Role of Local Therapy in Clinical Node-Positive Bladder Cancer - Beyond the Abstract

It is estimated that clinical node-positive urothelial carcinoma of the bladder (cN+UCaB) affects approximately 5-10% of the patients that are diagnosed with muscle-invasive bladder cancer (MIBC).¹ Its treatment presents a clinical challenge to the treating physician due to the ambiguity surrounding its regional versus metastatic classification. This is an important issue however as a significant proportion of these patients are still potentially ‘curable’ with timely care.^{2, 3} Given the paucity of literature on direct comparisons among the various available treatment options for these patients, we undertook the current study to examine the impact of local treatment regimens alongside systemic chemotherapy on outcomes in patients with cN+UCaB.

We utilized the National Cancer Data Base (NCDB) registry and identified 3,227 individuals with non-metastatic cN+UCaB disease that received multiagent systemic chemotherapy between 2004 and 2016. All of these patients were noted to have positive pelvic lymph nodes on imaging with or without biopsy confirmation. We then divided this cohort into two groups: those that received high-intensity local therapy (LT) (n=784) versus those that only got conservative LT (n=2,443) alongside multiagent systemic chemotherapy. High-intensity LT was defined as patients who underwent radical cystectomy with pelvic lymph node dissection (RC + PLND) or high-dose radiation (≥50 Gy) to the bladder plus transurethral resection of bladder tumor (TURBT). Conservative LT was defined as the observation, TURBT alone, or low-dose radiation therapy (<50 Gy) alone.

Given that this was an observational study, we employed non-parsimonious propensity score analysis in order to account for known confounders in baseline characteristics between patients receiving high-intensity versus conservative LT. We also performed Ding and VanderWeele analysis to assess the impact of unknown confounders on the study findings (none was present).

We noted several key findings. Our study suggested that in patients receiving multiagent systemic chemotherapy, high-intensity LT was associated with a 10% absolute improvement in 5-year overall survival over conservative LT (28.4 versus 18.3% overall survival), which corresponded to a number-needed-to-treat of 9.9. This benefit was true for all patients with cN+UCaB regardless of their comorbidities and life expectancy. There is good biological rationale for this. In human translational studies of metastatic malignancies, the principal tumor has been demonstrated to spread to the bloodstream not only by dissemination of cancer cells from the index lesion but also from the lymph-nodal deposits of the primary tumor. In fact, the latter is proposed to be the major route.⁴ Further, it has been shown that local disease promotes systemic seeding by priming the premetastatic niche — the ‘seed and soil’ theory.⁵ Controlling loco-regional tumor burden thus makes sense, somewhat akin to controlling an abscess cavity in the setting of sepsis.

Despite our data suggesting improvement in overall survival with high-intensity LT, concerningly we found that there is decreasing utilization of high-intensity LT for these patients — a 7.3% annual decrease in the utilization was noted over the duration of the study period.

Lastly, in a subgroup analysis of patients who received high-intensity LT, we found that RC + PLND offered an improved 5-year overall survival benefit compared to those who received trimodal therapy albeit this difference was not statistically significant (overall survival of 31.7% versus 20.5%, Log-rank p=0.092). This may be reflective of the generally poorer health of the patients that undergo radiation as compared to surgery but could also indicate increased efficacy of surgery in treating this condition.

Our study expands on the work by Galsky that suggested that a combined treatment modality approach was superior to a single modality treatment.⁶ The Galsky study however did not evaluate trimodal therapy, and also did not evaluate the usefulness of local treatments in the setting of life expectancy. Hence, our study explores these questions and adds to the literature in a meaningful way.

In conclusion, whether it is trimodal therapy or RC + PLND, our findings suggest that eligible patients should be considered for aggressive local therapy alongside multiagent systemic therapy. Our findings however should be interpreted in the context of the drawbacks of our study. The main bias to consider is the retrospective analysis. Despite using advanced statistical methods to account for both known and unknown confounders, it is not possible to completely overcome the bias of patient selection. Hence, our work underscores the need for additional investigation and primarily lays down the groundwork for prospective studies evaluating the comparative effectiveness of various treatment options for patients with cN+UCaB.

Written by: Isaac Palma-Zamora, MD, Henry Ford Health System and Akshay Sood, MD, The University of Texas MD Anderson Cancer Center

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