Benefits of Surgery in Older Adults with Metastatic Urothelial Carcinoma Evaluated Using Largest Dataset of its Kind

Bladder_FBUrothelial carcinoma is the most common type of bladder cancer, also affecting other parts of the urinary system. It is an aggressive disease and its treatment remains challenging for clinicians. Currently, each year there are nearly 80,000 new cases of urothelial cancer and approximately 16,000 deaths from the disease, according to the American Cancer Society. Unfortunately, there are limited therapeutic options for those with advanced urothelial carcinoma especially after the disease spreads to other distant organs (metastasis). Even with platinum-based chemotherapy and the introduction of immunotherapy, median overall survival is poor, and a five-year survival is only 15%.

The idea of metastasectomy (surgical removal of metastatic tumors) has been proven to be an established option in the treatment of patients with other solid tumors, however, little is known regarding the benefit and safety of this type of surgery for urothelial carcinoma patients because previous studies were mostly from single institutions and limited by small sample size.

Drs. Bishoy Faltas, Scott Tagawa, Jim Hu, along with others at Weill Cornell Medicine and NewYork-Presbyterian Hospital, partnered with the Center for Health Policy and Outcomes and Memorial Sloan Kettering Cancer Center to address this very question and their research has now been published in Urologic Oncology: Seminars and Original Investigations. Their goal was to examine the use and outcomes of surgery in older patients with urothelial carcinoma in a large population-based dataset. To do this, clinicians conducted a SEER-Medicare study. SEER is a database run by the National Institutes of Health (NIH) that collects large population-based data that provide detailed information about Medicare beneficiaries with cancer. The research was analyzed based on the billing codes the physician’s offices used when submitting insurance claims.

Using this data, clinicians found 70,648 urothelial carcinoma patients and from those, they identified 497 patients who had at least one surgery to remove a metastatic lesion during a median follow-up of 40 months. The median overall survival after the first surgery was 19 months. In this selected patient population, over a third of patients were alive at three years. The median length of stay after surgery was seven days with 10% of patients having at least one complication within 30 days of discharge.

Close-up of gloved hands passing the surgical scissors“It would be very difficult to conduct a randomized clinical trial testing surgery versus no surgery in those with urothelial carcinoma, so reviewing a large dataset retroactively is the next best thing,” says Dr. Bishoy Faltas, Assistant Professor and medical oncologist at Weill Cornell Medicine’s Genitourinary Oncology Program. “Our study shows that in well-selected patients with urothelial carcinoma with a reasonable life expectancy, resection of metastatic lesions is safe and associated with long-term survival and potential cures,” says Dr. Faltas.

What are Other Benefits of Surgery?

Aside from the fact that surgery can prolong life for those with urothelial carcinoma, there are other benefits as well. One of the benefits is enabling the testing of tissue that is removed. Studying this tissue allows clinicians to continue performing precision medicine and treating the individual, not the disease. As described in a previous research study conducted by Dr. Bishoy Faltas titled, “Clonal Evolution of Chemotherapy-Resistant Urothelial Carcinoma” published in Nature Genetics, it has been proven that tumors change and undergo clonal evolution over time especially in metastases after chemotherapy.

“Understanding the evolution of urothelial carcinoma is a central biological question and one that we can only truly begin to understand by testing tissue samples from patients at various periods throughout their treatment,” says Dr. Faltas.

Another potential benefit of surgery is the cost implication. With drug prices continuing to rise, depending on insurance carriers, there is the potential that surgery may be less costly than some of the long-term medications associated with treatment for urothelial cancer. Cost implications of course vary for each patient; however, it is one of the factors along with many others that should be addressed and discussed with healthcare teams.

“There is a lot more work to be done to help treat patients with urothelial cancer, however with the dataset we’ve compiled through our latest study, we’re able to glean the potential benefits of metastasectomy in older adults with urothelial cancer, which could lead to prolonged life and potential cures.”

ESMO 2017: Day 2 Recap

IMG_3948The second day of ESMO included the oral genitourinary (GU) oncology session that focused on renal cell (kidney) and urothelial (bladder) carcinoma.

Several years ago, the SWITCH study evaluated the sequence of sunitinib and sorafenib showing similar overall progression free survival and overall survival regardless of the order by which each drug was utilized. At ESMO 2017, results of the SWITCH-II trial were presented. This study tested the sequence of pazopanib and sorafenib in patients with advanced RCC of any histology (i.e. clear cell or non-clear cell).  The study sought to enroll 544 patients, but stopped after 377 patients due to slow accrual. Only half of the patients remained on study and switched to their assigned drug after tumor growth on drug #1. Overall, while the study didn’t complete planned accrual, there was a trend for improved progression-free and overall survival for the pazopanib → sorafenib sequence.

Historically when most patients were treated with cytokines (IL-2 and interferon), two randomized trials by U.S. and European cooperative groups showed that in the setting of metastatic kidney disease, patients live longer by first removing the kidney mass and then treating with interferon rather than treating with interferon without removal of the kidney. Since the introduction of new therapies in late 2005 which have higher rates of tumor shrinkage and longer lifespans for patients, it is unknown if patients should still have their kidney tumor removed prior to drug therapy.

IMG_3954In the EORTC 30073 SURTIME trial, European investigators decided to try to assess whether tumors remained under control longer and patients lived longer if surgery was performed first or if patients initiated sunitinib for 3 cycles prior to cytoreductive nephrectomy. Because enrollment was slow, the study design was changed to assess the percent of patients that were free of tumor progression at 28 weeks. Ninety-nine patients were randomized to immediate versus delayed surgery, most with large kidney tumors and intermediate-risk cancer. Overall there was no difference in the percent with cancer progression at 28 weeks with either approach.  With the caveat of a small study, there were trends for longer survival and less surgical complications in those with delayed surgery. While the amended study is not able to prove that delayed surgery is the better approach, it gives comfort for those physicians/patients that the choice to initiate medical therapy and then re-evaluate for surgery is acceptable. We await the results of the larger CARMENA study that is testing surgery followed by drug versus drug alone (with no surgery) to see if removal of the primary kidney tumor is necessary.

Additionally, two early-phase studies of novel drug combinations of immunotherapy + targeted therapy were presented. In a phase I study led by the NCI, the safety of the combinations of cabozantinib/nivolumab and cabozantinib/nivolumab/ipilimumab were tested in patients with a number of different treatment-refractory tumor types, especially urothelial and other types of bladder cancers. Overall, both combinations were deemed to be safe and are moving forward in a phase III trial. However, many toxicities did occur and most patients needed to reduce the dose of at least one drug so these combinations should only be used in a clinical trial setting.

IMG_3958The phase II portion of a phase I/II study testing the combination of lenvatinib + pembrolizumab. The initial (phase 1) portion of the study presented at ESMO 2016 determined the safe dose in patients with different types of tumors (mostly RCC). This year, new results were presented with 22 additional patients added to the 8 previously treated on the phase I portion. Overall, there was an impressive tumor response rate of 63%, with 83% significant tumor shrinkage in those patients treated in the 1st line setting. This combination is also being tested in a phase III study for patients with advanced RCC which will soon be opening at Weill Cornell Medicine and NewYork-Presbyterian.

Missed our Day 1 Recap of ESMO 2017? Check it out here.