-free survival from 40% to 55%, thus the target was set at 345 participants. Of note, recruitment into the trial was stopped after 261 participants because the preplanned interim analysis by the independent data monitoring committee demonstrated that the prespecified efficacy of chemotherapy had been achieved.

The median age of the 261 patients was 68.5 years and median follow-up was 30.3 months. Nearly two thirds of patients had a GFR of more than 50 ml/min after nephroureterectomy. The pathologic stage was T2-T3 in 94% of patients and 91% were stage N0 (although two thirds of patients did not have any nodes dissected). Of the 126 patients who started chemotherapy, 95 (75%) received the planned 4 cycles and 31 (25%) withdrew from chemotherapy for various reasons.

Adjuvant chemotherapy reduced the relative risk of disease recurrence or death by 55% (HR, 0.45; 

 = .0001). The 3-year disease-free survival estimate was 71% in the chemotherapy group and 46% in the surveillance group. Patients receiving chemotherapy had a lower risk of metastasis or death (HR, 0.48; 

 = .0007). For patients allocated to surveillance after nephroureterectomy, the median disease-free survival among patients was 29.8 months, and median survival had not been reached among those receiving chemotherapy. Overall survival estimates could not be performed at this point due to shorter follow-up and fewer events (deaths) than required for proper statistical analysis.

Significant adverse effects (AEs, grade 3 or worse) were reported by 44% of patients who started chemotherapy compared with 4% of those who were assigned initial surveillance (

 <.0001). There were 54 serious AEs in 42 patients (32%) who received chemotherapy.

Although the use of adjuvant chemotherapy using platinum-based agents following nephro-ureterectomy is not a new concept, it had been based primarily on heterogenous data showing mixed results. The POUT trial represents the largest study in this patient population assessing the benefit of adjuvant chemotherapy. Due to the rarity of this disease, it is difficult to recruit patients, which is further underscored by the fact that it took over 5 years, 71 centers, and the weight of a national health system to recruit 261 patients. With those inherent constraints, some questions remain unanswered.

As acknowledged by the authors, disease-free survival may not be a proven surrogate for overall survival but it may be the best we can achieve for some rare conditions. Adjuvant chemotherapy is suggested as the new standard of care after nephroureterectomy in those who are fit enough to qualify. However, the denominator is not provided which may be instructive; ie, how many patients underwent nephroureterectomy at these 71 centers who met the inclusion criteria but did not enroll in the study? Due to small numbers in the subset analysis, it is difficult to ascertain whether the benefit of adjuvant chemotherapy was noted primarily in organ-confined disease or in patients with positive margins or nodal disease.

Carboplatin use is born of necessity in many patients with low GFR, although data from previously conducted trials endorse the superiority of cisplatin against urothelial cancers. Further, there are some barriers to using cisplatin chemotherapy before a nephroureterectomy when renal function is still preserved. The main hurdle appears to be the difficulty in proper staging to identify stage T2 or higher, due to the limitations posed by the anatomy and available instruments. Thus, there is a valid concern about overtreatment of nearly 40% to 50% of patients with UTUC.

This important trial supports the use of adjuvant chemotherapy after nephroureterectomy for stage T2 or higher cases. Studies are ongoing to assess the feasibility of adjuvant vs neoadjuvant platinum-based chemotherapy for UTUC. As the quality of imaging and instrumentation improves, using a combination of antegrade, retrograde, and percutaneous techniques, it will help to identify candidates who may benefit from upfront chemotherapy.

"This important trial supports the use of adjuvant chemotherapy after nephroureterectomy for stage T2 or higher cases," writes Badar M M. Mian, MD.

Study shows benefit of adjuvant chemo after nephroureterectomy

Active surveillance (AS) for low-risk prostate cancer is recommended as a viable or preferred option by most professional organizations, and it has gradually gained acceptance by most physicians who manage this condition. Several reports over the last two decades demonstrated the safety of AS for men with very low- or low-risk prostate cancer. An AS approach, unlike watchful waiting, still retains the option to treat, with an intention to cure, if treatment becomes necessary. The natural history of PSA-detected, early-stage prostate cancer is quite long, so long-term safety and efficacy of AS is of particular interest.

Tosoian et al report that AS in men with very low- or low-risk, Grade Group 1 prostate cancer appears to be quite safe, with risk of metastasis or prostate cancer-specific mortality (PCSM) of <1% 

Jan. 6, 2020 [Epub ahead of print]). In their large, prospective AS program, 1,818 men were enrolled after the initial prostate biopsy revealed very low-risk (1,293, 71%) or low-risk (525, 29%) prostate cancer.

