Doctors Debate: Should Systemic Therapy for UTUC Be Given in the Adjuvant or Neoadjuvant Setting?

Bassel Nazha, MD, MPH

The rarity and aggressiveness of localized upper tract urothelial cancer (UTUC) mean that patients with the disease have poorer outcomes compared with those who have lower tract UC. Treatment of high-risk UTUC requires radical nephroureterectomy and consideration of perioperative chemotherapy, but genitourinary oncologists still question whether it is best to administer chemotherapy in a neoadjuvant or adjuvant fashion.

During the 2022 Debates and Didactics in Hematology and Oncology conference, Bassel Nazha, MD, MPH, assistant professor of genitourinary medical oncology at Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, argued in favor of adjuvant therapy for UTUC. The presentation by Jacqueline T. Brown, MD, assistant professor of genitourinary medical oncology at Winship Cancer Institute, supported neoadjuvant therapy for high-risk UTUC.^1,2

The management of UTUC is guided by tumor grade. Low-risk UTUC is characterized by unifocal disease, tumor size less than 2 cm, high-grade cytology negativity, low-grade ureteroscopy biopsy, and having no invasive aspect on CT.^1,2

The disease is considered high risk if there is multifocal disease, a tumor size of 2 cm or larger, high-grade cytology and ureteroscopy biopsy, local invasion on CT, hydronephrosis, and if the patient had previous radical cystectomy for high-grade bladder cancer and variant histology.

Endoscopic resection can be considered for low-risk tumors but for high-risk disease, the gold standard is radical nephroureterectomy with bladder cuff resection and regional lymphadenectomy. For high-risk urothelial cancer of the distal ureter, distal ureterectomy with lymphadenectomy along can be considered. The current guidelines recommend adjuvant chemotherapy in those with high-risk disease at the time of surgery (including continued muscle invasion or node positive disease) who did not receive neoadjuvant therapy, leaving the door open for both approaches.

Adjuvant Treatment for Localized UTUC

It is difficult for oncologists to establish the degree of muscle invasion in a patient with UTUC before definitive surgery, according to Nazha. However, the National Comprehensive Cancer Network (NCCN) makes the treatment decision less difficult by recommending that radical nephroureterectomy be performed first.1 The NCCN Clinical Practice Guidelines in Oncology, upper GU tract tumors, version 2.2022 also mentions that adjuvant cisplatin-based chemotherapy is an effective systemic treatment after surgery.¹

“I presented the arguments for adjuvant therapy, and the key point was the consistency with the guidelines. There’s level 1 evidence to support this approach with the results from the POUT trial [NCT01993979]. And the POUT trial supports switching from cisplatin to carboplatin when needed and if needed,” Nazha said in an interview with Targeted Oncology^TM.

POUT was a randomized phase 3 trial of perioperative chemotherapy vs surveillance in patients with UTUC. The study included 261 patients who were randomly assigned 1:1 to perioperative chemotherapy or to undergo surveillance. In the chemotherapy arm, most patients received four 21-day cycles of gemcitabine plus cisplatin. Patients with suboptimal renal function received gemcitabine plus carboplatin. The primary end point in the study was disease-free survival (DFS). The secondary end points included overall survival (OS), metastasis-free survival (MFS), incidence of bladder second primary tumors, incidence of contralateral primary tumors, acute and late toxicity, and quality of life.³

Initial results from POUT, which closed early at the recommendation of the independent monitoring committee after meeting early criteria for efficacy, showed a significant DFS advantage when gemcitabine and platinum-based chemotherapy were initiated within 90 days after nephroureterectomy (HR, 0.45; 95% CI, 0.30-0.68; P =.0001). Moreover, the estimated 3-year results for the secondary end points favored chemotherapy vs surveillance. The HR for MFS was 0.45 (95% CI, 0.30-0.68; P =.0001).

