This interesting manuscript was prepared by a multinational, multi-institutional group evaluating renal function change in patients undergoing radical nephro-ureterectomy (RNU) for upper tract urothelial cancer (UTUC) and how that may influence the proportion of patients that were eligibile for adjuvant cisplatin chemotherapy (ACT). As previously noted by others, surgery has been associated with a significant decline in renal function 3–6 months postoperatively [1, 2]. Measurement of renal function at multiple time points may have helped determine the relative contributions of RNU, obstructive nephropathy, other coorbidities and previous surgeries to the decline. Notably, 40% of the patients who died within the 4 years of follow-up did so from causes other than cancer. Whether this was attributable to complications of renal dysfunction is not clear. In the subset of patients who had no ACT or cancer recurrence, there was suggestion that a preoperative estimated GFR (eGFR) ≤60 mL/min/1.73 m2 or postoperative eGFR ≤ 45 mL/min/1.73 m2 had a worse prognosis, but this association was not apparent on multivariate analysis that incorporated clinicopathological features. Nonetheless, efforts to address comorbidities and preserve renal function in patients undergoing RNU are warranted.
In the present paper, Xylinas et al. found that the decrease in estimated GFR after RNU precluded the safe administration of ACT in ∼20% of the patients who were candidates before surgery, whether the thresholds chosen for avoiding superimposed cisplatin nephropathy were <60 or <45 mL/min/1.73 m2. This observation and those of others provide a solid rationale for treating patients with preoperative (neoaduvant) chemotherapy (NACT); however, it should be noted that there is no level 1 evidence of benefit for either pre- or postoperative chemotherapy in UTUC and the postulated benefit is based on extrapolation of the benefit of NACT in treatment of resectable urothelial bladder cancers [3-5]. Even in this setting, NACT is associated with a modestly improved survival and reduction in tumour recurrences of 5–10%. Also, the relative effectiveness of different NACT regimens is not known. It is hoped that a recently initiated prospective multicentre phase II study will provide reasonable estimates about the efficacy and risks of neoadjuvant cisplatin and gemcitabine chemotherapy in patients with UTUC [http://www.cancer.gov/clinicaltrials/search/view?cdrid=738618&protocolsearchid=11038944&version=healthprofessional#EntryCriteria_CDR0000738618].
Although NACT offers advantages, postoperative ACT remains an option. Patients with UTUC with a single kidney can be treated safely with standard cisplatin-based regimens (cisplatin and gemcitabine or MVAC) . About 16% of patients developed an eGFR ≤37.5 mL/min/1.73 m2 but all subsequently improved with dose modifications or discontinuation of treatment. Although toxicity correlated with a baseline eGFR <53.5 mL/min/1.73 m2 the hazard ratio of 3.2 (P = 0.1) was of borderline significance. Toxicity may be reduced and eligibility expanded by giving cisplatin as a split dose on days 1 and 8 along with gemcitabine every 3 weeks, or by using a carboplatin-based regimen [5, 7, 8], but these programmes have not been shown to be effective in the adjuvant setting and carboplatin appears to be less active against urothelial cancers than cisplatin .
In summary, we would agree with Xylinas et al. that, despite the limited data on efficacy, cisplatin-based NACT should be offered to eligible patients with locally advanced UTUC (clinical T3, T4, and or node-positive). The patient should be informed that the potential benefits are modest and not fully proven and that toxicity may be significant. For patients initially treated with RNU, the benefit of ACT is even less clear and may not outweigh the possible adverse effects. Nonetheless, treatment may be appropriate for carefully selected high-risk individuals with adequate renal function (eGFR > 60 mL/min/1.73 m2) who are likely to otherwise tolerate ACT. Certainly, the care of patients with urothelial cancers in general would be greatly improved by the development of better markers of prognosis and tumour responsiveness as well as effective non-nephrotoxic ACT.