Kidney Cancer Journal 27
found no significant difference in time to treatment failure
between therapies, although our analysis was certainly
not powered or designed to do so.
Park, et al undertook an analysis of 747 patients who
had undergone curative surgery for RCC, with 41 patients
found to have developed recurrent RCC >5 years. The researchers
focused their analysis on clinic-pathological features
found in late relapsing patients and indentifying
risk factors associated with late relapse. They found that
late relapsing patients had a higher hemoglobin level
and lower ESR, in addition to favorable pathological features,
such as lower pT stage, favorable Fuhrman’s nuclear
grade, and absence of: tumor necrosis, sarcomatoid differentiation,
and lymphovascular invasion. They identified
several clinical and pathological factors that were
strongly associated with high-er risk of late recurrence in
patients with RCC—the most important were more advanced
age and higher serum hs-CRP
levels at diagnosis.
The five-year cancer-specific survival
rate in this series of late relapsing patients
was 73.7%, compared to 41.1% in
earlier relapsing patients (P=<0.001). As
in previous studies Park and colleagues
also showed that a significant number of
patients with late recurrence developed
metastatic disease at unusual sites, such
as the pancreas, thyroid, scalp, and submandibular
gland.9
Santoni and colleagues pooled data
“As next generation
sequencing becomes more
widespread and informatics
continues to improve, it will
be fascinating to see if
patterns emerge that might
be able to select those at
higher risk for late recurrence
based on mutational analysis
or whole tumor genomic
sequencing.”
21 Italian centers and that out of 2,490
patients who had relapsed RCC after
nephrectomy, 269 (11%) occurred >5 years after surgery.10
Their study focused on outcomes with first line therapies,
of which 190 patients (71%) were treated with sunitinib,
58 (21%) with sorafenib and 21 (8%) with pazopanib. Median
progression-free survival was 20.0 months for sunitinib
(95% CI 17.0-25.1), and 14.1 months for both
sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI
11.2-NA). They found that MSKCC score and lymph
nodes, liver, and brain metastases were associated with
worst overall survival, while pancreatic metastases were
associated with longer survival, an observation Kalra and
others have also made.11
Santoni et al undertook another analysis aimed at assessing
the prognostic role of pretreatment immune status
as measured by neutrophilia, lymphocytopenia, and
neutrophil to lymphocyte ratio (NLR) in patients treated
with vascular endothelial growth factor-tyrosine kinase
inhibitors (VEGFR-TKIs) for late relapsing (>5 years) RCC.
Data was pooled from 13 medical centers in Italy. They
identified 151 patients, 56 (37 %) had NLR ≥3 at the start
of VEGFR-TKI therapy, while 95 had NLR <3 (63 %). They
found a significant difference in median overall survival
(OS) in the two groups with those with the higher NLR
having a medical OS of 28.8 months and those with a
lower NLR achieving an median OS of 68.7 months (p <
0.001). The median progression-free survival (PFS) was
15.8 months higher NLR group and 25.1 months in lower
NLR group, also a significant difference (p = 0.03). A multivariate
analysis revealed that MSKCC risk group and
NLR were independent prognostic factors for both OS and
PFS in patients with late relapsing RCC.12
While most studies suggest that higher stage is a risk
factor for relapse, late relapse can occur in early stage RCC
following nephrectomy. Ha and colleagues undertook a
large retrospective study of 3,567 patients who underwent
partial or complete nephrectomy for T1 clear cell
RCC between 1999 and 2011 at 5 institutions in Korea.
423 patients remained free of disease for at least 5 years
and had adequate follow-up for analysis. During a median
follow-up period of 83.9 months (range 60.0- 156.4
months) recurrence was observed in 14 of the 423 (3.3%)
patients studied. Symptoms at diagnosis and pathologic
T stage were independent predictive factors for late recurrence
and patients who presented
with symptoms at the time of original diagnosis
or who originally had stage T1b
disease had a significantly shorter time
to late recurrence as compared to those
who were asymptomatic or had stage T1a
disease at original diagnosis.13
Very Late Relapse - Beyond Ten Years
Single cases in the published literature report
relapses of RCC occurring 25 years
or more following nephrectomy,14 but
little is known about outcomes in patients
with very late relapsed RCC
(greater than 10 years after initial surgery).
It is generally thought that these patients tend to
have more indolent disease, and small retrospective series
tend to suggest this as well.
We undertook a retrospective study on consecutive patients
with RCC who had disease recurrence >10 years
after nephrectomy for curative intent and were treated
with targeted therapies between 11/1/2006 and 11/1/
2013 at our center. Among 720 RCC patients treated with
nephrectomy, we identified 8 who developed recurrent
metastatic disease after a >10 year disease free interval
(median: 16.7 years; range: 11.7-29.0). We were careful to
exclude patients who may have developed a second primary
RCC years after their first diagnosis. Although the
number is very small, the results were intriguing. All 8
patients presented with clear cell histology and 88% had
favorable disease by IMDC and MSKCC risk stratification
models.
All patients presented with multiple metastatic lesions,
with the most common sites being lung and bone, although
unusual sites, such as soft tissue, pancreas and adrenal
were also detected. These patients responded well
to targeted therapies (pazopanib and sunitinib) with the
median time on first-line treatment of 20.1 months. The
median number of sequential targeted therapies received
was 2 (with a range of 1-4). Four patients died prior to the
analysis. Median OS was found to be 46.6 months (range: