Metastatic non-clear cell renal cell carcinoma: current therapeutic options
Andres J. Schrader, Department of Urology, Philipps-University Medical School, Baldingerstrasse, D-35043 Marburg, Germany.
Non-clear cell (ncc) renal cell carcinoma (RCC) accounts for ≈25% of all patients with metastatic RCC. It is refractory to standard immuno(chemo)therapy and, to date, no specific trials have been reported to evaluate the efficacy of novel targeted drugs in the different subtypes of metastatic nccRCC. We review all available data from subgroup analyses of the global sorafenib and sunitinib expanded access programmes, current phase-III trials, and smaller multi- and single-centre studies focusing on the activity of targeted agents in these specific and rare RCC subtypes. Both sorafenib and sunitinib have significant activity in metastatic nccRCC, but the efficacy of each agent seems to vary between different nccRCC forms. Preliminary clinical data for temsirolimus appear to be promising but more extensive and long-term data are awaited. With the advent of novel therapeutic options, specific controlled multicentre trials are urgently needed to define their exact value and efficacy for treating the historically resistant nccRCC forms. The medium-term aim should be to tailor the most advantageous therapy for each patient with respect to his/her individual RCC subtype and physical condition.
(non) clear cell
Advanced RCC Sorafenib
expanded access trial.
Clear-cell (cc) RCC is the most common histopathological subtype of kidney tumours (70–75%), and consequently, clinical trials for advanced-stage kidney cancer have focused patients with this RCC subtype. By contrast, patients who had less common tumours, e.g. papillary, chromophobe, sarcomatoid variant and collecting-duct tumours, have often been excluded or ignored . However, genetic and clinical studies during the past two decades have shown that kidney cancer is not one disease but comprises several different types of cancer that occur in the same organ. Each can have a distinct histological type, a different clinical course, be caused by alteration of different genes, and respond differently to systemic therapy. Therefore, it is not surprising that immuno(chemo)therapy which has successfully been used for some patients with ccRCC does not appear to have any significant activity in other RCC subtypes [2,3]. Novel targeted therapies are currently under investigation in the treatment of non-cc (ncc) RCC.
In this article we discuss current clinical trials that include patients with metastatic nccRCC; the results of these early studies are summarized and translated into therapeutic options and recommendations.
METASTATIC PAPILLARY RCC
After nephrectomy for localized disease, whereas papillary and chromophobe cell types portend a favourable prognosis compared with ccRCC, metastatic nccRCC, especially metastatic papillary RCC, is characterized by a resistance to systemic therapy and poor survival . At 50–56%, papillary tumours are the largest subgroup of metastatic nccRCC [5,6]; the most aggressive potential was recently assigned to high-grade type 2 papillary tumours [7,8].
Ratain et al. were the first to administer sorafenib in metastatic papillary RCC. Within their phase-II trial, published in 2006, they used sorafenib to treat 152 and 15 patients with metastatic ccRCC and papillary RCC, respectively. The antitumour effect in papillary RCC was similar to that of the ccRCC population. Among those patients with papillary RCC there were two partial remissions, with an additional three having tumour shrinkage of 25–49%, indicating that sorafenib could have significant efficacy in patients with metastatic papillary RCC.
In 2007, Stadler et al. presented data from the USA Advanced RCC Sorafenib (US-ARCCS) expanded access trial (EAT), which included 212 patients with nccRCC; 118 with metastatic papillary RCC were evaluable for response . The disease was controlled in 95/118 (80%) patients including four (3%) and 23 (19%) confirmed and unconfirmed partial responses, respectively. Reported side-effects did not differ from those observed in patients with ccRCC. The authors concluded that sorafenib was well tolerated and had significant antitumour activity in patients with metastatic papillary RCC.
In 2007, Beck et al. presented similar results of the European (EU) ARCCS trial, an open-label, non-comparative phase-III study, that included 118 patients with metastatic papillary RCC, of whom 104 were evaluable for response. Comparable to the US-ARCCS data, sorafenib was confirmed as an active agent in papillary RCC. The disease control rate in this trial was 66.4%, and the median progression-free survival (PFS) was 5.8 months. However, in the EU-ARCCS trial the reported results for metastatic papillary RCC did not quite meet those for patients with ccRCC, of whom 75.7% achieved disease control and had a median PFS of 7.5 months.
On the contrary, within a recent French study , there were no objective responses in 28 patients with advanced papillary RCC treated with sorafenib. However, the median PFS and overall survival was 5.7 and 19.6 months, respectively.
Within the US-sunitinib EAT, 276 evaluable patients with nccRCC received sunitinib (4 weeks on, 2 weeks off), in most of whom previous cytokine-based therapy had failed . Even though the results were less remarkable than for ccRCC, sunitinib also showed significant activity against nccRCC. Overall response and disease control rates for nccRCC compared with all RCC subtypes were 5.4% vs 9.3% and 47.0% vs 52.4%, respectively. Unfortunately, the authors did not differentiate between different nccRCC subtypes.