Updated results from POUT were reported at the American Society of Clinical Oncology 2021 Genitourinary Cancers Symposium. The findings showed that the DFS benefit was maintained with longer follow-up without negatively impacting long-term toxicity.^1,4

The 3-year DFS rate was 71% (95% CI, 62%-78%) in the chemotherapy arm vs 63% (95% CI, 52%-71%) in the surveillance arm (HR, 0.51; 95% CI, 0.35-0.76; log-rank P =.0006). For MFS, the 3-year rate was 72% (95% CI, 62%-79%) with chemotherapy vs 63% (95% CI, 53%-72%) with surveillance (HR, 0.52; 95% CI, 0.36-0.77; log-rank P =.0007).

No significant OS advantage was observed with chemotherapy in the study. The 3-year OS rates were 79% (95% CI, 71%-86%) in the chemotherapy arm vs 67% (95% CI, 58%-75%) in the surveillance arm (HR, 0.70; 95% CI, 0.46-1.06; log-rank P =.09).

“There was a signal for improvement and the OS. But to do a trial that would allow a significant OS improvement in UTUC would be very difficult based on the rarity of this disease. And it would require a large trial that is just not feasible,” explained Nazha.

The study did not reveal any significant long-term toxicity associated with chemotherapy. The majority of grade 2 or higher adverse events observed during the study after 6 months were hypertension (10.4%), lethargy (10.4%), and urinary tract infection (5.8%). Quality-of-life outcomes were also better with chemotherapy vs surveillance.

Nazha noted that other phase 3 trials may lead (based on subgroup analyses) to the availability of targeted therapy and immunotherapy in the adjuvant setting for patients with high-risk UC. Such studies include the AMBASSADOR (NCT03244384; adjuvant pembrolizumab [Keytruda]), CheckMate 274 (NCT02632409; adjuvant nivolumab [Opdivo]), and PROOF 302 (NCT04197986; adjuvant infigratinib [Truseltiq]) trials.

Neoadjuvant Treatment for Localized UTUC

According to Brown, the standard-of-care strategy of administering cisplatin-based chemotherapy in the adjuvant setting can be difficult due to the patient recently having underwent radical nephroureterectomy which leads to decreased renal function. Cisplatin historically requires a creatinine clearance greater than or equal to 60 mL/min, although modern practice suggests a lower minimum is possible.

Jacqueline T. Brown, MD

“We know that with that standard-of-care therapy, patients will be losing 1 renal unit with their radical nephroureterectomy, and that’s half of their available nephrons. We know that their GFR [glomerular filtration rate] will be lower after the time of surgery, which can affect their ability to handle cisplatin-based chemotherapy even with appropriate mitigation techniques like aggressive hydration and split-dose cisplatin administration,” explained Brown during a separate interview with Targeted Therapies in Oncology™. “Although getting carboplatin chemotherapy is a possibility for those patients, the POUT trial did suggest an improvement in outcome with cisplatin over carboplatin, although that subgroup analysis was not statistically significant. A separate reason to consider neoadjuvant chemotherapy is the potential for surgical complications that can make it harder to administer chemotherapy after the fact. While we know that radical nephroureterectomy is overall a less morbid surgery than radical cystectomy for lower track disease, it is not without the risk of complications.”

According to Brown, research shows that after nephroureterectomy, only 16% of patients have a GFR score of at least 60 compared with 37% before surgery. Retrospective analyses have also shown that after such a procedure, only about 31% of patients receive adjuvant chemotherapy who had indications for it determined at the time of surgery.²

“We know that only a minority of [individuals] who should be getting chemotherapy actually go on to get it. As a result, the opportunity to give neoadjuvant chemotherapy is attractive because patients have both their kidneys to be able to tolerate that chemotherapy, and they haven’t had any of those surgical complications that may take place and later prevent the provision of adjuvant chemotherapy,” Brown said.