After enrollment, the initial monitoring protocol included repeat prostate biopsy every year. Multiparametric MRI and mpMRI/ultrasound-fusion targeted biopsy were used since 2013 and 2014, respectively. Five hundred thirty-seven men (30%) underwent pre-enrollment mpMRI, with nearly half (47%) with a positive MRI requiring image-fusion targeted biopsy.

The study enrolled 1,818 patients from January 1995 through June 2018, with 920 men followed for ≥5 years and 305 men for ≥10 years. The median interval between biopsies was 13 months. The cumulative incidence of loss to follow-up at 3, 5, and 10 years was quite low at 3%, 4%, and 6%, respectively. Definitive treatment was offered to all patients with grade reclassification (Grade Group ≥2) on any subsequent prostate biopsy. Treatment or continued AS was offered to men whose repeat biopsy showed increase in volume of cancer (more than two positive cores and/or >50% involvement of a core).

Of the entire cohort, 92 men (5%) died at a median age of 80 years, and of those, 88 were due to non-prostate cancer causes. The cumulative incidence of all-cause mortality was 6.8% at 10 years and 28% at 15 years. Death due to prostate cancer was quite rare, with only four men (0.2%) dying of prostate cancer during the study period. The cumulative incidence of PCSM or metastasis was 0.1% at both 10 and 15 years.

Seven hundred twenty-seven men (40%) underwent biopsy grade reclassification, with the 5-, 10-, and 15-year incidence of grade reclassification of 21%, 30%, and 32%, respectively. The incidence of reclassification to Grade Group ≥3 was 7%, 10%, and 11%, respectively. Of the 693 men who underwent treatment, 78% were due to biopsy reclassification while 22% were due to change in preference. The 5-, 10-, and 15-year incidence of receiving definitive treatment was 36%, 48%, and 52%, respectively.

On multivariable analysis, pre-enrollment mpMRI was associated with a reduced risk of grade reclassification 

=.03). Factors associated with grade reclassification included older age, later year of diagnosis, African-American race, and increased PSAD, number of positive cores, and core involvement. Although the data showed that older age, African-American race, and measures of cancer volume, as well as use of pre-enrollment mpMRI were associated with an increased risk of grade reclassification, these variables did not appear to negatively impact any of the survival outcomes. There does not appear to be any strong rationale to limit African-American patients from enrolling in an AS protocol.

Because the mortality rate (overall and cancer specific) and metastases were so infrequent, the Grade Group reclassification was the most frequent outcome reported. Clearly, grade reclassification should not be viewed as an ominous event since these patients were captured through AS and treated, without negatively affecting their overall survival. Nearly 38% of patients underwent treatment, including those who had a change of heart about AS. No data are provided about the type of definitive treatment received by these patients. It would be instructive to know their pathologic outcomes, recurrence rates, or the need for secondary therapies.

Pre-enrollment mpMRI was associated with a decreased risk of biopsy grade reclassification during follow-up, especially if the mpMRI was negative. It’s not clear from this study whether the mpMRI was used “during” AS and how often. It will be interesting to learn whether these patients with pre-enrollment and/or surveillance mpMRI benefitted in terms of fewer subsequent biopsy sessions or fewer cores taken.

The monitoring protocol reported by the authors is quite stringent, with frequent (annual) repeat biopsies. As active surveillance protocols for low-risk prostate cancer become more widely accepted, there are justifiable concerns about the AS-related morbidity of intensive monitoring. It’s likely that a less invasive surveillance protocol, incorporating better imaging (eg, mpMRI) or genomic testing and fewer biopsies, will not adversely impact the excellent survival outcomes while making AS a more readily acceptable option for low-risk prostate cancer.

"Death due to prostate cancer was quite rare, with only four men (0.2%) dying of prostate cancer during the study period," writes Badar M. Mian, MD.

Surveillance safe for patients with Grade Group 1 prostate Ca

Depending on tumor characteristics and length of follow-up, recurrent nonmuscle-invasive bladder cancer (NMIBC) can develop in 20% to 40% of patients following initial intravesical Bacillus Calmette-GuÃ©rin therapy. Most experts recommend radical cystectomy for patients with BCG-unresponsive NMIBC. Yet, many patients are either not good candidates for major surgery or they desire to preserve a functioning bladder. Many bladder preservation strategies, including various immunotherapy and chemotherapy agents, in various combinations and schedules, have been tested over the years but most have not provided durable control of this disease.