At meetings in 2007, Gore et al.[12,13] updated the results of global sunitinib EATs including patients with nccRCC; 542/3983 (13.6%) evaluable patients had metastatic nccRCC. There was a clinical benefit in 47.4% of patients with nccRCC, vs 55.9% for all patients with metastatic RCC; the median PFS was 7.3 and 9.2 months, respectively.
Plantade et al. used sunitinib to treat 13 patients with metastatic papillary RCC; there were partial responses in two and the median PFS was 11.9 months.
In 2007, Dutcher et al. presented a subgroup analysis of the temsirolimus vs interferon-α trial , comparing the activity of temsirolimus and interferon-α in metastatic nccRCC, and the efficacy of temsirolimus in ccRCC and nccRCC. That study included only treatment-naive patients with an intermediate and poor prognosis, and 76% of those with nccRCC had papillary tumours. The median PFS and overall survival in 36 patients with nccRCC who were treated with interferon-α was significantly shorter than in 37 who received temsirolimus, at respectively 1.8 vs 7.0 months and 4.3 vs. 11.6 months. Moreover, there was a trend towards even higher efficacy of temsirolimus in nccRCC than in ccRCC (median overall survival 11.6 vs 10.6 months). The authors concluded that temsirolimus might be the agent of choice for nccRCC, regardless of age and risk group (by contrast with ccRCC, where it is recommended only for those with a poor prognosis and aged <65 years).
METASTATIC CHROMOPHOBE RCC
This variant is rare and clinical data are limited; the US-ARCCS trial of 2502 patients included 18 with advanced chromophobe RCC . With 17 patients the disease control rate was high (95%) and included one confirmed and three unconfirmed partial responses. Plantade et al. used sorafenib and sunitinib to treat five and seven patients with metastatic chromophobe RCC, respectively. Within this small study the median PFS and overall survival were only 9.3 and 14.2 months. Two of five and one of seven patients who received sorafenib and sunitinib, respectively, achieved objective responses.
METASTATIC SARCOMATOID RCC
Sarcomatoid differentiation of RCC occurs in all histological subtypes of RCC, with an incidence of 1–23% of all RCCs. It is uniformly associated with a poor prognosis, with a median survival of 2–9 months [16,17]. Surgical resection alone does not seem to affect the clinical course significantly, because these tumours are usually metastatic or locally advanced at the time of diagnosis . Given its uncommon nature and the failure of traditional approaches (chemotherapy, immunotherapy), currently the efficacy of the novel targeted drugs is being investigated in sarcomatoid RCC.
Within the EU-ARCCS trial  46 patients with sarcomatoid tumours received standard-dose sorafenib (400 mg twice daily). At 67% and 4.3 months, respectively, the disease control rate and median PFS were considerable but significantly lower and shorter than in patients with conventional RCC (75% and 7.5 months).
Staehler et al. used sorafenib to treat 11 patients with metastatic progressive sarcomatoid RCC who had failed to respond to gemcitabine/doxorubicin. They reported one partial response; four patients achieved stable disease and six were progressive. In this small single-centre pilot study the median time to progression was 5 months.
Compared with ccRCC, metastatic papillary RCC is rare, but once the disease is systemic the prognosis is just as bad or worse. Immuno(chemo)therapy has been inactive in papillary RCC [2,3] and therefore, until recently, there was no rational therapeutic option for this tumour subtype.
Papillary RCC can be subclassified into type 1 and type 2; it can occur sporadically or as part of a hereditary syndrome. One causative gene responsible for hereditary papillary RCC has been identified on chromosome 7q31 and encodes the receptor tyrosine kinase MET proto-oncogene ; this proto-oncogene is also dysregulated/duplicated in a significant proportion of sporadic type 1-cases , but the exact role of c-MET in the development of papillary RCC is yet unknown. On the contrary, the loss of functional fumarate hydratase might have a role in the development of aggressive type 2-tumours . Finally, the KIT receptor tyrosine kinase, a gene with remarkable similarity to c-MET , is overexpressed in papillary RCC [22,24]. Both c-KIT and MET are involved in ras/raf-kinase activation. This could be one reason why both approved multikinase inhibitors (sorafenib and sunitinib) have shown significant activity in metastatic papillary RCC, even though the results tend to be slightly inferior to those achieved in patients with ccRCC [6,13].
In addition, early data indicate significant efficacy for temsirolimus in metastatic nccRCC . However, it remains to be seen whether it is suitable for all patients independent of age, risk profile and pretreatment .
Metastatic chromophobe RCC is extremely uncommon. Two small studies reported the successful use of sorafenib with (temporary) disease control rates of up to 95%[5,10].
The treatment of sarcomatoid RCC remains difficult. Even though positive data were reported for the use of sorafenib, the results are worse than those for metastatic conventional RCC . Specific results for the use of sunitinib in metastatic sarcomatoid tumours are awaited.
Finally, as none of the novel drugs has been able to induce complete and/or long-lasting remissions in either conventional or nccRCC, cytoreductive surgery should remain an important tool in the treatment algorithm for metastatic RCC . However, with the advent of novel targeted drugs it remains to be determined when surgery (particularly debulking nephrectomy and resection of single metastases) should be used within the sequence of therapeutic actions.
CONFLICT OF INTEREST