Prospective findings from the phase 2 ECOG-ACRIN 8141 study (NCT02412670) showed that neoadjuvant treatment with a chemotherapy combination was safe and showed signals of activity. The results support the use of neoadjuvant therapy in patients with high-grade UTUC.⁵

ECOG-ACRIN 8141 included 30 patients with high-grade UTUC who were treated with either the combination of accelerated methotrexate, vinblastine, doxorubicin, cisplatin, or gemcitabine plus carboplatin. The primary end point was complete pathologic response rate, and the secondary end points were recurrence-free survival, event-free survival, bladder cancer-free survival, the cumulative incidence of cancer-specific death at 24 months, the proportion of patients with renal insufficiency at the completion of chemotherapy, and the proportion of patients with renal insufficiency at the completion of surgery.

Of the 80% of patients who completed all planned treatments, the pathological complete response rate was 13.8% (90% CI, 4.9%-28.8%). In terms of safety, there was a 23% rate of grade 3/4 toxicity. Brown noted that by comparison, only 68% of patients completed all 4 cycles of adjuvant chemotherapy in POUT.⁶

According to Brown, more evidence in support of neoadjuvant therapy for high-grade UTUC may come from a trial in progress, which is evaluating gemcitabine and cisplatin before surgery (NCT01261728). Based on early results from the study presented during the 2022 Genitourinary Cancers Symposium by Wesley Yip and colleagues, the combination has a favorable pathologic response rate and is well tolerated in patients with high-grade UTUC.²

Making a Decision

Oncologists who treat patients with UTUC have guidelines, clinical trial evidence, and real-world evidence to support the adjuvant and neoadjuvant approaches. Choosing the setting in which to administer chemotherapy may vary depending on the patient’s characteristics.

“If you look at the NCCN guidelines and you’re dealing with somebody with high-risk disease, the standard of care would tell you that everyone should get surgery, which we know. But you’ll see an asterisk attached to that recommendation that says consider neoadjuvant chemotherapy in select patients. After that, if someone already has surgery, it will say consider adjuvant chemotherapy for high-risk disease found at the time of surgery. So, it’s wide open and leaves quite a bit of room for interpretation simply, because it’s such a rare disease, and we don’t have trials of 500 patients to draw from,” Brown stated. “The take home message is that the best chemotherapy is the one your patient is actually able to receive.”

The best course of treatment for a patient with UTUC may also require the expertise of physicians from multiple disciplines, according to Nazha. “I think that for every patient with [UTUC] who is being considered for surgery at the time of diagnosis, a multidisciplinary approach is needed. Our recommendation, and our practice at Emory, is for those patients to be treated under the guidance of a multidisciplinary team, where they're meeting initially both the medical oncologist and the urologist for decisions on neoadjuvant vs adjuvant therapy. In our practice, we present most of these patients at the tumor board, and we come up with a consensus on the best approach,” said Nazha.

_References:

_{1. Nazha B. Adjuvant treatment in localized upper tract urothelial cancer. Presented at: 2022 Debates and Didactics in Hematology and Oncology Conference; July 20-24, 2022; Sea Island, GA.}

_{2. Brown J. Debate: neoadjuvant vs adjuvant chemotherapy in localized upper tract urothelial cancer. Presented at: 2022 Debates and Didactics in Hematology and Oncology Conference; July 20-24, 2022; Sea Island, GA.}

_{3. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395(10232):1268-1277. doi:10.1016/S0140-6736(20)30415-3}

_{4. Birtle AJ, Chester JD, Jones RJ, et al. Updated outcomes of POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol. 2021;39(suppl 6):455. doi:10.1200/JCO.2021.39.6_suppl.455}

_{5. Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma. J Urol. 2020;203(4):690-698. doi:10.1097/JU.0000000000000644}

_{6. Yip W, Coleman JA, Wong NC, et al. Final results of a multicenter prospective phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma. J Clin Oncol. 2022;40(suppl 6):440. doi:10.1200/JCO.2022.40.6_suppl.440}