EURURO Vol. 72 No. 6

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Very little progress has been made for the extremely rare
carcinoma of the collecting ducts of Bellini and renal
medullary carcinoma (RMC). For collecting duct tumors, the
Groupe d’Etudes des Tumeurs Uro-Ge´ nitales performed a
phase II study of gemcitabine plus platinum suggesting
limited efficacy For RMC, a different chemotherapy
regimen including cyclophosphamide, doxorubicin, cisplat-
in, topotecan, methotrexate, and vinblastine has been
reported with very limited efficacy in retrospective series
(Supplementary Table 2). Treatment of both tumor entities
is an unmet need.
4. Conclusions
4.1. Organization of care
Multiple noncomparative studies suggest that RKC sub-
types require an individual subtype and gene analysis–
driven approach to improve therapeutic strategies in the
future. Owing to small sample size, many of these studies
are hypothesis generating at best, and multi-institutional
cooperation is required to conduct studies for selected
subtypes. Optimal care of patients with RKC would be in
specialized centers experienced in clinical trials and
personalized medicine, and for hereditary RCC syndromes,
also capable of multidisciplinary care.
Prompt referral of patients with RKC, preferably imme-
diately after pathological examination, to expert centers for
surveillance and data collection is in the best interest of all
stakeholders. Central pathology review is also recom-
mended for RKC tumors. Registries such as the International
mRCC Database Consortium or the USA-based National
Clinical Trials Network biorepository can help identify
patients with rare tumors among a large pool of thousands
of patients worldwide and centralize tissue specimens for
important research that is not otherwise feasible in a single-
institution setting. In order to support this goal, we have
created a portal targeting RKCs’ key stakeholders at
. For scientists, the website is a source
of clinical and research data, whereas physicians and
patients can find information about RKCs and access a
clinical trial search tool that currently indexes 309 clinical
trials for RKCs. is working with
patient organizations to address common issues such as
sharing resources to bring together biological samples for
sequencing and patient outcome data with appropriate
standardized information release forms.
4.2. Design of future trials
Therapies with combinations of targeted agents and
immune checkpoint inhibitors that have shown efficacy in
ccRCCs are currently being investigated in studies that enroll
in part or exclusively patients with RKCs. For example, a
phase IIIb/IV safety trial of nivolumab plus ipilimumab
(CheckMate 920; NCT02982954) is ongoing and a phase II
trial to evaluate efficacy and safety of lenvatinib in
combination with everolimus (NCT02915783) will start
recruitment soon. While it is laudable that potentially more
effective therapies are being investigated for patients with
RKCs, candidates with RKCs are indiscriminately eligible as
long as they have one of the subtypes summarized under
‘‘non-ccRCCs’’. Subtype-dependent differences in OS have
long been recognized A previous large-scale retrospec-
tive dataset in ‘‘non-ccRCCs’’ confirms similar results as
did a recent comprehensive molecular analysis Accord-
ingly, patients with RKCs should no longer be included
collectively in ‘‘non-ccRCC’’ trials solely based on light
microscopy–based diagnosis. In addition to histological
characterization, full analysis of genomic alterations will
be crucial in RKCs. Regarding subsets, it is becoming
increasingly important to stratify patients by their genetic
lesions as opposed to phenotypic subtype. It will be
important that these patients are treated in the context of
multicenter trials to ensure sufficient power for meaningful
results and conclusions. In addition, these studies should
include subsets of reasonable size from which to draw
definitive conclusions to avoid interpretation of small
subgroups that severely limited the ASPEN and ESPN studies.
Owing to its sample size, PAPMET (n = 180) will allow to
assess the prognostic and predictive value of MET pathway
dysregulation and papillary subtype in metastatic pRCC
patients. Likewise, the first phase III biomarker-based RCC
trial randomizes pRCC patients with MET alterations to
savolitinib versus sunitinib (SAVOIR; NCT03091192). Owing
to the relative paucity of patients with RKCs, prioritization of
such trials is essential and should be strictly peer reviewed
involving key stakeholders and other bodies of interest,
making them accessible and referable, with a strong
pathological, genomic, and biological program (pathology
review, tissue banking, and genomic characterization) and
international alternatives for countries with no trials.
Rarer tumors that cannot reach a critical number of
patients should be enrolled in rare tumor trials, and real-
world databases should collect information on these to get
insights into activity. Alternatively, pharmaceutical compa-
nies and academic centers could consider treating RKCs as
orphan diseases, which fall under different categories with
regard to approval requirements (for European Medicines
Agency and Food and Drug Administration). Direct outreach
to the patient community using tools (eg,
or timeline tool at
) will help in patient recruitment, and
alternative trial design approaches could be utilized to focus
on patient series.
4.3. Trials
There is a dearth of knowledge about RKCs: pathophysio-
logical mechanisms that drive tumor growth, natural
history of each RKC tumor subtype, and most importantly,
effective treatment management strategies. This has led to
the prevailing medical opinion that RKCs are difficult to
treat. Knowledge sharing and supporting well-designed
clinical trials are the only way forward to improve RKC
management, and collaboration between academia and
pharmaceutical industry will be particularly critical to
achieve these goals. Even though urologists and oncologists
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