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"This important trial supports the use of adjuvant chemotherapy after nephroureterectomy for stage T2 or higher cases," writes Badar M 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.
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 (Lancet 2020; 395:1268-77).
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; P = .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; P = .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 (P <.0001). There were 54 serious AEs in 42 patients (32%) who received chemotherapy.
Next: Some questions still unansweredSome questions still unanswered
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.