1.1 Patients’ characteristics
Among 468 patients who underwent RNU, 61 were excluded for their pathological stage or since they received ACT more than 90 days after RNU, and nine were also excluded because they had received neoadjuvant chemotherapy. A total of 398 patients with≥pT2 UTUC with RNU and bladder cuff excision were ascertained and included in the study.
Of these patients, 105(26.4%) received adjuvant chemotherapy and 293(73.6%) did not (Table.1). The median age was 61.5 years (mean66, range 33.0 to 90). There was a male predominance (68.6%) in the adjuvant chemotherapy group. The median follow-up for the whole cohort after surgery was 64 months (mean34.7, range 1 to 129). The proportion of patients with tumor location in the ureter, age<75, T-stage, N-stage, the grade was significantly higher in the adjuvant chemotherapy group than in the non-adjuvant group (p=0.016, p<0.001,p=0.01,p<0.001, p<0.001, respectively). There was no significant difference in gender and concomitant bladder tumor status between patients who did or did not receive adjuvant chemotherapy. At the end of follow-up, 180 (45.2%) patients died of cancer-related causes and 41 (10.3%) died of other causes.
IVQ after RNU was presented in 60 (15.1%) patients after a median follow-up of 58.5 (range 4 to 113) months. Recurrent bladder tumors were treated with transurethral resection and subsequent intravesical chemotherapy. One patient was identified with refractory muscle-invasive bladder cancer and underwent radical cystectomy after.
1.2Results of the univariate and multivariate analysis with Cox hazards regression analysis.
First, we analyzed the role of most reported predictive clinicopathological factors in OS and CSS (Table 2). Univariate analysis revealed that gender, adjuvant chemotherapy, flank pain, N stage, ureteroscopy(URS), grade, <3 were associated with OS. However, location, concomitant bladder tumor, hydronephrosis, and multifocality were not associated with OS. Multivariate analysis suggested that gender (p= 0.023; HR 0.721), adjuvant chemotherapy(p<0.001; HR 0.381), URS, grade, and N stage (p<0.001; HR 2.650) were independent clinical risk factors for predicting OS. Univariate and multivariate analyses were also performed to determine indicators for predicting CSS (Table 3). Multivariate analysis exhibited that gender (p= 0.041; HR 0.726) and adjuvant chemotherapy (p<0.001; HR 0.355) were independent clinical risk factors for CSS, in addition to lymph node metastasis (p<0.001; HR 2.741), grade (p=0.02; HR 1.912).
As aforementioned, ACT is a significant predictor of better OS and CSS. To address the clinical significance of adjuvant chemotherapy, we looked at OS and CSS and performed a Kaplan–Meier analysis. As shown, the OS (p< 0.001) (Fig. 1A) and CSS (p< 0.001) (Fig. 1B) curves of UTUC patients using the ACT+RNU strategy were meaningfully higher than the non-chemotherapy group.
To compare the role of ACT in patients with lymph node metastasis, we applied the Kaplan–Meier analysis. As shown in Figure 2A, the OS curve of ACT was significantly improved in patients with lymph node metastasis.
CSS also shows that RNU+ACT is better than RNU (Figure 2B). The median CSS times for the patients with lymph node metastasis and non-lymph node metastasis were 42 and 38.5. Thus, the ACT+RNU strategy significantly increased the incidence of CSS in patients with lymph node metastasis.
1.3Adverse events were recorded in 105 patients, as shown in Table.3.
All patients enrolled in the present study achieved complete >4 cycles of full-dose chemotherapy. The main side effects were bone marrow suppression and gastrointestinal reaction. There were only 6 (5.7%) cases with severe nausea/vomiting, 5 (4.8%) cases with severe granulocytopenia, 3 (2.9%) cases with leukocyte, platelet, and hemoglobin III degree decrease, 2 (1.9%) cases with III degrees erythema/pruritus and alopecia, and 1 (0.9%) cases with creatinine III degrees increase, which were all relieved after symptomatic treatment. No serious heart, brain, lung, and other organ toxicity and allergic reactions, no treatment-related deaths.
2.1Risk factors for IVQ in patients with UTUC who underwent RNU.
We conducted univariate and multivariate Cox regression analyses to clarify the risk factors for developing subsequent IVQ after RNU, with these listed in Table 4. Fascinatingly, all patients with bladder tumors underwent transurethral resection of the bladder mass during the RNU operation, and none of them underwent radical cystectomy. Based on the univariate analysis, ≥pT3, concomitant bladder tumor, tumor multifocality, and hydronephrosis were significantly associated with subsequent IVQ both in OS and CSS. Furthermore, multivariate analysis revealed concomitant bladder tumors to be independent risk factors for IVQ after RNU.
To see if adjuvant therapy can improve survival in UTUC patients with bladder cancer the Kaplan–Meier curves were employed. Depressingly, this study found that adjuvant chemotherapy with gemcitabine and platinum did not improve the survival rate of UTUC associated with bladder cancer within 90 days of surgery(Fig.3).