Adjuvant Radiation for Bladder Cancer: The Who, What, How, and Why of NRG-GU001

NRG Oncology has recently launched a randomized phase II trial of post-cystectomy intensity-modulated radiation therapy (IMRT) for patients with pT3/pT4 urothelial bladder cancer (NRG-GU001).1 This trial was developed in response to (1) a growing appreciation of the burden of pelvic failure after radical cystectomy and perioperative chemotherapy in patients with adverse pathologic features, (2) a greater understanding of which subregions within the pelvis are most likely to harbor subclinical disease, and (3) the development of radiation delivery methods that may enable both effective and safe treatment of this challenging cohort.

It is remarkable that in 2016, adjuvant radiation does not already have a clearly established role in locally advanced bladder cancer. Clinical experience and formal experimentation have established multimodality treatment involving varying combinations of surgery, radiotherapy, and systemic treatments as pivotal in securing optimal cure rates in the preponderance of locally advanced solid tumors, except for bladder cancer.  A partial list of malignancies for which adjunctive radiation is established includes melanomatous and non-melanomatous skin cancers, sarcomas, central nervous system tumors, and head and neck, thyroid, breast, lung, esophageal, gastric, pancreatic, rectal, anorectal, endometrial, cervical, vulvovaginal, and prostate cancers. Moreover, there are already reports from two randomized trials performed within an Egyptian population that suggest adjuvant radiation is reasonably well tolerated and effective.

These studies have not changed the patterns of care within Western health systems likely because of the high proportion of patients included who had pure squamous cell carcinoma, an uncommon histology in the West. To be clear, the role of adjuvant radiation in locally advanced urothelial carcinoma has not been clearly established, but we are well positioned now to rigorously and safely study this approach in a population of patients who clearly have unacceptably poor cancer control outcomes.

Who Is Most Likely to Benefit?

NRG-GU001 is enrolling patients with pT3/pT4 pN0-2 urothelial (pure or mixed) bladder cancer following radical cystectomy with ileal conduit. Patients will be stratified by whether they have received perioperative chemotherapy and by pelvic relapse risk category.

Three important points emerge from these eligibility criteria. First, the inclusion criteria and the pelvic relapse stratification used here have been validated in at least four diverse radical cystectomy cohorts. Retrospective series from the United States2 and South Korea3 and prospective multi-institutional studies representing North American2 and European4 cohorts have consistently shown that this subset of patients with locally advanced disease have a 20% to 45% cumulative incidence of pelvic failure within 5 years of surgery depending on surgical margin status and the number of lymph nodes identified in the pelvic nodal dissection.

Second, although pT status, surgical margin status, and the number of nodes identified clearly and meaningfully modulate pelvic failure risk, the use of perioperative chemotherapy does not. Although the reason is not clear, it may be that patients who have local recurrence after cystectomy simply have too great a burden of disease to be addressed by currently established chemotherapies. Nonetheless, NRG-GU001 has been designed to accommodate neoadjuvant or adjuvant chemotherapy to ensure that pursuit of maximal pelvic control does not come at the expense of currently achievable systemic control.

Third, pelvic node involvement also does not independently predict pelvic relapse when accounting for distant metastases as a competing risk. This is counterintuitive because, as discussed in the next section, the subregions within the pelvis where local recurrences most commonly occur are along the pelvic lymph node regions. However, multiple careful pelvic failure risk-stratification studies suggest that patients with pathologic lymph node involvement in the absence of other adverse pathologic features are not likely to benefit from adjuvant radiation, probably because the competing risk of isolated distant metastases is so high.

These insights about pelvic failure risk are powerful. They have allowed NRG Oncology to target NRG-GU001 enrollment at patients most likely to benefit from adjuvant radiation and to minimize the risks of over treating patients who would respond well (or poorly) regardless of additional local-regional treatments.

What Subregions of the Pelvis Should Be Targeted?

The ever-improving accuracy of radiation therapy techniques enables better sparing of normal tissue but also raises concern that treatments may inadvertently exclude at-risk tissue. More than ever, radiation oncologists must clearly define their target when establishing novel strategies.

Baumann et al. have published estimates of the cumulative incidence of failure within subregions of the pelvis.5 This study suggested that the majority of failures after radical cystectomy are along the pelvic sidewalls and that the central pelvis could reasonably be spared. The study also found that the pattern of failure within the pelvis was different for patients who had positive surgical margins than for those who had negative surgical margins. The result suggested that the cystectomy bed could reasonably be spared in the subset of patients with negative margins. Because the bowel falls primarily within the central pelvis and cystectomy bed after radical cystectomy, these observations may allow trials to further improve the therapeutic ratio of adjuvant radiation.

An international and multidisciplinary team of urologists and radiation oncologists recently reported recommendations on which subregions of the pelvis should be targeted in adjuvant radiation clinical trials.6 The collaboration proposed that patients at elevated risk of pelvic failure but with negative surgical margins should receive treatment to their pelvic lymph node regions alone, including the internal iliac, external iliac, distal common iliac, and presacral nodes. The team recommended that patients with positive surgical margins receive treatment to both the pelvic lymph nodes and the cystectomy bed. Finally, the team developed and validated a definition of the cystectomy bed because there were previously no consensus guidelines on how this region should be contoured.

NRG-GU001 incorporates the recommendations of the countering collaboration. A greater understanding of the subregions of the pelvis that are at risk and a consistent description of how these regions should be identified in a multi-institutional setting will enable NRG-GU001 and other clinical trials to optimize safety and efficacy of adjuvant radiation by using the most modern and conformal radiation therapy techniques.

How Should Radiation Be Delivered?

The major concern about including adjuvant radiation in the treatment paradigm of locally advanced bladder cancer is increasing the already substantial risk of post-cystectomy bowel obstruction. A recent paper suggests that modern radiation techniques could reduce this risk compared to historical radiation approaches.7 This study compared the low-, intermediate-, and high-dose baths received by the bowel and rectum when using 3D conformal (3DC) radiation, IMRT, and single-field uniform dose (SFUD) proton therapy. Both IMRT and SFUD yield plans that were consistently superior to 3DC with respect to bowel and rectal sparing. This conclusion held when only the pelvic nodal regions were targeted and when both the pelvic nodes and cystectomy beds were targeted.

Although modern approaches are more resource intensive than 3DC, the magnitude of bowel and rectal sparing appears to justify their use. In addition, the international radiation oncology community now has broad experience with IMRT in other clinical scenarios, which means that a positive adjuvant radiation trial using IMRT would be generalizable. As such, NRG-GU001 requires the use of IMRT.

The Rationale for NRG-GU001

Patients with locally advanced bladder cancer have unacceptable pelvic failure rates (20% to 45% at 5 years), and, as has been established in numerous other solid tumor types, adjuvant radiation could improve locoregional control. NRG Oncology has designed a rigorous and promising clinical trial that takes advantage of a greater appreciation of the pathologic features that predict for pelvic recurrence, a more precise identification of target tissues, and advances in radiation delivery. NRG-GU001 potentially represents an important step forward for this cohort of patients who historically have been challenging to treat.