chRCC has an overall better prognosis than other subtypes of RCC. The improved prognosis is more evident in local stages, with survival rates approximately 90% at 5 years.48–50
In chRCC, RFS at 5 years for those after surgical resection is 83% and CSS is 89%.51 (Table 1).
Table 1. RFS and CSS according to T stage and grade in patients with chRCC
|T||RFS 5 years (%)||CSS 5 years (%)||Fuhrman grade||RFS 5 years (%)||CSS 5 years (%)|
The majority of trials have reported a similar outcome.52,53 Patard et al. have reported better outcomes compared with ccRCC in cases of localized or high-grade disease.54 When controlling for stage and size, chRCC was a significant predictor of DFS compared with ccRCC.17
Clinical characteristics at diagnosis and DFS of patients with chRCC support an indolent nature of this disease.
When there are recurrences, the sites more commonly involved are the lung, liver and retroperitoneal nodes. Two sites of relapse are frequently observed (66.7%), compared with ccRCC and pRCC, where there is more often solitary recurrence. For chRCC, the liver is the commonest site of recurrence.55
Even in the setting of metastatic disease, chRCC has a better prognosis than pRCC, and a similar prognosis to ccRCC, with a median survival of approximately 29 months compared with 5.5 months in pRCC.56
Metastatic disease treatment
Despite the great advances achieved in the treatment of advanced RCC over the past 10 years, there is no standard of treatment for chRCC yet.8–10,14,57 All the information comes from retrospective studies within expanded access programs or small prospective series.
Current evidence for the different available drugs in advanced RCC will now be summarized:
Two major intracellular pathways, the c-erbB2/HER2 and the mTOR signaling pathway have been shown to be deregulated in chRCC patients in some exploratory analysis of mRNA expression.58 Phosphorylation and overexpression of energy pathway genes have also been reported in this population.59 Thus, agents targeting the PI3K–Akt–mTOR pathway seem a reasonable option for the treatment of this tumor type.
Unlike the registration studies with tyrosine kinase inhibitors that were restricted to patients with clear cell histology, the pivotal trial of the mTOR inhibitor, temsirolimus, in patients with advanced RCC included up to 18% of patients with non-clear cell histology. This was a phase III, randomized, open-label study comparing IFN alone, temsirolimus alone and temsirolimus in combination with IFN in patients with previously untreated advanced RCC who had at least three of six protocol-specified risk factors for short survival. The primary end-point was OS.14 The study was positive, favoring the arm of temsirolimus alone with a median OS of 10.9 months. A recent subgroup analysis of this study aimed to evaluate the effect of temsirolimus in patients with non-clear cell histologies. For the purpose of these analyses, only patients in the single-agent IFN or single-agent temsirolimus arms were compared. Patients' characteristics were balanced for both clear cell and other histologies in the IFN and temsirolimus groups. A total of 170 patients (83%) in the IFN group and 169 (82%) patients in the temsirolimus group had RCC with clear cell histology. A total of 36 (17%) patients in the IFN group and 37 (18%) patients in the temsirolimus groups had other primary histology, non-clear or indeterminate. Among patients treated with temsirolimus, those with tumors of clear cell or other histologies showed comparable median OS (clear cell median 10.7 months, 95% CI 8.5–13.0; other median 11.6 months, 95% CI 8.9–14.5). In contrast, patients with tumors of other histologies treated with IFN showed a shorter median OS than patients with tumors of clear cell histology (clear cell median 8.2 months, 95% CI 6.6–10.4; other median 4.3 months, 95% CI 3.2–7.3). When looking at subtypes, most of the non-clear cell patients were papillary, and just five and seven patients were chRCC in the temsirolimus and IFN arm, respectively. Thus, temsirolimus appears to benefit patients regardless of histology, although the small numbers limit the conclusions. More recent evidence in the literature corresponds to several case reports underlying the efficacy of mTOR inhibitors in these type of patients, normally in the second- or third-line setting, after progressing on other treatment strategies, such as cytokines and/or tyrosine kinase inhibitors.60–62
chRCC tumors express CD117 (KIT), a membrane receptor that plays an important role in signal transduction. However, mutations have not been detected in this population in contrast with the findings in other tumor types, such as gastrointestinal stromal tumors. KIT inhibitors, such as imatinib, dasatinib or nilotinib, could be effective in this type of renal cell cancer, but no hard data are yet available.19
3 Tyrosine kinase inhibitors
Both sorafenib and sunitinib have been evaluated in patients with advanced chRCC.63 In North America, the expanded access program of sorafenib included 20 patients with chRCC, and one achieved a partial response (5%).64 Choueiri et al. reported their experience with non-clear cell patients, and among the 12 chRCC patients included, seven were treated with sunitinib and five were treated with sorafenib. Two patients treated with sorafenib and one patient treated with sunitinib achieved a partial response, corresponding to a response rate of 25% (three of 12 patients). PFS for chRCC patients was 10.6 months. Sorafenib-treated patients tended to have a more prolonged median PFS (27.5 months).65
Characteristics of this research (retrospective, non-randomized) and the limited number of patients evaluated argue against a definitive conclusion in the treatment of this subgroup of patients. Even when the number of patients included for evaluation is small, this retrospective analysis is the largest to report treatment outcomes for patients with chRCC.
Sunitinib was evaluated in an expanded access program driven mainly in European hospitals; inclusion of non-clear RCC was allowed and a total of 588 (13%) patients where included for evaluation. Unfortunately, distribution by subtypes was not carried out. Objective responses were reported in 11% of patients (<1% complete responses and 11% partial responses), stability for >3 months was described in 57% of patients. Median progression-free survival and median overall survival were 7.8 months and 13.4 months, respectively; for ccRCC after cytokine therapy, the median progression-free survival and median overall survival were 11.1 months and 18.1 months, respectively.66 It shows that sunitinib is an active treatment option. Case reports have also been reported to discuss efficacy and sequencing of treatment.62