Adopting the rationale from combination systemic chemotherapy used in advanced bladder cancer, some centers have utilized combination intravesical chemotherapy with sequential use of gemcitabine (Gemzar) and docetaxel (Taxotere) as a salvage strategy for patients with recurrent NMIBC. To determine the effectiveness of this approach, Steinberg et al performed a retrospective analysis of the data from multiple institutions showing promising results in this difficult cohort of patients 

The authors pooled the data from 11 different centers and identified 276 patients with recurrent NMIBC (median age, 73 years) treated with sequential gemcitabine and docetaxel from 2009 to 2018. The patients had undergone a median of two previous intravesical induction courses and a median of one BCG induction course (range, 1-4). Of these, 38% were classified as BCG unresponsive, ie, early recurrence (within 6-12 months) of various NMIBC pathology.

The instillation protocol included gemcitabine, 1 gram in 50 mL saline or water instilled via Foley catheter and allowed to remain in the bladder for 60 to 90 minutes. After drainage of the gemcitabine, docetaxel, 37.5 mg in 50 mL saline, was instilled. The catheter was removed and patients were instructed to not void for 60 to 120 minutes. This induction regimen was administered once per week for 6 weeks.

Study compares prostate cancer treatment functional outcomes

Most institutions used this combination intravesical chemotherapy once per month for 24 months. Side effects were reported by 41% of patients, requiring modification of schedule in 10%. The most frequently noted side effects included irritative urinary symptoms (22%), dysuria (16%), and hematuria (11%).

The data were presented separately for any recurrence or high-grade recurrence after treatment. Any recurrence-free survival (RFS) in all treated patients was 60% at 1 year and 46% at 2 years, with a median follow-up of 13.9 months. Median time to recurrence was 6.8 months (range, 2.0 to 67.3). RFS for patients with any carcinoma in situ was 60% at 1 year and 43% at 2 years, and RFS for those with papillary disease alone was 62% at 1 year and 51% at 2 years.

High-grade RFS in all patients was 65% at 1 year and 52% at 2 years. In the BCG-unresponsive group, 50% of those with carcinoma in situ and 58% of those with papillary disease were free of high-grade recurrence at 2 years. Using the maintenance protocol was associated with lower recurrence rate, both low grade and high grade 

<.01). Of the 43 patients undergoing cystectomy (at median of 11.3 months), 38 were due to recurrent disease. Final pathology showed stage T0 in seven patients and T2 or higher in 11 patients, four of whom had lymph node metastases.

Forty-four patients (16%) died at median follow-up of 22.9 months, and 13 (5%) died of metastatic bladder cancer. In patients dying of bladder cancer, carcinoma in situ was the initial diagnosis in eight of 13 patients. The bladder cancer-specific mortality rate was 1% at 1 year and 4% at 2 years, while the all-cause mortality rate was 3% and 13%, respectively.

This report on sequential intravesical gemcitabine and docetaxel for BCG-recurrent NMIBC shows promising results. The recurrence-free rates appear to be better than many previously reported attempts at controlling recurrent or resistant disease. This may be due in part to the fact that these patients were treated early in the salvage paradigm (history of one or two inductions) and not heavily pre-treated with multiple induction or maintenance courses. This regimen appears to be well tolerated and with an acceptable rate of schedule modification. Because there was no standardized method for collecting the data, the rate and severity of adverse effects are likely underreported.

Could mpMRI replace prostate Bx for surveillance protocols?

In this era of BCG shortage, we may be forced to develop new standards and alternative strategies for bladder preservation. Can the sequential intravesical chemotherapy replace BCG in patients with newly diagnosed NMIBC with sufficient efficacy? Or can it replace maintenance BCG so that the precious supply of available BCG can be reserved for patients with initial high-risk NMIBC?

Radical cystectomy is probably the most complex urologic surgery, with a high rate of short-term complications. While it can be a life-saving intervention, it can also be life-changing event with significant implications related to quality of life and survivorship. Thus, bladder preservation will always be desired by patients. The challenges created by the BCG shortages also provide the rationale and opportunity for prospective validation of this and other bladder preservation strategies.

"In this era of BCG shortage, we may be forced to develop new standards and alternative strategies for bladder preservation," writes Badar M. Mian, MD.

Author | Badar M. Mian, MD

Articles

Is a reduced bacillus Calmette-Guérin regimen feasible?

Study shows benefit of adjuvant chemo after nephroureterectomy

Surveillance safe for patients with Grade Group 1 prostate Ca

Sequential gemcitabine/docetaxel promising for recurrent NMIBC